Single‐stage, three‐arm, adaptive test strategies for non‐inferiority trials with an unstable reference

Brannath, Werner; Scharpenberg, Martin; Schmidt, Sylvia

doi:10.1002/sim.9552

Cited by 3 publications

(46 citation statements)

References 21 publications

(38 reference statements)

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“…The maximum observed loss in probability of success observed in our simulations was about 1%, which is quite low considering the benefit in interpretation the SCIs offer. Throughout all simulations, we observed that the single-step confidence intervals interpreted with the help of the superiority filter yielded a lower probability of success than the procedure of Brannath et al 3 or the informative SCIs. The loss in probability of success compared to using the informative SCIs amounted up to ∼ 10% in some scenarios.…”

Section: Probability Of Successmentioning

confidence: 76%

“…The method presented by Brannath et al 3 can also be applied to our setup with the IU filter (3). We want to compare the optimal sample sizes derived for this setup to those derived for the superiority filter (4).…”

Section: Optimal Sample Sizesmentioning

confidence: 99%

“…Table 1 and Figure 4 show the optimal sample sizes for the approach derived by Brannath et al 3 ('superiority filter') and for the procedures involving SCIs as introduced in Section 2. As we can see, the informative SCIs require only slightly larger sample sizes than the procedure of Brannath et al 3 throughout all scenarios.…”

Section: Optimal Sample Sizesmentioning

confidence: 99%

“…ER is rejected, then the level 𝛼 is shifted further to the hypothesis family (H 𝜗 Λ ) 𝜗>0 , improving the confidence bounds L EP and L ER simultaneously. This procedure modifies the hierarchical test design introduced by Brannath et al, 3 where the hypothesis H 𝛿 1…”

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confidence: 99%

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Simultaneous confidence intervals for an extended Koch-Röhmel design in three-arm non-inferiority trials

Scharpenberg

Brannath

2023

Stat Methods Med Res

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Three-arm ‘gold-standard’ non-inferiority trials are recommended for indications where only unstable reference treatments are available and the use of a placebo group can be justified ethically. For such trials, several study designs have been suggested that use the placebo group for testing ’assay sensitivity’, that is, the ability of the trial to replicate efficacy. Should the reference fail in the given trial, then non-inferiority could also be shown with an ineffective experimental treatment and hence becomes useless. In this article, we extend the so-called Koch-Röhmel design where a proof of efficacy for the experimental treatment is required in order to qualify for the non-inferiority test. While the efficacy of the experimental treatment is an indication of assay sensitivity, it does not guarantee that the reference is sufficiently efficient to let the non-inferiority claim be meaningful. It has, therefore, been suggested to adaptively test the non-inferiority only if the reference demonstrates superiority to placebo and otherwise to test [Formula: see text]-superiority of the experimental treatment over placebo, where [Formula: see text] is chosen in such a way that it provides proof of non-inferiority with regard to the reference’s historical effect. In this article, we extend the previous work by complementing its adaptive test with compatible simultaneous confidence intervals. Confidence intervals are commonly used and suggested by regulatory guidelines for non-inferiority trials. We show how to adopt different approaches to simultaneous confidence intervals from the literature to the setting of three-arm non-inferiority trials and compare these methods in a simulation study. Finally, we apply these methods to a real clinical trial example.

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Section: Probability Of Successmentioning

confidence: 76%

Section: Optimal Sample Sizesmentioning

confidence: 99%

Section: Optimal Sample Sizesmentioning

confidence: 99%

mentioning

confidence: 99%

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Simultaneous confidence intervals for an extended Koch-Röhmel design in three-arm non-inferiority trials

Scharpenberg

Brannath

2023

Stat Methods Med Res

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“…While Homma and Daimon already present operating characteristics for optimally chosen allocation ratios for their rerandomization procedure, one could try to find optimal design parameters for this design with added futility boundaries or an additional group sequential recruitment stage. Another interesting modification of the gold‐standard design, introduced by Brannath et al 31 is the idea of adaptively switching from testing non‐inferiority of treatment against control to testing delta‐superiority of treatment over placebo in cases where the control treatment turns out to be non‐effective. Especially in group sequential recruiting procedures, this modification might also benefit from optimal design parameter choices.…”

Section: Discussionmentioning

confidence: 99%

Optimization of the two‐stage group sequential three‐arm gold‐standard design for non‐inferiority trials

Meis

Pilz

Herrmann

et al. 2022

Statistics in Medicine

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If design parameters are chosen appropriately, group sequential trial designs are known to be able to reduce the expected sample size under the alternative hypothesis compared to single‐stage designs. The same holds true for the so‐called ‘gold‐standard’ design for non‐inferiority trials, a design involving an experimental group, an active control group, and a placebo group. However, choosing design parameters that maximize the advantages of a two‐stage approach for the three‐arm gold‐standard design for non‐inferiority trials is not a straightforward task. In particular, optimal choices of futility boundaries for this design have not been thoroughly discussed in existing literature. We present a variation of the hierarchical testing procedure, which allows for the incorporation of binding futility boundaries at interim analyses. We show that this procedure maintains strong control of the family‐wise type I error rate. Within this framework, we consider the futility and efficacy boundaries as well as the sample size allocation ratios as optimization parameters. This allows the investigation of the efficiency gain from including the option to stop for futility in addition to the ability to stop for efficacy. To analyze the extended designs, optimality criteria that include the design's performance under the alternative as well as the null hypothesis are introduced. On top of this, we discuss methods to limit the allocation of placebo patients in the trial while maintaining relatively good operating characteristics. The results of our numerical optimization procedure are discussed and a comparison of different approaches to designing a three‐arm gold‐standard non‐inferiority trial is provided.

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Non-Parametric Non-Inferiority Assessment in a Three-Arm Trial with Non-Ignorable Missing Data

Zhang

Tang

2023

Mathematics

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A three-arm non-inferiority trial including a placebo is usually utilized to assess the non-inferiority of an experimental treatment to a reference treatment. Existing methods for assessing non-inferiority mainly focus on the fully observed endpoints. However, in some clinical trials, treatment endpoints may be subject to missingness for various reasons, such as the refusal of subjects or their migration. To address this issue, this paper aims to develop a non-parametric approach to assess the non-inferiority of an experimental treatment to a reference treatment in a three-arm trial with non-ignorable missing endpoints. A logistic regression is adopted to specify a non-ignorable missingness data mechanism. A semi-parametric imputation method is proposed to estimate parameters in the considered logistic regression. Inverse probability weighting, augmented inverse probability weighting and non-parametric methods are developed to estimate treatment efficacy for known and unknown parameters in the considered logistic regression. Under some regularity conditions, we show asymptotic normality of the constructed estimators for treatment efficacy. A bootstrap resampling method is presented to estimate asymptotic variances of the estimated treatment efficacy. Three Wald-type statistics are constructed to test the non-inferiority based on the asymptotic properties of the estimated treatment efficacy. Empirical studies show that the proposed Wald-type test procedure is robust to the misspecified missingness data mechanism, and behaves better than the complete-case method in the sense that the type I error rates for the former are closer to the pre-given significance level than those for the latter.

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Single‐stage, three‐arm, adaptive test strategies for non‐inferiority trials with an unstable reference

Cited by 3 publications

References 21 publications

Simultaneous confidence intervals for an extended Koch-Röhmel design in three-arm non-inferiority trials

Simultaneous confidence intervals for an extended Koch-Röhmel design in three-arm non-inferiority trials

Optimization of the two‐stage group sequential three‐arm gold‐standard design for non‐inferiority trials

Non-Parametric Non-Inferiority Assessment in a Three-Arm Trial with Non-Ignorable Missing Data

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