Conducting the non-inferiority test for the means with unknown coefficient of variation in a three-arm trial.

BACKGROUND: The non-inferiority test is a reasonable approach to assessing a new treatment in a three-arm trial. The three-arm trial consists of a placebo, reference, and an experimental treatment. The non-inferiority is often measured by the mean differences between the experimental and the placebo groups relative to the mean differences between the reference and the placebo groups. METHODS: To cope with possible estimation distortion due to the allowance of heteroskedasticity, we adjust the measurement of non-inferiority by the incorporation of coefficient of variation (CV) of the experimental, the reference and the placebo groups. In this research, we propose a generalized [Formula: see text]-value based method (GPV-based method) to facilitate non-inferiority tests for the means with unknown coefficient of variation in a three-arm trial. RESULTS: The simulation results show that the GPV-based method can not only adequately control type I error rate at nominal level better but also provide power higher than those from Delta method and the empirical bootstrap method, which verifies the feasibility of our adjustment. CONCLUSIONS: We revise the measurement of non-inferiority by deducting the CV of each kind of treatment from the average effect of trials. CVs are included in the non-inferiority explicitly to help prevent possible estimating distortion if heteroskedasticity is allowed. Through the simulation study, the performance of GPV-based method for facilitating non-inferiority tests for the means with unknown CV in a three-arm trial is better than those from empirical bootstrap method and Delta method for small, medium and large sample sizes. Hence, the GPV-based method is recommended to be used to conduct the non-inferiority test for the means with unknown CV in a three-arm trial. The GPV-based method still performs well in non-normality cases.

Use of multivariate distance measures for high-dimensional data in tests for difference, superiority, equivalence and non-inferiority.

Tests based on pairwise distance measures for multivariate sample vectors are common in ecological studies but are usually restricted to two-sided tests for differences. In this paper, we investigate extensions to tests for superiority, equivalence and non-inferiority.

Efficacy and safety of breast milk eye drops in infants with eye discharge.

AIM: Breast milk (BM) contains various protective components, such as immunoglobulins, lactoferrin, lysozyme, oligosaccharides and immune cell subsets. We evaluated the effectiveness of BM eye drops in infants with eye discharge in a randomised controlled study. METHODS: Subjects were breastfed infants aged ≤180 days, with eye discharge. We randomly assigned patients to receive eye drops of BM or sodium azulene sulphonate hydrate 0.02% ophthalmic solution (OS). The patients received drop of BM or OS for 7 days. Improvement score of eye discharge in the groups was compared using a non-inferiority test. RESULTS: The number of patients improved eye discharge was 119/155 (76.8%) and 119/157 (75.8%) in BM and OS groups, respectively. There were no significant differences between groups. The improvement score in eye discharge was 1.76 ± 0.91 in the BM group and 1.71 ± 0.96 in the OS group. The BM group was considered non-inferior to the OS group. CONCLUSIONS: This study demonstrated that BM is no less effective than OS in infants with eye discharge aged ≤6 months. The results suggested that the use of breast milk as eye drops could be considered as a first-line treatment for infants aged ≤6 months with eye discharge.

Non-inferiority tests for binary endpoints with variable margins.

Non-inferiority comparison between binary response rates of test and reference treatments is often performed in clinical studies. The most common approach to assess non-inferiority is to compare the difference between the estimated response rates with some margin. Previous methods use a variety of margins, including fixed margin, step-wise constant margin, and piece-wise smooth margin, where the latter two are functions of the reference response rate. The fixed margin approach assumes that the margin can be determined from historical trials with the consistent difference between the reference treatment and placebo, which may not be available. The step-wise constant margin approach suffers discontinuity in the power function which can cause trouble in sample size determination. Furthermore, many methods ignore the variability in margins dependent on the estimated reference response rate, leading to poor type I error control and power function approximation. In this study, we propose a variable margin approach to overcome the difficulties in fixed and step-wise constant margin approaches. We discuss several test statistics and evaluate their performance through simulation studies.

Comparison of oral and intravenous lansoprazole for the prevention of bleeding from artificial ulcers after endoscopic submucosal dissection for gastric tumors: a prospective randomized phase II study (KDOG 0802).

BACKGROUND: Very few studies have evaluated the effectiveness of oral proton-pump inhibitors for the prevention of bleeding after endoscopic submucosal dissection (ESD) for gastric tumors. The aim of our study was to establish the non-inferiority of lansoprazole orally disintegrating (OD) tablets to intravenous lansoprazole for the prevention of bleeding from artificial ulcers after ESD. PATIENTS AND METHODS: Consecutive patients who underwent ESD for gastric tumors were randomly assigned to receive lansoprazole OD tablets (OD group) or intravenous lansoprazole (IV group). In the OD group, lansoprazole OD tablets (30 mg) were given orally once daily for 8 weeks (56 days), starting on the day before ESD. In the IV group, lansoprazole (30 mg) was given as a continuous intravenous infusion twice daily for 3 days, starting on the day before ESD, and lansoprazole OD tablets (30 mg) were given orally once daily on days 4-56. The primary endpoint was the incidence of bleeding events within 8 weeks after ESD. RESULTS: Among 310 enrolled patients, 304 patients (152 in the OD group and 152 in the IV group) were included in the analysis. Endoscopic hemostasis was performed in 38 patients (19 in the OD group and 19 in the IV group). The incidence of bleeding events within 8 weeks after ESD did not differ significantly between the groups (p = 0.487). Endoscopic hemostasis was performed at second-look endoscopy in 17 patients (11.2%) in the OD group and 19 patients (12.5%) in the IV group (difference, 1.3 percentage points; 90% confidence interval, - 4.8-7.4%; non-inferiority, p < 0.001). CONCLUSIONS: The effectiveness of lansoprazole OD tablets for the prevention of bleeding from artificial ulcers after ESD was similar to that of intravenous lansoprazole. Lansoprazole OD tablets are thus considered a treatment option in patients who undergo ESD.

Likelihood ratio and score tests to test the non-inferiority (or equivalence) of the odds ratio in a crossover study with binary outcomes.

We consider the non-inferiority (or equivalence) test of the odds ratio (OR) in a crossover study with binary outcomes to evaluate the treatment effects of two drugs. To solve this problem, Lui and Chang (2011) proposed both an asymptotic method and a conditional method based on a random effects logit model. Kenward and Jones (1987) proposed a likelihood ratio test (LRTM ) based on a log linear model. These existing methods are all subject to model misspecification. In this paper, we propose a likelihood ratio test (LRT) and a score test that are independent of model specification. Monte Carlo simulation studies show that, in scenarios considered in this paper, both the LRT and the score test have higher power than the asymptotic and conditional methods for the non-inferiority test; the LRT, score, and asymptotic methods have similar power, and they all have higher power than the conditional method for the equivalence test. When data can be well described by a log linear model, the LRTM has the highest power among all the five methods (LRTM , LRT, score, asymptotic, and conditional) for both non-inferiority and equivalence tests. However, in scenarios for which a log linear model does not describe the data well, the LRTM has the lowest power for the non-inferiority test and has inflated type I error rates for the equivalence test. We provide an example from a clinical trial that illustrates our methods. Copyright © 2016 John Wiley & Sons, Ltd.

[Efficacy and safety of Choudongning capsule (CDN)in children with Tourette's syndrome of spleen deficiency and phlegm accumulation].

To evaluate the efficacy and safety of Choudongning (CDN)capsule in children with Tourette's syndrome of spleen deficiency and phlegm accumulation through a randomized double-blind three-arm controlled phase Ⅲ study in 588 patients from 8 hospitals. The included patients were randomly divided into test group, positive control group and placebo group at the ratio of 3∶1∶1. Patients in the test group orally took CDN capsules and simulated Tiapridal tablets; the patients in positive control group took Tiapridal tablets and simulated CDN capsules; whereas the patients in placebo group orally took the simulated agents of the above two drugs. The treatment course was 6 weeks for three groups. The global grading rates, YGTSS scores and its factor scores, the degree of social function damage, as well as traditional Chinese medicine syndrome efficacy were evaluated as the outcome measures on efficacy. The AEs/ADRs, vital signs and laboratory testing were observed as outcome measures on safety. The total effective rate of YGTSS was 75.92% in the test group, 72.65% in the positive control group, and 37.29% in the placebo group. Non inferiority test stands between the test group and the positive control group, and they were superior to placebo group in efficacy with statistical difference. Significant difference had also been found among the 3 groups in YGTSS tics score, motor tics score, vocal tics, degree of social function damage and traditional Chinese medicine syndrome efficacy. During the study, there were 5 (1.42%)ADRs in the test group, 10 (8.55%)in the positive control group and 3 (2.54%)in the placebo group. The incidence of ADRs in the test group was lower than that in the positive control group, with statistical difference. It is clear to say that CDN capsule can effectively treat the Tourette's syndrome of spleen deficiency and phlegm accumulation. Its efficacy is not inferior to the commonly used Tiapridal tablets, with even less adverse reactions, so it has clinical application value.

Comparative efficacy of vericiguat to sacubitril/valsartan for patients with heart failure reduced ejection fraction: Systematic review and network meta-analysis.

BACKGROUND: Despite the established efficacy of vericiguat compared to placebo, uncertainties remain regarding its comparative efficacy to sacubitril/valsartan for patients with heart failure reduced ejection fraction (HFrEF). This study aimed to assess the relative efficacy of vericiguat and sacubitril/valsartan through a systematic review, network meta-analysis, and non-inferiority tests. METHODS: A systematic review was conducted to identify the randomized phase 3 clinical trials involving vericiguat and sacubitril/valsartan. The hazard ratios (HRs) with 95% confidence intervals (CI) for cardiovascular death (CVD) and hospitalization due to HF (hHF) were extracted from these trials and synthesized via network meta-analysis. Non-inferiority testing of vericiguat was performed using a fixed-margin method with a predefined non-inferiority margin (1.24). Sensitivity analyses explored the impact of the time from hHF to screening. RESULTS: Among the 1366 studies, two trials (VICTORIA and PARADIGM-HF) met the inclusion criteria. Network meta-analysis demonstrated that the HR for CVD or hHF with vericiguat did not significantly differ from that for sacubitril/valsartan (HR: 0.88, 95% CI:0.62-1.23). The upper limit of the 95% CI was less than the predefined margin of 1.24, confirming vericiguat's non-inferiority to sacubitril/valsartan. Sensitivity analyses affirmed the robustness of the base-case results. CONCLUSION: Vericiguat exhibited a comparable risk of CVD or hHF when contrasted with sacubitril/valsartan. Importantly, in patients with HFrEF, vericiguat's efficacy was not statistically inferior to that of sacubitril/valsartan. These findings reinforce the potential of vericiguat as a viable treatment option for this patient population.

Nonconformance probability of an air quality index.

Air pollution is one of the most important global environmental issues. Taiwan Environmental Protection Agency (EPA) is currently using an Air Quality Index (AQI) to measure and monitor its national air quality. The main objective of this study is to assess the air quality per hour every month in Taichung City of Taiwan from 2014 to 2016 based on the nonconformance probability of the AQI index. The nonconformance probability is defined as the probability that a characteristic of interest falls outside of an acceptance region. A lower confidence bound for the nonconformance probability is applied to test whether the AQI index value exceeds a warning threshold, and then the government could issue warnings according to the decision made by such statistical inference. An unbalanced two-way random effects model is presented for fitting the AQI index values. We evaluate three different lower confidence bound construction methods, including a t-based, an adjusted t-based and a generalized pivotal quantity (GPQ) based methods, through a detailed simulation study. Finally, a hybrid method of the t-based and the adjusted t-based estimators is recommended for practical use.

A note on the determination of non-inferiority margins with application in oncology clinical trials.

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. Determination of an appropriate non-inferiority margin is critical to the demonstration of non-inferiority. A commonly used method is called the fixed-margin approach recommended by the FDA. The fixed-margin approach consists of two steps: first the lower limit of the 1 - α * two-sided confidence interval (CI) of the active-control effect versus placebo is calculated from relevant historical trials or meta-analysis; second, the non-inferiority margin is obtained as a fraction of the lower confidence limit of the control effect to preserve partial control effect. An alternative method is to use the point estimate, instead of the lower confidence limit, of the active-control effect. The fixed-margin approach based on the lower limit may be ultra-conservative with unconditional Type 1 error rate much smaller than target α / 2 level, while the margin based on the point estimate is liberal. We derive the Type 1 error rate as a function of variances of the effect estimates in the historical and the current non-inferiority trials. We also propose an alternative approach for the non-inferiority margin that maintains the target Type 1 error rate. For the endpoint of landmark survival, we conduct simulations to compare the fixed-margin methods and the proposed method. For illustration, we apply the proposed method to an oncology non-inferiority clinical trial to determine an alternative non-inferiority margin.

Sustainable use of tainted boar meat: Blending is a strategy for processed products.

While forming mixtures is a widely used approach for other raw materials in food industry, it has not yet been systematically analyzed for boar tainted meat. That is why we simultaneously studied four factors relevant for the production of emulsion-type sausages: percentage boar meat (skatole concentrations up to 0.3 µg/g, androstenone up to 3.8 µg/g in melted backfat), duration of traditional smoke and concentration levels of two spices. 16 variants of Frankfurters were produced in two independent studies and evaluated by in total 211 consumers. A linear mixed effects model revealed that increased levels of boar tainted meat significantly reduced consumer acceptance which could not be compensated by increased smoke or spice levels. We propose a non-inferiority test to identify the mixture which is similarly accepted as the reference made without boar tainted meat. Up to 33% tainted boar meat is proposed, assuming a liking drop of 0.5 on a 9 point liking scale as benchmark for an inferior product.

Comparison of Sample Size by Bootstrap and by Formulas Based on Normal Distribution Assumption.

Bootstrapping technique is distribution-independent, which provides an indirect way to estimate the sample size for a clinical trial based on a relatively smaller sample. In this paper, sample size estimation to compare two parallel-design arms for continuous data by bootstrap procedure are presented for various test types (inequality, non-inferiority, superiority, and equivalence), respectively. Meanwhile, sample size calculation by mathematical formulas (normal distribution assumption) for the identical data are also carried out. Consequently, power difference between the two calculation methods is acceptably small for all the test types. It shows that the bootstrap procedure is a credible technique for sample size estimation. After that, we compared the powers determined using the two methods based on data that violate the normal distribution assumption. To accommodate the feature of the data, the nonparametric statistical method of Wilcoxon test was applied to compare the two groups in the data during the process of bootstrap power estimation. As a result, the power estimated by normal distribution-based formula is far larger than that by bootstrap for each specific sample size per group. Hence, for this type of data, it is preferable that the bootstrap method be applied for sample size calculation at the beginning, and that the same statistical method as used in the subsequent statistical analysis is employed for each bootstrap sample during the course of bootstrap sample size estimation, provided there is historical true data available that can be well representative of the population to which the proposed trial is planning to extrapolate.

An efficient test based on the inferential model for the non-inferiority of odds ratio in matched-pairs design.

Non-inferiority of one treatment to another based on odds ratio for the matched-pair design is a common issue in the medical research. Liu et al. derived two asymptotic tests, delta method and score test, which can be applicable for large samples but may tend to be liberal for small sample sizes. Jin et al. proposed an IM-based method that can control the type I risk well but may be somewhat conservative. In this paper, we extend the IM-based method to RIM-based test using the randomized plausibility function. We prove that our new proposed method is not only valid but also efficient. Simulation studies confirm that the RIM-based test is better than other methods. A numerical example illustrates the proposed method.

Validation of Milliflex® Quantum for Bioburden Testing of Pharmaceutical Products.

This article reports the validation strategy used to demonstrate that the Milliflex® Quantum yielded non-inferior results to the traditional bioburden method. It was validated according to USP <1223>, European Pharmacopoeia 5.1.6, and Parenteral Drug Association Technical Report No. 33 and comprised the validation parameters robustness, ruggedness, repeatability, specificity, limit of detection and quantification, accuracy, precision, linearity, range, and equivalence in routine operation. For the validation, a combination of pharmacopeial ATCC strains as well as a broad selection of in-house isolates were used. In-house isolates were used in stressed state. Results were statistically evaluated regarding the pharmacopeial acceptance criterion of ≥70% recovery compared to the traditional method. Post-hoc test power calculations verified the appropriateness of the used sample size to detect such a difference. Furthermore, equivalence tests verified non-inferiority of the rapid method as compared to the traditional method. In conclusion, the rapid bioburden on basis of the Milliflex® Quantum was successfully validated as alternative method to the traditional bioburden test.LAY ABSTRACT: Pharmaceutical drug products must fulfill specified quality criteria regarding their microbial content in order to ensure patient safety. Drugs that are delivered into the body via injection, infusion, or implantation must be sterile (i.e., devoid of living microorganisms). Bioburden testing measures the levels of microbes present in the bulk solution of a drug before sterilization, and thus it provides important information for manufacturing a safe product. In general, bioburden testing has to be performed using the methods described in the pharmacopoeias (membrane filtration or plate count). These methods are well established and validated regarding their effectiveness; however, the incubation time required to visually identify microbial colonies is long. Thus, alternative methods that detect microbial contamination faster will improve control over the manufacturing process and speed up product release. Before alternative methods may be used, they must undergo a side-by-side comparison with pharmacopeial methods. In this comparison, referred to as validation, it must be shown in a statistically verified manner that the effectiveness of the alternative method is at least equivalent to that of the pharmacopeial methods. Here we describe the successful validation of an alternative bioburden testing method based on fluorescent staining of growing microorganisms applying the Milliflex® Quantum system by MilliporeSigma.