Methodological and reporting rigor in noninferiority and equivalence trials for multimodality cancer treatment: lessons from breast cancer radiotherapy.

To comprehensively evaluate the therapeutic equivalence and switching between biosimilar insulins and reference insulins in efficacy, safety and immunogenicity in diabetes. MEDLINE (via PubMed), Embase and Cochrane Library were searched (inception to March 2025) for randomised controlled trials (RCTs) employing two designs: (1) therapeutic equivalence trials directly compared biosimilar insulins vs. reference insulins; (2) switching trials where participants initially received reference insulin during a run-in period and were then randomised to either switch to biosimilar insulins or continue reference insulins. Outcomes included change in glycated hemoglobin (HbA1c) (%), achievement of HbA1c < 7%, change in fasting blood glucose (FBG), adverse events and immunogenicity. Heterogeneity was examined with I2 statistics. Data were pooled using mean differences (MDs) for continuous variables and odds ratios (ORs) for binary outcomes with 95% confidence intervals (CIs). A total of 25 RCTs involving 10 617 patients were included: equivalence analysis of 16 RCTs (n = 6548 patients) and switching analysis of nine RCTs (n = 4069 patients). No significant differences were found for change in HbA1c (equivalence: MD 0.01%, 95% CI -0.04, 0.06; switching: MD -0.01%, 95% CI -0.06, 0.05), the proportion achieving HbA1c <7.0% (equivalence: OR 0.99, 95% CI 0.88, 1.12; switching: OR 1.05, 95% CI 0.86, 1.27), or change in FBG (equivalence: MD 0.08 mmol/L, 95% CI -0.06, 0.22; switching: MD 0.11 mmol/L, 95% CI -0.18, 0.40). No statistically significant differences were found in the efficacy, primary safety and immunogenicity between biosimilar insulins and reference insulins. These findings support biosimilar insulins' adoption to enhance treatment access and cost-effectiveness.

Adjusting confidence intervals under covariate-adaptive randomization in non-inferiority and equivalence trials.

Effect of metoclopramide on gastric volume and nausea and vomiting in fasted patients undergoing elective cesarean delivery: a randomized clinical equivalence trial.

Cognitive Reappraisal as a Potential Mechanism of Unified Protocol for Emotional Disorders.

Point-of-care ultrasound (POCUS) is an important skill for healthcare professionals. However, adding POCUS training to medical education can be difficult because ultrasound simulators can be expensive. This study assessed whether an interactive, PowerPoint-based computer tool could be a valid alternative to an entry-level ultrasound simulator for teaching medical students how to perform thoracic and abdominal ultrasounds. This randomized controlled equivalence trial employed a two-arm, multi-station design involving 455 third-year medical students participating in an "Approach to Ultrasound" internship. Students underwent different training methodologies, including simulation-based sessions and hands-on practice with healthy volunteers, utilizing either a traditional ultrasound simulator or an interactive PowerPoint-based application designed to simulate ultrasound scenarios. Skills in image optimization ("OSAUS score in Healthy Volunteer") and pathology recognition ("Recognizing Pathologic score") were evaluated pre-and post-training. The margin for confirming the equivalence analysis was set at 0.5 points for the primary outcome. 408 students completed the training. Both groups improved significantly after training, with mean OSAUS scores increasing by more than 1.9 points and pathology recognition scores increasing by over 1.5 points. Differences between the two groups were minimal (OSAUS: 0.06 points; pathology recognition: 0.02 points) and within the equivalence margin, showing that the PC-based tool was as effective as the simulator. Simulation-based internships are essential to medical education, providing innovative and effective learning strategies for developing ultrasound skills. Exploring new tools, such as the PC-based solution tested in this study, is essential to making this method more accessible, especially in resource-limited settings.

IntroductionDistal radius fractures (DRFs) are common injuries, especially in older adults due to age-related frailty. Most DRFs in patients aged 60 and older are treated non-operatively since surgery offers no clinically important benefits. Although anatomical alignment has traditionally been the goal of the treatment, evidence suggests that in older populations, radiographic outcomes do not reliably correlate with functional outcomes. Current evidence, including one randomised trial, shows no functional benefit of closed reduction compared with casting alone, calling into question the routine use of the procedure in older patients. The primary objective is to evaluate whether no reduction is equivalent to closed reduction in patients aged 65 years or older with a displaced DRF, based on wrist-related pain and disability measured by the Patient-Rated Wrist Evaluation (PRWE) score at 12 months.Methods and analysisThis is a multi-centre, randomised controlled, equivalence trial conducted in hospitals in Finland, Denmark, Sweden and Estonia. We aim to enrol 532 patients aged ≥65 years with a displaced DRF (AO/OTA 23A/23C). Participants will be randomised (1:1) to receive either a dorsal cast without reduction (experimental intervention) or closed reduction followed by casting (control comparator). The primary endpoint is the difference between groups assessed using the PRWE outcome score at 12 months. The equivalence margin will be set at 6 PRWE points. Key secondary endpoints will include the Numeric Rating Scale for pain, patient satisfaction, quality of life (EQ-5D-5L Index) and serious adverse events at 3 months and 12 months and cosmesis at 3 months. Our main analyses will follow an intention-to-treat principle, analysed using repeated measures mixed model.Ethics and disseminationEthical approval has been granted by the Ethics Committee of Tampere University Hospital (R25001). Results of the trial will be disseminated through peer-reviewed journals.Protocol version6 July 2025, v1.0.Trial registration numberNCT07042139.

Mobile health (mHealth) is a novel model of care that may overcome barriers to pulmonary rehabilitation (PR) access. This study determined if mHealth PR was equivalent to centre-based PR (CB-PR) in improving exercise capacity and health status in people with chronic obstructive pulmonary disease (COPD). Single-blinded, multicentre, randomised controlled equivalence trial using an intention-to-treat analysis. Participants completed 8 weeks of either mHealth PR, using the mobile PR (m-PR) application and supported by telephone calls, or CB-PR. Co-primary outcomes, measured at baseline and end-intervention, were change in 6 minute walk distance (6MWD) and COPD assessment test (CAT) score, with an equivalence margin of 30 m and 2 points, respectively. 90 participants were randomised (mean (SD), m-PR n = 44: age 75 (7) years; forced expiratory volume in one second (FEV1) 58 (15) % predicted; CB-PR n = 46: age 75 (6) years; FEV1 55 (14) % predicted) with 38 m-PR participants and 42 CB-PR participants completing at least one primary outcome. At end-intervention, there was no between-group difference in 6MWD (mean difference (MD) 13 m, 95% CI -6 to 31), indicating equivalence of m-PR to CB-PR. There was a significant between-group difference in CAT score (MD -4.9 points, 95% CI -7.2 to -2.6), with both limits of the CI exceeding the equivalence margin, indicating superiority of m-PR. An mHealth PR programme resulted in equivalent improvements in exercise capacity and superior improvements in health status when compared with CB-PR in people with COPD. mHealth PR could be effective as a management option for people with COPD with adequate digital literacy. ACTRN12619001253190.

Comparison of Two Activated Clotting Time Targets During Cardiac Surgery With Cardiopulmonary Bypass: A Prospective Multicenter Randomized Controlled Trial.

BackgroundThe Estimands framework, introduced in the Addendum to ICH E9, provides a structured method to define treatment effects in clinical trials. The main novelty of the framework is the discussion of intercurrent events as part of the treatment effect definition. It is widely believed that the application of the framework to non-inferiority and equivalence trials deserves specific consideration.MethodsTo examine the current practices of using the estimand framework in non-inferiority and equivalence trials, we reviewed the scientific advice provided by the European Medicines Agency to drug developers in 2022. This review aimed to determine how often the estimands framework is used by drug developers and/or recommended by EMA and to describe what intercurrent events and handling strategies are being proposed by drug developers and recommended by EMA.ResultsThe use of the framework varied substantially by clinical development phases. While it was used for phase 3 trials in 47% (25/53) by developers, it was used in 5% (1/19) of the phase 1 trials. For 39% (11/28) of the trials where developers did not use the estimands framework in phase 3, there was no regulatory recommendation to adopt the framework in the response. The most discussed intercurrent event in our sample was ‘treatment discontinuation’ (n = 47), for which developers most often proposed either a treatment policy strategy (17/47, 36%) or a hypothetical strategy (11/47, 23%). In contrast, EMA most often recommended the use of two co-primary estimands with two different strategies (22/47, 47%).ConclusionsGenerally, the proposed and recommended strategies depend on the clinical setting and the respective intercurrent event. Developers almost always proposed a single primary estimand, whereas EMA often recommended two co-primary estimands differing in the strategies used to handle some or all the intercurrent events. Further interaction between academia, industry and regulators is necessary to progress the implementation process of the estimands framework for non-inferiority and equivalence trials.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13063-025-09068-2.

Prospective evaluation of mechanomyography versus triggered electromyography for intraoperative assessment of cortical breaches during instrumented lumbar surgery

Lumbar spinal stenosis (LSS) impairs quality of life and is commonly treated with microscopic laminectomy. Some have suggested that biportal endoscopic laminectomy may offer advantages through smaller incisions and reduced tissue trauma. However, it remains unclear whether these theoretical advantages translate into meaningful differences in patient-reported outcomes that patients would actually perceive. We performed an RCT in which we asked: (1) Does biportal endoscopic laminectomy result in equivalent functional outcomes as measured by the Oswestry Disability Index (ODI) at 1 year compared with microscopic laminectomy? (2) Are pain relief, quality of life measures, and surgery-related outcomes similar between biportal endoscopic laminectomy and microscopic laminectomy? (3) Are adverse event rates comparable between the two surgical techniques? We conducted an assessor-blind RCT at six centers in South Korea. Between July 19, 2021, and April 6, 2023, a total of 120 patients with LSS were randomized to undergo biportal endoscopic laminectomy (n = 60) or microscopic laminectomy (n = 60). At 1 year, 90% (54 of 60) of patients in the biportal endoscopic laminectomy group and 86.7% (52 of 60) of patients in the microscopic laminectomy group were accounted for and fully analyzed. No crossover occurred between treatment groups, and the primary analysis followed a modified intention-to-treat approach. The baseline characteristics were well balanced between the two groups. The primary outcome was the ODI score at 12 months postoperatively. Secondary outcomes included VAS pain scores, quality of life, perioperative parameters, and adverse events, assessed at baseline, 2 weeks, and at 3, 6, and 12 months. This was an equivalence trial using the ODI as the primary outcome for sample size calculation, with an equivalence margin of ± 12.8 points, which represents the minimum clinically important difference for the ODI. In the modified intention-to-treat analysis, we found no difference between the biportal endoscopic laminectomy and microscopic laminectomy groups in terms of ODI scores at 12 months (13 ± 12 versus 18 ± 18, mean difference -5 points [95% confidence interval -10 to 1]; p = 0.12), demonstrating equivalence between the techniques. Secondary outcomes including VAS pain scores, quality of life measures, functional recovery, satisfaction, surgical variables, and radiographic parameters were also similar between groups, with no clinically important differences observed. Adverse events were similar between biportal endoscopic laminectomy and microscopic laminectomy. This study found biportal endoscopic laminectomy to be equivalent to microscopic laminectomy in functional outcomes at 12 months. However, the observed differences do not represent clinically meaningful benefits that patients would perceive. Until high-quality evidence demonstrates patient-important advantages, we recommend against the wide adoption of this technique in clinical practice. Level I, therapeutic study.

Objective Prior research indicates that cognitive behavioral therapy (CBT) results in moderate-to-large increases in hope and well-being, though long-term treatment outcomes are less clear. This study examined whether gains in these outcomes were maintained up to 36 months after CBT and whether hope – an established change mechanism during treatment – was associated with sustained well-being during long-term follow-up when controlling for post-treatment anxiety and depression. Method A subset of 69 participants [Mage = 30.29 (SD = 9.94) yrs, 62.32% female, 89.86% White, 89.85% Non-Hispanic/Latinx] with anxiety disorders from a randomized equivalence trial of transdiagnostic and single-diagnosis CBT protocols were re-consented into a long-term follow-up study and completed assessments every 6 months across 3 years. Results Standardized mean gain scores and multilevel modeling (MLM) revealed no significant differences in well-being or hope between post-treatment and follow-up timepoints in either condition. MLM indicated that higher hope at the within-person (standardized γ10 = 0.26, p < .001) and between-person levels (standardized γ01 = 0.42, p < .001) were associated with greater well-being across long-term follow-up, whereas post-treatment anxiety and depression were not significant predictors. Conclusion Findings suggest sustained increases in hope may help preserve gains in well-being up to 3 years after CBT.

Surgical site infections (SSIs) significantly affect patient outcomes and healthcare costs. Alcohol-based chlorhexidine gluconate (CHG) is widely used for preoperative skin preparation; however, aqueous CHG is being considered as a safer alternative in certain settings. This study was designed as an equivalence randomized controlled trial to compare aqueous versus alcoholic CHG for surgical site infection (SSI) prevention in major abdominal operations. A single-centre, randomised controlled equivalence trial (Thai Clinical Trials Registry No. TCTR20211028001, Date October 28, 2021) enrolled 1,326 patients undergoing elective or emergency abdominal surgeries. Participants were randomised to receive skin preparation with either 2% aqueous CHG or 2% alcohol-based CHG. The primary outcome was 30-day total SSI incidence. Secondary outcomes included seroma, wound dehiscence, and hospital stay. Analyses were conducted using intention-to-treat, per-protocol, and as-treated approaches. In the modified intention-to-treat population, total SSI rates were 8.45% (95% CI: 6.44–10.83) in the aqueous CHG group and 10.26% (95% CI: 8.05–12.82) in the alcohol-based group. There was no significant difference in total SSI rates between groups (RD -0.7%, 95% CI: -3.3 to 1.8). Similar results were found in other analyses. Secondary outcomes showed no significant group differences. All findings were within the predefined equivalence margin. Although SSI rates were similar, statistical equivalence was not demonstrated due to wide confidence intervals. Aqueous CHG may still be a suitable alternative where alcohol-based CHG is contraindicated.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-15379-w.

Direct comparisons of non-pharmacological interventions are becoming increasingly common. Many randomised clinical trials are designed to assess whether the effect of one intervention is either equivalent to, or not inferior to, that of a criterion standard. This article provides an accessible introduction to such equivalence and non-inferiority designs. Topics covered include the choice of hypothesis and comparator, the choice of equivalence or non-inferiority margin and the benefits and drawbacks of common methods of analysis. While equivalence and non-inferiority trials offer unique possibilities, there are also challenges. Some of these are particularly pronounced in the non-pharmacological setting, such as the difficulty in establishing margins informed by placebo effects and structural barriers to achieving sufficient statistical power. Under-recognised general threats to the equivalence and non-inferiority designs are also discussed, including the threat of poor intervention delivery leading to washed-out effects, the especially pronounced threat of rhetorical 'spin' in the reporting of inconclusive findings and the threat of increasingly indirect evidence due to the sequential change of criterion standards. Implications for the non-pharmacological field are brought to the reader's attention, and suggestions are given to improve methodological rigour.

Non-inferiority and clinical equivalence clinical trials can be used to determine whether a health technology is no worse than an existing treatment. This study identified international guidance for conducting non-inferiority and clinical equivalence trials and investigated the current practices in conducting and reporting such trials, especially in the context of Health Technology Assessment (HTA). A pragmatic approach was used to identify international guidelines and published literature reporting approaches for the conduct and reporting of non-inferiority or clinical equivalence studies. Guidelines from both HTA and regulatory bodies were considered, and literature reviews from 2010 to 2023 were identified. The results of the reviews were supplemented by stakeholder interviews and synthesised to form a series of recommendations for the UK National Institute for Health and Care Excellence in the appraisal of non-inferiority and equivalence trials. The majority of guidelines (13/15) discussed methods to determine the non-inferiority margin and how the analysis should be conducted. Despite this, the quality of reporting in non-inferiority and clinical equivalence trials is consistently poor. Prior to presentation of trial evidence, HTA submissions that claim non-inferiority or equivalence should present the technical, biological and/or pharmacokinetic reasonings that support the claim.

Abstract: Advancements in pharmacology and medicine have led to the establishment of the best efficacy drugs for most clinical conditions (standard of care) is already established; thus, the chance of emergence of newer drugs with exceeding efficacy is much less. But the new drugs developed may have other preferable features such as easy administration and lesser adverse effects. Noninferiority (NI) trials are designed to test whether the new drug’s diminished efficacy is within an acceptable limit, or not clinically, compared to the “standard of care” drug. If the new drug proves to be noninferior clinically, then it can become a preferred choice for the particular medical condition, provided the drug offers its other claimed benefits. NI trials are distinct from superiority and equivalence trials. Furthermore, a failed superiority trial/conventional parallel group trial cannot be used to claim equivalence or NI. One of the main reasons on choosing the NI design is that placebo cannot be used, as a standard of care drug is already available, and it would be unethical to deprive the trial participants. Most of the NI trials are performed in oncology, the cardiovascular system, and infectious diseases. NI trials have important concerns and specific issues regarding their design, conduct, and analysis like the choice of the active comparator and NI margin. NI trials make conclusions with confidence intervals instead of P values, and it is crucial to interpret them properly. NI trials should be carefully designed and carried out to avoid false conclusions of NI and accepting a drug with considerably less efficacy which is clinically unethical and hazardous. However, a well-designed and properly executed NI trial can discern alternative therapies with preferred attributes.

The estimand framework, introduced in the ICH E9 (R1) Addendum, provides a structured approach for defining precise research questions in randomised clinical trials. It suggests five strategies for addressing intercurrent events (ICE). This case study examines the principal stratum strategy, highlighting its potential for estimating causal treatment effects in specific subpopulations and the challenges involved. The occurrence of anti-drug antibodies (ADAs) and their potential clinical impact are important factors in evaluating biosimilars. Typically, analyses focus on subgroups of patients who develop ADAs during the study. However, conducting subgroup analyses based on post-randomisation variables, such as immunogenicity, can introduce substantial bias into treatment effect estimates and is therefore methodologically not optimal. The principal stratum strategy provides a statistical pathway for estimating treatment effects in subpopulations that cannot be anticipated at baseline. By leveraging counterfactuals to assess treatment outcomes, with and without the incidence of intercurrent events (ICEs), this approach can be implemented through a missing data perspective. We demonstrate the implementation of the principal stratum strategy in a phase 3 equivalence trial of a biosimilar for the treatment of rheumatoid arthritis. Using a multiple imputation approach, we leverage longitudinal measurements to create analysis datasets for subpopulations who develop ADAs as ICE. Our results highlight the principal stratum strategy's potential and challenges, emphasising its reliance on unobserved ICE states and the need for complex and rigorous modelling. This study contributes to a nuanced understanding and practical implementation of the principal stratum strategy within the ICH E9 (R1) framework.

BackgroundEpilepsy and other seizure disorders are medical conditions that impose a substantial health economic burden on society given their considerable costs of illness and use of healthcare resources. The ALVEEG trial aims to tackle resource shortages in clinical settings and optimize patient management by evaluating outpatient ambulatory long-term video electroencephalograms (ALVEEGs) as a new diagnostic pathway to diagnose and manage epilepsy and other seizure disorders. The health economic evaluation alongside this trial aims to determine the cost-effectiveness and cost-utility of ALVEEGs for affected patients presenting themselves at participating epilepsy centers in Germany.MethodsThis study protocol comprises the rationale and methods of the health economic evaluation of ALVEEGs embedded into the ALVEEG project. We will perform cost-effectiveness and cost-utility analyses, with the outcomes being a priori defined endpoint measures of the main trial. We will consider the proportion of solved clinical queries (primary endpoint), the number of hospital stays, the in-patient length of stay, and quality-adjusted life years for the here presented health economic evaluation. Costs will be collected by the participating health insurance companies alongside the trial, with the evaluation being conducted from a statutory health insurance perspective within the German healthcare system. The reporting of the economic evaluation follows the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist.DiscussionThe health economic evaluation of ALVEEGs for patients affected by epilepsy and other seizure disorders within the German healthcare system will deliver insightful evidence on the cost-effectiveness and cost-utility of the intervention and hence guide policy and decision makers regarding a potential inclusion of ALVEEGs into the health benefit basket of the statutory health insurance scheme.Trial registrationGerman Clinical Trials Register (DRKS00032220), date registered: December 11, 2023.

Background/Objectives: This study aimed to demonstrate the safety and suitability of an infant formula manufactured from partially hydrolysed whey protein (PHF) compared to standard formula manufactured from intact cow's milk proteins (IPF; whey-casein ratio, 60:40) in healthy term infants. Methods: This multicentre, randomised, double-blinded, placebo-controlled trial included infants of mothers who intended to exclusively formula feed. Infants ≤ 28 days of age received PHF or IPF for at least 90 and up to 180 days. A group of exclusively breastfed infants was included for reference. The safety evaluation consisted of an equivalence analysis of weight gain within +/-3 g/d after 90 days, further growth parameters, and adverse events. Results: Of the 249 infants randomised, 143 (76 IPF; 67 PHF), as well as 45 breastfed infants, completed the study per protocol. The mean difference in daily weight gain between the formula groups was within the equivalence margins (-2.4 g/d (95% CI 0.3-4.5)) with estimated means (SEM) of 34.9 (0.78) g/d (IPF) and 32.5 (0.76) g/d (PHF). No significant differences in weight gain, length, and head circumference or in the number, severity, or type of adverse events were observed. Comparable growth patterns were observed in the breastfed group. Conclusions: The PHF is safe and supports adequate infant growth with a daily weight gain non-inferior to a standard IPF.