Do You Want to Stay Single? Considerations on Single-Arm Trials in Drug Development and the Postregulatory Space.

Single-arm trials (SATs), while not preferred, remain in use throughout the drug development cycle. They may be accepted by regulators in particular contexts (e.g., in oncology or rare diseases) when the potential effects of new treatments are very large and placebo treatment is unethical. However, in the postregulatory space, SATs are common, and perhaps even more poorly suited to address the questions of interest. In this manuscript, we review regulatory and HTA positions on SATs; challenges posed by SATs to address research questions beyond regulators, evolving statistical methods to provide context for SATs, case studies where SATs could and could not address questions of interest, and communication strategies to influence decision making and optimize study design to address evidence needs.

Eribulin for patients with metastatic extramammary Paget disease: Study protocol for a single-arm phase II trial.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy that predominantly affects the anogenital areas of the elderly. Although the efficacy of docetaxel and other cytotoxic agents for advanced EMPD has been reported in small retrospective case studies, no treatment has been proven effective in prospective clinical trials. We established the world's first in vivo EMPD experimental model (a patient-derived xenograft model). In our treatment experiment, xenograft tumours showed a remarkable response to eribulin. This study evaluates the efficacy of eribulin for patients with advanced EMPD. In October 2022, we started a single-arm phase II trial to evaluate the efficacy of eribulin as a treatment for adult patients with unresectable EMPD with measurable lesions. Enrolment in this clinical trial is open to patients with any prior treatment for EMPD. The primary endpoint is overall response rate; the secondary endpoints include disease control rate, overall survival, progression-free survival and adverse events. The study protocol was approved by the Ethics Committee of Hokkaido University and the other collaborating institutions. If the primary endpoint is met, it is our hope that eribulin will be regarded as a standard medication for patients with advanced EMPD.

Justifying the source of external comparators in single-arm oncology health technology submissions: a review of NICE and PBAC assessments.

Background: The drive to expedite patient access for diseases with high unmet treatment needs has come with an increasing use of single-arm trials (SATs), especially in oncology. However, the lack of control arms in such trials creates challenges to assess and demonstrate comparative efficacy. External control (EC) arms can be used to bridge this gap, with various types of sources available to obtain relevant data. Objective: To examine the source of ECs in single-arm oncology health technology assessment (HTA) submissions to the National Institute for Health and Care Excellence (NICE) and the Pharmaceutical Benefits Advisory Committee (PBAC) and how this selection was justified by manufacturers and assessed by the respective HTA body. Methods: Single-arm oncology HTA submission reports published by NICE (England) and PBAC (Australia) from January 2011 to August 2021 were reviewed, with data qualitatively synthesized to identify themes. Results: Forty-eight oncology submissions using EC arms between 2011 and 2021 were identified, with most submissions encompassing blood and bone marrow cancers (52%). In HTA submissions to NICE and PBAC, the EC arm was typically constructed from a combination of data sources, with the company's justification in data source selection infrequently provided (PBAC [2 out of 19]; NICE [6 out of 29]), although this lack of justification was not heavily criticized by either HTA body. Conclusion: Although HTA bodies such as NICE and PBAC encourage that EC source justification should be provided in submissions, this review found that this is not typically implemented in practice. Guidance is needed to establish best practices as to how EC selection should be documented in HTA submissions.

An evaluation of confidence intervals for a cumulative proportion to enable decisions at interim reviews of single-arm trials.

BACKGROUND: Clinical trials often include interim analyses of the proportion of participants experiencing an event by a fixed time-point. A pre-specified proportion excluded from a corresponding confidence interval (CI) may lead an independent monitoring committee to recommend stopping the trial. Frequently this cumulative proportion is estimated by the Kaplan-Meier estimator with a Wald approximate CI, which may have coverage issues with small samples. METHODS: We reviewed four alternative CI methods for cumulative proportions (Beta Product Confidence Procedure (BPCP), BPCP Mid P, Rothman-Wilson, Thomas-Grunkemeier) and two CI methods for simple proportions (Clopper-Pearson, Wilson). We conducted a simulation study comparing CI methods across true event proportions for 12 scenarios differentiated by sample sizes and censoring patterns. We re-analyzed interim data from A5340, a HIV cure trial considering the proportion of participants experiencing virologic failure. RESULTS: Our simulation study highlights the lower and upper tail error probabilities for each CI method. Across scenarios, we found differences in the performance of lower versus upper bounds. No single method is always preferred. The upper bound of a Wald approximate CI performed reasonably with some error inflation, whereas the lower bound of the BPCP Mid P method performed well. For a trial design similar to A5340, we recommend BPCP Mid P. CONCLUSIONS: The design of future single-arm interim analyses of event proportions should consider the most appropriate CI method based on the relevant bound, anticipated sample size and event proportion. Our paper summarizes available methods, demonstrates performance in a simulation study, and includes code for implementation.

Considerations for pooling real-world data as a comparator cohort to a single arm trial: a simulation study on assessment of heterogeneity.

BACKGROUND: Novel precision medicine therapeutics target increasingly granular, genomically-defined populations. Rare sub-groups make it challenging to study within a clinical trial or single real-world data (RWD) source; therefore, pooling from disparate sources of RWD may be required for feasibility. Heterogeneity assessment for pooled data is particularly complex when contrasting a pooled real-world comparator cohort (rwCC) with a single-arm clinical trial (SAT), because the individual comparisons are not independent as all compare a rwCC to the same SAT. Our objective was to develop a methodological framework for pooling RWD focused on the rwCC use case, and simulate novel approaches of heterogeneity assessment, especially for small datasets. METHODS: We present a framework with the following steps: pre-specification, assessment of dataset eligibility, and outcome analyses (including assessment of outcome heterogeneity). We then simulated heterogeneity assessments for a binary response outcome in a SAT compared to two rwCCs, using standard methods for meta-analysis, and an Adjusted Cochran's Q test, and directly comparing the individual participant data (IPD) from the rwCCs. RESULTS: We found identical power to detect a true difference for the adjusted Cochran's Q test and the IPD method, with both approaches superior to a standard Cochran's Q test. When assessing the impact of heterogeneity in the null scenario of no difference between the SAT and rwCCs, a lack of statistical power led to Type 1 error inflation. Similarly, in the alternative scenario of a true difference between SAT and rwCCs, we found substantial Type 2 error, with underpowered heterogeneity testing leading to underestimation of the treatment effect. CONCLUSIONS: We developed a methodological framework for pooling RWD sources in the context of designing a rwCC for a SAT. When testing for heterogeneity during this process, the adjusted Cochran's Q test matches the statistical power of IPD heterogeneity testing. Limitations of quantitative heterogeneity testing in protecting against Type 1 or Type 2 error indicate these tests are best used descriptively, and after careful selection of datasets based on clinical/data considerations. We hope these findings will facilitate the rigorous pooling of RWD to unlock insights to benefit oncology patients.

Data Challenges for Externally Controlled Trials: Viewpoint.

The preferred evidence of a large randomized controlled trial is difficult to adopt in scenarios, such as rare conditions or clinical subgroups with high unmet needs, and evidence from external sources, including real-world data, is being increasingly considered by decision makers. Real-world data originate from many sources, and identifying suitable real-world data that can be used to contextualize a single-arm trial, as an external control arm, has several challenges. In this viewpoint article, we provide an overview of the technical challenges raised by regulatory and health reimbursement agencies when evaluating comparative efficacy, such as identification, outcome, and time selection challenges. By breaking down these challenges, we provide practical solutions for researchers to consider through the approaches of detailed planning, collection, and record linkage to analyze external data for comparative efficacy.

Early phase clinical trial played a critical role in the Food and Drug Administration-approved indications for targeted anticancer drugs: a cross-sectional study from 2012 to 2021.

OBJECTIVES: To characterize the indications approved by the US Food and Drug Administration (FDA) on the basis of early phase clinical trials (EPCTs) and compared with that of phase three randomized controlled trials. STUDY DESIGN AND SETTING: We collected the publicly available FDA documents of targeted anticancer drugs approved between January 2012 and December 2021. RESULTS: We identified 95 targeted anticancer drugs with 188 indications approved by the FDA. One hundred and twelve (59.6%) indications were approved on the basis of EPCTs, with a significant increase of 22.2% per year. Of 112 EPCTs, 32 (28.6%) were dose-expansion cohort trials and 75 (67.0%) were single-arm phase 2 trials, respectively, with a significant increase of 29.7% and 18.7% per year. Compared with indications approved on the basis of phase three randomized controlled trials, the indications approved on the basis of EPCTs had significantly higher odds in receiving accelerated approval and lower odds in the number of entered patients of pivotal trials. CONCLUSIONS: Dose-expansion cohort trials and single-arm phase 2 trials played a critical role in EPCTs. EPCT was a major trial type in providing evidences for the FDA approvals of targeted anticancer drugs.

Prognosis of Patients With Heart Failure Receiving Autologous Myoblast Patches　- Comparison of Single-Arm Trial Data to Registry Data.

BACKGROUND: Clinical studies in regenerative medicine remain insufficient in Japan due to ethical concerns regarding the control group and a lack of statistical methodology to evaluate efficacy in a small treatment group. This study evaluated the efficacy of autologous myoblast patch (AMP) treatment for heart failure using restricted mean survival time (RMST) analysis by comparing data from a small single-arm trial to epidemiological data from a registry.Methods and Results: The clinical trial arm included 55 patients with advanced ischemic cardiomyopathy who received an AMP between 2010 and 2020. The registry-based control group comprised 937 participants with severely impaired left ventricular function who were hospitalized for heart failure during the study period. Due to the limited number of patients, RMST analysis was used to compare survival between the 2 groups. Cox regression analyses revealed non-significant differences in survival between the groups at 3, 3.5, and 4 years. In contrast, RMST analyses revealed significant differences in survival at 3 years (P=0.008) and 3.5 (P=0.024) years, but not at 4 years. CONCLUSIONS: This small single-arm trial using RMST analyses was able to detect the efficacy of AMP transplantation for advanced heart failure (compared with a registry-based control group), with better survival until 3.5 years. This approach may be useful for efficacy analyses in regenerative medicine, where traditional clinical trials are difficult.

[Rethinking the marketing strategy of anti-tumor drugs by single-arm trials supported].

Single-arm trial refers to a clinical trial design that does not set up parallel control group, adopts open design, and does not involve randomization and blind method. These features, on the one hand, speed up the process of clinical trials, significantly shorten the time to market and meet the needs of patients with advanced malignancies, but also lead to the uncertainty of single-arm clinical trials themselves. Recently, the US Food and Drug Administration held a meeting of the oncologic drug advisory committee to discuss six tumor indications that have been accelerated approved, which once again triggered the discussion of single-arm trials. The basis of accelerated approval by single-arm trial is actually a compromise on the level of evidence-based medical evidence requirements after assessing the benefit risk. Therefore, the sponsor should strictly grasp the applicable conditions of single-arm trial in anti-tumor drugs and conduct single-arm trial scientifically. Post-marketing clinical trial should be implement as early as possible to ensure the benefit of patients. Based on the characteristics of single-arm trial, combined with two guidance relevant to single-arm trial issued by National Medical Products Administration recently, this article is supposed to propose and summarize the strategy of single-arm trial supporting the marketing of anti-tumor drugs.

Stopping for efficacy in single-arm phase II clinical trials.

Phase II clinical trials investigate whether a new drug or treatment has sufficient evidence of effectiveness against the disease under study. Two-stage designs are popular for phase II since they can stop in the first stage if the drug is ineffective. Investigators often face difficulties in determining the target response rates, and adaptive designs can help to set the target response rate tested in the second stage based on the number of responses observed in the first stage. Popular adaptive designs consider two alternate response rates, and they generally minimise the expected sample size at the maximum uninterested response rate. Moreover, these designs consider only futility as the reason for early stopping and have high expected sample sizes if the provided drug is effective. Motivated by this problem, we propose an adaptive design that enables us to terminate the single-arm trial at the first stage for efficacy and conclude which alternate response rate to choose. Comparing the proposed design with a popular adaptive design from literature reveals that the expected sample size decreases notably if any of the two target response rates are correct. In contrast, the expected sample size remains almost the same under the null hypothesis.

Response rate of anticancer drugs approved by the Food and Drug Administration based on a single-arm trial.

BACKGROUND: In recent years, an increasing number of anticancer drugs have been approved based on the results of a single-arm trial (SAT). The magnitude of the objective response rate (ORR) in SATs is important for regulatory decisions, but there has been no clear guidance specifying the degree of ORR for approval. METHODS: All anticancer drugs approved by the US Food and Drug Administration (FDA) between January 2016 and December 2019 were identified through the FDA website. From these, we selected drugs approved for solid tumors based on SATs. For each indication, one regimen was selected from the standard-of-care as the best comparison therapy (BCT), which was defined as the latest regimen for the same tumor and treatment line. We compared the ORR of the investigated product with that of the BCT. RESULTS: Of the 31 solid tumor indications identified, we selected BCT for 28. In 23 of the 28 indications (82.1%), the ORR of the investigated product exceeded that of the BCT, and in 16 of these (69.6%), the lower limit of the 95% confidence interval (CI) of the ORR of the investigated product exceeded the point estimate of the BCT ORR. For seven products, the lower limit of the 95% CI was below the point estimate of the BCT ORR, with differences ranging from 1.0% to 3.4%. CONCLUSION: The lower limit of a 95% CI of the ORR of a new drug in an SAT exceeding the point estimate of the BCT ORR could be an important factor in obtaining regulatory approval.

A Phase 1/2 Single-arm Clinical Trial of Recombinant Bacillus Calmette-Guérin (BCG) VPM1002BC Immunotherapy in Non-muscle-invasive Bladder Cancer Recurrence After Conventional BCG Therapy: SAKK 06/14.

BACKGROUND: VPM1002BC is a genetically modified Mycobacterium bovis bacillus Calmette-Guérin (BCG) strain with potentially improved immunogenicity and attenuation. OBJECTIVE: To report on the efficacy, safety, tolerability and quality of life of intravesical VPM1002BC for the treatment of non-muscle-invasive bladder cancer (NMIBC) recurrence after conventional BCG therapy. DESIGN, SETTING, AND PARTICIPANTS: We designed a phase 1/2 single-arm trial (NCT02371447). Patients with recurrent NMIBC after BCG induction ± BCG maintenance therapy and intermediate to high risk for cancer progression were eligible. INTERVENTION: Patients were scheduled for standard treatment of six weekly instillations with VPM1002BC followed by maintenance for 1 yr. Treatment was stopped in cases of recurrence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was defined as the recurrence-free rate (RFR) in the bladder 60 wk after trial registration. The sample size was calculated based on the assumption that ≥30% of the patients would be without recurrence at 60 wk after registration. RESULTS AND LIMITATIONS: After exclusion of two ineligible patients, 40 patients remained in the full analysis set. All treated tumours were of high grade and 27 patients (67.5%) presented with carcinoma in situ. The recurrence-free rate in the bladder at 60 wk after trial registration was 49.3% (95% confidence interval [CI] 32.1-64.4%) and remained at 47.4% (95% CI 30.4-62.6%] at 2 yr and 43.7% (95% CI 26.9-59.4%) at 3 yr after trial registration. At the same time, progression to muscle-invasive disease had occurred in three patients and metastatic disease in four patients. Treatment-related grade 1, 2, and 3 adverse events (AEs) were observed in 14.3%, 54.8%, and 4.8% of the patients, respectively. No grade ≥4 AEs occurred. Two of the 42 patients did not tolerate five or more instillations during induction. Limitations include the single-arm trial design and the low number of patients for subgroup analysis. CONCLUSIONS: At 1 yr after treatment start, almost half of the patients remained recurrence-free after therapy with VPM100BC. The primary endpoint of the study was met and the therapy is safe and well tolerated. PATIENT SUMMARY: We conducted a trial of VPM100BC, a genetically modified bacillus Calmette-Guérin (BCG) strain for treatment of bladder cancer not invading the bladder muscle. At 1 year after the start of treatment, almost half of the patients with a recurrence after previous conventional BCG were free from non-muscle-invasive bladder cancer (NMIBC). The results are encouraging and VPM1002BC merits further evaluation in randomised studies for patients with NMIBC.

Rethinking the marketing strategy of anti-tumor drugs by single-arm trials supported / 中华肿瘤杂志

Single-arm trial refers to a clinical trial design that does not set up parallel control group, adopts open design, and does not involve randomization and blind method. These features, on the one hand, speed up the process of clinical trials, significantly shorten the time to market and meet the needs of patients with advanced malignancies, but also lead to the uncertainty of single-arm clinical trials themselves. Recently, the US Food and Drug Administration held a meeting of the oncologic drug advisory committee to discuss six tumor indications that have been accelerated approved, which once again triggered the discussion of single-arm trials. The basis of accelerated approval by single-arm trial is actually a compromise on the level of evidence-based medical evidence requirements after assessing the benefit risk. Therefore, the sponsor should strictly grasp the applicable conditions of single-arm trial in anti-tumor drugs and conduct single-arm trial scientifically. Post-marketing clinical trial should be implement as early as possible to ensure the benefit of patients. Based on the characteristics of single-arm trial, combined with two guidance relevant to single-arm trial issued by National Medical Products Administration recently, this article is supposed to propose and summarize the strategy of single-arm trial supporting the marketing of anti-tumor drugs.

Detecting deviations from the efficacy and safety results of single-arm trials using real-world data: The case of a CAR-T cell therapy in B-cell lymphoma.

PURPOSE: Personalized therapies are leading to an increasing number of marketing authorizations based on single-arm trials, which increases the demand for better post-authorization monitoring strategies. The aim of the present study was to estimate the power over time as data accrue in population-based registries for detecting deviations from the expected efficacy/safety of chimeric antigen receptor T cell (CAR-T) therapy approved for relapsed/refractory large B-cell lymphoma (RR-LBCL). METHODS: The number of real-world RR-LBCL patients was projected over time in a general population of 5, 15, and 25 million citizens using lymphoma registry data. For each scenario, we computed the power over time for detecting significant deviations in efficacy (1-year overall survival [1yOS]) when comparing to historical controls (SCHOLAR-1 study; 1yOS, 28%) and RR-LBCL patients treated with CAR-T cell therapy in a single-arm trial (ZUMA-1; 1yOS, 59%) as well as deviations in selected adverse events (grade ≥3 aphasia) from the ZUMA-1 trial. We assumed a 10% absolute deviation in 1yOS (efficacy) and a relative increase of 50% in grade ≥3 aphasia (safety). RESULTS: Assuming a general population of 5, 15, and 25 million, the accrual time needed to achieve 80% power for detecting a significant increase over the 1yOS reported in SCHOLAR-1 was 9, 4, and 3 years, respectively, while 80% power for detecting a significant decrease in 1yOS compared to ZUMA-1 required 10.5, 4.5, and 3 years of data accrual, respectively. However, corresponding estimates for aphasia were >20, 8, and 5 years, respectively. CONCLUSIONS: Projections of the statistical power for detecting important deviations in efficacy/safety from that reported in pivotal clinical trials(s) provide critical information about the expected performance of post-authorization monitoring programs.

BRIDGING RANDOMIZED CONTROLLED TRIALS AND SINGLE-ARM TRIALS USING COMMENSURATE PRIORS IN ARM-BASED NETWORK META-ANALYSIS.

Network meta-analysis (NMA) is a powerful tool to compare multiple treatments directly and indirectly by combining and contrasting multiple independent clinical trials. Because many NMAs collect only a few eligible randomized controlled trials (RCTs), there is an urgent need to synthesize different sources of information, e.g., from both RCTs and single-arm trials. However, single-arm trials and RCTs may have different populations and quality, so that assuming they are exchangeable may be inappropriate. This article presents a novel method using a commensurate prior on variance (CPV) to borrow variance (rather than mean) information from single-arm trials in an arm-based (AB) Bayesian NMA. We illustrate the advantages of this CPV method by reanalyzing an NMA of immune checkpoint inhibitors in cancer patients. Comprehensive simulations investigate the impact on statistical inference of including single-arm trials. The simulation results show that the CPV method provides efficient and robust estimation even when the two sources of information are moderately inconsistent.

The response rate of alternative treatments for drugs approved on the basis of response rate.

We assessed the frequency that oncology drugs approved by the U.S. Food and Drug Administration (FDA) based on a single-arm study when there is already evidence of existing and available treatments. For this, we conducted a retrospective cross-sectional analysis of FDA-approved oncology drugs based on a single-arm study. All FDA announcements for all oncology drugs approved from May 2014 through June 2019 on a single-arm trial were included. We then performed a systematic search in PubMed, looking for studies on other drugs for the same indication as the FDA drug approval. For the 60 indications, we found 38 instances (63%) of existing therapies being used for the same indication. Of those, we found that 20 drugs were approved based upon a response rate lower than response rates of existing therapies in the same indication. Among oncology drugs that were FDA-approved based on a single-arm study, we found evidence of existing, available therapies being used for the same indication as the FDA-approved drug in the majority of indications (63%), and in one-third of all indications, the response rates for existing therapies were numerically better than the FDA-approved drug. These results suggest that there are inconsistencies in the standards set for oncology drug approvals, and many uncontrolled trials leading to drug approvals could have contemporary controls for which equipoise exists.

New perspectives on the principle of intention to treat in clinical trials / 中国临床药理学与治疗学

The intention to treat (ITT) principle is widely applied in the randomized controlled trials (RCTs), which is based on the intention to treat a subject (i.e. the planned treatment regimen) rather than the actual treatment given. With the development and progress of clinical trials, ITT principle needs to be reinterpreted. In the standard definition of ITT principle, the intentional grouping of subjects does not specifically refer to randomization, but rather to planned treatment regimen. In non-randomized clinical trials, that subjects agree to be included in a certain treatment regimen is also a type of intention. ITT principles can be applied to evaluate the effectiveness of treatment regimens under patient/doctor determined intentionality in single-arm clinical trials and non-randomized RWS (real world study, RWS). In the practical application, the grouping strategy based on ITT principle should be considered comprehensively according to the research purpose.

Real-world survival outcomes of heavily pretreated patients with refractory HR+, HER2-metastatic breast cancer receiving single-agent chemotherapy-a comparison with MONARCH 1.

PURPOSE: In MONARCH 1 (NCT02102490), single-agent abemaciclib demonstrated promising efficacy activity and tolerability in a population of heavily pretreated women with refractory HR+, HER2- metastatic breast cancer (MBC). To help interpret these results and put in clinical context, we compared overall survival (OS) and duration of therapy (DoT) between MONARCH 1 and a real-world single-agent chemotherapy cohort. METHODS: The real-world chemotherapy cohort was created from a Flatiron Health electronic health records-derived database based on key eligibility criteria from MONARCH 1. The chemotherapies included in the cohort were single-agent capecitabine, gemcitabine, eribulin, or vinorelbine. Results were adjusted for baseline demographics and clinical differences using Mahalanobis distance matching (primary analysis) and entropy balancing (sensitivity analysis). OS and DoT were analyzed using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: A real-world single-agent chemotherapy cohort (n = 281) with eligibility criteria similar to the MONARCH 1 population (n = 132) was identified. The MONARCH 1 (n = 108) cohort was matched to the real-world chemotherapy cohort (n = 108). Median OS was 22.3 months in the abemaciclib arm versus 13.6 months in the matched real-world chemotherapy cohort with an estimated hazard ratio (HR) of 0.54. The median DoT was 4.1 months in MONARCH 1 compared to 2.9 months in the real-world chemotherapy cohort with HR of 0.76. CONCLUSIONS: This study demonstrates an approach to create a real-world chemotherapy cohort suitable to serve as a comparator for trial data. These exploratory results suggest a survival advantage and place the benefit of abemaciclib monotherapy in clinical context.

The Effects of Model Misspecification in Unanchored Matching-Adjusted Indirect Comparison: Results of a Simulation Study.

OBJECTIVES: To assess the performance of unanchored matching-adjusted indirect comparison (MAIC) by matching on first moments or higher moments in a cross-study comparisons under a variety of conditions. A secondary objective was to gauge the performance of the method relative to propensity score weighting (PSW). METHODS: A simulation study was designed based on an oncology example, where MAIC was used to account for differences between a contemporary trial in which patients had more favorable characteristics and a historical control. A variety of scenarios were then tested varying the setup of the simulation study, including violating the implicit or explicit assumptions of MAIC. RESULTS: Under ideal conditions and under a variety of scenarios, MAIC performed well (shown by a low mean absolute error [MAE]) and was unbiased (shown by a mean error [ME] of about zero). The performance of the method deteriorated where the matched characteristics had low explanatory power or there was poor overlap between studies. Only when important characteristics are not included in the matching did the method become biased (nonzero ME). Where the method showed poor performance, this was exaggerated if matching was also performed on the variance (ie, higher moments). Relative to PSW, MAIC provided similar results in most circumstances, although it exhibited slightly higher MAE and a higher chance of exaggerating bias. CONCLUSIONS: MAIC appears well suited to adjust for cross-trial comparisons provided the assumptions underpinning the model are met, with relatively little efficiency loss compared with PSW.