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Aim: Late-onset Pompe disease is characterized by progressive loss of muscular and respiratory function. Until recently, standard of care was enzyme replacement therapy (ERT) with alglucosidase alfa. Second-generation ERTs avalglucosidase alfa (aval) and cipaglucosidase alfa with miglustat (cipa+mig) are now available. Without head-to-head trials comparing aval with cipa+mig, an indirect treatment comparison is informative and timely for understanding potential clinical differentiation. Materials & methods: A systematic literature review was performed to identify relevant studies on cipa+mig and aval. Using patient-level and aggregate published data from randomized controlled trials (RCTs) and phase I/II and open-label extension (OLE) trials, a multi-level network meta-regression was conducted, adjusting for various baseline covariates, including previous ERT duration, to obtain relative effect estimates on 6-minute walk distance (6MWD, meters [m]) and forced vital capacity (FVC, % predicted [pp]). Analyses of two networks were conducted: Network A, including only RCTs, and network B, additionally including single-arm OLE and phase I/II studies. Results: Network B (full evidence analysis) showed that cipa+mig was associated with a relative increase in 6MWD (mean difference 28.93 m, 95% credible interval [8.26-50.11 m]; Bayesian probability 99.7%) and FVC (2.88 pp [1.07-4.71 pp]; >99.9%) compared with aval. The comparison between cipa+mig and aval became more favorable for cipa+mig with increasing previous ERT duration for both end points. Analysis of network A showed that cipa+mig was associated with a relative decrease in 6MWD (-10.02 m [-23.62 to 4.00 m]; 91.8%) and FVC (-1.45 pp [-3.01 to 0.07 pp]; 96.8%) compared with aval. Conclusion: Cipa+mig showed a favorable effect versus aval when all available evidence was used in the analysis.

Background: The treatment landscape for relapsed or refractory (R/R) follicular lymphoma (FL) has changed with the introduction of anti-CD19 chimeric antigen receptor T-cell therapies, including lisocabtagene maraleucel (liso-cel) and CD20 × CD3 bispecific T-cell–engaging monoclonal antibodies such as mosunetuzumab. Liso-cel and mosunetuzumab have demonstrated positive benefit-risk profiles for third-line or later (3L+) treatment of patients with R/R FL and are approved treatments for these patients. In the absence of a prospective, randomized study, we conducted an unanchored matching-adjusted indirect comparison (MAIC) to assess the efficacy and safety of liso-cel and mosunetuzumab for 3L+ treatment in patients with R/R FL. Methods: Unanchored MAICs were performed to estimate relative treatment effects between TRANSCEND FL (NCT04245839) and GO29781 (NCT02500407). For TRANSCEND FL, the leukapheresis set (N = 114) was used for primary comparisons of the following efficacy endpoints: objective response rate (ORR), complete response (CR) rate, duration of response (DOR), and progression-free survival (PFS). The treated set (N = 107) was used for comparisons of the following safety endpoints: cytokine release syndrome (CRS), neurological events (NE), serious infections, and use of corticosteroids or tocilizumab for CRS. Sensitivity analyses were conducted for efficacy using the TRANSCEND FL treated efficacy set (N = 101). Results: After adjustment, liso-cel was associated with higher ORR (odds ratio [OR] = 3.78, 95% confidence interval [CI] 1.48‒9.67]) and CR rate (OR = 6.46, 95% CI 2.85‒14.65), and improved DOR (hazard ratio [HR] = 0.45, 95% CI 0.26‒0.77) and PFS (HR = 0.28, 95% CI 0.16‒0.49) compared with mosunetuzumab. Results remained consistent across sensitivity analyses. Liso-cel had a lower incidence of grade ≥ 3 CRS (OR = 0.45, 95% CI 0.04‒5.13), grade 3‒4 serious infections (OR = 0.35, 95% CI 0.12‒1.03), and corticosteroid use for CRS management (OR = 0.14, 95% CI 0.03‒0.65); however, liso-cel exhibited higher incidence of any-grade CRS (OR = 1.86, 95% CI 1.01‒3.43), any-grade NEs (OR = 2.16, 95% CI 0.72‒6.44), and tocilizumab use for CRS management (OR = 2.27, 95% CI 0.86‒5.99). Conclusions: Findings highlight a potential positive benefit-risk profile of liso-cel over mosunetuzumab as a 3L+ treatment for R/R FL. [ABSTRACT FROM AUTHOR]

AbstractBackgroundObjectiveMethodsResultsConclusionCOVID-19 continues to pose a significant health burden, particularly among older adults. mRNA-1283 is a next-generation COVID-19 mRNA vaccine developed to enhance immune response. Findings from the Phase 3 NextCOVE trial comparing bivalent versions of mRNA-1273 and mRNA-1283 vaccines have recently become available. However, there are no head-to-head trials comparing mRNA-1283 and the BNT162b2 vaccine.To indirectly compare the effectiveness of mRNA-1283 and BNT162b2 against symptomatic COVID-19 among adults in the U.S.A targeted literature review was conducted to identify relevant studies comparing the mRNA-1273 and BNT162b2 bivalent vaccines. A real-world evidence (RWE) study by Kopel et al. (2023) assessing the relative vaccine effectiveness (rVE) of mRNA-1273 vs. BNT162b2, was selected for an indirect treatment comparison (ITC) against the NextCOVE trial using the Bucher method. Analyses were stratified by age group, and sensitivity analyses were conducted using alternative outcome definitions.Despite differences between NextCOVE and the Kopel study, comparability assessments supported a robust ITC. Among participants ≥18 years of age, the indirect rVE of mRNA-1283 vs. BNT162b2 against symptomatic COVID-19 was 15.3% (95% CI: 4.7–24.8%, p = 0.006). For adults ≥65 years of age, the rVE was 22.8% (95% CI: 3.7–38.1%, p = 0.022). Sensitivity analyses with alternative outcome definitions supported these estimates.This analysis provides consistent and statistically significant evidence indicating the next-generation mRNA-1283 vaccine is more effective in preventing symptomatic COVID-19 than BNT162b2, with the largest effect in individuals aged ≥65. Consistent results across sensitivity analyses underscore the robustness of the findings, offering important evidence to inform vaccination decisions by policymakers, providers, and payers. [ABSTRACT FROM AUTHOR]

Recurrent Clostridioides difficile infection (rCDI) is a major cause of increased morbidity, mortality, and healthcare costs. Fecal-microbiota-based therapies are recommended for rCDI on completion of standard-of-care (SoC) antibiotics to prevent further recurrence: these therapies include conventional fecal-microbiota transplantation and the US Food and Drug Administration-approved therapies REBYOTA® (RBL) and VOWST Oral Spores™ (VOS). As an alternative to microbiota-based therapies, bezlotoxumab, a monoclonal antibody, is used as adjuvant to SoC antibiotics to prevent rCDI. There are no head-to-head clinical trials comparing different microbiota-based therapies or bezlotoxumab for rCDI. To address this gap, we conducted a systematic literature review to identify clinical trials on rCDI treatments and assess the feasibility of using them to conduct an indirect treatment comparison (ITC). The feasibility analysis determined that trial heterogeneity, particularly relating to inclusion criteria, may significantly compromise ITC and prevent cross-trial comparisons. Our analysis underlines the need to adopt standardized protocols to ensure comparability across trials. [ABSTRACT FROM AUTHOR]

Introduction: This study compared the relative efficacy of first-line lenvatinib, a standard-of-care treatment for unresectable hepatocellular carcinoma (uHCC), vs licensed/license in-progress comparators. Using inverse probability of treatment weighting (IPTW) and network meta-analysis (NMA), updated evidence for lenvatinib monotherapy from LEAP-002, in addition to evidence from REFLECT, was included in the analyses. Methods: Randomized controlled trials (RCTs) were identified via systematic review. REFLECT and LEAP-002 investigated lenvatinib in uHCC, with patient-level data available for each; however, only REFLECT included a comparator arm of interest (sorafenib). The lenvatinib arm from LEAP-002 was adjusted to match aggregate data for confounding factors from REFLECT using IPTW. Weighted Cox regressions, including matching variables as covariates, were used to derive hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS). These HR estimates were included in Bayesian NMAs to compare lenvatinib with comparators; survival was significantly improved if the 95% credible interval for the HR did not include 1.0. Scenario analyses explored alternative choices for IPTW estimators. Results: Eight RCTs (including REFLECT) and the single-arm adjusted lenvatinib data from LEAP-002 were included in the NMA base case. Lenvatinib demonstrated significant improvement in OS compared with sorafenib 400 mg twice daily (BID) and significant improvement in PFS compared with sorafenib 400 mg BID, tremelimumab 300 mg plus durvalumab 1500 mg every 4 weeks (Q4W), and durvalumab 1500 mg Q4W. Conclusions: These results suggest that patients with uHCC treated with lenvatinib have similar or significantly improved OS and PFS compared with licensed/license in-progress therapies. [ABSTRACT FROM AUTHOR]

Introduction: In the Phase 3 XTEND-1 trial, (NCT04161495) efanesoctocog alfa prophylaxis provided superior bleed protection versus pre-study factor VIII (FVIII) replacement therapy in patients with severe haemophilia A. The aim of this study was to indirectly compare bleed outcomes between efanesoctocog alfa and standard/extended half-life (SHL and EHL) FVIII replacement therapies in adolescent and adult patients with severe haemophilia A without inhibitors. Methods: A systematic literature review was conducted to identify Phase 3 trials of EHL and SHL FVIII replacement therapies for comparison with efanesoctocog alfa data from XTEND-1. Matching-adjusted indirect comparisons were used to compare annualised bleeding rates (ABRs) for any, treated, joint, and spontaneous bleeds between efanesoctocog alfa and comparators. The estimates from respective comparisons were pooled using random-effect meta-analyses to evaluate the overall difference between efanesoctocog alfa and comparator therapies. Results: Four EHL therapies (rurioctocog alfa pegol, efmoroctocog alfa, turoctocog alfa pegol, damoctocog alfa pegol) and two octocog alfa SHL therapies were included. In meta-analyses, efanesoctocog alfa was associated with significantly lower ABRs for any [mean difference (95% CI) – 2.24 (– 3.24; – 1.25)], spontaneous [ – 1.52 (– 2.33; – 0.72)], and joint bleeds [ – 1.60 (– 2.32; – 0.88)] versus EHL therapies, and with significantly lower ABRs for any [ – 3.61 (– 4.43; – 2.79)], treated [ – 1.55 (– 1.89; – 1.20)], spontaneous [ – 2.52 (– 3.31; – 1.72)], and joint bleeds [ – 3.42 (– 4.77; – 2.08)] versus SHL therapies. Conclusion: Efanesoctocog alfa was associated with significantly lower ABRs (any, spontaneous and joint) compared with EHL or SHL prophylaxis therapies. Patients had, on average, 2.2 and 3.6 fewer bleeds per year versus EHL and SHL therapies, respectively. Plain Language Summary: Factor VIII (FVIII) replacement therapies to prevent bleeding in people with haemophilia A are either standard half-life (SHL) or extended half-life (EHL), and injections may be given two to four times per week. Efanesoctocog alfa is a new FVIII replacement therapy, which only requires a once-weekly injection. In the XTEND-1 clinical trial, people receiving efanesoctocog alfa had fewer bleeds than they did before the trial when they were receiving a different FVIII replacement therapy. However, efanesoctocog alfa has not been compared with available SHL and EHL therapies. Researchers searched medical journals to identify clinical trials of SHL and EHL. They compared the number of bleeds with efanesoctocog alfa in the XTEND-1 trial with each SHL or EHL trial found in the literature search. The results were combined and analysed to find the overall difference between the results with efanesoctocog alfa and each other type of therapy. Compared with SHL and EHL therapy, once-weekly efanesoctocog alfa therapy reduced the rates of any bleeds, including spontaneous (that happen for no apparent reason) and joint bleeds. Overall, people who received efanesoctocog alfa had, on average, 3.6 fewer bleeds per year than those on SHL therapy and 2.2 fewer bleeds per year than those on EHL therapy. As well as reducing the number of injections needed per week, efanesoctocog alfa may work better at preventing bleeds than current SHL or EHL FVIII replacement therapies. This could have a large impact on the lives of people with severe haemophilia A. [ABSTRACT FROM AUTHOR]

Introduction: The phase 3 XTEND-1 trial (NCT04161495) demonstrated that efanesoctocog alfa prophylaxis provided superior bleed protection compared with pre-trial factor VIII (FVIII) prophylaxis in patients with severe haemophilia A. The aim of this study was to indirectly compare the efficacy of efanesoctocog alfa with non-factor replacement therapy emicizumab in adolescent and adult patients with severe haemophilia A without inhibitors. Methods: A systematic literature review was conducted to identify phase 3 trials of emicizumab. Matching-adjusted indirect comparisons were used to compare annualised bleeding rates (ABRs) for any, treated, joint, and spontaneous bleeds, and joint health (measured using Hemophilia Joint Health Score [HJHS]), between efanesoctocog alfa and emicizumab. Estimated effects for different emicizumab regimens were pooled using random-effect meta-analysis to evaluate the overall difference in bleed outcomes between efanesoctocog alfa and emicizumab. Results: One emicizumab trial was included (HAVEN 3), which investigated three dosing regimens. In meta-analyses, efanesoctocog alfa once-weekly (Q1W) was associated with significantly lower ABRs for any (incidence rate ratio [95% CI] 0.33 [0.20; 0.53]), any treated (0.49 [0.30; 0.80]) and treated joint (0.51 [0.28; 0.91]) bleeds compared with emicizumab Q1W in non-inhibitor patients with prior prophylaxis or on-demand treatment. Efanesoctocog alfa Q1W was also associated with a significantly better improvement from baseline in HJHS Joint Score (mean difference [95% CI] −2.06 [−3.97; −0.14]) and Total Score (−2.37 [−4.36; −0.39]) versus emicizumab Q1W or every 2 weeks. Conclusion: Efanesoctocog alfa prophylaxis was associated with significantly lower rates of any, treated, and joint bleeds and improved joint health compared with emicizumab in patients with severe haemophilia A. Plain Language Summary: It is recommended that people with haemophilia A are treated prophylactically (treatment given regularly to prevent bleeding) with factor VIII (FVIII) replacement therapies or a non-factor replacement therapy called emicizumab. People with haemophilia who receive emicizumab may still have bleeds that need to be treated with additional FVIII therapy. In the XTEND-1 clinical trial, patients given efanesoctocog alfa, a new FVIII replacement therapy, had fewer bleeds than they did on the preventive therapy received before the trial. However, efanesoctocog alfa has not been compared with emicizumab. Researchers searched medical journals to identify clinical trials of emicizumab. They compared the number of bleeds and health status of joints in patients treated with efanesoctocog alfa in the XTEND-1 trial with patients treated with emicizumab in HAVEN 3, the trial found in the literature search. The results were analysed to find the overall difference between efanesoctocog alfa and emicizumab. Compared with once-weekly emicizumab, once-weekly efanesoctocog alfa reduced the number of overall bleeds, treated bleeds (additional therapy given to stop the bleeding), and treated joint bleeds. Patients who received efanesoctocog alfa also showed more joint health improvement over the treatment course than those given emicizumab either once-weekly or every 2 weeks. Efanesoctocog alfa may work better at preventing bleeds and improving joint health than the non-factor replacement therapy emicizumab. However, there were some differences between the groups of patients studied in the two trials. [ABSTRACT FROM AUTHOR]

Introduction: Indirect treatment comparisons (ITCs) evaluate novel treatments compared to appropriate comparators when direct evidence is unavailable or infeasible. The objective of this study was to highlight the prevalence of different ITC methods in oncology drug submissions and to provide insights into how ITCs have been used in recent regulatory approval, reimbursement recommendations, or pricing decisions across various regions and diverse assessment frameworks. Methods: A targeted literature review was conducted to identify assessment documents for oncology drug submissions that included ITCs. This included hand searches of the websites of four regulatory bodies and four health technology assessment (HTA) agencies with varying assessment frameworks across North America, Europe, and Asia-Pacific. Results: A total of 185 documents were included for synthesis. Documents were retrieved from all four HTA agencies and the European Medicines Agency (EMA), the only regulatory body with eligible records. Within these, 188 unique submissions included a total of 306 supporting ITCs of various methods. Authorities more frequently favored anchored or population-adjusted ITC techniques for their effectiveness in data adjustment and bias mitigation. Furthermore, ITCs in orphan drug submissions more frequently led to positive decisions compared to non-orphan submissions. Conclusions: This review highlights the crucial role and widespread use of ITCs in global healthcare decision-making, particularly when direct evidence is lacking, and in the discernment of market-specific clinical benefits. This work contributes to bolstering the credibility and recognition of ITCs across regulatory and HTA agencies of diverse regions and assessment frameworks. [ABSTRACT FROM AUTHOR]

To optimize patient outcomes, healthcare decisions should be based on the most up-to-date high-quality evidence. Randomized controlled trials (RCTs) are vital for demonstrating the efficacy of interventions; however, information on how an intervention compares to already available treatments and/or fits into treatment algorithms is sometimes limited. Although different therapeutic classes are available for the treatment of chronic obstructive pulmonary disease (COPD), assessing the relative efficacy of these treatments is challenging. Synthesizing evidence from multiple RCTs via meta-analysis can help provide a comprehensive assessment of all available evidence and a "global summary" of findings. Pairwise meta-analysis is a well-established method that can be used if two treatments have previously been examined in head-to-head clinical trials. However, for some comparisons, no head-to-head studies are available, for example the efficacy of single-inhaler triple therapies for the treatment of COPD. In such cases, network meta-analysis (NMA) can be used, to indirectly compare treatments by assessing their effects relative to a common comparator using data from multiple studies. However, incorrect choice or application of methods can hinder interpretation of findings or lead to invalid summary estimates. As such, the use of the GRADE reporting framework is an essential step to assess the certainty of the evidence. With an increasing reliance on NMAs to inform clinical decisions, it is now particularly important that healthcare professionals understand the appropriate usage of different methods of NMA and critically appraise published evidence when informing their clinical decisions. This review provides an overview of NMA as a method for evidence synthesis within the field of COPD pharmacotherapy. We discuss key considerations when conducting an NMA and interpreting NMA outputs, and provide guidance on the most appropriate methodology for the data available and potential implications of the incorrect application of methods. We conclude with a simple illustrative example of NMA methodologies using simulated data, demonstrating that when applied correctly, the outcome of the analysis should be similar regardless of the methodology chosen. Plain Language Summary: There are several different treatments available for chronic obstructive pulmonary disease (COPD). Finding out which of these treatments is the most effective is difficult, especially if conflicting results from clinical trials have been reported, or if treatments have never been directly compared to each other. Meta-analysis allows the results from multiple studies to be combined together to give a single summary of findings. This can be useful in cases where previous trials have shown contradictory findings. However, this method can only be used if there is more than one study looking at the same two treatments (e.g., several studies that compared treatment A to treatment B). For treatments that have never been compared in clinical trials, network meta-analysis (NMA) can be used. This method allows several treatments to be compared at the same time using the results from trials comparing different treatments. This method creates 'indirect evidence'. Indirect evidence refers to cases where two treatments have never been directly compared to each other in a clinical study, but both have been separately compared to a common treatment (e.g., treatment A and treatment C have never been directly compared to each other, but both have been separately compared to treatment B in a clinical study). NMA can be carried out using different methods. However, if the correct method is not chosen, this can lead to inaccurate results. It is becoming more common for NMA findings to be used to help make clinical decisions. Therefore, it is important that healthcare professionals are able to assess the results of published NMAs, including the methods used, to find the most appropriate results to support their clinical decisions. This tutorial provides an overview of different NMA methods, with a focus on the use of these methods within the context of COPD treatments. We also present an example where we use various NMA methods on the same data set to show that different methods should lead to similar results if the methods are used correctly. [ABSTRACT FROM AUTHOR]

Introduction: Treatment resistant depression (TRD) affects approximately 10-- 30% of patients with major depressive disorder, and most patients with TRD do not respond to real-world treatments (RWT). Treatment with esketamine nasal spray (NS) plus a selective serotonin or serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) has significant long-term clinical benefit over RWT in patients with TRD. However, the impact on patient-reported function remains to be determined. Methods: The ICEBERG analysis was an indirect treatment comparison performed using data from two studies of patients with TRD: SUSTAIN-2 (esketamine NS; NCT02497287) and the European Observational TRD Cohort (EOTC; RWT; NCT03373253; clinicaltrials.gov). Here, patient--reported functional remission, assessed using the Sheehan Disability Scale (SDS), was defined as SDS ≤6 at Month 6. Analyses were conducted using propensity score re--weighting and multivariable models based on 18 covariates. Results: At Month 6, the probability of functional remission in esketamine NS --treated patients from SUSTAIN-2 (n=512) was 25.6% (95% confidence interval [CI] 21.8-29.4), while the adjusted probability for RWT patients from the EOTC (n=184) was 11.5% (95% CI 6.9-16.1; relative risk: 2.226 [95% CI 1.451-3.416]; p=0.0003). In the total combined population (N=696), patients who did not achieve clinical response or remission had a low probability of achieving functional remission (5.84% and 8.76%, respectively). However, for patients who did achieve clinical response or remission, the probability of achieving functional remission was greater (43.38% and 54.15%, respectively), although many still did not achieve this status. Conclusions: For patients with TRD, esketamine NS had a significant functional benefit versus RWT after 6 months of treatment. Irrespective of treatment, achievement of clinical response or remission was insufficient to attain functional remission. Nevertheless, clinical remission increased the likelihood of achieving functional remission, further supporting an important role for clinical remission in for the path towards functional recovery. [ABSTRACT FROM AUTHOR]

Introduction: Evidence on the comparative efficacy and safety of approved therapies for ulcerative colitis (UC) during induction and maintenance, including upadacitinib (UPA), vedolizumab (VEDO), ustekinumab (UST), and tofacitinib (TOFA), is limited. Methods: Using data from phase 3 trials, three placebo (PBO)-anchored matching-adjusted indirect comparisons of the efficacy and safety of UPA versus VEDO, UST, and TOFA (U-ACHIEVE and U-ACCOMPLISH, GEMINI-1, UNIFI, and OCTAVE induction and maintenance trials) have been conducted. Baseline characteristics from UPA trials were weighted separately to match each comparator trial. Induction responders were re-randomized to oral UPA 15 or 30 mg, VEDO 300 mg intravenously every 8 weeks (Q8W), UST 90 mg SC Q8W, or oral TOFA 5 mg, or PBO in maintenance. Treat-through efficacy outcomes at weeks 44(UST)/46(VEDO)/52(UPA/TOFA) were adjusted by the likelihood of induction response and included clinical response, clinical remission, and endoscopic improvement. Safety outcomes included adverse events (AEs), serious AEs (SAEs), and AEs leading to discontinuation (except UPA vs. VEDO). Benefit–risk was assessed by numbers needed to treat (NNT)/harm, calculated as the inverse of the difference in proportions of patients achieving each efficacy/safety outcome for UPA versus comparator. Results: The proportions of patients who demonstrated clinical response or endoscopic improvement was greater with UPA 15 mg versus VEDO and TOFA (p < 0.05). The proportions of patients demonstrating all treat-through efficacy outcomes were significantly greater with UPA 30 mg versus VEDO, UST, or TOFA with NNTs 3.2–8.7. No significant differences in proportions of AEs, SAEs, and AEs leading to discontinuation were observed between the two doses of UPA and comparators. Conclusion: In patients with active UC, greater clinical efficacy, and similar safety after 1 year of maintenance were observed with UPA versus VEDO, UST, and TOFA, suggesting a favorable benefit-risk profile for UPA. Despite matched baseline characteristics, differences in trial design and endpoints may persist. [ABSTRACT FROM AUTHOR]

Aim: To compare the efficacy and safety of lanadelumab versus other approved long-term prophylaxis (LTP) treatments in patients with pediatric hereditary angioedema (HAE) aged

Abstract Introduction Efficacy of upadacitinib has been assessed in trials including Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and 2 assessed efficacy of upadacitinib 30 mg and upadacitinib 15 mg against placebo, while Heads Up assessed efficacy of upadacitinib 30 mg in a head-to-head trial against dupilumab 300 mg. A head-to-head trial of upadacitinib 15 mg against dupilumab 300 mg has not been conducted. Network meta-analysis has shown that upadacitinib 30 mg and upadacitinib 15 mg are among the most efficacious targeted systemic therapies, but prior indirect comparisons have not evaluated more stringent outcomes. Methods A population-adjusted indirect comparison was conducted using post hoc individual patient data from Measure Up 1 and 2 and Heads Up to estimate how upadacitinib 15 mg would have performed if included in Heads Up by adjusting for patient-level covariates. Absolute response rates at weeks 4, 16, and 24 were estimated for the following outcomes: no/minimal itch [Worst Pruritus Numerical Rating Scale (WP-NRS) score of 0/1], Eczema Area and Severity Index (EASI) score of ≤ 3 (EASI ≤ 3), 100% improvement in EASI (EASI 100), both ≥ 90% improvement in EASI (EASI 90) and WP-NRS 0/1, both EASI ≤ 3 and WP-NRS 0/1, and both EASI 100 and WP-NRS 0/1. The analysis was conducted on adult patients, aligned with the intention-to treat population for the clinical trials, and used non-responder imputation. Results Across all outcomes assessed, the estimated absolute response rates were greatest for upadacitinib 30 mg, followed by upadacitinib 15 mg and then dupilumab. This pattern was observed at week 4, week 16, and week 24. Conclusions For adults with moderate-to-severe AD, upadacitinib 30 mg appears to be the most efficacious treatment in attaining more stringent and composite outcomes across multiple timepoints, followed by upadacitinib 15 mg and then dupilumab 300 mg.

Aim: We compared the effectiveness of teclistamab versus real-world physicians choice of therapy (RWPC) in triple-class exposed relapsed/refractory multiple myeloma. Materials & methods: MajesTEC-1 eligibility criteria were applied to the RWPC cohort. Baseline covariate imbalances were adjusted using inverse probability of treatment weighting. Overall survival, progression-free survival and time to next treatment were compared. Results: After inverse probability of treatment weighting, baseline characteristics were similar between cohorts (teclistamab, n = 165; RWPC, n = 364 [766 observations]). Teclistamab treated patients had numerically better overall survival (hazard ratio [HR]: 0.82 [95% CI: 0.59-1.14]; p = 0.233) and significantly greater progression-free survival (HR: 0.43 [0.33-0.56]; p

In evidence synthesis, effect modifiers are typically described as variables that induce treatment effect heterogeneity at the individual level, through treatment‐covariate interactions in an outcome model parametrized at such level. As such, effect modification is defined with respect to a conditional measure, but marginal effect estimates are required for population‐level decisions in health technology assessment. For noncollapsible measures, purely prognostic variables that are not determinants of treatment response at the individual level may modify marginal effects, even where there is individual‐level treatment effect homogeneity. With heterogeneity, marginal effects for measures that are not directly collapsible cannot be expressed in terms of marginal covariate moments, and generally depend on the joint distribution of conditional effect measure modifiers and purely prognostic variables. There are implications for recommended practices in evidence synthesis. Unadjusted anchored indirect comparisons can be biased in the absence of individual‐level treatment effect heterogeneity, or when marginal covariate moments are balanced across studies. Covariate adjustment may be necessary to account for cross‐study imbalances in joint covariate distributions involving purely prognostic variables. In the absence of individual patient data for the target, covariate adjustment approaches are inherently limited in their ability to remove bias for measures that are not directly collapsible. Directly collapsible measures would facilitate the transportability of marginal effects between studies by: (1) reducing dependence on model‐based covariate adjustment where there is individual‐level treatment effect homogeneity or marginal covariate moments are balanced; and (2) facilitating the selection of baseline covariates for adjustment where there is individual‐level treatment effect heterogeneity. [ABSTRACT FROM AUTHOR]

There has been a transition from broad to more specific research questions in the practice of network meta‐analysis (NMA). Such convergence is also taking place in the context of individual registrational trials, following the recent introduction of the estimand framework, which is impacting the design, data collection strategy, analysis and interpretation of clinical trials. The language of estimands has much to offer to NMA, particularly given the "narrow" perspective of treatments and target populations taken in health technology assessment. [ABSTRACT FROM AUTHOR]

Objective: To estimate the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus idecabtagene vicleucel (ide-cel) in patients with relapsed/refractory multiple myeloma (RRMM) treated with 2–4 prior lines of therapy. Methods: Matching adjusted indirect comparison (MAICs) were performed using individual patient-level data (IPD) for cilta-cel from CARTITUDE-1 and CARTITUDE-4 and published aggregated data for ide-cel from KarMMa-3. Cilta-cel patients who met inclusion criteria from KarMMa-3 were selected, and outcomes were compared against data for ide-cel using simulated IPD derived from aggregate-level data from KarMMa-3. Patient characteristics were adjusted by reweighting cilta-cel IPD to match the distribution of prognostic factors in KarMMa-3. Comparative efficacy was estimated for response outcomes using a weighted logistic regression analysis and for progression-free survival using a weighted Cox proportional hazards model. Results: Patients treated with cilta-cel were 1.2 times more likely to achieve overall response (relative response ratio [RR]: 1.18 [95% confidence interval: 1.03–1.34]; p = 0.04), 1.3 times more likely to achieve very good partial response or better (RR: 1.34 [1.15–1.57]; p = 0.003), and 1.9 times more likely to achieve complete response or better (RR: 1.91 [1.54–2.37]; p < 0.0001) versus ide-cel patients from KarMMa-3. Cilta-cel was associated with a significant 49% reduction in risk of disease progression or death versus ide-cel (hazard ratio: 0.51 [95% confidence interval: 0.31, 0.84]; p = 0.0078). Conclusion: For patients with triple-class exposed RRMM treated with 2–4 prior lines of treatment, cilta-cel was found to provide superior clinical benefit over ide-cel in terms of response and progression-free survival. [ABSTRACT FROM AUTHOR]

Introduction: Efficacy of upadacitinib has been assessed in trials including Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and 2 assessed efficacy of upadacitinib 30 mg and upadacitinib 15 mg against placebo, while Heads Up assessed efficacy of upadacitinib 30 mg in a head-to-head trial against dupilumab 300 mg. A head-to-head trial of upadacitinib 15 mg against dupilumab 300 mg has not been conducted. Network meta-analysis has shown that upadacitinib 30 mg and upadacitinib 15 mg are among the most efficacious targeted systemic therapies, but prior indirect comparisons have not evaluated more stringent outcomes. Methods: A population-adjusted indirect comparison was conducted using post hoc individual patient data from Measure Up 1 and 2 and Heads Up to estimate how upadacitinib 15 mg would have performed if included in Heads Up by adjusting for patient-level covariates. Absolute response rates at weeks 4, 16, and 24 were estimated for the following outcomes: no/minimal itch [Worst Pruritus Numerical Rating Scale (WP-NRS) score of 0/1], Eczema Area and Severity Index (EASI) score of ≤ 3 (EASI ≤ 3), 100% improvement in EASI (EASI 100), both ≥ 90% improvement in EASI (EASI 90) and WP-NRS 0/1, both EASI ≤ 3 and WP-NRS 0/1, and both EASI 100 and WP-NRS 0/1. The analysis was conducted on adult patients, aligned with the intention-to treat population for the clinical trials, and used non-responder imputation. Results: Across all outcomes assessed, the estimated absolute response rates were greatest for upadacitinib 30 mg, followed by upadacitinib 15 mg and then dupilumab. This pattern was observed at week 4, week 16, and week 24. Conclusions: For adults with moderate-to-severe AD, upadacitinib 30 mg appears to be the most efficacious treatment in attaining more stringent and composite outcomes across multiple timepoints, followed by upadacitinib 15 mg and then dupilumab 300 mg. [ABSTRACT FROM AUTHOR]

Introduction: The prevalence of obesity has increased worldwide over the past decades. Regional variations exist in the relationship between body mass index (BMI), body fat, and health risks: Asians typically have a lower BMI than people of European descent, but a higher risk of obesity-related comorbidities. However, there is a paucity of evidence for anti-obesity medications (AOMs) in East Asian populations. In this study, we aimed to systematically review evidence regarding the safety and efficacy of AOMs among adults with obesity disease in East Asia, and to assess the feasibility of conducting an indirect treatment comparison (ITC) between the semaglutide and mazindol trials. Methods: The Embase, MEDLINE, and ICHUSHI databases were searched via the Ovid SP platform for randomized controlled trials, in English or Japanese, reporting data on semaglutide or mazindol therapy with placebo or diet and exercise as comparators. The potential risks of bias in conducting a population-adjusted ITC were determined based on the heterogeneity of potential effect modifiers and variations in study design. Results: Of 21 publications, 2 were included in this study based on the eligibility criteria. The STEP 6 study established the clinical efficacy of subcutaneous semaglutide compared with placebo in the reduction of body weight and cardiometabolic risk factors [glycated hemoglobin (HbA1c), total cholesterol, and systolic blood pressure] among Japanese and South Korean people with obesity disease. Mazindol also proved beneficial in reducing body weight and total cholesterol compared with placebo in Japan. Both semaglutide and mazindol were associated with higher rates of adverse events and treatment discontinuation than placebo. An ITC between the two studies was not deemed feasible based on the potential risks of bias. Conclusions: Semaglutide and mazindol are associated with significant body weight reduction among people with obesity in East Asia. Further research based on label indications and up-to-date real-world data among East Asian people with obesity would help determine additional clinical benefits. [ABSTRACT FROM AUTHOR]

Population‐adjusted indirect comparisons, developed in the 2010s, enable comparisons between two treatments in different studies by balancing patient characteristics in the case where individual patient‐level data (IPD) are available for only one study. Health technology assessment (HTA) bodies increasingly rely on these methods to inform funding decisions, typically using unanchored indirect comparisons (i.e., without a common comparator), due to the need to evaluate comparative efficacy and safety for single‐arm trials. Unanchored matching‐adjusted indirect comparison (MAIC) and unanchored simulated treatment comparison (STC) are currently the only two approaches available for population‐adjusted indirect comparisons based on single‐arm trials. However, there is a notable underutilisation of unanchored STC in HTA, largely due to a lack of understanding of its implementation. We therefore develop a novel way to implement unanchored STC by incorporating standardisation/marginalisation and the NORmal To Anything (NORTA) algorithm for sampling covariates. This methodology aims to derive a suitable marginal treatment effect without aggregation bias for HTA evaluations. We use a non‐parametric bootstrap and propose separately calculating the standard error for the IPD study and the comparator study to ensure the appropriate quantification of the uncertainty associated with the estimated treatment effect. The performance of our proposed unanchored STC approach is evaluated through a comprehensive simulation study focused on binary outcomes. Our findings demonstrate that the proposed approach is asymptotically unbiased. We argue that unanchored STC should be considered when conducting unanchored indirect comparisons with single‐arm studies, presenting a robust approach for HTA decision‐making. [ABSTRACT FROM AUTHOR]

Population‐adjusted indirect comparison (PAIC) is an increasingly used technique for estimating the comparative effectiveness of different treatments for the health technology assessments when head‐to‐head trials are unavailable. Three commonly used PAIC methods include matching‐adjusted indirect comparison (MAIC), simulated treatment comparison (STC), and multilevel network meta‐regression (ML‐NMR). MAIC enables researchers to achieve balanced covariate distribution across two independent trials when individual participant data are only available in one trial. In this article, we provide a comprehensive review of the MAIC methods, including their theoretical derivation, implicit assumptions, and connection to calibration estimation in survey sampling. We discuss the nuances between anchored and unanchored MAIC, as well as their required assumptions. Furthermore, we implement various MAIC methods in a user‐friendly R Shiny application Shiny‐MAIC. To our knowledge, it is the first Shiny application that implements various MAIC methods. The Shiny‐MAIC application offers choice between anchored or unanchored MAIC, choice among different types of covariates and outcomes, and two variance estimators including bootstrap and robust standard errors. An example with simulated data is provided to demonstrate the utility of the Shiny‐MAIC application, enabling a user‐friendly approach conducting MAIC for healthcare decision‐making. The Shiny‐MAIC is freely available through the link: https://ziren.shinyapps.io/Shiny_MAIC/. [ABSTRACT FROM AUTHOR]

Objectives: To assess through an indirect treatment comparison (ITC) the potential benefit of faricimab over the anti-vascular endothelial growth factor (VEGF) real-life scenario, hereby defined standard of care (SoC), in Italy, that is, aflibercept, bevacizumab, and ranibizumab, in patients with neovascular age-related macular degeneration (nAMD) naïve to any anti-VEGF treatment. Methods: Individual patient-level data from the phase III clinical trials TENAYA and LUCERNE (faricimab cohort) and the real-world study RADIANCE (RADIANCE cohort) were used. Efficacy was evaluated with changes in best corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline to 1 year (week 52 in the RADIANCE and week 48 in the faricimab cohorts, respectively). Propensity score-based inverse probability of treatment weighting was utilized to balance cohorts and mitigate bias due to potential confounding. Sensitivity analyses were performed to evaluate treatment differences adjusted for the number of injections. Results: The ITC included 513 patients treated with faricimab and 263 patients treated with SoC. At 1 year, faricimab showed a greater mean BCVA gain (treatment difference +5.4 letters, p

Aim: Health technology assessment (HTA) and payer organizations are often faced with early decisionmaking in oncology. To design and conduct robust indirect treatment comparisons (ITCs), it is important to better understand HTA and payer decision-maker perceptions of ITCs. Here we aim to describe what individuals with HTA and payer experience see as the acceptability of ITCs for HTA and payer organization coverage and reimbursement decision-making. Materials & methods: This survey included 30 current and former HTA and payer decision-makers from five countries: Australia, France, Germany, the UK (n = 5 each) and the US (n = 10). Main outcomes included the ratings of acceptance of ITCs and the presence of welldefined methodological guidance for ITCs. Results: ITCs are generally accepted by participants in Australia and the UK but are more likely evaluated on a case-by-case basis in France, Germany and the US. Four of five participants in Germany and the UK, two of five in Australia and one of five in France reported that well-defined and prescribed criteria regarding the use of ITCs were in place. Conclusion: There is a need for harmonization of methods used to assess ITCs by HTA and payers, especially in the rapidly evolving treatment landscape in oncology.

IntroductionTreatment resistant depression (TRD) affects approximately 10–30% of patients with major depressive disorder, and most patients with TRD do not respond to real-world treatments (RWT). Treatment with esketamine nasal spray (NS) plus a selective serotonin or serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) has significant long-term clinical benefit over RWT in patients with TRD. However, the impact on patient-reported function remains to be determined.MethodsThe ICEBERG analysis was an indirect treatment comparison performed using data from two studies of patients with TRD: SUSTAIN-2 (esketamine NS; NCT02497287) and the European Observational TRD Cohort (EOTC; RWT; NCT03373253; clinicaltrials.gov). Here, patient−reported functional remission, assessed using the Sheehan Disability Scale (SDS), was defined as SDS ≤6 at Month 6. Analyses were conducted using propensity score re−weighting and multivariable models based on 18 covariates.ResultsAt Month 6, the probability of functional remission in esketamine NS−treated patients from SUSTAIN-2 (n=512) was 25.6% (95% confidence interval [CI] 21.8–29.4), while the adjusted probability for RWT patients from the EOTC (n=184) was 11.5% (95% CI 6.9–16.1; relative risk: 2.226 [95% CI 1.451–3.416]; p=0.0003). In the total combined population (N=696), patients who did not achieve clinical response or remission had a low probability of achieving functional remission (5.84% and 8.76%, respectively). However, for patients who did achieve clinical response or remission, the probability of achieving functional remission was greater (43.38% and 54.15%, respectively), although many still did not achieve this status.ConclusionsFor patients with TRD, esketamine NS had a significant functional benefit versus RWT after 6 months of treatment. Irrespective of treatment, achievement of clinical response or remission was insufficient to attain functional remission. Nevertheless, clinical remission increased the likelihood of achieving functional remission, further supporting an important role for clinical remission in for the path towards functional recovery.

Abstract Background Acupuncture showed better improvement than sham acupuncture in reducing attack frequency of tension-type headache (TTH), but its effectiveness relative to first-line drugs for TTH is unknown, which impedes the recommendation of acupuncture for patients who are intolerant to drugs for TTH. We aimed to estimate the relative effectiveness between acupuncture and tricyclic antidepressants (TCAs) through indirect treatment comparison (ITC) meta-analysis. Methods We searched Ovid Medline, Embase, and Cochrane Library from database inception until April 13, 2023. Randomized controlled trials of TCAs or acupuncture in the prevention of TTH in adults were included. The primary outcome was headache frequency. The secondary outcomes were headache intensity, responder rate, and adverse event rate. Bayesian random-effect models were used to perform ITC meta-analysis, and confidence of evidence was evaluated by using the GRADE approach. Results A total of 34 trials involving 4426 participants were included. Acupuncture had similar effect with TCAs in decreasing TTH frequency (amitriptyline: mean difference [MD] -1.29, 95% CI -5.28 to 3.02; amitriptylinoxide: MD -0.05, 95% CI -6.86 to 7.06) and reducing TTH intensity (amitriptyline: MD 2.35, 95% CI -1.20 to 5.78; clomipramine: MD 1.83, 95% CI -4.23 to 8.20). Amitriptyline had a higher rate of adverse events than acupuncture (OR 4.73, 95% CI 1.42 to 14.23). Conclusion Acupuncture had similar effect as TCAs in reducing headache frequency of TTH, and acupuncture had a lower adverse events rate than amitriptyline, as shown by very low certainty of evidence.

Introduction: Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disease characterized by a loss of motor neurons and progressive muscle weakness. Children with untreated type 1 SMA never sit independently and require increasing levels of ventilatory support as the disease progresses. Without intervention, and lacking ventilatory support, death typically occurs before the age of 2 years. There are currently no head-to-head trials comparing available treatments in SMA. Indirect treatment comparisons are therefore needed to provide information on the relative efficacy and safety of SMA treatments for healthcare decision-making. Methods: The long-term efficacy and safety of risdiplam versus nusinersen in children with type 1 SMA was evaluated using indirect treatment comparison methodology to adjust for differences between population baseline characteristics, to reduce any potential bias in the comparative analysis. An unanchored matching-adjusted indirect comparison was conducted using risdiplam data from 58 children in FIREFISH (NCT02913482) and published aggregate nusinersen data from 81 children obtained from the ENDEAR (NCT02193074) and SHINE (NCT02594124) clinical trials with at least 36 months of follow-up. Results: Children with type 1 SMA treated with risdiplam had a 78% reduction in the rate of death, an 81% reduction in the rate of death or permanent ventilation, and a 57% reduction in the rate of serious adverse events compared with children treated with nusinersen. Children treated with risdiplam also had a 45% higher rate of achieving a Hammersmith Infant Neurological Examination, Module 2 motor milestone response and a 186% higher rate of achieving a ≥ 4-point improvement in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders compared with children treated with nusinersen. Conclusion: Long-term data supported risdiplam as a superior alternative to nusinersen in children with type 1 SMA. Video abstract available for this article. 638oXLJWPmBYCECGcdmcJZ Video abstract (MP4 184542 KB) Plain Language Summary: Risdiplam and nusinersen are two approved treatments for patients with type 1 spinal muscular atrophy (SMA). There are currently no head-to-head trials that compare the outcomes of these treatments in patients. This study conducted a statistical comparison of the efficacy and safety of risdiplam and nusinersen in children with type 1 SMA who received treatment for at least 36 months. Risdiplam data were collected from 58 children who participated in the FIREFISH trial (NCT02913482). Published combined data were collected from 81 children treated with nusinersen who participated in the ENDEAR (NCT02193074) and SHINE (NCT02594124) trials. Outcomes from the two studies were compared using matching-adjusted indirect comparison (MAIC) methodology. MAIC adjusts for differences in baseline characteristics between patients in two trials to make the populations more similar and reduce bias in the comparison. Results suggested that children with type 1 SMA treated with risdiplam had a 78% reduction in the rate of death and an 81% reduction in the rate of death or permanent ventilation compared with children treated with nusinersen. With risdiplam, children also had a higher rate of achieving motor function responses, and a longer time to the first serious adverse event compared with children treated with nusinersen. These results support risdiplam as a superior alternative to nusinersen in children with type 1 SMA over 36 months of follow-up. Access to long-term data beyond 36 months would allow for additional indirect comparisons between SMA treatments. These comparisons are key to guiding treatment decision-making in the absence of head-to-head trials. [ABSTRACT FROM AUTHOR]

Introduction: Daratumumab plus lenalidomide and dexamethasone (D-Rd) and bortezomib plus lenalidomide and dexamethasone (VRd) are commonly used treatment combinations for transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). D-Rd and VRd demonstrated superior efficacy relative to lenalidomide and dexamethasone (Rd) in the MAIA and SWOG S0777 trials, respectively, but have not been compared directly in a head-to-head trial. Naïve comparisons of efficacy across the two trials may be biased because MAIA enrolled only TIE patients (median age 73 years), whereas SWOG S0777 enrolled both TIE patients and transplant-eligible patients who chose to defer/refuse frontline stem cell transplantation (median age 63 years). The present study compared progression-free survival (PFS) in TIE patients with NDMM treated with D-Rd versus VRd based on an adjusted indirect treatment comparison (ITC) that leveraged individual patient-level data from MAIA and SWOG S0777. Methods: Harmonized inclusion/exclusion criteria (including age ≥ 65 years as a proxy for transplant ineligibility) and propensity-score weighting were used to balance the trial populations on measured baseline characteristics. After differences in trial populations were adjusted for, an anchored ITC was performed wherein within-trial PFS hazard ratios (HRs) for D-Rd versus Rd and VRd versus Rd were estimated and used to make indirect inference about PFS for D-Rd versus VRd. Results: PFS HRs were 0.52 (95% confidence interval [CI] 0.41–0.67) for D-Rd versus Rd based on MAIA data, 0.88 (95% CI 0.63–1.23) for VRd versus Rd based on SWOG S0777 data, and 0.59 (95% CI 0.39–0.90) for the Rd-anchored ITC of D-Rd versus VRd. Sensitivity and subgroup analyses produced results consistent with the primary results. Conclusion: This anchored ITC demonstrated a greater PFS benefit for D-Rd versus VRd in TIE patients with NDMM. In the absence of head-to-head trials comparing D-Rd and VRd, the present trial may help inform treatment selection in this patient population. Plain Language Summary: Multiple drug combinations can be used to treat patients with newly diagnosed multiple myeloma (NDMM) who are not eligible for a stem cell transplant. Two of these combinations—daratumumab plus lenalidomide and dexamethasone (D-Rd) and bortezomib plus lenalidomide and dexamethasone (VRd)—have each been studied in clinical trials (MAIA and SWOG S0777) against the combination of lenalidomide plus dexamethasone (Rd), but D-Rd and VRd have not been compared directly in a head-to-head clinical trial. Our study used data from the MAIA and SWOG S0777 trials to indirectly compare outcomes observed with D-Rd and VRd. For this indirect comparison between D-Rd and VRd, we first made adjustments to the patient populations of each trial to make them more similar to each other; this helped to make sure any differences we saw in treatment outcomes between D-Rd and VRd would not be because of differences in the characteristics of the patients who participated in the trials. After we made these adjustments to the patient populations of each trial, both D-Rd and VRd lowered the risk of disease progression or death compared with Rd alone. However, when indirectly compared in our study, D-Rd lowered the risk of disease progression or death by 41% compared with VRd. As data directly comparing treatment outcomes for D-Rd and VRd are not available, this indirect comparison can contribute to the information used to make treatment decisions for patients with NDMM who are not eligible for a stem cell transplant. [ABSTRACT FROM AUTHOR]

Background: Acupuncture showed better improvement than sham acupuncture in reducing attack frequency of tension-type headache (TTH), but its effectiveness relative to first-line drugs for TTH is unknown, which impedes the recommendation of acupuncture for patients who are intolerant to drugs for TTH. We aimed to estimate the relative effectiveness between acupuncture and tricyclic antidepressants (TCAs) through indirect treatment comparison (ITC) meta-analysis. Methods: We searched Ovid Medline, Embase, and Cochrane Library from database inception until April 13, 2023. Randomized controlled trials of TCAs or acupuncture in the prevention of TTH in adults were included. The primary outcome was headache frequency. The secondary outcomes were headache intensity, responder rate, and adverse event rate. Bayesian random-effect models were used to perform ITC meta-analysis, and confidence of evidence was evaluated by using the GRADE approach. Results: A total of 34 trials involving 4426 participants were included. Acupuncture had similar effect with TCAs in decreasing TTH frequency (amitriptyline: mean difference [MD] -1.29, 95% CI -5.28 to 3.02; amitriptylinoxide: MD -0.05, 95% CI -6.86 to 7.06) and reducing TTH intensity (amitriptyline: MD 2.35, 95% CI -1.20 to 5.78; clomipramine: MD 1.83, 95% CI -4.23 to 8.20). Amitriptyline had a higher rate of adverse events than acupuncture (OR 4.73, 95% CI 1.42 to 14.23). Conclusion: Acupuncture had similar effect as TCAs in reducing headache frequency of TTH, and acupuncture had a lower adverse events rate than amitriptyline, as shown by very low certainty of evidence. Highlights: Acupuncture showed better improvement than sham acupuncture in reducing headache frequency of tension-type headache (TTH), but the lack of comparisons between acupuncture and first-line drugs impedes recommendation of acupuncture for TTH. Our indirect treatment comparison meta-analysis found similar effect between acupuncture and tricyclic antidepressants (TCAs) in reducing TTH frequency with very low certainty of evidence. Similar effect between acupuncture and TCAs were also observed in reducing headache intensity with very low certainty of evidence. Acupuncture had a lower rate of adverse events than amitriptyline with very low certainty of evidence. [ABSTRACT FROM AUTHOR]

Nearly all patients with multiple myeloma eventually relapse or become refractory to treatment. Lenalidomide is increasingly administered in the frontline until disease progression or intolerance to therapy, resulting in the need for highly effective, lenalidomide-sparing options. In this study, carfilzomib plus daratumumab and dexamethasone were evaluated against lenalidomide-sparing, pomalidomide-containing triplets using matching-adjusted indirect comparison in the absence of head-to-head data. The analyses utilized long-term follow-up data from the CANDOR study (NCT03158688). Treatment with carfilzomib, daratumumab, and dexamethasone resulted in significantly longer progression-free survival (hazard ratio 0.60 [95% confidence interval: 0.37, 0.88])vs. pomalidomide plus bortezomib and dexamethasone, and numerically longer progression-free survival (hazard ratio 0.77 [95% confidence interval: 0.50, 1.08]) vs. daratumumab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma and previous lenalidomide exposure, the majority of whom were lenalidomide refractory. Carfilzomib plus daratumumab and dexamethasone offers a highly effective, lenalidomide-sparing treatment option for this population. [ABSTRACT FROM AUTHOR]

Aim: Late-onset Pompe disease is characterized by progressive loss of muscular and respiratory function. Until recently, standard of care was enzyme replacement therapy (ERT) with alglucosidase alfa. Secondgeneration ERTs avalglucosidase alfa (aval) and cipaglucosidase alfa with miglustat (cipa+mig) are now available. Without head-to-head trials comparing aval with cipa+mig, an indirect treatment comparison is informative and timely for understanding potential clinical differentiation. Materials & methods: A systematic literature review was performed to identify relevant studies on cipa+mig and aval. Using patient-level and aggregate published data from randomized controlled trials (RCTs) and phase I/II and open-label extension (OLE) trials, a multi-level network meta-regression was conducted, adjusting for various baseline covariates, including previous ERT duration, to obtain relative effect estimates on 6- minute walk distance (6MWD, meters [m]) and forced vital capacity (FVC, % predicted [pp]). Analyses of two networks were conducted: Network A, including only RCTs, and network B, additionally including single-arm OLE and phase I/II studies. Results: Network B (full evidence analysis) showed that cipa+mig was associated with a relative increase in 6MWD (mean difference 28.93 m, 95% credible interval [8.26– 50.11 m]; Bayesian probability 99.7%) and FVC (2.88 pp [1.07–4.71 pp]; >99.9%) compared with aval. The comparison between cipa+mig and aval became more favorable for cipa+mig with increasing previous ERT duration for both end points. Analysis of network A showed that cipa+mig was associated with a relative decrease in 6MWD(-10.02m[-23.62 to 4.00 m]; 91.8%) and FVC (-1.45 pp [-3.01 to 0.07 pp]; 96.8%) compared with aval. Conclusion: Cipa+mig showed a favorable effect versus aval when all available evidence was used in the analysis.

Background Renal cell carcinoma is the most common type of kidney cancer, comprising approximately 85% of all renal malignancies. Patients with advanced renal cell carcinoma are the focus of this National Institute for Health and Care Excellence multiple technology appraisal. A patient’s risk of disease progression depends on a number of prognostic risk factors; patients are categorised as having intermediate/poor risk or favourable risk of disease progression. Objectives The objectives of this multiple technology appraisal were to appraise the clinical effectiveness and cost-effectiveness of lenvatinib plus pembrolizumab versus relevant comparators listed in the final scope issued by the National Institute for Health and Care Excellence: sunitinib, pazopanib, tivozanib, cabozantinib and nivolumab plus ipilimumab. Methods The assessment group carried out clinical and economic systematic reviews and assessed the clinical and cost-effectiveness evidence submitted by Eisai, Hatfield, Hertfordshire, UK (the manufacturer of lenvatinib) and Merck Sharp & Dohme, Whitehouse Station, NJ, USA (the manufacturer of pembrolizumab). The assessment group carried out fixed-effects network meta-analyses using a Bayesian framework to generate evidence for clinical effectiveness. As convergence issues occurred due to sparse data, random-effects network meta-analysis results were unusable. The assessment group did not develop a de novo economic model, but instead modified the partitioned survival model provided by Merck Sharp & Dohme. Results The assessment group clinical systematic review identified one relevant randomised controlled trial (CLEAR trial). The CLEAR trial is a good-quality, phase III, multicentre, open-label trial that provided evidence for the efficacy and safety of lenvatinib plus pembrolizumab compared with sunitinib. The assessment group progression-free survival network meta-analysis results for all three risk groups should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons owing to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. The assessment group overall survival network meta-analysis results for the intermediate-/poor-risk subgroup suggested that there was a numerical, but not statistically significant, improvement in the overall survival for patients treated with lenvatinib plus pembrolizumab compared with patients treated with cabozantinib or nivolumab plus ipilimumab. Because of within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption, the assessment group overall survival network meta-analysis results for the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons. Only one cost-effectiveness study was included in the assessment group review of cost-effectiveness evidence. The study was limited to the all-risk population, undertaken from the perspective of the US healthcare system and included comparators that are not recommended by the National Institute for Health and Care Excellence for patients with untreated advanced renal cell carcinoma. Therefore, the extent to which resource use and results are generalisable to the NHS is unclear. The assessment group cost-effectiveness results from the modified partitioned survival model focused on the intermediate-/poor-risk and favourable-risk subgroups. The assessment group cost-effectiveness results, generated using list prices for all drugs, showed that, for all comparisons in the favourable-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated fewer benefits than all other treatments available to NHS patients. For the intermediate-/poor-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated more benefits than treatment with cabozantinib and nivolumab plus ipilimumab. Conclusions Good-quality clinical effectiveness evidence for the comparison of lenvatinib plus pembrolizumab with sunitinib is available from the CLEAR trial. For most of the assessment group Bayesian hazard ratio network meta-analysis comparisons, it is difficult to reach conclusions due to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. However, the data (clinical effectiveness and cost-effectiveness) used to populate the economic model are relevant to NHS clinical practice and can be used to inform National Institute for Health and Care Excellence decision-making. The assessment group cost-effectiveness results, generated using list prices for all drugs, show that lenvatinib plus pembrolizumab is less cost-effective than all other treatment options. Study registration This study is registered as PROSPERO CRD4202128587. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR134985) and is published in full in Health Technology Assessment; Vol. 28, No. 49. See the NIHR Funding and Awards website for further award information. Plain language summary What was the problem? Renal cell carcinoma is the most common type of kidney cancer. Several drug treatment options are available for NHS patients with advanced or metastatic disease, and the choice of treatment varies depending on a patient’s risk of disease progression. A new drug combination, lenvatinib plus pembrolizumab, may soon become available to treat NHS patients. This review explored whether treatment with lenvatinib plus pembrolizumab offered value for money to the NHS. What did we do? We reviewed the effectiveness of treatment with lenvatinib plus pembrolizumab versus other NHS treatment options. We also estimated the costs and benefits of treatment with lenvatinib plus pembrolizumab versus current NHS treatments for patients with higher and lower risks of disease progression. What did we find? Compared with current NHS treatments, treatment with lenvatinib plus pembrolizumab may increase the time that people with a higher risk of disease progression (i.e. worsening disease) were alive. However, for patients with a lower risk of disease progression, the available evidence is limited and only shows that treatment with lenvatinib plus pembrolizumab may prolong the time that patients have a stable level of disease. For all patients, compared to all current NHS treatments, treatment with lenvatinib plus pembrolizumab is very expensive. What does this mean? Compared with current NHS treatments for untreated renal cell carcinoma, using published prices (which do not include any discounts that are offered to the NHS), treatment with lenvatinib plus pembrolizumab may not provide good value for money to the NHS. Scientific summary Background Renal cell carcinoma (RCC) is the most common type of kidney cancer, comprising approximately 85% of all renal malignancies. Patients with advanced RCC (aRCC) have Stage 3 (locally advanced) or Stage 4 (metastatic) disease. A patient’s risk of disease progression depends on a number of prognostic risk factors. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is used in NHS clinical practice to categorise patients into one of two groups, namely favourable risk or intermediate/poor risk. This systematic review and cost-effectiveness analysis has been conducted to inform the following National Institute for Health and Care Excellence (NICE) multiple technology appraisal: lenvatinib with pembrolizumab for untreated aRCC (ID3760). In November 2021, the Medicines and Healthcare products Regulatory Agency approved the use of lenvatinib plus pembrolizumab as a treatment for all patients with untreated aRCC. Objectives The comparators listed in the final scope issued by NICE differ depending on the risk of disease progression. The objectives of this assessment were to appraise the clinical effectiveness and cost-effectiveness of lenvatinib plus pembrolizumab versus: cabozantinib and nivolumab plus ipilimumab in the intermediate-/poor-risk subgroup sunitinib, pazopanib and tivozanib in the favourable-risk subgroup sunitinib, pazopanib and tivozanib in the all-risk population. Clinical and economic systematic review methods The assessment group (AG) carried out a systematic review of clinical effectiveness evidence following the general principles outlined by the Centre for Reviews and Dissemination (CRD). The review was reported using the criteria recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Searches were conducted between 11 October 2021 and 22 November 2021 in accordance with the general principles recommended by the European Network for Health Technology Assessment. The protocol is registered with PROSPERO (registration number: CRD42021285879). The AG reviewed only randomised controlled trials (RCTs) and full economic analyses identified by the searches. However, the group also considered evidence provided by the manufacturers of lenvatinib (Eisai Ltd) and pembrolizumab (Merck Sharp & Dohme, Whitehouse Station, NJ, USA) provided in submissions to NICE; company submission (CS) reference lists were searched for relevant RCTs. In line with the final scope issued by NICE, the outcomes considered by the AG were overall survival (OS), progression-free survival (PFS), objective tumour response rate, adverse events (AEs), health-related quality of life (HRQoL), incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained. Clinical effectiveness results Direct clinical effectiveness evidence (CLEAR trial) The AG systematic review included one RCT, the CLEAR trial. The CLEAR trial was a good-quality, phase III, multicentre, open-label RCT (with an ongoing extension phase) that provided evidence for the comparison of the efficacy of lenvatinib plus pembrolizumab versus sunitinib. Results for all outcomes were assessed at the third interim analysis (August 2020, median OS follow-up of 26.6 months), that is the final data cut-off for PFS. The companies also presented OS results from an updated OS analysis (March 2021, median OS follow-up of approximately 33 months). At the time of the third interim analysis, the CLEAR trial hazard ratio (HR) results showed statistically significant improvements in PFS and objective tumour response rate for patients treated with lenvatinib plus pembrolizumab versus patients treated with sunitinib for the intermediate-/poor-risk subgroup, the favourable-risk subgroup and the all-risk population. The HR results from the updated OS analysis showed a statistically significant improvement for patients treated with lenvatinib plus pembrolizumab versus patients treated with sunitinib for the intermediate-/poor-risk subgroup and the all-risk population; there were too few events in the favourable-risk subgroup for robust OS conclusions to be drawn. Eisai carried out a treatment-switching analysis to test whether adjusting for the effect of subsequent treatments affected OS results. Results were generated only for the all-risk population and were marked as academic-in-confidence. Nearly all the patients in the CLEAR trial lenvatinib plus pembrolizumab and sunitinib arms experienced at least one all-grade AE, with more Grade ≥ 3 AEs reported in the lenvatinib plus pembrolizumab arm than in the sunitinib arm. The proportion of patients who discontinued treatment of either lenvatinib or pembrolizumab due to AEs was approximately twice as high as patients who discontinued treatment of sunitinib; the proportion of patients who withdrew treatment of both lenvatinib and pembrolizumab due to AEs was approximately the same as the proportion of patients who withdrew treatment with sunitinib. Health-related quality of life was measured using three tools, including the EuroQol-5 Dimensions, three-level version questionnaire. When compared with treatment with sunitinib, treatment with lenvatinib plus pembrolizumab did not result in any clinically meaningful differences (as measured by predefined minimally important differences) in HRQoL measured using any of the three tools. Indirect clinical effectiveness evidence To compare the effectiveness of lenvatinib plus pembrolizumab versus relevant comparators other than sunitinib, the AG carried out Bayesian HR network meta-analyses. It was decided not to undertake a flexible modelling approach for network meta-analysis (NMA), which relaxes the proportional hazards (PH) assumption, such as fractional polynomial network meta-analyses because interpretation of the estimates provided by these complex modelling techniques can be difficult and results are often not intuitive. While deviance information criterion (DIC) statistics provide an approach to compare the fit of different models, they do not provide information about whether a model is a good fit to the data or whether the estimates generated by the model, including projections of results beyond the follow-up times of trials included in the NMA, are clinically plausible. Furthermore, flexible models, which appear similar according to model fit (i.e. according to DIC statistics), may generate very different long-term survival estimates. The AG assessed the feasibility of conducting Bayesian HR NMAs for the three population risk groups (intermediate-/poor-risk subgroup, favourable-risk subgroup and all-risk population) for all outcomes listed in the final scope issued by NICE. However, due to limited data availability, it was not possible to carry out NMAs for all outcomes for all three patient risk groups. Further, as networks were sparse, it was only possible to generate results using fixed-effect NMAs. The AG PFS NMA results for the intermediate-/poor-risk subgroup, the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons because of within-trial PH violations or uncertainty regarding the validity of the PHs assumption. The AG OS NMA results for the intermediate-/poor-risk subgroup suggested that there was a numerical, but not statistically significant, improvement in the OS for patients treated with lenvatinib plus pembrolizumab compared with patients treated with cabozantinib or nivolumab plus ipilimumab. Because of within-trial PH violations or uncertainty regarding the validity of the PH assumption, the AG OS NMA results for the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons. The AG objective tumour response rate NMA results for the intermediate-/poor-risk subgroup suggested that, although treatment with lenvatinib plus pembrolizumab led to a statistically significant improvement in objective tumour response rate compared to treatment nivolumab plus ipilimumab, it did not lead to a statistically significant improvement in objective tumour response rate for the comparison of lenvatinib plus pembrolizumab versus cabozantinib. It was not possible to generate results for the IMDC/MSKCC (Memorial Sloan-Kettering Cancer Center) favourable-risk subgroup due to data limitations. The AG objective tumour response rate NMA results for the all-risk population suggest that treatment with lenvatinib plus pembrolizumab led to a statistically significant improvement in objective tumour response rate versus treatment with sunitinib and versus treatment with pazopanib. The AG Grade ≥ 3 AE NMA results for the intermediate-/poor-risk subgroup suggested that treatment with lenvatinib plus pembrolizumab led to statistically significantly more Grade ≥ 3 AEs versus treatment with cabozantinib. It was not possible to generate results for the IMDC/MSKCC favourable-risk subgroup. The AG Grade ≥ 3 AE NMA results for the all-risk population suggested that treatment with lenvatinib led to statistically significantly more Grade ≥ 3 AEs versus treatment with sunitinib and versus treatment with pazopanib. Economic systematic review results The AG systematic review identified one relevant cost-effectiveness study. This study compared the cost-effectiveness of lenvatinib plus pembrolizumab versus sunitinib (and vs. other treatments). However, the study was undertaken from the perspective of the US healthcare system and generated results only for the all-risk population and included comparators that are not recommended by NICE as treatment options for patients with aRCC. Therefore, the extent to which these results were generalisable to the NHS was unclear. Cost-effectiveness analysis methods The Eisai and Merck Sharp & Dohme CSs to NICE included partitioned survival models built in Microsoft Excel. The AG considered that results from both models could be used to inform decision-making but that, in some instances, the companies could have made more appropriate assumptions and parameter choices. The AG did not develop a de novo economic model; instead, it modified the model provided by Merck Sharp & Dohme [referred to as the Merck Sharp & Dohme/Assessment Group (MSD/AG) model]. Neither of the companies produced cost-effectiveness results for the comparison of lenvatinib plus pembrolizumab versus nivolumab plus ipilimumab (intermediate-/poor-risk subgroup) despite both models having the functionality for this comparison. Furthermore, Eisai did not generate any cost-effectiveness results for the favourable-risk subgroup. The MSD/AG model was populated with OS, PFS and time to treatment discontinuation (TTD) data from the CLEAR trial (lenvatinib plus pembrolizumab versus sunitinib for favourable-risk subgroup and the all-risk population). The AG PFS and OS NMA results were used to estimate effectiveness for the comparison of lenvatinib plus pembrolizumab versus cabozantinib and versus nivolumab plus ipilimumab for the intermediate-/poor-risk population. NICE appraisal committees have concluded that sunitinib and pazopanib are of equivalent effectiveness and that, at best, tivozanib may have a similar effect to sunitinib or pazopanib. These conclusions were based on all-risk population data; the AG has assumed that this assumption holds for the favourable-risk population. The most important changes made by the AG to the Merck Sharp & Dohme model were different choices for estimating PFS, OS and TTD for the intervention and comparator treatments and for modelling two lines, rather than one line, of subsequent treatment. Cost-effectiveness analysis results The AG cost-effectiveness results presented in this report were estimated using list prices. Also, the AG cost-effectiveness results generated using confidential discounted prices were supplied to NICE in a confidential appendix, but cannot be presented here. For the intermediate-/poor-risk subgroup, the AG base-case cost-effectiveness results suggested that treatment with lenvatinib plus pembrolizumab generated more QALYs versus treatment with cabozantinib and versus nivolumab plus ipilimumab, but at a greater overall cost than either of these two treatments. Using list prices, the incremental cost-effectiveness ratios per QALY gained for the comparison of lenvatinib plus pembrolizumab versus cabozantinib and versus nivolumab plus ipilimumab exceed £100,000. For the favourable-risk subgroup, the AG base-case cost-effectiveness results suggested that treatment with sunitinib generated more QALYs than treatment with lenvatinib plus pembrolizumab at a lower overall cost, that is treatment with lenvatinib plus pembrolizumab was dominated by treatment with sunitinib (and, using the assumption of equivalent effectiveness, by pazopanib and tivozanib). The AG carried out extensive one-way sensitivity analyses, scenario analyses and probabilistic sensitivity analyses. Results from these analyses demonstrate that the AG base-case cost-effectiveness results are robust. Clinical and cost-effectiveness conclusions Good-quality clinical effectiveness evidence for the comparison of lenvatinib plus pembrolizumab versus sunitinib was available from the CLEAR trial. For most of the AG Bayesian HR NMA comparisons, it was difficult to reach conclusions due to within-trial PH violations or uncertainty regarding the validity of the PHs assumption. However, the data (clinical effectiveness and cost-effectiveness) used to populate the MSD/AG model are relevant to NHS clinical practice and can be used to inform NICE decision-making. The all-risk population comprises patients with intermediate-/poor-risk and patients with favourable-risk disease. The AG cost-effectiveness analyses have focused on the two subgroups, and the AG cost-effectiveness results, generated using list prices for all drugs, show that lenvatinib plus pembrolizumab is less cost-effective than all other treatment options. Study registration This study is registered as PROSPERO CRD4202128587. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR134985) and is published in full in Health Technology Assessment; Vol. 28, No. 49. See the NIHR Funding and Awards website for further award information.

Lea Monday,1 Glenn Tillotson,2 Teena Chopra1 1Division of Infectious Diseases, Wayne State University School of Medicine, Detroit, MI, USA; 2GlennTillotson PhD, FIDSA, GSTMicro, Henrico, VA, USACorrespondence: Lea Monday, Harper University Hospital, Division of Infectious Diseases, 3990 John R Street, 5 Hudson, Suite 5911, Detroit, MI, 48201, USA, Tel +1 734-344-8392, Fax +1 313-9930302, Email lmonday@med.wayne.eduAbstract: Clostridioides difficile infection (CDI) remains a significant contributor to healthcare costs and morbidity due to high rates of recurrence. Currently, available antibiotic treatment strategies further disrupt the fecal microbiome and do not address the alterations in commensal flora (dysbiosis) that set the stage for CDI. Advances in microbiome-based research have resulted in the development of new agents, classified as live biotherapeutic products (LBPs), for preventing recurrent CDI (rCDI) by restoring eubiosis. Prior to the LBPs, fecal microbiota transplantation (FMT) was available for this purpose; however, lack of large-scale availability and safety concerns have remained barriers to its widespread use. The LBPs are an exciting development, but questions remain. Some are derived directly from human stool while other developmental products contain a defined microbial consortium manufactured ex vivo, and they may be composed of either living bacteria or their spores, making it difficult to compare members of this heterogenous drug class to one another. None have been studied head-to head or against FMT in preventing rCDI. As a class, they have considerable variability in their biologic composition, biopharmaceutic science, route of administration, stages of development, and clinical trial data. This review will start by explaining the role of dysbiosis in CDI, then give the details of the biopharmaceutical components for the LBPs which are approved or in development including how they differ from FMT and from one another. We then discuss the clinical trials of the LBPs currently approved for rCDI and end with the future clinical directions of LBPs beyond C. difficile.Keywords: Clostridioides difficile infection, microbiome, microbiome therapeutic, indirect treatment comparison

Objectives Immunogenicity between 15-valent V114 (PCV15) and 20-valent PCV20 pneumococcal conjugate vaccines in healthy infants is compared in an indirect treatment comparison and matching-adjusted indirect comparison. Hypotheses: immunogenicity of V114 is non-inferior to PCV20 for all PCV13 serotypes, and superior to PCV20 for serotype 3 based on lower bound margins. Methods Two phase 3 pivotal studies on 3 + 1 pediatric vaccination schedule at age 2, 4, 6, and 12–15 months compared V114 (N = 858) to PCV13 (N = 856) and PCV20 (N = 1001) to PCV13 (N = 987). Infant’s age and race in V114 study were matched to those in PCV20 study. Primary endpoints were serotype-specific Immunoglobulin G (IgG) response rate difference (RRD) 30 days post-dose (PD)3; IgG geometric mean concentration (GMC) ratios 30 days PD3 and PD4. Results V114 was non-inferior (${\rm{margi}}{{\rm{n}}_{RRD}}$>-10%-point; ${\rm{margi}}{{\rm{n}}_{GMCratio}}$ >0.5) to PCV20 (p-value 0%-point; ${\rm{margi}}{{\rm{n}}_{GMCratio}}$ >1.2) to PCV20 (p-value

Abstract Introduction Deucravacitinib, a newly approved oral medication for the treatment of patients with moderate to severe plaque psoriasis, demonstrated efficacy versus apremilast and placebo in two phase 3 randomized controlled trials (RCTs). A systematic review and network meta-analysis (NMA) indirectly compared deucravacitinib with other relevant systemic biologic/nonbiologic treatments. Methods Online databases were searched for RCTs published through October 2021. Eligible studies were head-to-head comparisons between systemic therapies and/or placebo reporting 50%, 75%, 90%, or 100% improvement in Psoriasis Area and Severity Index (PASI) from baseline in adults with moderate to severe plaque psoriasis. Comparisons included tumor necrosis factor inhibitors, interleukin (IL)-17, IL-23, and IL 12/23 inhibitors, and systemic nonbiologics. A multinomial Bayesian NMA was used to derive estimates of the relative efficacy of deucravacitinib and other systemic therapies. Response probabilities for each treatment and corresponding 95% credible intervals (CrIs) for achieving a PASI response were calculated over short-, mid-, and long-term follow-up (weeks 10–16, 24–28, and 44–60). Results The NMA included 47 RCTs. Deucravacitinib showed the highest PASI 75 response rates among nonbiologic systemic therapies across time points. Deucravacitinib PASI 75 response rate (95% CrI) over short-term follow-up was 54.1% (46.5–61.6), within the range of first-generation biologics (etanercept, 39.7% [31.6–48.3]; infliximab, 79.0% [74.0–83.5]). At mid-term follow-up, deucravacitinib PASI 75 increased to 63.3% (58.0–68.4). At long-term follow-up, deucravacitinib PASI 75 was 65.9% (58.0–73.4), comparable to first-generation biologics adalimumab (62.8%; 55.3–69.6) and ustekinumab (68.0%; 64.6–71.5). Conclusions Patients receiving deucravacitinib were more likely to achieve PASI 75 response versus apremilast and methotrexate across all time points. The long-term PASI 75 response rate for deucravacitinib was similar to those of adalimumab and ustekinumab. The approval of deucravacitinib offers patients the choice of an oral therapy with long-term efficacy similar to that of some biologics.

Background: Evidence from network meta-analyses (NMAs) and real-world propensity score (PS) analyses suggest monoclonal antibodies (mAbs) offer a therapeutic advantage over currently available oral therapies and, therefore, warrant consideration as a distinct group of high-efficacy disease-modifying therapies (DMTs) for patients with relapsing multiple sclerosis (RMS). This is counter to the current perception of these therapies by some stakeholders, including payers. Objectives: A multifaceted indirect treatment comparison (ITC) approach was undertaken to clarify the relative efficacy of mAbs and oral therapies. Design: Two ITC methods that use individual patient data (IPD) to adjust for between-trial differences, PS analyses and simulated treatment comparisons (STCs), were used to compare the mAb ofatumumab versus the oral therapies cladribine, fingolimod, and ozanimod. Data sources and methods: As IPD were available for trials of ofatumumab and fingolimod, PS analyses were conducted. Given summary-level data were available for cladribine, fingolimod, and ozanimod trials, STCs were conducted between ofatumumab and each of these oral therapies. Three efficacy outcomes were compared: annualized relapse rate (ARR), 3-month confirmed disability progression (3mCDP), and 6-month CDP (6mCDP). Results: The PS analyses demonstrated ofatumumab was statistically superior to fingolimod for ARR and time to 3mCDP but not time to 6mCDP. In STCs, ofatumumab was statistically superior in reducing ARR and decreasing the proportion of patients with 3mCDP compared with cladribine, fingolimod, and ozanimod and in decreasing the proportion with 6mCP compared with fingolimod and ozanimod. These findings were largely consistent with recently published NMAs that identified mAb therapies as the most efficacious DMTs for RMS. Conclusion: Complementary ITC methods showed ofatumumab was superior to cladribine, fingolimod, and ozanimod in lowering relapse rates and delaying disability progression among patients with RMS. Our study supports the therapeutic superiority of mAbs over currently available oral DMTs for RMS and the delineation of mAbs as high-efficacy therapies. [ABSTRACT FROM AUTHOR]

Introduction: Immune-mediated inflammatory diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), non-radiographic axial spondylarthritis (nr-axSpA), atopic dermatitis (AD), ulcerative colitis (UC), and Crohn's disease (CD) pose a substantial burden on patients and their quality of life. Upadacitinib is an orally administered, selective, and reversible Janus kinase inhibitor indicated for seven conditions, but data on its safety versus other active treatments are limited. A systematic literature review of indirect and direct treatment comparisons of randomized controlled trials (RCTs) was conducted to assess the safety profile of upadacitinib. Methods: MEDLINE, Embase, and Cochrane Library databases were searched for indirect and direct treatment comparisons of RCTs that (1) included licensed upadacitinib dosages; (2) studied any of the seven conditions; (3) reported any adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, major adverse cardiovascular event, venous thromboembolism, malignancies, infections or serious infections, and death; and (4) were published between January 2018 and August 2022. Results: A total of 25 studies were eligible for inclusion. SAEs, AEs leading to discontinuation, and any AEs were commonly studied. RA was the most studied condition, followed by AD and UC. Most studies (16/25, 64%) reported no statistically significant difference in the studied safety outcomes between upadacitinib and other active treatments (e.g., tumor necrosis factor blockers, interleukin receptor antagonists, integrin receptor antagonists, T cell co-stimulation modulator), or placebo (placebo ± methotrexate or topical corticosteroids). Other studies (9/25, 36%) reported mixed results of no statistically significant difference and either statistically higher (8/25, 32%) or lower rates (1/25, 4%) on upadacitinib. Conclusion: Most studies suggested that upadacitinib has no statistically significant difference in the studied safety outcomes compared to active treatments or placebo in patients with RA, PsA, AS, AD, UC, and CD. A few studies reported higher rates, but findings were inconsistent with limited interpretation. [ABSTRACT FROM AUTHOR]

Introduction: Etranacogene dezaparvovec gene therapy for haemophilia B demonstrated superior efficacy at 24 months in reducing bleeds versus a ≥6‐month lead‐in period of prophylaxis with FIX products in the phase 3 trial, HOPE‐B. In the absence of head‐to‐head comparisons of etranacogene dezaparvovec versus FIX products, indirect treatment comparisons (ITC) can be used. Aim: To compare the efficacy of etranacogene dezaparvovec versus rIX‐FP, rFIXFc and N9‐GP using ITC, and support HOPE‐B results. Methods: Data were leveraged from Phase 3 pivotal trials: HOPE‐B, PROLONG‐9FP, B‐LONG and Paradigm 2. Annualised bleeding rates (ABR), spontaneous (AsBR) and joint (AjBR) bleeding rates, percentage of patients with no bleeds, and FIX consumption were assessed using inverse probability of treatment weighting and matching adjusted indirect comparisons. Results: Etranacogene dezaparvovec demonstrated statistically significantly lower bleeding rates versus all comparators. Rate ratios for ABR, AsBR and AjBR versus rIX‐FP were 0.19 (p <.0001), 0.08 (p <.0001) and 0.09 (p <.0001), respectively. Rate ratios for ABR, AsBR and AjBR versus rFIXFc were 0.14 (p <.0001), 0.13 (p =.0083) and 0.15 (p =.0111), respectively. Rate ratios for ABR and AsBR, versus N9‐GP were 0.24 (p =.0231) and 0.13 (p =.0071), respectively. Etranacogene dezaparvovec demonstrated significantly higher percentage of patients with no bleeds versus rIX‐FP and rFIXFc; odds ratios: 17.60 (p <.0001) and 5.65 (p =.0037), respectively. Etranacogene dezaparvovec resulted in significantly lower FIX consumption than all comparators. Conclusions: ITC suggests that etranacogene dezaparvovec offers patients with haemophilia B (≤2% of normal FIX expression) a single dose treatment that can significantly reduce bleeding rates and eliminate routine infusions associated with FIX therapies. [ABSTRACT FROM AUTHOR]

The SCHOLAR-2 retrospective study highlighted poor overall survival (OS) with standard of care (SOC) regimens among patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) who failed a covalent Bruton tyrosine kinase inhibitor (BTKi). In the ZUMA-2 single-arm trial, brexucabtagene autoleucel (brexu-cel; autologous anti-CD19 CAR T-cell therapy) demonstrated high rates of durable responses in patients with R/R MCL who had previous BTKi exposure. Here, we compared OS in ZUMA-2 and SCHOLAR-2 using three different methods which adjusted for imbalances in prognostic factors between populations: inverse probability weighting (IPW), regression adjustment (RA), and doubly robust (DR). Brexu-cel was associated with improved OS compared to SOC across all unadjusted and adjusted comparisons. Hazard ratios (95% confidence intervals) were 0.38 (0.23, 0.61) for IPW, 0.45 (0.28, 0.74) for RA, and 0.37 (0.23, 0.59) for DR. These results suggest a substantial survival benefit with brexu-cel versus SOC in patients with R/R MCL after BTKi exposure. [ABSTRACT FROM AUTHOR]

Background: In the absence of head-to-head comparative data from randomized controlled trials, indirect treatment comparisons (ITCs) may be used to compare the relative effects of treatments versus a common comparator (either placebo or active treatment). For acute pain management, the effects of oliceridine have been compared in clinical trials to morphine but not to fentanyl or hydromorphone. Aim: To assess the comparative safety (specifically differences in the incidence of nausea, vomiting and opioidinduced respiratory depression [OIRD]) between oliceridine and relevant comparators (fentanyl and hydromorphone) through ITC analysis. Methods: A systematic literature review identified randomized clinical trials with oliceridine versus morphine and morphine versus fentanyl or hydromorphone. The ITC utilized the common active comparator, morphine, for the analysis. Results: A total of six randomized controlled trials (oliceridine – 2; hydromorphone – 3; fentanyl – 1) were identified for data to be used in the ITC analyses. The oliceridine data were reported in two studies (plastic surgery and orthopedic surgery) and were also reported in a pooled analysis. The ITC focused on nausea and vomiting due to limited data for OIRD. When oliceridine was comparedwith hydromorphone in the ITC analysis, oliceridine significantly reduced the incidence of nausea and/or vomiting requiring antiemetics compared with hydromorphone (both orthopedic surgery and pooled data), while results in plastic surgery were not statistically significant. When oliceridine was compared with hydromorphone utilizing data from Hong, the ITC only showed a trend toward reduced risk of nausea and vomiting with oliceridine that was not statistically significant across all three comparisons (orthopedic surgery, plastic surgery and combined). An ITC comparing oliceridine with a study of fentanyl utilizing the oliceridine orthopedic surgery data and combined orthopedic and plastic surgery data showed a trend toward reduced risk that was not statistically significant. Conclusion: In ITC analyses, oliceridine significantly reduced the incidence of nausea and/or vomiting or the need for antiemetics in orthopedic surgery comparedwith hydromorphone and a non-significant trend toward reduced risk versus fentanyl.

Introduction: Ready-to-use glucagon represents a significant advancement in the management of severe hypoglycemia for people with diabetes and their caregivers. This indirect treatment comparison (ITC) evaluated the efficacy and safety differences among the three ready-to-use glucagon treatments, Baqsimi® (nasal glucagon), Gvoke® (glucagon injection) and Zegalogue® (dasiglucagon injection), in adults and children with type 1 diabetes (T1D) or type 2 diabetes (T2D). Methods: A systematic literature review was conducted to identify randomized clinical trials assessing the efficacy and safety of Baqsimi, Gvoke or Zegalogue versus reconstituted, injectable glucagon (IG) in reversing insulin-induced hypoglycemia. Bayesian fixed-effect network meta-analysis was used to perform the ITC. Study endpoints included proportion of participants achieving treatment success, maximum blood glucose achieved, time to achieve treatment success and maximum blood glucose and treatment-emergent adverse events (TEAE). Results: Ten clinical trials were included in the ITC (four for Baqsimi, three for Gvoke, and three for Zegalogue). All three treatments achieved high proportions of treatment success (> 98%). In adults, the efficacy results from combined T1D and T2D analysis were consistent with the T1D analysis, except statistically significantly faster in achieving treatment success for Baqsimi vs Gvoke in the combined analysis (13.96 vs 14.66 min). The mean maximum blood glucose values were also statistically significantly lower for Baqsimi (168 mg/dl) vs Gvoke (220 mg/dl) and Zegalogue (190 mg/dl). There was a trend towards a lower number of adults experiencing ≥ 1 TEAE with Baqsimi compared to Gvoke or Zegalogue, but no statistical significance was reached. Conclusion: Baqsimi, Gvoke and Zegalogue had comparable high proportions of treatment success in reversing insulin-induced hypoglycemia. Baqsimi achieved a lower mean maximum blood glucose value, which may have implications for the re-establishment of euglycemia. These findings may help support patients, caregivers and health care providers in their decision-making process when discussing various ready-to-use glucagon treatment options. [ABSTRACT FROM AUTHOR]

Introduction: Deucravacitinib, a newly approved oral medication for the treatment of patients with moderate to severe plaque psoriasis, demonstrated efficacy versus apremilast and placebo in two phase 3 randomized controlled trials (RCTs). A systematic review and network meta-analysis (NMA) indirectly compared deucravacitinib with other relevant systemic biologic/nonbiologic treatments. Methods: Online databases were searched for RCTs published through October 2021. Eligible studies were head-to-head comparisons between systemic therapies and/or placebo reporting 50%, 75%, 90%, or 100% improvement in Psoriasis Area and Severity Index (PASI) from baseline in adults with moderate to severe plaque psoriasis. Comparisons included tumor necrosis factor inhibitors, interleukin (IL)-17, IL-23, and IL 12/23 inhibitors, and systemic nonbiologics. A multinomial Bayesian NMA was used to derive estimates of the relative efficacy of deucravacitinib and other systemic therapies. Response probabilities for each treatment and corresponding 95% credible intervals (CrIs) for achieving a PASI response were calculated over short-, mid-, and long-term follow-up (weeks 10–16, 24–28, and 44–60). Results: The NMA included 47 RCTs. Deucravacitinib showed the highest PASI 75 response rates among nonbiologic systemic therapies across time points. Deucravacitinib PASI 75 response rate (95% CrI) over short-term follow-up was 54.1% (46.5–61.6), within the range of first-generation biologics (etanercept, 39.7% [31.6–48.3]; infliximab, 79.0% [74.0–83.5]). At mid-term follow-up, deucravacitinib PASI 75 increased to 63.3% (58.0–68.4). At long-term follow-up, deucravacitinib PASI 75 was 65.9% (58.0–73.4), comparable to first-generation biologics adalimumab (62.8%; 55.3–69.6) and ustekinumab (68.0%; 64.6–71.5). Conclusions: Patients receiving deucravacitinib were more likely to achieve PASI 75 response versus apremilast and methotrexate across all time points. The long-term PASI 75 response rate for deucravacitinib was similar to those of adalimumab and ustekinumab. The approval of deucravacitinib offers patients the choice of an oral therapy with long-term efficacy similar to that of some biologics. [ABSTRACT FROM AUTHOR]

BackgroundNo trials have compared cabozantinib and regorafenib for the second-line treatment of advanced hepatocellular carcinoma (HCC).ObjectivesConduct a matching-adjusted indirect comparison (MAIC) of the efficacy and safety of second-line cabozantinib and regorafenib in patients with advanced HCC and disease progression after prior sorafenib.MethodsThe CELESTIAL and RESORCE trials were used for indirect comparison of second-line cabozantinib and regorafenib in advanced HCC. Population-level data were available for RESORCE, individual patient data (IPD) for CELESTIAL. To align with RESORCE, the CELESTIAL population was limited to patients who received first-line sorafenib only. To minimize potential effect-modifying population differences, the CELESTIAL IPD were weighted to balance the distribution of clinically relevant baseline characteristics with those of RESORCE. Overall survival (OS) and progression-free survival (PFS) were evaluated for the matching-adjusted second-line CELESTIAL population and compared with those for RESORCE using weighted Kaplan-Meier curves and parametric modeling. Rates of grade 3/4 treatment-emergent adverse events (TEAEs) affecting > 5% of patients in any study arm were compared.ResultsIn the matching-adjusted second-line populations (CELESTIAL, effective sample size = 266; RESORCE, n = 573), median (95% confidence interval) OS was similar for cabozantinib and regorafenib (11.4 [8.9-17.0] versus 10.6 [9.1-12.1] months; p = 0.3474, log-rank test). Median PFS was longer for cabozantinib than regorafenib (5.6 [4.9-7.3] versus 3.1 [2.8-4.2] months; p = 0.0005, log-rank test). There was a trend for lower rates of some grade 3/4 TEAEs with regorafenib than with cabozantinib, which may reflect the exclusion of sorafenib-intolerant patients from RESORCE but not from CELESTIAL, a difference that the MAIC methods could not remove. Only diarrhea rates were statistically significantly lower for regorafenib (p  ≤ 0.001).ConclusionsCabozantinib may achieve similar OS and prolonged PFS compared with regorafenib in patients with progressive advanced HCC after prior sorafenib.

Abstract Introduction Biologic disease-modifying anti-rheumatic drugs (bDMARDs), including certolizumab pegol (CZP), are effective treatment options for the management of non-radiographic spondyloarthritis (nr-axSpA). In the absence of head-to-head comparisons in nr-axSpA, we conducted a systematic literature review (SLR) and indirect treatment comparison (ITC) to better understand the comparative efficacy of CZP vs. other bDMARDs. Methods Literature searches were conducted in October 2020 in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials in patients with nr-axSpA who had failed at least one non-steroidal anti-inflammatory drug and were treated with bDMARDs. Outcomes of interest included the Assessment of Spondyloarthritis international Society (ASAS), Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Functional Index (BASFI) and Disease Activity Index (BASDAI), and spinal pain score. Comparative efficacy was examined using a series of Bucher ITCs in subgroups matched by prior exposure to bDMARDs, disease duration, baseline C-reactive protein (CRP) levels/magnetic resonance imaging (MRI) status, and timepoints, to ensure comparability between studies. Results At 12–16 weeks, treatment with CZP was significantly more likely to achieve ASAS20/40 response and ASDAS-inactive disease status vs. etanercept (ETN), ixekizumab (IXE), and secukinumab (SEC). CZP showed statistically significant improvement in BASDAI, BASFI, and total spine pain score over adalimumab (ADA), ETN, and IXE, and in BASFI over SEC. Among patients with objective signs of inflammation (OSI; elevated CRP levels and/or inflammation on MRI at baseline), CZP had a statistically significant advantage over ETN and SEC (with or without loading dose) in achieving ASAS40, whereas the comparisons with other bDMARDs did not show any statistically significant differences. Conclusion In the overall matched population, CZP performed significantly better than most comparators in improving the clinical outcomes. Among patients with OSI, CZP was found to be superior to SEC (in the MRI−/CRP + and MRI + /CRP− subgroups) and ETN (in the MRI + /CRP− subgroup) and it was comparable to golimumab and IXE across the different OSI subgroups.

Aim: To compare the efficacy and safety of insulin glargine‐300 once daily (Gla‐300) with insulin degludec/aspart (IDegAsp) once daily in patients with type 2 diabetes (T2D) inadequately controlled on oral anti‐diabetic drugs (OADs). Materials and methods: A systematic literature review of randomized controlled trials was followed by an indirect treatment comparison of studies involving insulin naïve adults, inadequately controlled [glycated haemoglobin (HbA1c) ≥7.0%] on OADs, who received Gla‐300 or IDegAsp once daily. Outcomes of interest were change in HbA1c, blood glucose, weight and insulin dose, as well as incidence and event rate of hypoglycaemia and other adverse events. Results: Four trials with broadly similar baseline patient characteristics were included in the meta‐analyses and indirect treatment comparison. At 24‐28 weeks, the indirect comparison of Gla‐300 to IDegAsp once daily estimated no statistically significant difference for change in HbA1c (%) from baseline [mean difference of 0.10% (95% CI: −0.20, 0.39; p =.52)]; a statistically significant mean difference of −1.31 kg (95% CI: −1.97, −0.65; p <.05) for change in body weight from baseline; statistically significant odds ratios of 0.62 (95% CI: 0.41, 0.93; p <.05) for incidence of any hypoglycaemia; and 0.47 (95% CI: 0.25, 0.87; p <.05) for incidence of anytime confirmed hypoglycaemia (plasma glucose <3.0‐3.1 mmol/L). No significant differences were observed for insulin dose and adverse events. Conclusion: In insulin‐naïve patients with T2D inadequately controlled on OADs, commencing Gla‐300 shows a comparable HbA1c reduction, but with significantly less weight gain and a lower incidence of any and confirmed hypoglycaemia compared with commencing IDegAsp. [ABSTRACT FROM AUTHOR]

Purpose: The current standard of care for chronic-phase chronic myeloid leukemia (CP-CML) is tyrosine kinase inhibitors (TKIs). Treatment recommendations are unclear for CP-CML failing ≥ 2 lines of treatment, partly due to the paucity of head-to-head trials evaluating TKIs. Thus, matching-adjusted indirect comparisons (MAICs) were conducted to compare asciminib with competing TKIs in third- or later line (≥ 3L) CP-CML. Methods: Individual patient-level data for asciminib (ASCEMBL; follow-up: ≥ 48 weeks) and published aggregate data for comparator TKIs (ponatinib, nilotinib, and dasatinib) informed the analyses. Major molecular response (MMR), complete cytogenetic response (CCyR), and time to treatment discontinuation (TTD) were assessed, where feasible. Results: Asciminib was associated with statistically significant improvements in MMR by 6 (relative risk [RR]: 1.55; 95% confidence interval [CI]: 1.02, 2.36) and 12 months (RR: 1.48; 95% CI: 1.03, 2.14) vs ponatinib. For CCyR, the results vs ponatinib were similar by 6 (RR: 1.11; 95% CI: 0.81, 1.52) and 12 months (RR: 0.97; 95% CI: 0.73, 1.28). Asciminib was associated with improvements in MMR by 6 months vs dasatinib but with a CI overlapping one (RR 1.52; 95% CI: 0.66, 3.53). Asciminib was associated with statistically significant improvements in CCyR by 6 (RR: 3.57; 95% CI: 1.42, 8.98) and 12 months (RR: 2.03; 95% CI: 1.12, 3.67) vs nilotinib/dasatinib. Median TTD was unreached for asciminib in ASCEMBL. However, post-adjustment asciminib implied prolonged TTD vs nilotinib and dasatinib, but not vs ponatinib. Conclusion: These analyses demonstrate favorable outcomes with asciminib versus competing TKIs, highlighting its therapeutic potential in ≥ 3L CP-CML. [ABSTRACT FROM AUTHOR]

Summary: We conducted two indirect comparisons to estimate the efficacy of zanubrutinib versus orelabrutinib in Chinese patients with relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or R/R mantle cell lymphoma (MCL). An unanchored matching-adjusted indirect comparison (MAIC) was performed in R/R CLL/SLL patients. Individual patient data from zanubrutinib trial (BGB-3111-205) were adjusted to match the aggregated data from the orelabrutinib trial (ICP-CL-00103). A naïve comparison was performed in R/R MCL for the different response assessment methodology and efficacy analysis set between the zanubrutinib (BGB-3111-206) and orelabrutinib (ICP-CL-00102) trials. Efficacy outcomes included ORR and PFS. In R/R CLL/SLL patients, after matching, IRC-assessed ORR was comparable (86.6% vs. 92.5%; risk difference, -5.9% [95% CI: -15.8%-3.8%]); IRC-assessed PFS was similar with a favorable trend in zanubrutinib over orelabrutinib (HR, 0.74 [95% CI: 0.37-1.47]) and the 18-month PFS rate was numerically higher in zanubrutinib (82.9% vs. 78.7%). In R/R MCL patients, naïve comparison showed investigator-assessed ORR was similar (83.7% vs. 87.9%; risk difference, -4.2% [95% CI: -14.8%-6.0%]), and CR rate was significantly higher in zanubrutinib over orelabrutinib (77.9% vs. 42.9%; risk difference, 35.0% [95% CI: 14.5%, 53.7%]). Investigator-assessed PFS was similar with a favorable trend (HR, 0.77 [95% CI: 0.45-1.32]) in zanubrutinib over orelabrutinib and the 12-month PFS rate was numerically higher in zanubrutinib (77.5% vs. 70.8%). MAIC result showed zanubrutinib demonstrated favorable PFS over orelabrutinib for R/R CLL/SLL patients. The naïve comparison showed zanubrutinib had favorable PFS and higher CR rate than orelabrutinib for R/R MCL patients. [ABSTRACT FROM AUTHOR]

We examine four important considerations in the development of covariate adjustment methodologies for indirect treatment comparisons. First, we consider potential advantages of weighting versus outcome modeling, placing focus on bias‐robustness. Second, we outline why model‐based extrapolation may be required and useful, in the specific context of indirect treatment comparisons with limited overlap. Third, we describe challenges for covariate adjustment based on data‐adaptive outcome modeling. Finally, we offer further perspectives on the promise of doubly robust covariate adjustment frameworks. [ABSTRACT FROM AUTHOR]