A targeted review of worldwide indirect treatment comparison (ITC) guidelines and best practices.

OBJECTIVES: Controls and governance over the methodology and reporting of indirect treatment comparisons (ITCs) have been introduced to minimize bias and ensure scientific credibility and transparency in healthcare decision-making. The objective of this study was to highlight ITC techniques that are key to conducting objective and analytically-sound analyses, and to ascertain circumstantial suitability of ITCs as a source of comparative evidence for healthcare interventions. METHODS: Ovid MEDLINE® was searched from January 2010 through August 2023 to identify publicly available ITC-related documents (i.e., guidelines and best practices) in the English language. This was supplemented with hand-searches of websites of various international organizations, regulatory agencies, and reimbursement agencies of Europe, North America, and Asia-Pacific. The jurisdiction-specific ITC methodology and reporting recommendations were reviewed. RESULTS: Sixty-eight guidelines from 10 authorities worldwide were included for synthesis. Many of the included guidelines were updated within the last five years and commonly cited the absence of direct comparative studies as primary justification for employing ITCs. Most jurisdictions favored population-adjusted or anchored ITC techniques opposed to naïve comparisons. Recommendations on the reporting and presentation of these ITCs varied across authorities; however, there was some overlap among the key elements. CONCLUSIONS: Given the challenges of conducting head-to-head randomized controlled trials, comparative data from ITCs offer valuable insights into clinical effectiveness. As such, multiple ITC guidelines have emerged worldwide. According to the most recent versions of the guidelines, the suitability and subsequent acceptability of the ITC technique employed depends on the data sources, available evidence, and magnitude of benefit/uncertainty.

Electrode-Skin Impedance Model Parameter Estimation in the Frequency-Domain.

This paper presents a method for identifying parameter values for a double parallel resistor/constant-phase-element model of the electrode-skin interface for individual silver and silver/silver chloride electrodes. The impedance of each electrode was measured in five from 1 Hz-10 kHz. Phase features of these data were used to guide initial estimates for parameter values which were refined using a least squares algorithm. Resultant model impedances were compared with experimental data across a typical biosignal bandwidth (1 Hz-500 Hz). The method was effective in estimating component values in most datasets, and resulted in a mean relative RMS error of 7 % (σ = 8.3%) across the biosignal bandwidth.Clinical relevance- This work establishes a feature-based method for finding component parameter estimates for an electrode contact impedance model.

The burden of red blood cell transfusions in patients with lower-risk myelodysplastic syndromes and ring sideroblasts: an analysis of the prospective MDS-CAN registry.

Many patients with lower-risk myelodysplastic syndromes (LR MDS) require long-term red blood cell (RBC) transfusions to manage anemia. The consequences of RBC transfusions in LR MDS with ring sideroblasts (LR MDS-RS) are not well known. We estimated the association between cumulative RBC dose density and clinical and patient-reported outcomes using data from the MDS-CAN registry for patients enrolled between January 2008 and December 2018. Outcomes included overall survival, hospitalization, and health-related quality of life (HRQoL). A total of 145 enrolled patients with LR MDS and RS ≥5% had a median follow-up time of 27.1 months; 45 had no transfusions during follow-up, 51 had <1 transfusion per month, and 49 had ≥1 transfusion per month. The cumulative density of RBC transfusions was associated with significantly greater mortality, hospitalization, and inferior HRQoL, suggesting that exposure to RBC transfusion may constitute a significant treatment burden in patients with LR MDS-RS.

Building infrastructure for outcomes-based agreements in Canada: can administrative health data be used to support an outcomes-based agreement in oncology?

BACKGROUND: Outcomes-based agreements (OBAs) have the potential to provide more timely patient access to novel therapies, although they are not suitable for every new medication or reimbursement scenario. The authors of this paper studied how to operationalize an OBA in oncology by leveraging existing real-world data (RWD) infrastructure in the province of Alberta. OBJECTIVE: The main objectives were to (1) evaluate which health outcomes in oncology are suitable for OBAs and whether they can be tracked with existing infrastructure, and (2) determine how RWD in oncology can be used to implement an OBA and the expected timing for delivery. METHODS: Using the Oncology Outcomes (O2) Group infrastructure and Alberta administrative data, a review of five key oncology outcomes was performed to determine suitability to support an OBA. RESULTS: Overall survival and time-to-next-treatment were determined as potentially suitable oncology outcomes for OBAs; progression-free survival, patient-reported outcomes, and return to work were deemed inadequate for OBAs at the current time due to data limitations. CONCLUSIONS: Results indicate that it is feasible to leverage RWD to support OBAs in oncology in Alberta, with minimal additional data, resources, and infrastructure. The operational processes and steps to collect and analyze RWD for OBAs were identified, starting with performing an RWD feasibility study. The expected timeframe to fulfill the real-world evidence (RWE) requirements for an OBA is approximately 3 years for cancers with short trajectories.

A natural history of lower-risk myelodysplastic syndromes with ring sideroblasts: an analysis of the MDS-CAN registry.

Patients with lower-risk (LR) myelodysplastic syndromes (MDS) with ring sideroblasts (RS) have better prognosis than those without RS, but how they fare over time is not fully understood. This study's objective was to assess the natural history of LR MDS with RS ≥5% using MDS-CAN registry individual data. Kaplan-Meier estimates and generalized linear mixed models were used to describe time-to-event outcomes and continuous outcomes, respectively. One hundred and thirty-eight patients were enrolled; median times from diagnosis to enrollment and follow-up were 6.6 and 39.6 months, respectively. Within 5 years of enrollment, 65% of patients had ≥1 red blood cell transfusion dependence episode. Within 5 years of diagnosis, 59% developed iron overload, 38% received iron chelation therapy, 14% progressed to acute myeloid leukemia, and 42% died. Patients exhibited inferior health-related quality of life trends. These first real-world data in LR MDS-RS in Canada indicate a high level of morbidity and mortality over a 5-year period. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02537990.

Simulated treatment comparison of efficacy outcomes for ofatumumab in ASCLEPIOS I/II versus ocrelizumab in OPERA I/II for the treatment of patients with relapsing multiple sclerosis.

BACKGROUND: Ofatumumab is a subcutaneously administered anti-CD20 monoclonal antibody (MoAb) therapy that has been evaluated in two identically designed randomized controlled trials (RCTs), ASCLEPIOS I (NCT02792218) and ASCLEPIOS II (NCT02792231), in patients with relapsing multiple sclerosis (RMS). Ocrelizumab is another anti-CD20 MoAb therapy, administered intravenously, that has been evaluated in two identically designed RCTs, OPERA I (NCT01247324) and OPERA II (NCT01412333) in RMS. Given the absence of published RCTs with head-to-head comparisons between these MoAbs, this study assessed the indirect comparative efficacy of ofatumumab and ocrelizumab. METHODS: Given the availability of individual patient data for ASCLEPIOS I/II and summary-level data for OPERA I/II, simulated treatment comparisons were used to assess the comparative efficacy of ofatumumab versus ocrelizumab while adjusting for differences in baseline characteristics between trials. Comparative efficacy was estimated for the proportion of patients with 3- and 6-month confirmed disability progression (CDP) and for annualized relapse rate (ARR). Exploratory analyses were conducted for the outcome of no evidence of disease activity based on three parameters (NEDA-3) and magnetic resonance imaging (MRI) outcomes (proportion of patients with gadolinium-enhancing T1 lesions and brain volume change). RESULTS: Although comparative results were not significant for 3-month CDP (hazard ratio [HR]: 0.90 [95% confidence interval [CI]: 0.57-1.42]) or 6-month CDP (HR: 0.84 [95% CI: 0.47-1.49]), ofatumumab showed a significant improvement in ARR (rate ratio: 0.60 [95% CI: 0.43-0.84]) compared with ocrelizumab. Significantly favorable results were also associated with ofatumumab for NEDA-3 and MRI outcomes. CONCLUSION: Ofatumumab was associated with more favorable efficacy results compared with ocrelizumab for clinical, NEDA-3, and MRI outcomes.

Low cost circulatory pressure acquisition and fluid infusion rate measurement system for clinical research.

Acquiring patient physiological waveforms is useful for studying hemodynamic management and developing medical monitoring systems. A low cost, Arduino controlled data acquisition system acquires arterial pressure waveforms (Edwards Lifesciences TruWave compatible) and measures fluid infusion rate using hanging scales. This system can be used at the same time as a clinical monitor, enabling recording of patient arterial pressure and fluid delivery for clinical research. The system is powered via a USB connection, which additionally provides serial output, aiding compatibility and customisation. A simple software user interface, developed in Python, shows outputs. Each data acquisition system, including all necessary connection cables costs ~US$90 and is multiple-use.

Proptosis and Diplopia Response With Teprotumumab and Placebo vs the Recommended Treatment Regimen With Intravenous Methylprednisolone in Moderate to Severe Thyroid Eye Disease: A Meta-analysis and Matching-Adjusted Indirect Comparison.

IMPORTANCE: Thyroid eye disease can be a debilitating autoimmune disorder characterized by progressive proptosis or diplopia. Teprotumumab has been compared with placebo in randomized clinical trials, but not with intravenous methylprednisolone (IVMP), which sometimes is used in clinical practice for this condition. OBJECTIVE: To conduct a matching-adjusted indirect comparison of teprotumumab vs IVMP vs placebo. DATA SOURCES: Deidentified patient-level data from teprotumumab trials and aggregate-level data from literature on the most recommended regimen of IVMP. STUDY SELECTION: PubMed and Embase were searched for randomized/observational studies using key terms and controlled vocabulary. Full texts of eligible articles were reviewed and cataloged. DATA EXTRACTION AND SYNTHESIS: Conducted by 1 reviewer (R.A.Q.) and 1 verifier (R.B.), including study characteristics, eligibility criteria, baseline characteristics, and outcomes. MAIN OUTCOMES AND MEASURES: Changes in proptosis by millimeter and diplopia response (percentage with ≥1 grade reduction) from baseline to week 12 in patients receiving IVMP and placebo, and to week 24 in patients receiving teprotumumab. RESULTS: The search identified 1019 records, and 6 through manual searches, alerts, and secondary references. After excluding duplicates and screening full-text records, 12 IVMP studies were included in the matching-adjusted indirect comparison (11 for proptosis change [n = 419], 4 for diplopia response [n = 125], and 2 teprotumumab [n = 79] and placebo [n = 83] comparator studies). Treatment with IVMP resulted in a proptosis difference of -0.16 mm (95% CI, -1.55 to 1.22 mm) from baseline to week 12 vs placebo. The proptosis treatment difference between IVMP and teprotumumab of -2.31 mm (95% CI, -3.45 to -1.17 mm) favored teprotumumab. Treatment with IVMP (odds ratio, 2.69; 95% CI, 0.94-7.70) was not favored over placebo in odds of diplopia response; however, teprotumumab was favored over IVMP (odds ratio, 2.32; 95% CI, 1.07-5.03). CONCLUSIONS AND RELEVANCE: This meta-analysis suggests that use of IVMP is associated with a small, typically not clinically relevant, change from baseline in proptosis vs placebo, with modest changes in diplopia. While this nonrandomized comparison suggests that use of teprotumumab, compared with IVMP, is associated with greater improvements in proptosis and may be twice as likely to have a 1 grade or higher reduction in diplopia, randomized trials comparing these 2 treatments would be warranted to determine if 1 treatment is superior to the other to a clinically relevant degree.

Palbociclib versus abemaciclib in HR+/HER2- advanced breast cancer: an indirect comparison of patient-reported end points.

Aim: To assess the relative impact of palbociclib plus fulvestrant (PAL + FUL) and abemaciclib plus fulvestrant (ABEM + FUL) on patient-reported outcomes in patients with hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer. Patients & methods: Anchored matching-adjusted indirect comparisons were conducted using individual patient data from PALOMA-3 (PAL + FUL) and summary-level data from MONARCH-2 (ABEM + FUL). Outcomes included the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items (EORTC QLQ-C30) and its breast cancer-specific module (QLQ-BR23). Results: Significantly different changes from baseline favoring PAL + FUL compared with ABEM + FUL were observed in global quality of life (6.95 [95% CI: 2.19-11.71]; p = 0.004) and several functional/symptom scales, including emotional functioning, nausea/vomiting, appetite loss, diarrhea and systemic therapy side effects. Conclusion: PAL + FUL was associated with more favorable patient-reported outcomes than ABEM + FUL in patients with HR+/HER2- advanced breast cancer.

Indirect comparisons of siponimod with fingolimod and ofatumumab in multiple sclerosis: assessing the feasibility of propensity score matching analyses.

OBJECTIVE: Head-to-head trials comparing siponimod with fingolimod or ofatumumab in patients with multiple sclerosis (MS) are lacking. Instead, the comparative efficacy of siponimod can be derived from indirect treatment comparisons (ITCs). We assessed the suitability of ITCs leveraging individual patient data from relevant phase III trials across different MS phenotypes. METHODS: One siponimod trial in patients with secondary progressive MS (SPMS), four fingolimod trials (three in relapsing-remitting MS [RRMS], and one in primary progressive MS [PPMS]), and two ofatumumab trials in relapsing MS (RMS) were considered. The suitability of ITCs was evaluated based on trial design, patient eligibility criteria, baseline patient characteristics, placebo response, and outcome definitions for each trial. Analyses deemed feasible were conducted using one-to-one propensity score matching (PSM). RESULTS: An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible because of insufficient overlap in key patient characteristics (e.g. disability level and relapse history) and differences in placebo response. However, a comparison between siponimod in SPMS and fingolimod in PPMS was feasible because of sufficient overlap in eligibility criteria and baseline characteristics. One-to-one PSM demonstrated siponimod was favored relative to fingolimod for time to 6- and 3-month confirmed disability progression though not significantly different (hazard ratio 0.76 [95% confidence interval 0.48-1.20; p-value = .240] and hazard ratio 0.80 [95% confidence interval 0.52-1.22; p-value = .300], respectively). CONCLUSIONS: For trials in MS, clinical phenotype is an important determinant of ITC feasibility. An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible. The only feasible comparison was between siponimod in SPMS and fingolimod in PPMS.

Improved survival with enasidenib versus standard of care in relapsed/refractory acute myeloid leukemia associated with IDH2 mutations using historical data and propensity score matching analysis.

BACKGROUND: The present study evaluated the relative survival benefits associated with enasidenib and current standard of care (SoC) therapies for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and an isocitrate dehydrogenase 2 (IDH2) mutation who are ineligible for hematopoietic stem cell transplantation (HSCT). METHODS: Propensity score matching (PSM) analysis compared survival outcomes observed with enasidenib 100 mg daily in the phase I/II AG221-C-001 trial and SoC outcomes obtained from a real-world chart review of patients in France. RESULTS: Before matching, enasidenib (n = 195) was associated with numerically improved overall survival (OS) relative to SoC (n = 80; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.61-1.11). After matching and adjusting for covariates (n = 78 per group), mortality risk was significantly lower with enasidenib than with SoC (HR, 0.67; 95% CI, 0.47-0.97). The median OS was 9.26 months for enasidenib (95% CI, 7.72-13.24) and 4.76 months for SoC (95% CI, 3.81-8.21). Results remained robust across all sensitivity analyses conducted. CONCLUSIONS: PSM analyses indicate that enasidenib significantly prolongs survival relative to SoC among patients with R/R AML and an IDH2 mutation who are ineligible for HSCT. Future prospective studies are needed to validate these findings using other data sources and to assess the comparative efficacy of enasidenib for other treatment outcomes.

Matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma.

OBJECTIVE: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the approved idecabtagene vicleucel (ide-cel) dose range of 300-460 × 106 CAR-positive T-cells for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed) using matching-adjusted indirect treatment comparisons (MAICs). METHODS: MAICs were performed with individual patient data for cilta-cel (CARTITUDE-1; NCT03548207) and published summary-level data for ide-cel (KarMMa; NCT03361748). Treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa were included in the analyses. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was estimated for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). RESULTS: Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p < .0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.49 [95% CI: 2.47, 12.21; p < .0001]; RR: 2.21), DoR (hazard ratio [HR]: 0.50 [95% CI: 0.29, 0.87; p = .0137]), and PFS (HR: 0.37 [95% CI: 0.22, 0.62; p = .0002]) when compared with ide-cel. For OS, the results were in favor of cilta-cel and clinically meaningful but with a CI overlapping one (HR: 0.55 [95% CI: 0.29, 1.05; p = .0702]). CONCLUSIONS: These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes, highlighting its therapeutic potential in patients with triple-class exposed RRMM.

Risk of recurrence among patients with HR-positive, HER2-negative, early breast cancer receiving adjuvant endocrine therapy: A systematic review and meta-analysis.

BACKGROUND: A systematic review and meta-analysis was conducted to assess breast cancer (BC) outcomes among patients with early-stage hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) BC, receiving adjuvant endocrine therapy. METHODS: Randomized controlled trials (RCTs) and real-world evidence (RWE) studies were identified using Ovid MEDLINE®, Embase, and Evidence-Based Medicine Reviews. Clinical and methodological similarities including alignment of outcome definitions with standardized definitions for efficacy endpoints criteria were assessed to evaluate feasibility of conducting a meta-analysis. Where feasible, 5-year probabilities of BC recurrence or death were estimated using a Bayesian hierarchical arm-based model. RESULTS: Of 21 included studies, 8 RCTs and 4 RWE studies reported outcome data of interest. There was heterogeneity in outcome reporting, as well as variation in recurrence risk amongst studies with aligned reporting. Of the 12 studies, 10 were considered for inclusion in a meta-analysis of BC recurrence or death. Only a subgroup analysis of node-positive patients (3 studies; n = 7307) was deemed feasible. The 5-year probability of BC recurrence or death was 17.2% (95% credible interval: 14.6%-20.3%). CONCLUSION: Although studies reporting recurrence outcomes were limited, there remains a high risk of BC recurrence, especially among node-positive patients. Approximately 1 in 6 women with node-positive HR+/HER2- early-stage BC receiving endocrine therapy experience recurrence or death within 5-years of initiating treatment, suggesting a need for novel treatments for this population.

CDK4/6 inhibitors in HR+/HER2- advanced/metastatic breast cancer: a systematic literature review of real-world evidence studies.

Background: This review aims to qualitatively summarize the published real-world evidence (RWE) for CDK4/6 inhibitors (CDK4/6i) approved for treating HR+, HER2-negative advanced/metastatic breast cancer (HR+/HER2- a/mBC). Materials & methods: A systematic literature review was conducted to identify RWE studies of CDK4/6i in HR+/HER2- a/mBC published from 2015 to 2019. Results: This review identified 114 studies, of which 85 were only presented at scientific conferences. Most RWE studies investigated palbociclib and demonstrated improved outcomes. There are limited long-term and comparative data between CDK4/6i and endocrine monotherapy, and within the CDK4/6i class. Conclusion: Available RWE suggests that CDK4/6i are associated with improved outcomes in HR+/HER2- a/mBC, although additional studies with longer follow-up periods are needed.

Efficacy classification of modern therapies in multiple sclerosis.

Background: The Association of British Neurologists (ABN) 2015 guidelines suggested classifying multiple sclerosis therapies according to their average relapse reduction. We sought to classify newer therapies (cladribine, ocrelizumab, ofatumumab, ozanimod) based on these guidelines. Materials & methods: Therapies were classified by using direct comparative trial results as per ABN guidelines and generating classification probabilities for each therapy based on comparisons versus placebo in a network meta-analysis for annualized relapse rate. Results: For both approaches, cladribine and ofatumumab were classified as high efficacy. Ocrelizumab and ozanimod (1.0 mg) were classified as moderate or high efficacy depending on the approach used. Conclusion: Cladribine and ofatumumab have an efficacy comparable with therapies classified in the ABN guidelines as high efficacy.

Matching-adjusted indirect comparison of palbociclib versus ribociclib and abemaciclib in hormone receptor-positive/HER2-negative advanced breast cancer.

Aim: Palbociclib (PAL), ribociclib (RIB) and abemaciclib (ABM), in combination with fulvestrant (FUL), are approved for the treatment of hormone receptor-positive, HER2-negative advanced breast cancer. This study aims to determine relative efficacy of PAL+FUL versus RIB+FUL and ABM+FUL using matching-adjusted indirect treatment comparisons. Patients & methods: Anchored matching-adjusted indirect treatment comparisons were conducted using individual patient data from PALOMA-3 and published summary-level data from MONARCH 2 and MONALEESA-3. The primary outcome was overall survival (OS). Results: OS was similar for PAL+FUL versus ABM+FUL (hazard ratio: 0.87; 95% CI: 0.54-1.40) and RIB+FUL (hazard ratio: 0.89; 95% CI: 0.48-1.63). Conclusion: Adjusting for cross-trial differences suggests similar OS between treatments, underscoring the importance of accounting for these differences when indirectly comparing treatments.

Lay abstract Palbociclib (PAL), ribociclib (RIB) and abemaciclib (ABM) are used with fulvestrant to treat hormone receptor-positive, HER2-negative advanced breast cancer. This study aims to use data from clinical trials to compare how long patients live after starting treatment with PAL versus RIB and ABM. Since patients who enroll in different trials may have different characteristics, it is important to adjust for these differences for a more accurate comparison. Adjusting for these differences showed that patients with hormone receptor-positive, HER2-negative advanced breast cancer treated with PAL lived for a similar length of time compared with those treated with RIB or ABM.