IQVIA

Understanding causality, over mere association, is vital for researchers wishing to inform policy and decision making – for example, when seeking to improve population health outcomes. Yet, contemporary causal inference methods have not fully tackled the complexity of data hierarchies, such as the clustering of people within households, neighbourhoods, cities, or regions. However, complex data hierarchies are the rule rather than the exception. Gaining an understanding of these hierarchies is important for complex population outcomes, such as non-communicable disease, which is impacted by various social determinants at different levels of the data hierarchy. The alternative of analysing aggregated data could introduce well-known biases, such as the ecological fallacy or the modifiable areal unit problem. We devise a hierarchical causal diagram that encodes the multilevel data generating mechanism anticipated when evaluating non-communicable diseases in a population. The causal diagram informs data simulation. We also provide a flexible tool to generate synthetic population data that captures all multilevel causal structures, including a cross-level effect due to cluster size. For the very first time, we can then quantify the ecological fallacy within a formal causal framework to show that individual-level data are essential to assess causal relationships that affect the individual. This study also illustrates the importance of causally structured synthetic data for use with other methods, such as Agent Based Modelling or Microsimulation Modelling. Many methodological challenges remain for robust causal evaluation of multilevel data, but this study provides a foundation to investigate these.

Gonadotropin-releasing hormone (GnRH) agonist injection frequency does not affect prostate cancer treatment efficacy; however, it may influence treatment satisfaction, adherence, and overall healthcare utilization. This study addressed the limited information available on real-world patient experience with GnRH treatments by surveying a diverse population of patients with prostate cancer in Europe. This noninterventional, cross-sectional study included adults with locally advanced or metastatic prostate cancer in Belgium, France, Italy, Spain, and the UK. Data were collected via a one-time self-administered electronic survey (October–December 2023) that assessed patient preferences for injection frequency, satisfaction, healthcare resource utilization, and involvement in treatment decision-making. Of 414 participants, 53.9% preferred a 6-month injection frequency, while 27.3% preferred a 3-month frequency. Among those receiving injections every 6 months, 77.0% were satisfied; 62.7% of those receiving injections every 3 months were satisfied. Two-thirds of participants (65.7%) were aware of different frequencies of injections. Among those who preferred a 3-month injection frequency, routine and perceived control over their disease were important factors, with 38.1% receiving injections at the same frequency as doctor visits. Among those preferring a 6-month frequency, convenience and routine were important; however, 7.2% indicated that their preference was based on a dislike or fear of injections. Of those with no preference, 60.3% indicated that this was because they deferred to their doctor’s advice. Most patients required transport to their injection appointment, and of those who were employed, 79.2% required time off from work. Accompaniment to an injection appointment was also important, with 66.2% of patients never attending alone. The high satisfaction rates, particularly among those receiving injections every 6 months, suggest that less-frequent injections may be more convenient and preferable for many patients. These insights can help to guide patient-centric care and treatment decisions in prostate cancer management.

Objectives We assessed rates of cardiovascular events, all-cause death, baseline risk factors, and treatment patterns in a population qualifying for initiation of dual combination blood pressure (BP)-lowering therapy. We also evaluated the association between dual versus monotherapy during follow-up and incidence of cardiovascular events. Methods This study utilized integrated databases in England: Clinical Practice Research Datalink, Hospital Episode Statistics, and Office for National Statistics. Individuals aged at least 18 years qualifying for dual therapy were identified during 15-year period (2005–2019). The primary endpoint was composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, and cardiovascular death. The secondary endpoint was all-cause death. Results Total 1 426 079 individuals met selection criteria. The 15-year event rates for the primary and secondary endpoints were 27.1 and 32.6%, respectively. Atherosclerotic cardiovascular disease, diabetes on insulin therapy, heart failure, atrial fibrillation, chronic kidney disease, and advanced age were associated with two to four-fold higher risk of primary and secondary endpoints. The estimated hazard ratio for dual versus monotherapy as a time-varying covariate was 0.82 (95% confidence interval 0.81–0.83) for the primary endpoint. At variance with guidelines, monotherapy was most common treatment pattern over 5-year follow-up. Conclusion Baseline characteristics conveying a multifold higher risk for cardiovascular events and all-cause death mostly represented nonmodifiable risk factors. Treatment with dual therapy as compared to monotherapy was associated with reduction in cardiovascular events. Monotherapy remained most common BP-lowering treatment indicating substantial opportunity for risk reduction by treatment intensification.

Background This study was designed to evaluate content validity of the Dimensional Anhedonia Rating Scale (DARS), a patient-reported outcome measure, in adults with anhedonia in the context of major depressive disorder (MDD). To accomplish this, a conceptual model including the symptoms and impacts of anhedonia in the context of MDD was developed and refined through a targeted literature review, clinician interviews (N = 6), and participant interviews (N = 20). Results Using the final conceptual model, an item mapping exercise was conducted for the DARS, demonstrating that it provided suitable concept coverage in this population. Cognitive debriefing of the DARS with participants demonstrated that it was generally well understood and clear. Conclusions Overall, the study established that the DARS demonstrates content validity in adults with anhedonia in the context of MDD. Other measurement properties of the DARS will be evaluated in planned psychometric analyses.

Limited evidence on relative effectiveness is common in Health Technology Assessment (HTA), often due to sparse evidence on the population of interest or study-design constraints. When evidence directly relating to the policy decision is limited, the evidence base could be extended to incorporate indirectly related evidence. For instance, a sparse evidence base in children could borrow strength from evidence in adults to improve estimation and reduce uncertainty. In HTA, indirect evidence has typically been either disregarded (‘splitting’; no information-sharing) or included without considering any differences (‘lumping’; full information-sharing). However, sophisticated methods that impose moderate degrees of information-sharing have been proposed. We describe and implement multiple information-sharing methods in a case-study evaluating the effectiveness, cost-effectiveness and value of further research of intravenous immunoglobulin for severe sepsis and septic shock. We also provide metrics to determine the degree of information-sharing. Results indicate that method choice can have significant impact. Across information-sharing models, odds ratio estimates ranged between 0.55 and 0.90 and incremental cost-effectiveness ratios between £16,000–52,000 per quality-adjusted life year gained. The need for a future trial also differed by information-sharing model. Heterogeneity in the indirect evidence should also be carefully considered, as it may significantly impact estimates. We conclude that when indirect evidence is relevant to an assessment of effectiveness, the full range of information-sharing methods should be considered. The final selection should be based on a deliberative process that considers not only the plausibility of the methods’ assumptions but also the imposed degree of information-sharing.

Background: Retinal diseases are major contributors to disability, significantly affecting patients’ quality of life. Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) represent a significant disease and economic burden in Colombia. Assessing the economic evaluation of available treatments is essential for the efficient allocation of healthcare resources. Objective: To estimate the cost-effectiveness and budget impact of using faricimab for the treatment of patients with DME and nAMD within the Colombian health system. Methods: This study used a 25-year Markov cohort model to estimate the cost-effectiveness of faricimab vs aflibercept, ranibizumab, and brolucizumab. We used the methodological guidelines of the local health technology assessment agency for conducting the cost-effectiveness and budget impact analysis. Transition probabilities and injection frequencies were derived from the literature. Drug prices were retrieved from public local databases. Quality-adjusted life years (QALYs) were assessed. The potential patient population for the budget impact analysis was estimated based on disease prevalence and expert consultations. Results: Faricimab treat-and-extend (T&E) was dominant vs aflibercept T&E (+0.22 QALYs), ranibizumab T&E (+0.55 QALYs), and brolucizumab for 8 to 12 weeks (+0.06 QALYs) in DME, generating cost savings (in US dollars) of 3849, 1375, and $2824, respectively. In nAMD, faricimab also showed dominance vs aflibercept as needed (+0.12 QALYs), ranibizumab as needed (+0.05 QALYs), and brolucizumab 8 to 12 weeks (+0.12 QALYs) with savings in (US)$7223, $5792, and$6798, respectively. Assuming an annual market share increase for faricimab of 15% for DME and 13% for nAMD, the Colombian Health System could save $144 million over 3 years. Of these savings,$122.7 million are attributed to drug costs and $21.3 million to administration costs (US$1 = Col$4325). Conclusion: Considering a willingness to pay threshold of$5988 per additional QALY, faricimab is a cost-effective alternative for both DME and nAMD for the Colombian healthcare system, showing dominance over other anti–vascular endothelial growth factor agents. Faricimab provides better health outcomes at lower costs vs other treatments.

Objectives This study aimed to assess preferences of patients and doctors regarding treatment attributes for early-stage triple-negative breast cancer (eTNBC) in the Asia–Pacific region. Design A discrete choice experiment (DCE) by cross-sectional survey was conducted with patients and doctors. Key attributes relevant to eTNBC treatment decision-making were verified through a consultative process with clinical experts. The levels and description of seven attributes were refined through cognitive interviews. A D-efficient fractional-factorial design was employed to create 15 choice sets with seven key attributes. Setting An online web-based DCE with the 15 choice sets was developed and made available to participants in Australia, Japan, Korea, the Philippines and Taiwan. Participants The final dataset comprised 115 patients who self-reported a diagnosis of eTNBC and 86 medical oncologists, breast and general surgeons with at least five years of experience managing eTNBC patients. Primary outcomes Patients’ and doctors’ preferences on seven attributes: pathological complete response (pCR), disease-free/event-free survival (DFS/EFS), chance of undergoing breast-conserving surgery after receiving anticancer treatment, febrile neutropenia, peripheral sensory neuropathy (PSN), diarrhoea and irreversible endocrine-related side effects requiring lifelong medication. Data were analysed using a mixed logit model to determine preference weights for attribute levels, which were then used to compute the relative importance score (RIS) for each attribute. Results The median age of patients was 44.0 (IQR 38.0–56.5) years. Most patients (68%) were married, and 77% had children. Additionally, 40% were employed full-time, and 70% held a college degree. Nearly half (46%) were diagnosed before the age of 40. Among the doctors, 58% were medical oncologists and the remaining breast or general surgeons. pCR, DFS/EFS and PSN were the three most important attributes in both doctor and patient groups. pCR had the highest weighted preference among patients and doctors (RIS, 28.5 and 32.9, respectively). In general, patients assigned more weight to safety attributes compared with doctors, while doctors assigned more weight to efficacy attributes than patients did. Surgeons assigned more weight to irreversible endocrine-related side effects than medical oncologists (RIS, 14.4 vs 5.4). Differences in preferences within the regions were noted. Conclusions While our study revealed a concordance between patients’ and doctors’ ranking of the seven assessed treatment attributes, patients generally assigned greater emphasis on safety-related attributes in comparison to doctors.

Loss of glutamatergic terminals is hypothesised to contribute to excitation-inhibition imbalance in schizophrenia, supported by evidence that the normal positive association between glutamate concentrations and synaptic terminal density is not found in patients with chronic schizophrenia. However, it is unknown whether the relationship between synaptic terminal density and glutamate levels is altered early in the course of illness. To address this, we investigated [¹¹C]UCB-J distribution volume ratio (DVR) and glutamatergic markers in healthy volunteers (HV) and in antipsychotic-naïve/free patients with schizophrenia (SCZ) recruited from first-episode psychosis services. Forty volunteers (HV n = 19, SCZ n = 21) underwent [¹¹C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (¹H-MRS) imaging in the anterior cingulate cortex (ACC) and left hippocampus to index [¹¹C]UCB-J DVR and creatine-scaled glutamate (Glu/Cr) and glutamate in combination with glutamine (Glx/Cr). In the HV but not SCZ group, [¹¹C]UCB-J DVR was significantly positively associated with Glu/Cr (Spearman’s rho = 0.55, p = 0.02) and Glx/Cr (Spearman’s rho = 0.73, p = 0.0004) in the ACC, and with Glu/Cr in the left hippocampus (Spearman’s rho = 0.77, p = 0.0001). DVR was significantly lower in the ACC in the SCZ group compared to the HV group (Kolmogorov-Smirnov Z = 1.44, p = 0.03). Together, these findings indicate that the normal relationship between levels of a synaptic terminal density marker and levels of glutamate is disrupted early in the course of schizophrenia. This is consistent with the hypothesis that there is loss of glutamatergic terminals at illness onset.

Background Matching Adjusted Indirect Comparison (MAIC) is a statistical method used to adjust for potential biases when comparing treatment effects between separate data sources, with aggregate data in one arm, and individual patients data in the other. However, acceptance of MAIC in health technology assessment (HTA) is challenging because of the numerous biases that can affect the estimates of treatment effects – especially with small sample sizes, increasing the risk of convergence issues. We suggest statistical approaches to address some of the challenges in supporting evidence from MAICs, applied to a case study. Methods The proposed approaches were illustrated with a case study comparing an integrated analysis of three single-arm trials of entrectinib with the French standard of care using the Epidemio-Strategy and Medical Economics (ESME) Lung Cancer Data Platform, in metastatic ROS1-positive Non-Small Cell Lung Cancer (NSCLC) patients. To obtain convergent models with balanced treatment arms, a transparent predefined workflow for variable selection in the propensity score model, with multiple imputation of missing data, was used. To assess robustness, multiple sensitivity analyses were conducted, including Quantitative Bias Analyses (QBA) for unmeasured confounders (E-value, bias plot), and for missing at random assumption (tipping-point analysis). Results The proposed workflow was successful in generating satisfactory models for all sub-populations, that is, without convergence problems and with effectively balanced key covariates between treatment arms. It also gave an indication of the number of models tested. Sensitivity analyses confirmed the robustness of the results, including to unmeasured confounders. The QBA performed on the missing data allowed to exclude the potential impact of the missing data on the estimate of comparative effectiveness, even though approximately half of the ECOG Performance Status data were missing. Conclusions To the best of our knowledge, we present the first in-depth application of QBA in the context of MAIC. Despite the real-world data limitations, with this MAIC, we show that it is possible to confirm the robustness of the results by using appropriate statistical methods. Trial registration NA.

Background: In the nucleos(t)ide analog (NA)-control arm of the REEF-2 study (NCT04129554), virologic relapse (confirmed increase in HBV DNA >2000 IU/mL) and biochemical flare (ALT increases ≥3× upper limit of normal) were frequently observed after stopping NA treatment. We characterized the posttreatment virologic relapses and biochemical flares and assessed their association with end-of-treatment (EOT) HBV serum markers. Methods: In REEF-2, a randomized-controlled study, virologically suppressed HBeAg-negative patients stopped treatment at week 48, followed by 48 weeks of follow-up. EOT HBV RNA, hepatitis B core-related antigen, and quantitative anti-hepatitis B core (HBc) IgG levels were assessed in 41/45 NA-control arm patients; their association with off-treatment response was evaluated. Results: A similar proportion of patients with EOT HBV RNA or hepatitis B core-related antigen detectable and target not detectable had virologic relapse or ALT flares (p>0.05). A higher frequency of severe virologic relapse (peak HBV DNA >100,000 IU/mL) and/or severe biochemical flares (peak ALT ≥10× upper limit of normal) was observed in patients with EOT detectable hepatitis B core-related antigen levels, HBsAg <1000 IU/mL, and/or anti-HBc IgG titers <300 IU/mL, respectively (p<0.05). None of the 11 patients with EOT anti-HBc titers ≥300 IU/mL had severe virologic or biochemical flare off treatment (100% positive predictive value and 48% negative predictive value). Conclusions: In this prospective study of patients who stopped NA, anti-HBc levels ≥300 IU/mL were associated with a low risk of developing virologic relapse and severe biochemical flares. Future research should confirm a potential protective effect of high anti-HBc IgG levels.

Aim: Describe real-world epidemiology, treatment patterns, health care resource utilization, and costs of locally advanced or metastatic urothelial carcinoma (la/mUC) in France. Patients & methods: Retrospective study including all adults with la/mUC diagnosis during January 2017 to December 2020 in the PMSI database. Results: Annual prevalence and incidence ranged from 36.4 to 38.9 and 16.4 to 18.5 cases per 100,000 people, respectively. Of the 25,314 patients with incident la/mUC, 37.6% did not receive first-line systemic treatment. Of the 14,656 patients who started first-line systemic treatment, 66.6%, 22.5%, and 10.9% received 1, 2, and 3 lines of therapy, respectively. Annual per-patient costs in second-/third-line setting ranged from €8803 to €16,012. Conclusion: The substantial disease burden of la/mUC in France highlights the unmet need for new therapies.

Importance Semaglutide, a glucagonlike peptide-1 receptor agonist (GLP-1RA), has recently been implicated in cases of nonarteritic anterior ischemic optic neuropathy (NAION), raising safety concerns in the treatment of type 2 diabetes (T2D). Objective To investigate the potential association between semaglutide and NAION in the Observational Health Data Sciences and Informatics (OHDSI) network. Design, Setting, and Participants This was a retrospective study across 14 databases (6 administrative claims and 8 electronic health records). Included were adults with T2D taking semaglutide, other GLP-1RA (dulaglutide, exenatide), or non–GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from December 1, 2017, to December 31, 2023. The incidence proportion and rate of NAION were calculated. Association between semaglutide and NAION was assessed using 2 approaches: an active-comparator cohort design comparing new users of semaglutide with those taking other GLP-1RAs and non–GLP-1RA drugs, and a self-controlled case-series (SCCS) analysis to compare individuals’ risks during exposure and nonexposure periods for each drug. The cohort design used propensity score–adjusted Cox proportional hazards models to estimate hazard ratios (HRs). The SCCS used conditional Poisson regression models to estimate incidence rate ratios (IRRs). Network-wide HR and IRR estimates were generated using a random-effects meta-analysis model. Exposures GLP-1RA and non–GLP-1RAs. Main Outcomes and Measures NAION under 2 alternative definitions based on diagnosis codes: one more inclusive and sensitive, the other more restrictive and specific. Results The study included 37.1 million individuals with T2D, including 810 390 new semaglutide users. Of the 43 620 new users of semaglutide in the Optum’s deidentified Clinformatics Data Mart Database, 24 473 (56%) were aged 50 to 69 years, and 26 699 (61%) were female. The incidence rate of NAION was 14.5 per 100 000 person-years among semaglutide users. The HR for NAION among new users of semaglutide was not different compared with that of the non–GLP-1RAs using the sensitive NAION definition—empagliflozin (HR, 1.44; 95% CI, 0.78-2.68; P = .12), sitagliptin (HR, 1.30; 95% CI, 0.56-3.01; P = .27), and glipizide (HR, 1.23; 95% CI, 0.66-2.28; P = .25). The risk was higher only compared with patients taking empagliflozin (HR, 2.27; 95% CI, 1.16-4.46; P = .02) using the specific definition. SCCS analysis of semaglutide exposure showed an increased risk of NAION (meta-analysis IRR, 1.32; 95% CI, 1.14-1.54; P < .001). Conclusions and Relevance Results of this study suggest a modest increase in the risk of NAION among individuals with T2D associated with semaglutide use, smaller than that previously reported, and warranting further investigation into the clinical implications of this association.

Introduction This study describes treatment and retreatment patterns and outcomes in patients in France following nivolumab as a second-line or later (2L+) treatment in locally advanced or metastatic non-small cell lung cancer (LAM NSCLC). Materials and methods This analysis included adults with tumor, node, metastasis stage IIIB–IV NSCLC (as defined in the 7th or 8th edition American Joint Committee on Cancer/Union for International Cancer Control) treated with nivolumab monotherapy in 2L+ using data from the retrospective Epidemiological-Strategy and Medical Economics Lung Cancer database. The inclusion period was from January 1, 2015, to September 30, 2020, with a follow-up until September 30, 2021. Analyses were stratified according to the duration of index nivolumab treatment and tumor programmed death ligand 1 expression levels. Results In total, the study included 4,001 patients (68% male; mean age [standard deviation] at index date, 63.6 [9.7] years) with a median follow-up of 34.3 months. The median nivolumab duration was 2.5 months (interquartile range, 1.4–6.3). The median overall survival (OS) from nivolumab initiation was 10.2 months (95% confidence interval [CI], 9.6–10.8). The median real-world progression-free survival and time to treatment discontinuation or death (95% CI) were 2.2 (2.1–2.3) and 2.7 (2.5–2.8) months, respectively. In total, 2,985 (74.6%) patients discontinued index nivolumab treatment: 226 (7.6% of discontinuers) received a further immune checkpoint inhibitor (ICI; 12.3% of discontinuers receiving further systemic treatment), and 1,604 (53.7%) received chemotherapy and/or targeted therapy. The proportion of ICI-retreated patients was the highest among those with the longest index treatment duration (15.8% among discontinuers receiving ≥26 weeks’ index nivolumab). The median OS from retreatment was longer in the resumption (ICI restart without another therapy for ≥6 weeks) compared with the rechallenge (ICI restart following non-ICI therapy) patient subgroup. Conclusion Few patients with LAM NSCLC in France received ICI retreatment following index nivolumab discontinuation, but the proportion increased with a longer duration of index nivolumab.

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is often associated with persistent symptoms and impaired quality of life despite treatment with intranasal corticosteroids. Biologics (dupilumab, mepolizumab, omalizumab) have been recently approved for CRSwNP. This study aims to characterize biologic use and real-world outcomes, including medication use and nasal polyps (NP) surgeries, following biologic treatment in US patients with CRSwNP. This retrospective cohort study analyzed linked data from IQVIA longitudinal prescription and medical claims databases (July 2018–June 2023). Patients evaluated included those with ≥ 2 diagnoses of CRSwNP and ≥ 12 months of baseline data (overall cohort, index = first observed CRSwNP diagnosis) as well as patients with CRSwNP who received ≥ 2 consecutive biologic doses and had ≥ 24 months of follow-up data (biologic cohort, index = first biologic). Of 74,480 patients with CRSwNP, 8716 (12.0%) received a biologic and 2208 met all inclusion criteria. Dupilumab was the most frequently received biologic (89.8%; mepolizumab, 5.3%; omalizumab, 4.8%). Relative to the overall cohort, the biologic cohort was younger (mean age: 52.6 vs. 57.6 years), had more women (54.0% vs. 46.1%) and had a higher baseline prevalence of asthma (72.4% vs. 30.9%), allergic rhinitis (70.6% vs. 37.4%), NP surgery (15.8% vs. 5.8%), oral corticosteroid (OCS) use (84.0% vs. 51.8%), and antibiotic use (84.2% vs. 68.7%). During the 24 months after biologic initiation, 65.6% of patients had ≥ 1 OCS use (≥ 2 OCS uses during months 1–12, 27.0%; during months 13–24, 27.0%) and 77.9% had ≥ 1 antibiotic use; and 7.1% of patients without NP surgery before biologic initiation had ≥ 1 NP surgery during follow-up. Almost half of patients (49.3%) discontinued (≥ 90 days without receipt) their initial biologic during follow-up. Biologic use was relatively low among US patients with CRSwNP. OCS and antibiotic usage among patients with CRSwNP remained substantial despite use of currently approved biologics, indicating an unmet need for improved treatment options.