A flexible, computationally efficient method for fitting the proportional hazards model to interval-censored data: A Novel Method for Fitting the Proportional Hazards Model to Interval-Censored Data

The proportional hazards model (PH) is currently the most popular regression model for analyzing time-to-event data. Despite its popularity, the analysis of interval-censored data under the PH model can be challenging using many available techniques. This paper presents a new method for analyzing interval-censored data under the PH model. The proposed approach uses a monotone spline representation to approximate the unknown nondecreasing cumulative baseline hazard function. Formulating the PH model in this fashion results in a finite number of parameters to estimate while maintaining substantial modeling flexibility. A novel expectation-maximization (EM) algorithm is developed for finding the maximum likelihood estimates of the parameters. The derivation of the EM algorithm relies on a two-stage data augmentation involving latent Poisson random variables. The resulting algorithm is easy to implement, robust to initialization, enjoys quick convergence, and provides closed-form variance estimates. The performance of the proposed regression methodology is evaluated through a simulation study, and is further illustrated using data from a large population-based randomized trial designed and sponsored by the United States National Cancer Institute

Cost-per-responder analysis of patients with lenalidomide-refractory multiple myeloma receiving ciltacabtagene autoleucel in CARTITUDE-4

IntroductionCiltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated improved efficacy vs. standard of care (SOC; daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with a ≥ complete response (≥CR) rate of 73.1% vs. 21.8%.MethodsA cost-per-responder model was developed to assess the value of cilta-cel and SOC (87% DPd and 13% PVd) based on the CARTITUDE-4 trial data from a US mixed payer perspective (76.7% commercial, 23.3% Medicare). The model was developed using progression-free survival (PFS), overall survival (OS), and ≥CR endpoints from CARTITUDE-4 over a period of 25.4 months. Inpatient stays, outpatient visits, drug acquisition, administration, and monitoring costs were included. The base-case model assumed an inpatient setting for each cilta-cel infusion; another scenario included 30% outpatient and 70% inpatient infusions. Costs of managing grade 3-4 adverse events (AEs) and grade 1-4 cytokine release syndrome and neurotoxicity were included. Subsequent therapy costs were incurred after disease progression; terminal care costs were considered upon death events. Outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS between cilta-cel and SOC. Costs were adjusted to 2024 US dollars.ResultsTotal cost per treated patient, total cost per complete responder, and total cost per month in PFS were estimated at $704,641,$963,941, and $30,978 for cilta-cel, respectively, and$840,730, $3,856,559, and$42,520 for SOC over the 25.4-month period. Cost drivers included treatment acquisition costs before progression and subsequent treatment costs ($451,318 and$111,637 for cilta-cel; $529,795 and$265,167 for SOC). A scenario analysis in which 30% of patients received an outpatient infusion (assuming the same payer mix) showed a lower cost per complete responder for cilta-cel ($956,523) than those with an infusion in the inpatient setting exclusively.DiscussionThis analysis estimated that cost per treated patient, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower than for DPd or PVd, highlighting the substantial clinical and economic benefit of cilta-cel for patients with RRMM

Clinician and administrator perspectives on outpatient administration of ciltacabtagene autoleucel in relapsed or refractory multiple myeloma

IntroductionChimeric antigen receptor (CAR) T-cell therapy (CAR T therapy) is a treatment option for patients with relapsed or refractory multiple myeloma that has led to unprecedented treatment outcomes. Among CAR T therapies available, ciltacabtagene autoleucel (cilta-cel) is a good candidate for outpatient administration due to its generally predictable safety profile. There are multiple advantages of outpatient administration of cilta-cel, including reduced healthcare burden, expanded access, and patient autonomy. This mixed methods qualitative study aimed to identify key factors for outpatient administration of CAR T and best practice recommendations by combining a targeted literature review with expert interviews and panels.MethodsThe targeted review (Phase 1) aimed to identify factors for outpatient CAR T administration in the US and determine key topics for the exploratory interviews (Phase 2) and expert panels (Phase 3), which aimed to inform on best practices and challenges of outpatient CAR T administration (focusing on cilta-cel). Participants in clinical and administrative positions based in treatment centers that had experience with real-world outpatient administration of cilta-cel were recruited.ResultsSeventeen studies were identified in Phase 1. Key factors for outpatient administration included the development of protocols for CAR T complications, education for caregivers, outpatient specialists, hospital staff, and emergency services staff for identification and referral after possible adverse events, the creation of multidisciplinary teams for effective communication and management, straightforward patient intake processes encompassing financial eligibility review and provision of patient education materials, and close patient monitoring throughout the treatment journey. In Phase 2, 5 participants from 2 centers were interviewed. In Phase 3, 14 participants across 6 treatment centers were interviewed. Two 90-minute virtual panel discussions took place. All participants agreed that cilta-cel can be safely and effectively administered in an outpatient setting. Key recommendations included the creation of educational resources for patients and caregivers, the development of standard operating procedures, dedicated outpatient infrastructure and establishment of interdisciplinary teams, outpatient monitoring for toxicity management, and monitoring of the reimbursement landscape.DiscussionThis study offers a comprehensive understanding of the feasibility of outpatient cilta-cel administration in participating CAR T centers and provides actionable recommendations while acknowledging existing challenges

Burden of Insomnia and Sleep Disturbances and the Impact of Sleep Treatments in Patients with Probable or Possible Alzheimer's Disease: A Structured Literature Review.

BackgroundSleep disturbances are frequent in Alzheimer's disease (AD).ObjectiveTo summarize the impact of sleep disturbances on AD patients and their caregivers and the effects of currently available sleep therapies.MethodsPublished studies (January 1985-March 2020) assessing the burden associated with insomnia/sleep disturbances in the AD population and insomnia treatment effects were identified by searching PubMed, Embase, and Cochrane Library and screened against inclusion criteria.Results58 studies assessing patient and caregiver burden, institutionalization, and insomnia treatments in AD patients with sleep disturbances were identified. Sleep disturbances were associated with worse cognition, functional ability, and behavioral and neuropsychological functioning. Health status and quality of life of both patients and caregivers were reduced in the presence of sleep disturbances. Sleep disturbances were also associated with institutionalization. Although significant associations between sleep problems and clinical outcomes were apparent, there was generally no control for other influencing factors (e.g., cognitive status). Bright light and behavioral therapies as well as drugs showed some promise in AD patients, but studies were primarily small and limited data were available, particularly in regard to the effect on associated clinical burden.ConclusionSleep disturbances are a significant problem for AD patients and caregivers, associated with behavioral and psychological problems and cognitive decline. However, they remain poorly characterized and under-researched. As the global population is aging and AD is on thes rise, data from larger, prospective trials are required to fully understand the clinical correlates of sleep disturbances and the impact insomnia treatments can have

Factors Associated with Prescriptions for an Orexin Receptor Antagonist Among Japanese Patients with Insomnia: Analysis of a Nationwide Japanese Claims Database

Abstract Background Few studies have examined the prescribing patterns of orexin receptor antagonists (ORAs) in the real-world clinical setting in Japan. Objective We sought to analyze the factors associated with ORA prescriptions for patients with insomnia in Japan. Methods Outpatients (aged ≥ 20 to < 75 years old) prescribed one or more hypnotic for insomnia between April 1, 2018 and March 31, 2020 with continuous enrollment for ≥ 12 months were extracted from the JMDC Claims Database. We performed multivariable logistic regression to identify factors (patient demographics and psychiatric comorbidities) associated with ORA prescription in new or non-new users of hypnotics (patients without or with hypnotics prescription history, respectively). Results Of 58,907 new users, 11,589 (19.7%) were prescribed ORA at the index date. Male sex (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.12–1.22) and presence of bipolar disorders (OR 1.36, 95% CI 1.20–1.55) were associated with greater odds of ORA prescription. Among 88,611 non-new users, 15,504 (17.5%) were prescribed ORA at the index date. Younger age and several psychiatric comorbidities, such as neurocognitive disorders (OR 1.64, 95% CI 1.15–2.35), substance use disorders (OR 1.19, 95% CI 1.05–1.35), bipolar disorders (OR 1.14, 95% CI 1.07–1.22), schizophrenia spectrum disorders (OR 1.07, 95% CI 1.01–1.14), and anxiety disorders (OR 1.05, 95% CI 1.00–1.10), were associated with greater odds of ORA prescription. Conclusion This is the first study to determine the factors associated with ORA prescriptions in Japan. Our findings could help guide appropriate insomnia treatment using ORAs

Determining Patterns of Opioid Misuse and Misprescribing in South Carolina

OBJECTIVES Although opioids play a central role in the treatment, and palliation of many medical conditions, there is a large and growing problem of abuse nationally and in South Carolina particularly. According to the 2009 National Survey on Drug Use and Health, more than 5 million Americans abused prescription opioid painkillers in January 2011. Reports show an increase in cases of doctor shopping, prescription forgery, illicit prescribing and dispensing, and other diversion activities. We determine patterns of opioid prescribing in South Carolina through an epidemiologic analysis and geo-spatial mapping of South Carolina prescription data for 2010-2011. METHODS Using de-identified data from the South Carolina Reporting and Identification Prescription Tracking System (SCRIPTS), we conducted a state-wide epidemiological analysis of patient and prescriber opioid prescribing patterns including distributions of number of prescriptions, number of prescribers and of pharmacies used by each patient. Additionally, we conducted County- and Zip Code-level analyses of opioid prescribing patterns. RESULTS Prescriber deciles were created representing 10% groupings of prescribers based on controlled substances (CS) II – IV prescription volume. The top 10% of SC prescribers wrote more than 60% (N=2,158,574) of the total CS II – IV prescriptions in 2010, and 58% of total opioid prescriptions. The top pharmacy decile dispensed about 44% of total prescriptions and about 37% of opioid prescriptions. Five Zip Codes had the highest percent of opioid prescriptions out of total prescriptions (Charleston, Richland, Greenville, Barnwell and Aiken). In 2010 counties with the highest percent of prescriptions (\u3e61%) were Greenville, Richland, Barnwell and Charleston, whereas in 2011 the counties with the highest percent of prescriptions were Greenville, Chester, Richland and Charleston. CONCLUSIONS Our findings indicate a relatively small percentage of providers, concentrated in a few counties, account for most opioid prescriptions. This group represents a potential target for physician education and engagement in handling pain management and appropriate use of opioids

Changes in Healthcare Resource Use and Costs in Commercially Insured Insomnia Patients Initiating Suvorexant.

IntroductionInsomnia diagnosis has been associated with a significant clinical and economic burden on patients and healthcare systems. This study examined changes in healthcare resource use (HCRU) and costs in insomnia patients before and after initiation of suvorexant treatment.MethodsThis retrospective cohort study analyzed Optum Clinformatics Data Mart claims data (Jan 2010-Dec 2018). Patients with&nbsp;≥&nbsp;2 insomnia diagnosis claims and&nbsp;≥&nbsp;1 prescription for suvorexant were included. Prevalent and incident insomnia patients were analyzed separately. The change in the trends of HCRU and costs were examined for 12&nbsp;months before and 12&nbsp;months after suvorexant initiation. An interrupted time series (ITS) analysis was conducted to assess the level and slope changes. Subgroups of patients with mental health comorbidities were examined.ResultsThe study included 18,919 and 5939 patients in the prevalent and incident insomnia cohorts, respectively. For the prevalent cohort, mean (SD) age was 64.5 (14.1) years, 65% were female, 74% had Medicare Advantage coverage, and 61% had a Charlson comorbidity index score&nbsp;≥&nbsp;1. Characteristics for the incident cohort were similar. The ITS results suggested that the trend for monthly total healthcare cost (THC) was increasing before suvorexant initiation (US$52.51 in the prevalent cohort,$74.93 in incident insomnia cohort), but, after suvorexant initiation, the monthly total cost showed a decreasing trend in both cohorts. The decrease in slope for THC after suvorexant initiation were $72.66 and$112.07 per month in the prevalent and incident cohorts, respectively. The monthly trends in HCRU rates also decreased. The subgroup analysis showed that decreases were 1.5-3 times greater for patients with mental health comorbidities.ConclusionsIn this real-world study, suvorexant initiation was associated with immediate and continued decreases in HCRU and costs in insomnia patients. Further research is needed to understand the effect of suvorexant initiation on direct medical costs as well as costs associated with lost productivity in other real-world settings

Assessment of Real-Life Outcomes in Schizophrenia Patients according to Compliance

Objective. To describe and compare demographics, outcomes and comorbidities in schizophrenia patients by treatment compliance. Methods. This was a cross-sectional survey of hospital- or office-based psychiatrists who saw ≥6 schizophrenia patients per week and were responsible for treatment decisions. Recruited physicians completed a patient record form (PRF) for their first 10 consulted schizophrenia patients aged ≥18. These patients voluntarily completed a patient self-completion form (PSC). Compliance was measured by subjective physician assessment. Drivers of and outcomes associated with compliance were identified by regression analyses. Results. A total of 150 physicians completed PRFs for 1489 patients (706 sometimes compliant (SC), 636 always compliant (AC)). A total of 680 patients completed a PSC (327 SC, 295 AC). AC patients were less likely to be male (52.2% vs. 58.6%; P=0.021) and unemployed (odds ratio (OR) 0.91, 95% confidence interval (CI) 0.82–1.00; P<0.001) or to have had a treatment regimen change (OR 0.56, 95% CI 0.40–0.80; P=0.001) than SC patients. AC patients were less likely to have had more comorbidities (OR 0.91, 95% CI 0.82–1.00; P=0.045) and hospitalizations in the past 12 months (OR 0.59, 95% CI 0.43–0.80; P=0.001) than SC patients. Overall, AC patients had better clinical and humanistic outcomes. Weight gain was a common side effect for all patients; SC patients with weight gain had poorer outcomes than those without weight gain. Conclusion. Schizophrenia patients that were SC experienced poorer clinical outcomes and quality of life. Weight gain may exacerbate these poorer outcomes