Time to next treatment in patients with chronic lymphocytic leukemia initiating first-line ibrutinib or acalabrutinib.

Aim: To investigate real-world time to next treatment in patients with chronic lymphocytic leukemia initiating first-line (1L) ibrutinib or acalabrutinib. Materials & methods: US specialty pharmacy electronic medical records (21/11/2018-30/4/2022) were used; patients initiated 1L on/after 21/11/2019 (acalabrutinib approval). Results: Among 710 patients receiving ibrutinib, 5.9% initiated next treatment (mean time to initiation = 9.2 months); among 373 patients receiving acalabrutinib, 7.5% initiated next treatment (mean time to initiation = 5.9 months). Adjusting for baseline characteristics, acalabrutinib-treated patients were 89% more likely to initiate next treatment (hazard ratio = 1.89; p = 0.016). Conclusion: This study addresses a need for real-world comparative effectiveness between 1L ibrutinib and acalabrutinib and shows that next treatment (a clinically meaningful measure for real-world progression) occurred less frequently with 1L ibrutinib.

Ibrutinib and acalabrutinib are oral medications taken once-daily and twice-daily, respectively. They are recommended as initial treatment for chronic lymphocytic leukemia (CLL). The goal of this study was to compare the efficacy of these treatments as initial treatment for CLL. To meet this goal, real-world US specialty pharmacy electronic medical records between 11/21/2018­4/30/2022 were used. Patients treated with ibrutinib or acalabrutinib as initial treatment for CLL were studied. Treatment had to be started on or after the date of acalabrutinib approval for CLL (11/21/2019). Time to next treatment was used to estimate real-world disease progression. It was defined as the time from the initiation of initial treatment with ibrutinib or acalabrutinib to the initiation of a next treatment. Study results showed that patients were observed for a median of up to 1.5 years. Over this period, next treatment was more likely for acalabrutinib (7.5%) compared with ibrutinib (5.9%). After adjusting for differences in patient characteristics, next treatment was 89% more likely with acalabrutinib than ibrutinib. This study addresses a need to compare the effectiveness of initial treatment with ibrutinib and acalabrutinib in the real-world. It helps better contextualize results from clinical trial data and shows that next treatment occurred less frequently with ibrutinib.

Hypnotic prescription trends and patterns for the treatment of insomnia in Japan: analysis of a nationwide Japanese claims database.

BACKGROUND: There is limited consensus regarding the optimal treatment of insomnia. The recent introduction of orexin receptor antagonists (ORA) has increased the available treatment options. However, the prescribing patterns of hypnotics in Japan have not been comprehensively assessed. We performed analyses of a claims database to investigate the real-world use of hypnotics for treating insomnia in Japan. METHODS: Data were retrieved for outpatients (aged ≥ 20 to < 75 years old) prescribed ≥ 1 hypnotic for a diagnosis of insomnia between April 1st, 2009 and March 31st, 2020, with ≥ 12 months of continuous enrolment in the JMDC Claims Database. Patients were classified as new or long-term users of hypnotics. Long-term use was defined as prescription of the same mechanism of action (MOA) for ≥ 180 days. We analyzed the trends (2010-2019) and patterns (2018-2019) in hypnotics prescriptions. RESULTS: We analyzed data for 130,177 new and 91,215 long-term users (2010-2019). Most new users were prescribed one MOA per year (97.1%-97.9%). In 2010, GABAA-receptor agonists (benzodiazepines [BZD] or z-drugs) were prescribed to 94.0% of new users. Prescriptions for BZD declined from 54.8% of patients in 2010 to 30.5% in 2019, whereas z-drug prescriptions remained stable (~ 40%). Prescriptions for melatonin receptor agonist increased slightly (3.2% to 6.3%). Prescriptions for ORA increased over this time from 0% to 20.2%. Prescriptions for BZD alone among long-term users decreased steadily from 68.3% in 2010 to 49.7% in 2019. Prescriptions for ORA were lower among long-term users (0% in 2010, 4.3% in 2019) relative to new users. Using data from 2018-2019, multiple (≥ 2) MOAs were prescribed to a higher proportion of long-term (18.2%) than new (2.8%) users. The distribution of MOAs according to psychiatric comorbidities, segmented by age or sex, revealed higher proportions of BZD prescriptions in elderly (new and long-term users) and male (new users) patients in all comorbidity segments. CONCLUSION: Prescriptions for hypnotics among new and long-term users in Japan showed distinct patterns and trends. Further understanding of the treatment options for insomnia with accumulating evidence for the risk-benefit balance might be beneficial for physicians prescribing hypnotics in real-world settings.

Dose-Dependent Hyperkalemia Among Hospitalized, HIV-Infected Patients Receiving Sulfamethoxazole/Trimethoprim.

Background: Sulfamethoxazole-trimethoprim (SXT) therapy is commonly used in HIV-infected patients and is associated with hyperkalemia and elevated serum creatinine (SCr). Objective: The purpose of this study was to examine the frequency of hyperkalemia and elevated SCr in hospitalized, HIV-infected patients receiving SXT. Methods: This was a retrospective, single-center cohort study. HIV-infected hospitalized patients receiving a minimum of 3 consecutive days of SXT were included. Patients were grouped according to high dose (≥10 mg/kg/d) and low dose (<10 mg/kg/d) trimethoprim. The primary end point was the frequency of hyperkalemia, severe hyperkalemia, and elevated SCr. Secondary end points included an evaluation of concomitant potassium-altering medications and concomitant nephrotoxic drugs. Results: A total of 100 consecutive patients were selected from all possible patients who met inclusion criteria. Overall, 47 patients experienced at least 1 adverse drug event (ADE) of either hyperkalemia or increased SCr, with 20 patients experiencing these ADEs in the low-dose group and 27 patients experiencing these ADEs in the high-dose group (P = 0.229). The ADEs of hyperkalemia or increased SCr occurred after a shorter period (5.5 vs 8.7 days) in the high-dose group (P = 0.049). Overall frequency of elevated SCr was 24% and of elevated serum K was 36%. Hyperkalemia requiring a therapeutic intervention occurred in 12 patients in the high-dose group compared with 2 in the low-dose group (P = 0.009). Conclusion and Relevance: Rates of elevated SCr and hyperkalemia in hospitalized HIV-infected patients receiving SXT are significant. Hyperkalemia requiring intervention is more common in patients receiving high-dose SXT.

Generic oncology drugs: are they all safe?

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.

A flexible, computationally efficient 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 article 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.

Regulatory and clinical considerations for biosimilar oncology drugs.

Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents-molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs-provide opportunities both to improve health-care access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns.

Real-World Treatment Patterns and Outcomes by Line of Therapy and Race in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Treated in the United States: Results From the Final Analysis of the Prospective, Observational, informCLL Registry.

BACKGROUND: informCLL is the largest US-based prospective, observational registry of patients with chronic lymphocytic leukemia (CLL) initiating FDA-approved treatment in the era of targeted therapy. PATIENTS AND METHODS: Patients were enrolled between October 2015 and June 2019. Data were collected for baseline characteristics, treatment patterns, outcomes, and safety. RESULTS: In total, 1459 eligible patients were enrolled (first line, n = 854; relapsed/refractory, n = 605). The most common index treatments were ibrutinib (first line, 45%; relapsed/refractory, 49%) and chemoimmunotherapy (first line, 43%; relapsed/refractory, 20%). With median follow-up of 31.8 and 30.9 months in first-line and relapsed/refractory cohorts, respectively, median time to next treatment (TTNT) in patients who received any index treatment was not reached (NR) and 48.6 months; estimated proportions without next-line therapy at 48 months were 64% and 50%. Median overall survival (OS) was NR for both cohorts; estimated 48-month OS rates were 81% and 64% in first-line and relapsed/refractory cohorts, respectively. In match-adjusted analyses, TTNT was improved with first-line ibrutinib versus chemoimmunotherapy (median NR vs. 56.5 months; hazard ratio, 0.74; 95% CI, 0.56-0.98). Exposure-adjusted rates of AEs leading to discontinuation and serious AEs were lower with ibrutinib versus chemoimmunotherapy. Estimated 36-month OS rates were similar in Black versus White patients who received any index treatment (first line, 87% vs. 83%; relapsed/refractory, 74% vs. 74%) or ibrutinib (first line, 97% vs. 85%; relapsed/refractory, 81% vs. 77%). CONCLUSION: In this prospective, large, real-world CLL registry, first-line ibrutinib was associated with longer TTNT than chemoimmunotherapy, with sustained benefit up to 4 years of follow-up.

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

Introduction: Chimeric 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. Methods: The 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. Results: Seventeen 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. Discussion: This 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.

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

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.

Real-World Comparison of First-Line Treatment Adherence Between Single-Agent Ibrutinib and Acalabrutinib in Patients with Chronic Lymphocytic Leukemia.

Purpose: Increased dosing frequency adversely affects treatment adherence and outcomes in chronic diseases; however, such data related to treatment adherence is lacking in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This study compared adherence between patients treated with ibrutinib (once-daily) versus acalabrutinib (twice-daily) as first-line (1L) therapy for CLL/SLL. Patients and Methods: Specialty pharmacy electronic medical records were used to identify adults with CLL/SLL initiating 1L ibrutinib or acalabrutinib between 01/01/2018 and 11/30/2020. Adherence was measured by the proportion of days covered (PDC) and medication possession ratio (MPR) and was compared between cohorts using odds ratios (ORs) obtained from logistic regression models adjusted for baseline characteristics. Results: Between 01/01/2018 and 11/30/2020, 1374 and 140 patients initiated ibrutinib and acalabrutinib, respectively. Based on PDC/MPR ≥80%, patients treated with once-daily ibrutinib were more likely to be adherent than those treated with twice-daily acalabrutinib (OR ranges: PDC: 1.04-1.76; MPR: 1.03-1.58). At 6 months, patients on ibrutinib had a 58-76% higher likelihood of staying adherent compared to patients on acalabrutinib (PDC: 75.9% for ibrutinib vs 63.6% for acalabrutinib, OR: 1.76, P=0.008; MPR: 76.8% vs 66.9%, OR: 1.58, P=0.036) with a similar trend noted for the entire line of treatment (LOT) (PDC: 53.0% vs 41.4%, OR: 1.53, P=0.021; MPR: 58.7% vs 47.1%, OR: 1.50, P=0.027). Conclusion: In this real-world analysis, CLL/SLL patients initiating 1L once-daily ibrutinib had >50% higher treatment adherence than those initiating twice-daily acalabrutinib during their LOT. Given the importance of sustained adherence for disease control in CLL/SLL, dosing frequency may be an important consideration for patients and physicians.

Real-world time to discontinuation of first-line venetoclax + obinutuzumab in chronic lymphocytic leukemia/small lymphocytic lymphoma.

OBJECTIVE: To evaluate the time to discontinuation (TTD) and baseline characteristics among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) treated with first-line (1L) venetoclax + obinutuzumab (VO) in the United States. METHODS: A nationwide electronic health record-derived database was used to select adults with CLL/SLL initiating a 1L venetoclax-based regimen between April 11, 2016-July 31, 2020. Study measures included TTD (defined as >120-day treatment gap or switching therapy) and baseline characteristics by discontinuation status. RESULTS: A total of 113 patients receiving 1L VO on/before July 31, 2020 were eligible for analysis (mean age: 65.9 years; 31.9% women). During the first 60 days post-treatment initiation, 3.5% had tumor lysis syndrome (TLS). The proportion of patients using corticosteroids, anti-hyperuricemics, and anti-emetics was higher during the first 60 days post-treatment initiation (100.0%, 78.8%, and 52.2%, respectively) than the period from day 61 onward (67.0%, 45.5%, and 33.9%, respectively). Mean (median) duration of active treatment was 11.6 (12.1) months; 16.8% discontinued treatment before completing 12 cycles, 68.1% completed ≥12 cycles (among which 29.9% completed ≥15 cycles), and 15.0% who did not discontinue treatment were censored before completing 12 cycles. Kaplan-Meier analysis showed that median TTD was 13.8 months. Relative to those completing ≥12 cycles, patients discontinuing treatment before completing the prescribed 12 cycles were older (70.4 vs. 65.1 years) and had poorer renal function (36.8% vs. 13.0% with creatinine clearance <60 mL/min). CONCLUSION: A small proportion of CLL/SLL patients who were older and had poorer baseline renal function discontinued 1L VO prior to completing 12 treatment cycles. Additionally, treatment utilization, including medications related to TLS mitigation and management, was more intense during the initiation phase of VO. Further research with longer follow-up to assess long-term outcomes of VO treatment after early discontinuation is warranted.

A review of safety, efficacy, and utilization of erythropoietin, darbepoetin, and peginesatide for patients with cancer or chronic kidney disease: a report from the Southern Network on Adverse Reactions (SONAR).

The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin prevent transfusions among chemotherapy-associated anemia patients. Clinical trials, meta-analyses, and guidelines identify mortality, tumor progression, and venous thromboembolism (VTE) risks with ESA administration in this setting. Product labels advise against administering ESAs with potentially curative chemotherapy (United States) or to conduct risk-benefit assessments (Europe/Canada). Since 2007, fewer chemotherapy-associated anemia patients in the United States and Europe receive ESAs. ESAs and the erythropoietin receptor agonist peginesatide prevent transfusions among chronic kidney disease (CKD) patients; clinical trials, guidelines, and meta-analyses demonstrate myocardial infarction, stroke, VTE, or mortality risks with ESAs targeting high hemoglobin levels. U.S. labels recommend administering ESAs or peginesatide at doses sufficient to prevent transfusions among dialysis CKD patients. For dialysis CKD patients, Canadian and European labels recommend targeting hemoglobin levels of 10 to 12 g/dL and 11 to 12 g/dL, respectively, with ESAs. ESA utilization for dialysis CKD patients has decreased in the United States.

Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: a 20-year review from the Southern Network on Adverse Reactions (SONAR).

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

Linking drugs to obscure illnesses: lessons from pure red cell aplasia, nephrogenic systemic fibrosis, and Reye's syndrome. a report from the Southern Network on Adverse Reactions (SONAR).

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States' NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

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.

BACKGROUND: Sleep disturbances are frequent in Alzheimer's disease (AD). OBJECTIVE: To summarize the impact of sleep disturbances on AD patients and their caregivers and the effects of currently available sleep therapies. METHODS: Published 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. RESULTS: 58 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. CONCLUSION: Sleep 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.

Health-Care and Societal Costs Associated with Non-Persistence with Subcutaneous TNF-α Inhibitors in the Treatment of Inflammatory Arthritis (IA): A Retrospective Observational Study.

OBJECTIVE: A few studies have suggested that patients with inflammatory arthritis (IA) who remain persistent with subcutaneous TNF-α inhibitors (SC-TNFi) incur lower health care costs than patients who discontinue treatment, whereas data on the impact of non-persistence on indirect costs are largely lacking. Furthermore, existing estimates are based on fixed follow-ups, in relation to treatment initiation, and therefore do not measure costs in direct relation to treatment discontinuation. Therefore, by capturing costs in direct relation to treatment discontinuation, this study aimed to estimate direct and indirect costs associated with non-persistence with SC-TNFis in IA. METHODS: Adult Swedish biologic-naïve IA patients initiating biologic treatment with a SC-TNFi (adalimumab, etanercept, certolizumab or golimumab) between May 6, 2010, and December 31, 2017, were identified in population-based registers with almost complete coverage. IA was defined as a diagnosis of rheumatic arthritis, ankylosing spondylitis/unspecified spondyloarthritis or psoriatic arthritis. Non-persistent patients were matched on propensity score to patients persistent with treatment by at least an additional 12 months. This enabled comparisons of direct healthcare costs and indirect costs for sick leave and disability pension, respectively, 12 months before and 12 months after treatment discontinuation. RESULTS: A balanced cohort of 486 matched pairs was generated. The total direct and indirect costs were significantly higher among non-persistent patients already during the 12 months before index ($20,802 [18,335-23,429] vs. $16,600 [14,331-18,696]). However, while non-persistent patients increased their total direct and indirect costs, persistent patients significantly decreased the same, further widening the difference in costs during the 12-month period after index date ($22,161 [19,754-24,556] vs. $13,465 [11,415-15,729]). CONCLUSIONS: Among biologic-naïve Swedish IA patients treated with SC-TNFis, persistent patients incurred about 40% lower aggregated direct and indirect costs compared to non-persistent patients the year following SC-TNFi discontinuation. This highlights the impact of treatment persistence from an economic viewpoint, adding further aspects to the clinical perspective.

A Feasibility Study: Testing Whether a Sleep Application Providing Objective Sleep Data to Physicians Improves Patient-Physician Communication Regarding Sleep Experiences, Habits, and Behaviors.

INTRODUCTION: Sleep tracker data have not been utilized routinely in sleep-related disorders and their management. Sleep-related disorders are common in primary care practice and incorporating sleep tracker data may help in improving patient care. We conducted a pilot study to assess the feasibility of a sleep program using the Fitbit Charge 2™ device and SleepLife® application. The main aim of the study was to examine whether a program using a commercially available wearable sleep tracker device providing objective sleep data would improve communication in primary care settings between patients and their providers. Secondary aims included whether patient satisfaction with care would improve as result of the program. METHODS: A prospective, randomized, parallel group, observational pilot study was conducted in 20 primary care clinics in Indianapolis, IN from June 2018 to February 2019. Inclusion criteria included patients over the age of 18, have a diagnosis of insomnia identified by electronic medical record and/or a validated questionnaire, and were on a prescription sleep aid. The study was not specific to any sleep aid prescription, branded or generic, and was not designed to evaluate a drug or drug class. Each primary care clinic was randomized to either the SleepLife® intervention or the control arm. All patients were provided with a Fitbit Charge 2™ device. Only patients in the intervention arm were educated on how to use the SleepLife® application. Physicians in the intervention arm were set up with the SleepLife® portal on their computers. RESULTS: Forty-nine physicians and 75 patients were enrolled in the study. Patients had a mean age of 57 (SD 12.8) years and 61% were female. Mean age of physicians was 47 (SD 10.6) years. Patients showed high rates of involvement in the program with 83% completing all survey questions. Physician survey completion rate was 55%. Only one physician logged into the SleepLife portal to check their patients' sleep status. At the end of the 6-week intervention, patients' composite general satisfaction scores with sleep health management decreased significantly in the intervention arm when compared to controls (p = 0.03). Patients' satisfaction with communication also decreased significantly in the intervention group (p = 0.01). The sleep outcomes, which were calculated on the basis of study questionnaire answers, improved significantly in the intervention group as compared to the control group (p = 0.04). Physician communication satisfaction scores remained unchanged (p = 0.12). CONCLUSIONS: SleepLife® and its related physician portal can facilitate physician-patient communication, and it captures patient sleep outcomes including behaviors and habits. Patients were highly engaged with the program, while physicians did not demonstrate engagement. The study design and questionnaires do not specifically address the reasons behind the decreased patient satisfaction with care and communication, but it was perceived to be a result of physician non-responsiveness. Sleep quality scores on the other hand showed an improvement among SleepLife® users, suggesting that patients may have implemented good sleep practices on their own. Given that it was a feasibility study, and the sample size was small, we were not able to make major inferences regarding the difference between sleep disorder types. Additionally, we excluded patients with a history of alcohol use, substance abuse, or depression because of concerns that they may affect sleep independently. To promote the growth of technology in primary care, further research incorporating results from this study and physician engagement techniques should be included.

Market withdrawal of new molecular entities approved in the United States from 1980 to 2009.

PURPOSE: Economic factors, market dynamics, and safety issues are largely responsible for decisions to withdraw pharmaceutical products from the market. In this study, new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) were examined in the USA from 1980 to 2009. METHODS: Data were obtained from the FDA, Micromedex, Medline, and Lexis-Nexis. Descriptive analyses were used to classify product discontinuations by therapeutic category, time frame for discontinuation, and reason for withdrawal. RESULTS: There were 740 NMEs approved by the FDA during the study period. As of 1 December 2010, the number of drugs discontinued was 118 (15.9%). Discontinuations were the highest for antiparasitic products, insecticides, and repellents (6, 33.3% of approvals), systemic hormonal preparations excluding sex hormones and insulins (5, 33.3%), musculo-skeletal system (11, 32.4%), diagnostic agents (16, 28.1%), and anti-infectives for systemic use (27, 25.2%). Safety was the primary reason for withdrawing 26 drugs (3.5% of approvals). CONCLUSIONS: Approximately one in seven approved NMEs were discontinued from the market in the period of 1980-2009. Less than one-quarter (22%) of the total withdrawals were attributed to safety reasons. An ongoing evaluation of new drugs throughout their product life cycle is important to determine their efficacy, safety, and value to society.

Incremental Healthcare Utilization and Cost Burden of Comorbid Insomnia in Alzheimer's Disease Patients.

BACKGROUND: Insomnia is associated with worsened clinical outcomes among Alzheimer's disease dementia (AD) patients, increased caregiver burden, and healthcare utilization. OBJECTIVE: This study aimed to characterize the incremental healthcare burden of insomnia in AD using real-world data. METHODS: A retrospective observational study was conducted on AD patients selected from the IBM® MarketScan Commercial and Medicare Supplemental Databases. AD patients with claims-based evidence of insomnia were direct matched to a non-insomnia cohort based on demographic factors. Healthcare utilization and associated costs were assessed for a 12-month follow-up period. RESULTS: A total of 3,500 insomnia AD patients and 9,884 non-insomnia AD patients were analyzed. The insomnia cohort had a higher comorbidity burden at baseline (mean score on Charlson Comorbidity Index 2.5 versus 2.2, p < 0.001) and higher proportions of patients with baseline diagnoses for other conditions including depression: 40%, insomnia cohort versus 25%, non-insomnia (p < 0.001). AD patients with insomnia were more likely to have a claim for inpatient hospitalizations (39.8%versus 32.3%), emergency room services (56.4%versus 48.0%), and skilled-nursing services (42.6%versus 31.9%) (all p < 0.05). Mean total annual healthcare costs during the 12-month follow-up period were significantly higher among AD patients with insomnia as compared to those without. (Mean costs: $37,356 versus $27,990, p < 0.001). CONCLUSION: AD patients with comorbid insomnia are more likely to use higher-cost healthcare services such as inpatient hospitalization, and skilled nursing, and have higher total healthcare costs. This real-world analysis provides evidence that AD disease management should consider proper treatment of comorbid insomnia due to the incremental burden and cost implications.

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

INTRODUCTION: Insomnia 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. METHODS: This retrospective cohort study analyzed Optum Clinformatics Data Mart claims data (Jan 2010-Dec 2018). Patients with ≥ 2 insomnia diagnosis claims and ≥ 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 months before and 12 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. RESULTS: The 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 ≥ 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. CONCLUSIONS: In 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.