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Introduction: During the COVID‐19 pandemic, inpatient electronic health records (EHRs) have been used to conduct public health surveillance and assess treatments and outcomes. Invasive mechanical ventilation (MV) and supplemental oxygen (O2) use are markers of severe illness in hospitalized COVID‐19 patients. In a large US system (n = 142 hospitals), we assessed documentation of MV and O2 use during COVID‐19 hospitalization in administrative data versus nursing documentation. Methods: We identified 319 553 adult hospitalizations with a COVID‐19 diagnosis, February 2020–October 2022, and extracted coded, administrative data for MV or O2. Separately, we developed classification rules for MV or O2 supplementation from semi‐structured nursing documentation. We assessed MV and O2 supplementation in administrative data versus nursing documentation and calculated ordinal endpoints of decreasing COVID‐19 disease severity. Nursing documentation was considered the gold standard in sensitivity and positive predictive value (PPV) analyses. Results: In nursing documentation, the prevalence of MV and O2 supplementation among COVID‐19 hospitalizations was 14% and 75%, respectively. The sensitivity of administrative data was 83% for MV and 41% for O2, with both PPVs above 91%. Concordance between sources was 97% for MV (κ = 0.85), and 54% for O2 (κ = 0.21). For ordinal endpoints, administrative data accurately identified intensive care and MV but underestimated hospitalizations with O2 requirements (42% vs. 18%). Conclusions: In comparison to nursing documentation, administrative data under‐ascertained O2 supplementation but accurately estimated severe endpoints such as MV. Nursing documentation improved ascertainment of O2 among COVID‐19 hospitalizations and can capture oxygen requirements in adults hospitalized with COVID‐19 or other respiratory illnesses. [ABSTRACT FROM AUTHOR]

Purpose: Few studies have examined how the absolute risk of thromboembolism with COVID-19 has evolved over time across different countries. Researchers from the European Medicines Agency, Health Canada, and the United States (US) Food and Drug Administration established a collaboration to evaluate the absolute risk of arterial (ATE) and venous thromboembolism (VTE) in the 90 days after diagnosis of COVID-19 in the ambulatory (eg, outpatient, emergency department, nursing facility) setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability. Patients and Methods: We conducted cohort studies of patients initially diagnosed with COVID-19 in the ambulatory setting from the seven specified countries. Patients were followed for 90 days after COVID-19 diagnosis. The primary outcomes were ATE and VTE over 90 days from diagnosis date. We measured country-level estimates of 90-day absolute risk (with 95% confidence intervals) of ATE and VTE. Results: The seven cohorts included 1,061,565 patients initially diagnosed with COVID-19 in the ambulatory setting before COVID-19 vaccines were available (through November 2020). The 90-day absolute risk of ATE during this period ranged from 0.11% (0.09– 0.13%) in Canada to 1.01% (0.97– 1.05%) in the US, and the 90-day absolute risk of VTE ranged from 0.23% (0.21– 0.26%) in Canada to 0.84% (0.80– 0.89%) in England. The seven cohorts included 3,544,062 patients with COVID-19 during vaccine availability (beginning December 2020). The 90-day absolute risk of ATE during this period ranged from 0.06% (0.06– 0.07%) in England to 1.04% (1.01– 1.06%) in the US, and the 90-day absolute risk of VTE ranged from 0.25% (0.24– 0.26%) in England to 1.02% (0.99– 1.04%) in the US. Conclusion: There was heterogeneity by country in 90-day absolute risk of ATE and VTE after ambulatory COVID-19 diagnosis both before and during COVID-19 vaccine availability. Plain Language Summary: Cohort studies of patients diagnosed with COVID-19 in both the ambulatory and hospital settings have suggested that SARS-CoV-2 infection promotes hypercoagulability that could lead to arterial or venous thromboembolism. However, few studies have examined how the risk of thromboembolism with COVID-19 has evolved over time across different countries. A new collaboration was established among the regulatory authorities of Canada, Europe, and the US within the International Coalition of Medicines Regulatory Authorities to evaluate the 90-day risk of both arterial and venous thromboembolism after initial diagnosis of COVID-19 in the ambulatory or hospital setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability. The study found that there was variability in the risk of both arterial and venous thromboembolism by month across the countries among patients initially diagnosed with COVID-19 in the ambulatory or hospital setting. Differences in the healthcare systems, prevalence of comorbidities in the study cohorts, and approaches to the case definitions of thromboembolism likely contributed to the variability in estimates of thromboembolism risk across the countries. [ABSTRACT FROM AUTHOR]

Purpose: Immediate‐release forms of generic mixed amphetamine salts (MAS) have been the subject of passive surveillance reports signaling lack of effectiveness. We examined switching patterns that might suggest whether long‐term users of specific MAS are more likely to switch away or switch back after use of the MAS of interest in the FDA's Sentinel Distributed Database. Methods: We required at least 60‐day continuous supply of selected MAS grouped by Abbreviated New Drug Application (ANDA) to describe patterns of switching away from and to generics approved under the ANDAs of interest among individuals ages 15–64 years with attention deficit hyperactivity disorder or narcolepsy during 2013–2019. Results: We observed the greatest number of treatment episodes for ANDA 040422 (n = 525 771), followed by ANDA 202424 (n = 181 693), ANDA 040439 (n = 62 363), ANDA 040440 (n = 21 143), and ANDA 040480 (n = 8792). Of those with switches away from their original ANDA, episodes initiated on generic products under ANDA 040422 (48.6%) and ANDA 202424 (43.0%) were most likely to switch back, while those initiated on generic product under ANDA 040480 were least likely (24.1%). Of those episodes with switches to a generic under an ANDA of interest, about one‐third (range 27.1% to 37.0%) switched back to the same product. These switches back had a median time to switch of about 30 days. Conclusions: These descriptive analyses, although subject to limitations, did not suggest increased switching away or switching back after use of the generics of interest. Continued post‐marketing surveillance is warranted. [ABSTRACT FROM AUTHOR]

Congress mandated the creation of a postmarket Active Risk Identification and Analysis (ARIA) system containing data on 100 million individuals for monitoring risks associated with drug and biologic products using data from disparate sources to complement the US Food and Drug Administration's (FDA's) existing postmarket capabilities. We report on the first 6 years of ARIA utilization in the Sentinel System (2016–2021). The FDA has used the ARIA system to evaluate 133 safety concerns; 54 of these evaluations have closed with regulatory determinations, whereas the rest remain in progress. If the ARIA system and the FDA's Adverse Event Reporting System are deemed insufficient to address a safety concern, then the FDA may issue a postmarket requirement to a product's manufacturer. One hundred ninety‐seven ARIA insufficiency determinations have been made. The most common situation for which ARIA was found to be insufficient is the evaluation of adverse pregnancy and fetal outcomes following in utero drug exposure, followed by neoplasms and death. ARIA was most likely to be sufficient for thromboembolic events, which have high positive predictive value in claims data alone and do not require supplemental clinical data. The lessons learned from this experience illustrate the continued challenges using administrative claims data, especially to define novel clinical outcomes. This analysis can help to identify where more granular clinical data are needed to fill gaps to improve the use of real‐world data for drug safety analyses and provide insights into what is needed to efficiently generate high‐quality real‐world evidence for efficacy. [ABSTRACT FROM AUTHOR]

We described care received by hospitalized children with COVID-19 or multi-system inflammatory syndrome (MIS-C) prior to the 2021 COVID-19 Omicron variant surge in the US. We identified hospitalized children <18 years of age with a COVID-19 or MIS-C diagnosis (COVID-19 not required), separately, from February 2020-September 2021 (n = 126 hospitals). We described high-risk conditions, inpatient treatments, and complications among these groups. Among 383,083 pediatric hospitalizations, 2,186 had COVID-19 and 395 had MIS-C diagnosis. Less than 1% had both COVID-19 and MIS-C diagnosis (n = 154). Over half were >6 years old (54% COVID-19, 70% MIS-C). High-risk conditions included asthma (14% COVID-19, 11% MIS-C), and obesity (9% COVID-19, 10% MIS-C). Pulmonary complications in children with COVID-19 included viral pneumonia (24%) and acute respiratory failure (11%). In reference to children with COVID-19, those with MIS-C had more hematological disorders (62% vs 34%), sepsis (16% vs 6%), pericarditis (13% vs 2%), myocarditis (8% vs 1%). Few were ventilated or died, but some required oxygen support (38% COVID-19, 45% MIS-C) or intensive care (42% COVID-19, 69% MIS-C). Treatments included: methylprednisolone (34% COVID-19, 75% MIS-C), dexamethasone (25% COVID-19, 15% MIS-C), remdesivir (13% COVID-19, 5% MIS-C). Antibiotics (50% COVID-19, 68% MIS-C) and low-molecular weight heparin (17% COVID-19, 34% MIS-C) were frequently administered. Markers of illness severity among hospitalized children with COVID-19 prior to the 2021 Omicron surge are consistent with previous studies. We report important trends on treatments in hospitalized children with COVID-19 to improve the understanding of real-world treatment patterns in this population. [ABSTRACT FROM AUTHOR]

Key Points: Question: Is the 90-day incidence of arterial thromboembolism and venous thromboembolism higher in patients hospitalized with COVID-19 vs in patients hospitalized with influenza? Findings: In this retrospective cohort study that included 93 906 patients, hospitalization with COVID-19 before vaccine availability and during vaccine availability was significantly associated with higher 90-day risk of venous thromboembolism (adjusted hazard ratios, 1.60 and 1.89, respectively) vs hospitalization with influenza in 2018-2019, but there was no significant difference in the risk of arterial thromboembolism among those hospitalized with COVID-19 during either period (adjusted hazard ratios, 1.04 and 1.07) vs those hospitalized with influenza. Meaning: Hospitalization with COVID-19 both before and during vaccine availability was significantly associated with a higher risk of venous thromboembolism, but not arterial thromboembolism, vs hospitalization with influenza in 2018-2019. Importance: The incidence of arterial thromboembolism and venous thromboembolism in persons with COVID-19 remains unclear. Objective: To measure the 90-day risk of arterial thromboembolism and venous thromboembolism in patients hospitalized with COVID-19 before or during COVID-19 vaccine availability vs patients hospitalized with influenza. Design, Setting, and Participants: Retrospective cohort study of 41 443 patients hospitalized with COVID-19 before vaccine availability (April-November 2020), 44 194 patients hospitalized with COVID-19 during vaccine availability (December 2020-May 2021), and 8269 patients hospitalized with influenza (October 2018-April 2019) in the US Food and Drug Administration Sentinel System (data from 2 national health insurers and 4 regional integrated health systems). Exposures: COVID-19 or influenza (identified by hospital diagnosis or nucleic acid test). Main Outcomes and Measures: Hospital diagnosis of arterial thromboembolism (acute myocardial infarction or ischemic stroke) and venous thromboembolism (deep vein thrombosis or pulmonary embolism) within 90 days. Outcomes were ascertained through July 2019 for patients with influenza and through August 2021 for patients with COVID-19. Propensity scores with fine stratification were developed to account for differences between the influenza and COVID-19 cohorts. Weighted Cox regression was used to estimate the adjusted hazard ratios (HRs) for outcomes during each COVID-19 vaccine availability period vs the influenza period. Results: A total of 85 637 patients with COVID-19 (mean age, 72 [SD, 13.0] years; 50.5% were male) and 8269 with influenza (mean age, 72 [SD, 13.3] years; 45.0% were male) were included. The 90-day absolute risk of arterial thromboembolism was 14.4% (95% CI, 13.6%-15.2%) in patients with influenza vs 15.8% (95% CI, 15.5%-16.2%) in patients with COVID-19 before vaccine availability (risk difference, 1.4% [95% CI, 1.0%-2.3%]) and 16.3% (95% CI, 16.0%-16.6%) in patients with COVID-19 during vaccine availability (risk difference, 1.9% [95% CI, 1.1%-2.7%]). Compared with patients with influenza, the risk of arterial thromboembolism was not significantly higher among patients with COVID-19 before vaccine availability (adjusted HR, 1.04 [95% CI, 0.97-1.11]) or during vaccine availability (adjusted HR, 1.07 [95% CI, 1.00-1.14]). The 90-day absolute risk of venous thromboembolism was 5.3% (95% CI, 4.9%-5.8%) in patients with influenza vs 9.5% (95% CI, 9.2%-9.7%) in patients with COVID-19 before vaccine availability (risk difference, 4.1% [95% CI, 3.6%-4.7%]) and 10.9% (95% CI, 10.6%-11.1%) in patients with COVID-19 during vaccine availability (risk difference, 5.5% [95% CI, 5.0%-6.1%]). Compared with patients with influenza, the risk of venous thromboembolism was significantly higher among patients with COVID-19 before vaccine availability (adjusted HR, 1.60 [95% CI, 1.43-1.79]) and during vaccine availability (adjusted HR, 1.89 [95% CI, 1.68-2.12]). Conclusions and Relevance: Based on data from a US public health surveillance system, hospitalization with COVID-19 before and during vaccine availability, vs hospitalization with influenza in 2018-2019, was significantly associated with a higher risk of venous thromboembolism within 90 days, but there was no significant difference in the risk of arterial thromboembolism within 90 days. This cohort study uses data from the US Food and Drug Administration Sentinel System to measure the 90-day risk of arterial thromboembolism and venous thromboembolism among patients hospitalized with COVID-19 before and during COVID-19 vaccine availability vs patients hospitalized with influenza. [ABSTRACT FROM AUTHOR]

Observational studies of oseltamivir use and influenza complications could suffer from residual confounding. Using negative control risk periods and a negative control outcome, we examined confounding control in a health-insurance-claims–based study of oseltamivir and influenza complications (pneumonia, all-cause hospitalization, and dispensing of an antibiotic). Within the Food and Drug Administration's Sentinel System, we identified individuals aged ≥18 years who initiated oseltamivir use on the influenza diagnosis date versus those who did not, during 3 influenza seasons (2014–2017). We evaluated primary outcomes within the following 1–30 days (the primary risk period) and 61–90 days (the negative control period) and nonvertebral fractures (the negative control outcome) within days 1–30. We estimated propensity-score–matched risk ratios (RRs) per season. During the 2014–2015 influenza season, oseltamivir use was associated with a reduction in the risk of pneumonia (RR = 0.72, 95% confidence interval (CI): 0.70, 0.75) and all-cause hospitalization (RR = 0.54, 95% CI: 0.53, 0.55) in days 1–30. During days 61–90, estimates were near-null for pneumonia (RR = 1.04, 95% CI: 0.95, 1.15) and hospitalization (RR = 0.94, 95% CI: 0.91, 0.98) but slightly increased for antibiotic dispensing (RR = 1.14, 95% CI: 1.08, 1.21). The RR for fractures was near-null (RR = 1.09, 95% CI: 0.99, 1.20). Estimates for the 2016–2017 influenza season were comparable, while the 2015–2016 season had conflicting results. Our study suggests minimal residual confounding for specific outcomes, but results differed by season. [ABSTRACT FROM AUTHOR]

Purpose Health plan claims may provide complete longitudinal data for timely, real‐world population‐level COVID‐19 assessment. However, these data often lack laboratory results, the standard for COVID‐19 diagnosis. Methods: We assessed the validity of ICD‐10‐CM diagnosis codes for identifying patients hospitalized with COVID‐19 in U.S. claims databases, compared to linked laboratory results, among six Food and Drug Administration Sentinel System data partners (two large national insurers, four integrated delivery systems) from February 20–October 17, 2020. We identified patients hospitalized with COVID‐19 according to five ICD‐10‐CM diagnosis code‐based algorithms, which included combinations of codes U07.1, B97.29, general coronavirus codes, and diagnosis codes for severe symptoms. We calculated the positive predictive value (PPV) and sensitivity of each algorithm relative to laboratory test results. We stratified results by data source type and across three time periods: February 20–March 31 (Time A), April 1–30 (Time B), May 1–October 17 (Time C). Results: The five algorithms identified between 34 806 and 47 293 patients across the study periods; 23% with known laboratory results contributed to PPV calculations. PPVs were high and similar across algorithms. PPV of U07.1 alone was stable around 93% for integrated delivery systems, but declined over time from 93% to 70% among national insurers. Overall PPV of U07.1 across all data partners was 94.1% (95% CI, 92.3%–95.5%) in Time A and 81.2% (95% CI, 80.1%–82.2%) in Time C. Sensitivity was consistent across algorithms and over time, at 94.9% (95% CI, 94.2%–95.5%). Conclusion: Our results support the use of code U07.1 to identify hospitalized COVID‐19 patients in U.S. claims data. [ABSTRACT FROM AUTHOR]

Background: We assessed the ability to identify key data relevant to influenza and other respiratory virus surveillance in a large‐scale US‐based hospital electronic medical record (EMR) dataset using seasonal influenza as a use case. We describe characteristics and outcomes of hospitalized influenza cases across three seasons. Methods: We identified patients with an influenza diagnosis between March 2017 and March 2020 in 140 US hospitals as part of the US FDA's Sentinel System. We calculated descriptive statistics on the presence of high‐risk conditions, influenza antiviral administrations, and severity endpoints. Results: Among 5.1 million hospitalizations, we identified 29,520 hospitalizations with an influenza diagnosis; 64% were treated with an influenza antiviral within 2 days of admission, and 25% were treated >2 days after admission. Patients treated >2 days after admission had more comorbidities than patients treated within 2 days of admission. Patients never treated during hospitalization had more documentation of cardiovascular and other diseases than treated patients. We observed more severe endpoints in patients never treated (death = 3%, mechanical ventilation [MV] = 9%, intensive care unit [ICU] = 26%) or patients treated >2 days after admission (death = 2%, MV = 14%, ICU = 32%) than in patients treated earlier (treated on admission: death = 1%, MV = 5%, ICU = 23%, treated within 2 days of admission: death = 1%, MV = 7%, ICU = 27%). Conclusions: We identified important trends in influenza severity related to treatment timing in a large inpatient dataset, laying the groundwork for the use of this and other inpatient EMR data for influenza and other respiratory virus surveillance. [ABSTRACT FROM AUTHOR]

The total administration by product class includes the reference product, all biosimilars, and related biological products, if applicable (i.e., tbo-filgrastim) Graph: Figure 2. The month of first observed biosimilar administration, percent discount from reference product in wholesale acquisition cost, total administrations over 12 months, and product type are shown for each product. The Biologics Price Competition and Innovation Act of 2009 created an abbreviated US approval pathway for biosimilar and interchangeable biological products. [Extracted from the article]

Purpose Lymphoma is a health outcome of interest for drug safety studies. Studies using administrative claims data require the accurate identification of lymphoma cases. We developed and validated an International Classification of Diseases, Tenth Revision, Clinical Modification (ICD‐10‐CM)‐based algorithm to identify lymphoma in healthcare claims data. Methods: We developed a three‐component algorithm to identify patients aged ≥15 years who were newly diagnosed with Hodgkin (HL) or non‐Hodgkin (NHL) lymphoma from January 2016 through July 2018 among members of four Data Partners within the FDA's Sentinel System. The algorithm identified potential cases as patients with ≥2 ICD‐10‐CM lymphoma diagnosis codes on different dates within 183 days; ≥1 procedure code for a diagnostic procedure (e.g., biopsy, flow cytometry) and ≥1 procedure code for a relevant imaging study within 90 days of the first lymphoma diagnosis code. Cases identified by the algorithm were adjudicated via chart review and a positive predictive value (PPV) was calculated. Results: We identified 8723 potential lymphoma cases via the algorithm and randomly sampled 213 for validation. We retrieved 138 charts (65%) and adjudicated 134 (63%). The overall PPV was 77% (95% confidence interval: 69%–84%). Most cases also had subtype information available, with 88% of cases identified as NHL and 11% as HL. Conclusions: Seventy‐seven percent of lymphoma cases identified by an algorithm based on ICD‐10‐CM diagnosis and procedure codes and applied to claims data were true cases. This novel algorithm represents an efficient, cost‐effective way to target an important health outcome of interest for large‐scale drug safety and public health surveillance studies. [ABSTRACT FROM AUTHOR]

Purpose To describe utilization of filgrastim and infliximab, the first two products with biosimilars approved in the United States. Methods: We identified use of filgrastim (reference, tbo‐filgrastim, and filgrastim‐sndz) and infliximab (reference, infliximab‐dyyb, and infliximab‐abda) in the Sentinel Distributed Database using Healthcare Common Procedure Coding System (HCPCS) codes and National Drug Codes (NDCs) from January 2015 to August 2018. We calculated the proportion of use by code type and assessed uptake over time. We compared baseline patient characteristics and treatment indications. Among patients with >1 exposure episode, we characterized gaps between episodes. Results: Use was identified primarily via HCPCS codes (filgrastim: 86.4%‐97.7%; infliximab: 87.8%‐100%) although some was identified via NDCs (filgrastim: 2.2%‐13.5%; infliximab: <0.1%‐6.5%). Filgrastim reference product use declined from 89.4% in January 2015 to 30.3% in June 2018, with corresponding increases in filgrastim‐sndz (0% to 49.3%) and tbo‐filgrastim (10.6% to 20.4%). Infliximab biosimilar uptake was low (9.7% in June 2018). We identified 94 846 filgrastim reference product, 27 143 tbo‐filgrastim, and 38 264 filgrastim‐sndz users. For infliximab, we identified 125 412 reference product, 1034 infliximab‐dyyb, 49 infliximab‐abda, and 4855 undetermined biosimilar users. Patients receiving filgrastim products were largely similar, but differences in age, sex, and indication were observed across infliximab product users. The median exposure episode gap ranged from 1 to 3 days for filgrastim and 48 to 50 days for infliximab. Conclusion: Use of biosimilar filgrastim has increased in the United States, but infliximab biosimilar use remains low. Data on identification of biosimilars in claims data and observed gaps between exposure episodes can be used to support drug safety studies of biosimilars. [ABSTRACT FROM AUTHOR]

The anticoagulant response to warfarin, a narrow therapeutic index drug, increases with age, which may make older patients susceptible to adverse outcomes resulting from small differences in bioavailability between generic and brand products. Using US Medicare claims linked to electronic medical records from two large hospitals in Boston, we designed a cohort study of ≥ 65‐year‐old patients. Patients were followed for a composite effectiveness outcome of ischemic stroke or venous thromboembolism, a composite safety outcome, including major hemorrhage, and a 1‐year all‐cause mortality outcome. After propensity score fine‐stratification and weighting to account for > 90 confounders, hazard ratios comparing brand vs. generic warfarin initiators (95% confidence intervals) for the effectiveness, safety, and all‐cause mortality outcomes, were 0.97 (0.65–1.46), 0.94 (0.65–1.35), and 0.84 (0.62–1.13), respectively. Results from subgroup analyses of patients with atrial fibrillation, CHADS‐VASc score ≥ 3, and HAS‐BLED score ≥ 3 were consistent with the primary analysis. [ABSTRACT FROM AUTHOR]

Purpose: Generic levothyroxine has been approved and available since 2004 but its substitution remains controversial. Therefore, the objective was to examine patterns of and identify factors associated with initiation and substitution of generic levothyroxine treatment. Methods: This was a retrospective observational study, including new users of brand and generic levothyroxine in 2013–2015 Medicare (n = 15,877) or 2011–2012 Medicaid (n = 9390) administrative claim databases. The primary outcomes included (1) generic levothyroxine initiation, and (2) among brand-new users, generic levothyroxine substitution in 12 months. The factors associated with generic levothyroxine initiation and substitution were measured. Results: Among all levothyroxine new users, Medicare beneficiaries had a higher proportion of generic levothyroxine initiation than Medicaid beneficiaries (66.40% vs. 44.04%, respectively). Medicare beneficiaries' demographic factors, and health service utilizations were associated with generic levothyroxine initiation. Medicaid beneficiaries who were male and residing in the northeast region and rural areas were more likely to initiate generic levothyroxine. Among brand levothyroxine new users, the generic substitution rate was higher in the Medicare than the Medicaid cohort (18.26 vs. 3.88%). Medicare brand levothyroxine new users' demographic factors and health service utilizations were associated with generic levothyroxine substitution. Medicaid brand levothyroxine new users who were residing in the northeast region, with more prior hospitalization, and initiating a lower dosage of brand levothyroxine, had higher rates of generic substitution. Conclusion: Patient demographic factors and health service utilizations are associated with generic levothyroxine initiation and substitution. Educational outreach programs targeted to increase generic levothyroxine use and prescription savings should be tailored based on different patient populations. [ABSTRACT FROM AUTHOR]

Objective: To estimate real-world off-label use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 1 diabetes, estimate rates of diabetic ketoacidosis (DKA), and compare them with DKA rates observed in sotagliflozin clinical trials.Research Design and Methods: We identified initiators of SGLT2 inhibitors in the Sentinel System from March 2013 to June 2018, determined the prevalence of type 1 diabetes using a narrow and a broad definition, and measured rates of DKA using administrative claims data. Standardized incidence ratios (SIRs) were calculated using age- and sex-specific follow-up time in Sentinel and age- and sex-specific DKA rates from sotagliflozin trials 309, 310, and 312.Results: Among 475,527 initiators of SGLT2 inhibitors, 0.50% and 0.92% met narrow and broad criteria for type 1 diabetes, respectively. Rates of DKA in the narrow and broad groups were 7.3/100 person-years and 4.5/100 person-years, respectively. Among patients who met narrow criteria for type 1 diabetes, rates of DKA were highest for patients aged 25-44 years, especially females aged 25-44 years (19.7/100 person-years). More DKA events were observed during off-label use of SGLT2 inhibitors in Sentinel than would be expected based on sotagliflozin clinical trials (SIR = 1.83; 95% CI 1.45-2.28).Conclusions: Real-world off-label use of SGLT2 inhibitors among patients with type 1 diabetes accounted for a small proportion of overall SGLT2 inhibitor use. However, the risk for DKA during off-label use was notable, especially among young, female patients. Although real-word rates of DKA exceeded the expectation based on clinical trials, results should be interpreted with caution due to differences in study methods, patient samples, and study drugs. [ABSTRACT FROM AUTHOR]

Methodologic research evaluating confounding due to socioeconomic status (SES) in observational studies of medications is limited. We identified 7,109 patients who initiated brand or generic atorvastatin from Medicare claims (2011–2013) linked to electronic medical records and census data. We created a propensity score (PS) containing only claims‐based covariates and augmented it with additional claims‐based proxies for SES, ZIP code, and block group level SES. Cox models with PS fine‐stratification and weighting were used to compare rates of a cardiovascular end point and emergency department visits. Adjustment with only claims‐based variables substantially improved balance on all SES variables compared with the unadjusted. Although inclusion of SES in PS models further improved balance on SES variables compared with models with claims‐based covariates only, it did not materially change point estimates for either outcome. Inclusion of claims‐based proxies may mitigate confounding by SES when aggregate‐level SES information is unavailable. [ABSTRACT FROM AUTHOR]

Background: To the extent that outcomes are mediated through negative perceptions of generics (the nocebo effect), observational studies comparing brand-name and generic drugs are susceptible to bias favoring the brand-name drugs. We used authorized generic (AG) products, which are identical in composition and appearance to brand-name products but are marketed as generics, as a control group to address this bias in an evaluation aiming to compare the effectiveness of generic versus brand medications.Methods and Findings: For commercial health insurance enrollees from the US, administrative claims data were derived from 2 databases: (1) Optum Clinformatics Data Mart (years: 2004-2013) and (2) Truven MarketScan (years: 2003-2015). For a total of 8 drug products, the following groups were compared using a cohort study design: (1) patients switching from brand-name products to AGs versus generics, and patients initiating treatment with AGs versus generics, where AG use proxied brand-name use, addressing negative perception bias, and (2) patients initiating generic versus brand-name products (bias-prone direct comparison) and patients initiating AG versus brand-name products (negative control). Using Cox proportional hazards regression after 1:1 propensity-score matching, we compared a composite cardiovascular endpoint (for amlodipine, amlodipine-benazepril, and quinapril), non-vertebral fracture (for alendronate and calcitonin), psychiatric hospitalization rate (for sertraline and escitalopram), and insulin initiation (for glipizide) between the groups. Inverse variance meta-analytic methods were used to pool adjusted hazard ratios (HRs) for each comparison between the 2 databases. Across 8 products, 2,264,774 matched pairs of patients were included in the comparisons of AGs versus generics. A majority (12 out of 16) of the clinical endpoint estimates showed similar outcomes between AGs and generics. Among the other 4 estimates that did have significantly different outcomes, 3 suggested improved outcomes with generics and 1 favored AGs (patients switching from amlodipine brand-name: HR [95% CI] 0.92 [0.88-0.97]). The comparison between generic and brand-name initiators involved 1,313,161 matched pairs, and no differences in outcomes were noted for alendronate, calcitonin, glipizide, or quinapril. We observed a lower risk of the composite cardiovascular endpoint with generics versus brand-name products for amlodipine and amlodipine-benazepril (HR [95% CI]: 0.91 [0.84-0.99] and 0.84 [0.76-0.94], respectively). For escitalopram and sertraline, we observed higher rates of psychiatric hospitalizations with generics (HR [95% CI]: 1.05 [1.01-1.10] and 1.07 [1.01-1.14], respectively). The negative control comparisons also indicated potentially higher rates of similar magnitude with AG compared to brand-name initiation for escitalopram and sertraline (HR [95% CI]: 1.06 [0.98-1.13] and 1.11 [1.05-1.18], respectively), suggesting that the differences observed between brand and generic users in these outcomes are likely explained by either residual confounding or generic perception bias. Limitations of this study include potential residual confounding due to the unavailability of certain clinical parameters in administrative claims data and the inability to evaluate surrogate outcomes, such as immediate changes in blood pressure, upon switching from brand products to generics.Conclusions: In this study, we observed that use of generics was associated with comparable clinical outcomes to use of brand-name products. These results could help in promoting educational interventions aimed at increasing patient and provider confidence in the ability of generic medicines to manage chronic diseases. [ABSTRACT FROM AUTHOR]

Background: Generic versions of a drug can vary in appearance, which can impact adherence.Objective: To assess the preferences, perceptions, and responses of patients who experienced a change in the appearance of a generic medication.Design: Cross-sectional survey of patients from a large commercial health plan.Participants: Adults receiving generic versions of lisinopril, fluoxetine, lamotrigine, or simvastatin who experienced a change in the color or shape of their pills between March 2014 and November 2015.Main Measures: Likert-scale responses to questions concerning perceptions of generic drug safety and effectiveness, reliance on and preferences for pill appearance, and responses to pill appearance changes. Multivariable logistic regression-modeled predictors of seeking advice and adjusting use following a pill appearance change.Key Results: Of 814 respondents (response rate = 41%), 72% relied on pill appearance to ensure they took the correct medication. A similar percentage wanted their pills to remain the same color (72%), shape (71%), and size (75%) upon refill, but 58% would not have paid a $1 premium on a $5 co-pay to ensure such consistency. Most respondents (86%) wanted their pharmacists to notify them about pill appearance changes, but only 37% recalled such notification; 21% thought they received the wrong medication, and 8% adjusted medication use. Younger respondents (18-33 vs. 50-57 years) were more likely to seek advice (odds ratio [OR] = 1.91; 95% confidence interval [CI],1.02-3.59), and respondents with lower household income (< $30,000 vs. > $100,000) were more likely to adjust medication use (OR = 3.40; 95% CI,1.09-10.67).Conclusions: Requiring uniform pill appearance may help increase adherence but presents challenges. Standardized pharmacy notification and education policies may be a more feasible short-term solution. [ABSTRACT FROM AUTHOR]

Introduction: Nearly 90% of drugs dispensed in the US are generic products.Objective: The aim of this study was to develop and implement a tool for analyzing manufacturer-level drug utilization and switching patterns within the US Food and Drug Administration's Sentinel system.Methods: A descriptive tool was designed to analyze data in the Sentinel common data model and was tested with two case studies-metoprolol extended release (ER) and lamotrigine ER-using claims data from four Sentinel data partners. We plotted initiators of each brand and generic product over time. For metoprolol ER, we evaluated rates of switching from generics around the time of manufacturing issues. For lamotrigine ER, we examined rates of switching back to the brand among those who switched from brand to generic.Results: We identified 1,651,285 initiators of metoprolol ER products between July 2008 and September 2015. We observed a large decrease in monthly metoprolol ER initiators (from 25,465 in December 2008 to 13,128 in February 2009), corresponding to recalls by generic manufacturers. We observed simultaneous increases in utilization of the authorized generic and brand products. We identified 4266 initiators of lamotrigine ER with an epilepsy diagnosis between January 2012 and September 2015. Among those who switched from brand to generic, the cumulative incidence of switching back was close to 20% at 2 years. Switchback rates were higher for the first available generic products.Conclusions: This developed tool was able to elucidate novel utilization and switching patterns in two case studies. Such information can be used to support surveillance of generic drugs and biosimilars. [ABSTRACT FROM AUTHOR]

However, as shown in Table 1 of our article, the differences among the 2 COVID-19 cohorts and the influenza cohort were not large for the baseline variables. COVID-19 vs Influenza for Risk of Thrombotic Events in Hospitalized Patients - Reply We agree that there were differences in our study[1] in observed baseline characteristics between the cohorts of patients hospitalized with COVID-19 and influenza. [Extracted from the article]

Small changes in bioavailability of narrow therapeutic index (NTI) drugs can alter clinical outcomes, raising concern over generic NTI substitution. We surveyed pharmacists to identify their perceptions of generic NTI drugs, their frequency of performing generic NTI substitution, and predictors of this behavior. Of 710 respondents (33% response rate), 87% perceived generic NTI drugs as effective as their brand‐name versions and 94% as safe. Whereas 82% almost always performed generic NTI substitution for initial prescriptions, only 60% did for refills. Pharmacists in non‐chain settings (odds ratio (OR) = 2.37; 95% confidence interval (CI) = 1.40–4.02), in practice longer (per year OR = 1.04; 95% CI = 1.02–1.06), in states with affirmative patient consent laws (OR = 1.88; 95% CI = 1.06–3.32), and in states with NTI‐specific substitution requirements (OR = 1.95; 95% CI = 1.16–3.26) were more likely not to substitute initial prescriptions. Education of non‐chain and veteran pharmacists and elimination of affirmative patient consent and NTI‐specific substitution requirements could increase generic NTI substitution. [ABSTRACT FROM AUTHOR]

Study Objective Generic drugs contain identical active ingredients as their corresponding brand drugs and are pharmaceutically equivalent and bioequivalent, whereas authorized generic drugs (AGs) contain both identical active and inactive ingredients as their corresponding brand drugs but are marketed as generics. This study compares generic-to-brand switchback rates between generic and AGs. Design Retrospective cohort study. Data Source Claims and electronic health record data from a regional U.S. health care system. Patients The full cohort consisted of 5542 unique patients who received select branded drugs during the 6 months prior to their generic drug market availability (between 1999 and 2014) and then were switched to an AG or generic drug within 30 months of generic drug entry. For these patients, 5929 unique patient-drug combinations (867 with AGs and 5062 with generic drugs) were evaluated. Measurements and Main Results Ten drugs with AGs and generics marketed between 1999 and 2014 were evaluated. The date of the first generic prescription was considered the index date for each drug, and it marked the beginning of follow-up to evaluate the occurrence of generic-to-brand switchback patterns over the subsequent 30 months. Switchback rates were compared between patients receiving AGs versus those receiving generics using multivariable Cox proportional hazards models, controlling for individual drug effects, age, sex, Charlson Comorbidity Score, pre-index drug use characteristics, and pre-index health care utilization. Among the 5542 unique patients who switched from brand to generic or brand to AG, 264 (4.8%) switched back to the brand drug. Overall switchback rates were similar for AGs compared with generics (hazard ratio [ HR] 0.86, 95% confidence interval [ CI] 0.65-1.15). The likelihood of switchback was higher for alendronate ( HR 1.64, 95% CI 1.20-2.23) and simvastatin ( HR 1.81, 95% CI 1.30-2.54) and lower for amlodipine ( HR 0.27, 95% CI 0.17-0.42) compared with the other drugs evaluated. Conclusion Overall switchback rates were similar between AG and generic drug users, indirectly supporting similar efficacy and tolerability profiles for brand and generic drugs. Reasons for differences in switchback rates among specific products need to be explored further. [ABSTRACT FROM AUTHOR]

Purpose US Food and Drug Administration approval for generic drugs relies on demonstrating pharmaceutical equivalence and bioequivalence; however, some drug products have unique attributes that necessitate product-specific approval pathways. We evaluated rates of patients' switching back to brand-name versions from generic versions of four drugs approved via such approaches. Methods We used data from Optum LifeSciences Research Database to identify patients using a brand-name version of a study drug (acarbose tablets, salmon calcitonin nasal spray, enoxaparin sodium injection, and venlafaxine extended release tablets) or a control drug. We followed patients to identify switching to generic versions and then followed those who switched to identify whether they switched back to brand-name versions. We calculated switch and switch-back rates and used Kaplan-Meier and log-rank tests to compare rates between study and control drugs. Results Our cohort included 201 959 eligible patients. Brand-to-generic switch rates ranged from 66 to 106 switches per 100 person-years for study drugs and 80 to 110 for control drugs. Rates of switch-back to brand-name versions ranged from 5 to 37 among study drugs and 3 to 53 among control drugs. Switch-back rates were higher for venlafaxine vs. sertraline ( p < 0.01) and calcitonin vs. alendronate ( p = 0.01). Switch-back rates were lower for venlafaxine vs. paroxetine ( p < 0.01) and acarbose vs. nateglinide ( p < 0.01). Rates were similar for acarbose vs. glimepiride ( p = 0.97) and for enoxaparin vs. fondiparinux ( p = 0.11). Conclusion As compared to control drugs, patients were not more likely to systematically switch back from generic to brand-name versions of the four study drugs. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives To assess the effectiveness of medications used in the management of Alzheimer's disease and related dementias ( ADRD) on cognition and activity of daily living ( ADL) trajectories and to determine whether sex modifies these effects. Design Two-year (2007-2008) longitudinal study. Setting Medicare enrollment and claims data linked to the Minimum Dataset 2.0. Participants Older nursing home ( NH) residents with newly diagnosed ADRD (n = 18,950). Measurements Exposures included four medication classes: antidementia medications ( ADMs), antipsychotics, antidepressants, and mood stabilizers. Outcomes included ADLs and cognition (Cognitive Performance Scale ( CPS)). Marginal structural models were employed to account for time-dependent confounding. Results The mean age was 83.6, and 76% of the sample was female. Baseline use of ADMs was 15%, antidepressants was 40%, antipsychotics was 13%, and mood stabilizers was 3%. Mean baseline ADL and CPS scores were 16.6 and 2.1, respectively. ADM use was not associated with change in ADLs over time but was associated with a slower CPS decline (slope difference: −0.09 points/year, 99% confidence interval ( CI) = −0.14 to −0.03). Antidepressant use was associated with slower declines in ADL (slope difference: −0.36 points/year, 99% CI = −0.58 to −0.14) and CPS (slope difference: −0.12 points/year, 99% CI = −0.17 to −0.08). Sex modified the effect of both antipsychotic and mood stabilizer use on ADLs; female users declined most quickly. Antipsychotic use was associated with slower CPS decline (slope difference: −0.11 points/year, 99% CI = −0.17 to −0.06), whereas mood stabilizer use had no effect. Conclusion Despite the observed statistically significantly slower declines in cognition with ADMs, antidepressants, and antipsychotics and the slower ADL decline found with antidepressants, it is unlikely that these benefits are of clinical significance. [ABSTRACT FROM AUTHOR]

Objectives To describe population-based use of cognitive-enhancing and psychopharmacological medications across care settings in Medicare beneficiaries with dementia. Design One-year (2008) cross-sectional study. Setting Medicare administrative claims from a 5% random sample. Participants Medicare beneficiaries with dementia aged 65 and older with continuous Medicare Parts A, B, and D coverage and alive throughout 2008. To ascertain dementia, one or more medical claims with a dementia International Classification of Diseases, Ninth Revision, Clinical Modification code was required before 2008, and an additional claim was required in 2008 to confirm active disease. Measurements Use of medications commonly prescribed in managing dementia (cognitive enhancers, antidepressants, antipsychotics, and mood stabilizers) was assessed using three measures: annual prevalence of use, consistency of use, and count of psychopharmacological medication classes. Care setting was determined using the number of months of nursing home ( NH) residency: no NH (0 months), partial NH (1-11 months), and full NH (12 months). Results Community-dwellers represented 41.3% of the cohort, whereas 42.4% and 16.3% resided partially and fully in a NH, respectively. Annual prevalence of use was 57.1% for cognitive enhancers, 56.4% for antidepressants, 34.0% for antipsychotics, and 8.8% for mood stabilizers. Cognitive enhancer use was significantly lower in those with any NH stay (partial NH vs no NH, adjusted prevalence ratio ( APR) = 0.84, 99% confidence interval ( CI) = 0.83-0.86; full NH vs no NH, APR = 0.83, 99% CI = 0.81-0.85). In contrast, those with any NH residence had significantly higher use of all psychopharmacological medication classes than community-dwellers. More than half the cohort had consistent medication regimens during 2008 (64.8%). The number of psychopharmacological medication classes used increased with increasing NH stay duration. Conclusion This population-based study documents significant differences in medication use for managing dementia between care settings and substantial use of psychopharmacological medications in older adults with dementia. [ABSTRACT FROM AUTHOR]

This section presents a correction to the article "Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Type 1 Diabetes and Rates of Diabetic Ketoacidosis," by Christian Hampp and colleagues, published in a 2020 issue.

Page 432, Fig. 2 Plots of model-based outcome incidence rates (per 100 person-years of exposure) before and after introduction of first generic versions of study and control drugs. [ABSTRACT FROM AUTHOR]