Safety of Upadacitinib in Immune-Mediated Inflammatory Diseases: Systematic Literature Review of Indirect and Direct Treatment Comparisons of Randomized Controlled Trials.

INTRODUCTION: Immune-mediated inflammatory diseases including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), non-radiographic axial spondylarthritis (nr-axSpA), atopic dermatitis (AD), ulcerative colitis (UC), and Crohn's disease (CD) pose a substantial burden on patients and their quality of life. Upadacitinib is an orally administered, selective, and reversible Janus kinase inhibitor indicated for seven conditions, but data on its safety versus other active treatments are limited. A systematic literature review of indirect and direct treatment comparisons of randomized controlled trials (RCTs) was conducted to assess the safety profile of upadacitinib. METHODS: MEDLINE, Embase, and Cochrane Library databases were searched for indirect and direct treatment comparisons of RCTs that (1) included licensed upadacitinib dosages; (2) studied any of the seven conditions; (3) reported any adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, major adverse cardiovascular event, venous thromboembolism, malignancies, infections or serious infections, and death; and (4) were published between January 2018 and August 2022. RESULTS: A total of 25 studies were eligible for inclusion. SAEs, AEs leading to discontinuation, and any AEs were commonly studied. RA was the most studied condition, followed by AD and UC. Most studies (16/25, 64%) reported no statistically significant difference in the studied safety outcomes between upadacitinib and other active treatments (e.g., tumor necrosis factor blockers, interleukin receptor antagonists, integrin receptor antagonists, T cell co-stimulation modulator), or placebo (placebo ± methotrexate or topical corticosteroids). Other studies (9/25, 36%) reported mixed results of no statistically significant difference and either statistically higher (8/25, 32%) or lower rates (1/25, 4%) on upadacitinib. CONCLUSION: Most studies suggested that upadacitinib has no statistically significant difference in the studied safety outcomes compared to active treatments or placebo in patients with RA, PsA, AS, AD, UC, and CD. A few studies reported higher rates, but findings were inconsistent with limited interpretation.

Clinical and Economic Benefit of Advanced Therapies for the Treatment of Active Ankylosing Spondylitis.

INTRODUCTION: Recent changes to treatment guidelines for ankylosing spondylitis (AS) have listed first-line advanced therapies as tumor necrosis factor (TNF), interleukin (IL)-17, and Janus kinase (JAK) inhibitors. This study sought to assess the comparative clinical and economic benefit of advanced therapies approved for AS. METHODS: A systematic literature review was conducted to identify randomized clinical trials for JAK inhibitors (upadacitinib [UPA], tofacitinib [TOF]), anti-IL-17 therapies (secukinumab [SEC], ixekizumab [IXE]), and TNF inhibitors (adalimumab [ADA], etanercept [ETN], golimumab [GOL]) used for the treatment of active AS. Clinical efficacy was evaluated by Assessment of Spondyloarthritis International Society 40 (ASAS40) criteria and treatment discontinuation due to adverse events (AEs) was used to generate response rates synthesized via a Bayesian network meta-analysis. Number needed to treat (NNT) was calculated as the reciprocal of incremental response rate of each treatment versus placebo. Cost per ASAS40 responder (CPR) was calculated as the 12-week treatment costs divided by ASAS40 response rates. Data were stratified by biologic treatment status (i.e., biologic naïve [bio-naïve] or inadequate response or intolerance to biologics [bio-IR]) for efficacy and CPR analyses. RESULTS: Among bio-naïve patients, the response rate for ASAS40 was 53.6% for UPA-treated patients, whereas most other treatments had response rates between 41% and 49%. NNTs were lowest for UPA-treated patients at 2.8 (other therapies 3.2-4.8). Estimated CPR among UPA-treated patients was lowest (UPA $39.5k vs others $44.2k-102.5k). Efficacy and CPR trends were similar among bio-IR and TNF-IR patients. Among bio-naïve and bio-IR patients, the rate of AEs leading to discontinuation was lowest among UPA and SEC-treated patients (0.0, others 0.6-3.7%). CONCLUSIONS: Relative to other treatments assessed in this study, UPA demonstrated numerically greater clinical and economic benefit for the treatment of AS. Head-to-head or real-world comparisons of these therapies are warranted and may inform clinical decision-making.

Effect of Upadacitinib on Quality of Life and Work Productivity in Active Non-radiographic Axial Spondyloarthritis: Results From Randomized Phase 3 Trial SELECT-AXIS 2.

INTRODUCTION: To evaluate the effect of upadacitinib vs. placebo on health-related quality of life (HRQoL) and work productivity in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) enrolled in the SELECT-AXIS 2 phase 3 randomized controlled trial. METHODS: Adult patients with active nr-axSpA and an inadequate response to non-steroidal anti-inflammatory drugs were randomized 1:1 to receive upadacitinib 15 mg once daily or placebo. Mean changes from baseline in measures of HRQoL (Ankylosing Spondylitis QoL [ASQoL], Assessment of SpondyloArthritis international Society Health Index [ASAS HI], Short-Form 36 Physical Component Summary [SF-36 PCS] score) and Work Productivity and Activity Impairment (WPAI) were assessed through 14 weeks based on mixed-effects repeated measures or analysis of covariance models. The proportions of patients with improvements ≥ minimum clinically important differences (MCID) were assessed in HRQoL measures at week 14 using non-responder imputation with multiple imputation. RESULTS: At week 14, upadacitinib- vs. placebo-treated patients reported greater improvements from baseline in ASQoL and ASAS HI (ranked, P < 0.001) and in SF-36 PCS and WPAI overall work impairment (nominal P < 0.05). Improvements were observed as early as week 2 in ASAS HI. Greater proportions of upadacitinib vs. placebo-treated patients reported improvements ≥ MCID in ASQoL (62.6 vs. 40.9%), ASAS HI (44.8 vs. 28.8%), and SF-36 PCS (69.3 vs. 52.0%), with numbers needed to treat < 10 for all (nominal P ≤ 0.01). Improvements ≥ MCID were consistently observed irrespectively of prior exposure to tumor necrosis factor inhibitors. CONCLUSIONS: Upadacitinib provides clinically meaningful improvements in HRQoL and work productivity in patients with active nr-axSpA. CLINICAL REGISTRATION NUMBER: NCT04169373, SELECT-AXIS 2.

Effect of Upadacitinib on Disease Activity, Pain, Fatigue, Function, Health-Related Quality of Life and Work Productivity for Biologic Refractory Ankylosing Spondylitis.

INTRODUCTION: Patients with ankylosing spondylitis (AS) have significant unmet treatment needs, despite advancements in biologic therapies. This study evaluated the impact of upadacitinib on clinically meaningful improvement in patient-reported outcomes (PROs) assessing disease activity, pain, fatigue, function, health-related quality of life (HRQoL), and work productivity in patients with AS with inadequate responses or intolerance to biologic disease-modifying antirheumatic drugs (bDMARD-IR). METHODS: Patients enrolled in the phase 3 SELECT-AXIS 2 AS bDMARD-IR study received blinded once-daily oral upadacitinib 15 mg or placebo for 14 weeks. The percentage of patients achieving improvements ≥ minimum clinically important differences (MCID) at week 14 were compared between treatment groups for disease activity (Bath Ankylosing Spondylitis Disease Activity Index, BASDAI), patient global assessment of disease activity (PtGA), total and nocturnal back pain, fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue, FACIT-F), physical function (Bath Ankylosing Spondylitis Functional Index, BASFI), HRQoL (Assessment of SpondyloArthritis international Society Health Index [ASAS HI], Ankylosing Spondylitis Quality of Life [ASQoL], Short form-36 [SF-36] physical [PCS] and mental [MCS] component summary scores), and work productivity (Work Productivity and Activity Impairment [WPAI] Questionnaire). Mean changes from baseline through week 14 in fatigue and HRQoL were compared between treatment groups. RESULTS: A total of 420 patients with active AS who were bDMARD-IR were included. A higher proportion of patients reported MCIDs at week 14 across all PROs with upadacitinib compared with placebo (nominal p ≤ 0.05). Greater improvements in mean change from baseline through week 14 were reported with upadacitinib compared with placebo across FACIT-F, HRQoL, and WPAI, with improvements differentiated as early as week 1 for ASAS HI, ASQoL and SF-36 PCS and week 4 for SF-36 MCS. CONCLUSIONS: Upadacitinib 15 mg demonstrated rapid and clinically meaningful improvements in disease activity, pain, FACIT-F, function, HRQoL, and WPAI among bDMARD-IR patients with active AS. TRIAL REGISTRY: Clinical Registration number: NCT04169373, SELECT-AXIS 2.

Clinical and Economic Benefit of Achieving Disease Control in Psoriatic Arthritis and Ankylosing Spondylitis: A Retrospective Analysis from the OM1 Registry.

BACKGROUND: There is limited evidence on the clinical and economic benefit of achieving disease control in psoriatic arthritis (PsA) and ankylosing spondylitis (AS), thus we aimed to assess the impact of disease control on healthcare resource use (HCRU) and direct medical costs among US patients with PsA or AS over 1 year. METHODS: Data were derived from the US OM1 PsA/AS registries (PsA: 1/2013-12/2020; AS: 01/2013-4/2021) and the Optum Insight Clinformatics® Data Mart to identify adult patients with PsA or AS. Two cohorts were created: with disease control and without disease control. Disease control was defined as modified Disease Activity Index for Psoriatic Arthritis (DAPSA28) ≤ 4 for PsA and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) < 4 for AS. Outcomes were all-cause inpatient, outpatient, and emergency department (ED) visits and associated costs over a 1-year follow-up period. Mean costs per person per year (PPPY) were assessed descriptively and adjusted odds ratios (aOR) with 95% confidence intervals (CI) were estimated for the likelihood of HCRU by logistic regression. RESULTS: The study included 1235 PsA (with disease control: N = 217; without: N = 1018) and 581 AS patients (with disease control: N = 342; without: N = 239). Patients without disease control were more likely to have an inpatient (aOR [95% CI]; PsA: 3.0 [0.9, 10.1]; AS: 7.7 [2.3, 25.1]) or ED (PsA: 1.6 [0.6, 4.2]; AS: 3.5 [1.5, 8.3]) visit than those with disease control. Those without disease control, vs. those with disease control, had greater PPPY costs associated with inpatient (PsA: $1550 vs. $443), outpatient (PsA: $1789 vs. $1327; AS: $2498 vs. $2023), and ED (PsA: $114 vs. $57; AS: $316 vs. $50) visits. CONCLUSIONS: Findings from this study demonstrate lower disease activity among patients with PsA and AS is associated with less HCRU and lower costs over the following year.

Effect of upadacitinib on reducing pain in patients with active psoriatic arthritis or ankylosing spondylitis: post hoc analysis of three randomised clinical trials.

OBJECTIVE: Evaluate the effect of upadacitinib on pain outcomes in patients with active psoriatic arthritis (PsA) or ankylosing spondylitis (AS) across 3 randomised trials (SELECT-PsA 1 and 2 for PsA; SELECT-AXIS 1 for AS). METHODS: Patients were randomised to upadacitinib 15 mg once daily or placebo (all 3 studies), or adalimumab 40 mg every other week (SELECT-PsA 1 only). Pain outcomes included proportion of patients achieving ≥30%, ≥50% and ≥70% reduction from baseline in patient global assessment of pain and other end points. RESULTS: A higher proportion of patients receiving upadacitinib versus placebo achieved ≥30%, ≥50% and ≥70% reduction in pain end points as early as week 2; these improvements with upadacitinib were generally sustained or increased through year 1 (PsA 1/2 studies: 64%/48%, 58%/42% and 38%/22%, respectively; SELECT-AXIS 1 study: 76%, 72% and 54%). Results were similar with adalimumab in PsA 1 (59%, 49% and 32%). Patients who switched from placebo to upadacitinib 15 mg were able to reach a similar level of improvement as the continuous upadacitinib groups by year 1 (PsA 1/2 studies: 46%-60%, 35%-49% and 15%-34%; AS study: 83%, 72% and 46%). Results were similar with other pain end points. CONCLUSION: Rapid and sustained improvements in pain outcomes across several end points were consistently shown with upadacitinib over 1 year in patients with active PsA or AS who had either inadequate response to prior non-biologic or biologic disease-modifying antirheumatic drugs (PsA studies) or were biologic-naïve with inadequate response to non-steroidal anti-inflammatory drugs (AS study).

Development of a measure of prescriber satisfaction with academic detailing: the PSAD.

INTRODUCTION: Academic detailing (AD) is an educational outreach strategy to provide clinicians with current evidence-based information, which has been shown to change prescribing behaviours. The overall effectiveness of AD interventions is associated with prescriber satisfaction; however, most approaches use single items or non-validated measures. This study aims to develop and validate an instrument to assess prescriber satisfaction with AD interventions. METHODS: A group of candidate items was generated and refined based on constructs identified through a literature review and in consultation with an expert panel. The initial instrument was piloted with 183 primary care providers who participated in an AD intervention on opioid-related pain management. To support the validity and reliability of the measure, psychometric properties were examined. RESULTS: Ten candidate items were developed based on the following themes: acceptability, feasibility of implementation, usefulness, perception of efficacy, overall satisfaction, willingness to repeat and willingness to change. One item related to willingness to change did not contribute to assessing an individual's ability and lowered the measure's internal consistency and was therefore dropped. CONCLUSION: Results supported the validity and reliability of a refined 9-item measure of Provider Satisfaction with Academic Detailing (the PSAD). This measure should be considered for broad use across educational outreach programmes as a standardized measure to assess provider satisfaction and provide continuous quality improvement.

Geographic Variations in Diagnosis and Treatment of Ankylosing Spondylitis in the United States: A Real-World Study.

INTRODUCTION: Diagnosis difficulties are common for ankylosing spondylitis (AS) patients, leading to inadequate and inconsistent treatment. We evaluated the national and geographic variability in disease diagnosis and treatment in the United States. METHODS: This retrospective, cross-sectional analysis utilized the IBM® MarketScan® Administrative Claims Database from 2014 to 2019. AS patients ≥ 18 years of age with continuous medical and pharmacy enrollment during the calendar year and complete geographic information during the study period were included. Patient cohorts assessed were D1 (≥ 1 AS diagnoses within each calendar year of assessment between 2014 and 2019), D2 (≥ 2 non-rheumatologist AS diagnoses), and D3 (≥ 2 rheumatologist AS diagnoses). For D2 and D3, diagnoses were ≥ 6 months apart, but within 18 months. Annual AS diagnostic prevalence and treatment rates were determined from 2014 to 2019 nationally and per state in 2019. Treatments assessed were disease-modifying antirheumatic drugs (DMARDs), opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and methotrexate. RESULTS: Nationally, AS diagnostic prevalence increased from 2014 to 2019, with 2019 rates of 9.6 (D1), 5.1 (D2), and 3.5 (D3) per 10,000 persons. Diagnostic prevalence varied between states, which was not explained by age, sex, racial distribution, or rheumatologists per capita. Nationally, a greater percentage of D3 patients vs. D1 and D2 patients received biologic/targeted synthetic DMARDs (bDMARD/tsDMARDs) and conventional synthetic DMARD. Opioid use ranged from 37 to 40% in 2019 and decreased from 2014 for all cohorts. Corticosteroid and methotrexate use decreased slightly, while NSAID and bDMARD/tsDMARD use generally increased from 2014 to 2019. CONCLUSIONS: AS diagnostic prevalence is increasing nationally, though it remains low among some states. bDMARD/tsDMARDs use was more common among patients treated by rheumatologists. Opioid and corticosteroid use is decreasing, though national rates remain high with significant state variability. Further education is needed, particularly in states with low prevalence and inadequate treatment, to improve diagnosis and treatment.

Patient-Reported Outcomes in Psoriatic Arthritis Patients with an Inadequate Response to Biologic Disease-Modifying Antirheumatic Drugs: SELECT-PsA 2.

INTRODUCTION: Psoriatic arthritis (PsA) has a major impact on health-related quality of life (HRQOL) and other patient-reported outcomes (PROs), important components in the assessment of therapeutic efficacy. We evaluated the impact of upadacitinib on PROs in PsA patients with inadequate responses or intolerance to biologic disease-modifying anti-rheumatic drugs (bDMARD-IR). METHODS: Patients enrolled in the phase 3 SELECT-PsA 2 randomized controlled trial (RCT) received 56 weeks of oral upadacitinib 15 mg QD, upadacitinib 30 mg QD, or placebo switched to either dose of upadacitinib at week 24. PROs included patient global assessment of disease activity (PtGA), pain, physical function (HAQ-DI), health-related quality of life (SF-36 physical (PCS) and mental (MCS) component summary and domain scores), fatigue (FACIT-F), psoriasis symptom severity (SAPS), and work productivity (WPAI). Mean changes from baseline in PROs, improvements ≥ minimum clinically important differences (MCID) and scores ≥ normative values, and maintenance of improvements were assessed. RESULTS: At weeks 12 and 24, patients treated with either upadacitinib dose reported statistically and nominally significant improvements from baseline across all PROs versus placebo (p ≤ 0.05), except the WPAI absenteeism domain, which were maintained or further improved to week 56. A significantly greater proportion of patients receiving either upadacitinib dose reported improvements ≥ MCID and scores ≥ normative values versus placebo (nominal p ≤ 0.01) in most PROs at weeks 12 and 24, with clinically meaningful improvements continuing to week 56. Improvements ≥ MCID were reported as early as week 2 in PtGA, pain, and HAQ-DI. CONCLUSIONS: Upadacitinib provides rapid, clinically meaningful, and sustained improvements in PROs reported by bDMARD-IR PsA patients. SELECT-PsA 2 ClinicalTrials.gov number, NCT03104374.

Improvement in Patient-Reported Outcomes in Patients with Psoriatic Arthritis Treated with Upadacitinib Versus Placebo or Adalimumab: Results from SELECT-PsA 1.

INTRODUCTION: The aim of this work is to assess the effect of upadacitinib versus adalimumab and placebo on patient-reported outcomes (PROs) in psoriatic arthritis (PsA) patients with inadequate responses to ≥ 1 non-biologic disease-modifying anti-rheumatic drugs (non-bDMARD-IR) in SELECT PsA-1. METHODS: In this placebo- and active comparator, phase 3 randomized, controlled trial, patients received daily upadacitinib 15 or 30 mg, placebo, or adalimumab 40 mg every other week through 56 weeks. At week 24, placebo-assigned patients were rerandomized to upadacitinib 15 or 30 mg. PROs included Patient Global Assessment of Disease Activity (PtGA), pain, Health Assessment Questionnaire Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Short Form 36 Health Survey (SF-36), EQ-5D-5L index score, Bath Ankylosing Spondylitis Disease Activity Index, morning stiffness, Self-Assessment of Psoriasis Symptoms, and Work Productivity and Activity Impairment. Mean changes from baseline in PROs, improvements ≥ minimum clinically important differences (MCID), scores ≥ normative values, and sustained clinically meaningful responses were compared between treatment groups. RESULTS: At weeks 12 and 24, upadacitinib treatment resulted in improvements from baseline versus placebo across all PROs as well as improvements versus adalimumab in HAQ-DI and SF-36 Physical Component Summary score (nominal p < 0.05). Improvements in PtGA, pain, and HAQ-DI were reported as early as week 2. At week 12, significantly (nominal p < 0.05) more upadacitinib- versus placebo-treated patients reported improvements ≥ MCID across all PROs including seven SF-36 domains. The proportions of upadacitinib-treated patients reporting clinically meaningful improvements at week 12 were similar to or greater than with adalimumab and sustained through week 56. Significantly (nominal p < 0.05) more upadacitinib-treated (both doses) patients reported scores ≥ normative values at week 12 versus placebo, and scores were generally similar to or greater than adalimumab. CONCLUSIONS: Upadacitinib treatment provides rapid, sustained, and clinically meaningful improvements in PROs in non-bDMARD-IR patients with PsA. SELECT-PsA 1 ClinicalTrials.gov number, NCT03104400.

Racial Differences in Prevalence and Treatment for Psoriatic Arthritis and Ankylosing Spondylitis by Insurance Coverage in the USA.

INTRODUCTION: Patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS) may receive suboptimal care, and differences in care by race/ethnicity, sex, and insurance coverage are not well studied. METHODS: This was a descriptive, retrospective cross-sectional US claims database analysis utilizing the Medicaid multi-state segment of the IBM® MarketScan® Commercial Claims and Encounters Supplemental Database and Optum Insight Clinformatics® Data Mart database for 2019. Patients aged ≥ 18 years with PsA or AS and continuous medical and pharmacy coverage were included. Outcomes evaluated were prevalence and percentage of patients receiving biologic disease-modifying antirheumatic drugs (bDMARDs)/targeted synthetic DMARDs (tsDMARDs) or visiting a rheumatologist. Outcomes were stratified by race/ethnicity, sex, and insurance coverage, with outcomes determined for commercial insurance, Medicare, and Medicaid enrollees. Differences observed in outcomes were numerical in nature. RESULTS: Prevalences of PsA and AS were highest for Medicare enrollees (320 and 156 per 100,000 persons [0.32 and 0.16%], respectively) and lowest for Medicaid enrollees (132 and 71 per 100,000 persons [0.13 and 0.07%], respectively). White patients had the greatest prevalence versus patients of other races/ethnicities. Females had a higher prevalence of PsA than males, while AS prevalence was generally lower for females versus males for each insurance category. The percentage of patients prescribed bDMARDs/tsDMARDs was highest for commercial insurance enrollees (PsA 63%, AS 43%) and lowest for Medicare enrollees (PsA 21%, AS 11%). The proportion of patients who saw a rheumatologist was lower for Medicaid enrollees (PsA 12%, AS 10%) than for commercial insurance or Medicare enrollees (PsA 68%, 55%; AS 67%, 42%). For commercial insurance and Medicare enrollees, the percentage of patients visiting a rheumatologist was similar by race/ethnicity but higher for females versus males. CONCLUSIONS: The prevalence and treatment of PsA and AS differs by race/ethnicity, insurance coverage, and sex in the USA. Efforts for improving access to care are needed to improve outcomes among all patients.

Healthcare Resource Use in Patients with Immune-Mediated Conditions Treated with Targeted Immunomodulators During COVID-19 Pandemic: A Retrospective Claims Analysis.

INTRODUCTION: The impact of the COVID-19 pandemic on routine medical care may result in altered healthcare resource use in patients with immune-mediated conditions. The aim of this study was to determine the impact of treatment interruptions in patients with and without COVID-19 infections who were treated with targeted immunomodulators (TIMs) in the USA. METHODS: Data from the IBM® MarketScan® Research Databases were analyzed in patients with immune-mediated conditions from January 1, 2018, through December 31, 2020. Healthcare resource use (HCRU) including hospitalizations, emergency department (ED) visits, in-person outpatient visits, and respiratory outcomes was assessed in a cohort of patients without COVID-19 who had uninterrupted versus interrupted TIM use. The impact of treatment interruption on HCRU and respiratory outcomes was also evaluated in a cohort of patients with COVID-19. Results from adjusted logistic regression were reported as adjusted odds ratios (aORs) with 95% confidence intervals. RESULTS: Approximately 25% of patients in both the COVID-19 (N = 787) and non-COVID-19 cohorts (N = 77,178) experienced interruptions in TIM therapy. In the non-COVID-19 cohort, the likelihood of being hospitalized was 20% less in patients with uninterrupted versus interrupted TIM use (aOR = 0.80, 95% CI 0.71-0.90). Patients with uninterrupted TIM use had a similar likelihood of an ED visit (aOR = 0.99, 95% CI 0.91-1.08) and respiratory outcome (aOR = 0.97, 95% CI 0.71-1.31) versus patients with interrupted TIM use. The likelihood of having an in-person outpatient visit was 87% greater in patients with uninterrupted versus interrupted TIM use (aOR = 1.87, 95% CI 1.81-1.94). Similar findings were observed in the COVID-19 cohort. CONCLUSION: This analysis of real-world claims data showed that uninterrupted TIM use was not associated with an increased likelihood of hospitalizations, ED visits, or negative respiratory outcomes compared to interrupted TIM use among patients with immune-mediated conditions, regardless of COVID-19 diagnosis.

Secondary effects of an opioid-focused academic detailing program on non-opioid controlled substance prescribing in primary care.

Background: Educational outreach programs that focus on safe opioid prescribing and awareness of state prescription monitoring programs may modify clinicians' prescribing behavior. The objective of this study was to evaluate the secondary effects of an opioid-focused academic detailing (AD) program on non-opioid controlled substance prescribing in primary care. Methods: A quasi-experimental pre-post study of primary care clinicians exposed and unexposed to the AD program was conducted using data from the Illinois Prescription Monitoring Program from December 2017 to February 2019. Outcomes were mean monthly prescriptions for benzodiazepines (BZD), non-BZD sedative-hypnotics, and carisoprodol, per clinician. A difference-in-differences (DID) approach utilizing repeated-measures mixed-effects linear regression models was used to compare changes in outcomes six-months before and after the program. Results: Mean monthly BZD prescriptions declined in both groups of clinicians (AD-exposed n = 151; controls n = 399) after implementation of the AD program. Although the mean monthly number of BZD prescriptions decreased in both groups after the AD program, BZD prescribing in the AD-exposed group declined at a slower rate following the AD program (DID = 0.73; 95% CI: 0.14, 1.31). The AD-exposed group had a 0.06 (95% CI: -0.11, -0.01) lower rate of mean monthly carisoprodol prescriptions compared to the control group following the AD program. There was no change in the rate of mean monthly non-BZD sedative-hypnotic prescriptions between the two groups. Conclusions: The higher relative rate of BZD prescribing in the AD-exposed group compared to the control group following the AD program may be reflective of an unintended consequence of opioid-focused AD programs as clinicians learn to be cautious about opioid prescribing. Our findings may suggest the need for incorporation of targeted education on appropriate BZD prescribing into opioid-focused AD programs as a featured component. These findings warrant further consideration and investigation before large-scale implementation of opioid-focused educational outreach programs.

Evaluation of Adherence and Persistence Differences Between Adalimumab Citrate-Free and Citrate Formulations for Patients with Immune-Mediated Diseases in the United States.

INTRODUCTION: Our aim was to evaluate patient adherence and persistence with citrate-free adalimumab (ADA-CF), introduced in 2018 to reduce injection-site pain, compared with citrate-containing adalimumab (ADA-C). METHODS: This was a retrospective cohort study using a US claims database (IBM® MarketScan® Commercial and Medicare Supplemental Claims Database) from February 2018 to January 2020. Patients at least 18 years of age who were naïve to adalimumab 6 months before the index date (date of first adalimumab claim) and with at least 12 months of continuous medical and pharmacy coverage were eligible for the study. Adherence was assessed by determining the proportion of days covered (PDC) and the percentage of patients with PDC ≥ 80% during the 12-month follow-up period. Persistence was evaluated by measuring the rate of discontinuation and days to discontinuation (i.e., time on treatment) from the index date over the 12-month follow-up period. Continuous adherence outcomes (PDC) were evaluated using linear regression models. Binary adherence outcomes (PDC ≥ 80%) were assessed using logistic regression models. Kaplan-Meier analysis and Cox proportional hazards models were used to assess persistence outcomes. RESULTS: There were 2195 and 1005 patients in the ADA-CF and ADA-C cohorts, respectively, with most using adalimumab for rheumatoid arthritis (ADA-CF 29.7%, ADA-C 27.2%) and psoriasis (ADA-CF 24.5%, ADA-C 31.9%). Significantly greater adherence was achieved with ADA-CF compared with ADA-C (mean PDC [standard deviation] 0.68 [0.30] vs 0.61 [0.32], P < 0.0001). A significantly greater percentage of patients receiving ADA-CF (47.2%) vs ADA-C (39.6%) had PDC ≥ 80% (P < 0.0001). The discontinuation rate was significantly lower for the ADA-CF cohort (46.4%) compared with ADA-C (55.9%, P < 0.0001), resulting in a 27% lower likelihood of discontinuation during the 12-month follow-up period (hazard ratio 0.73; 95% confidence interval 0.66, 0.82; P < 0.0001) and longer time on treatment (260 vs 232 days, P < 0.0001). CONCLUSION: Adherence and persistence are significantly improved with ADA-CF compared with ADA-C.

Development of an Instrument to Assess the Perceived Effectiveness of Academic Detailing.

INTRODUCTION: Academic detailing (AD) is an effective, evidence-based education outreach method of promoting clinician behavior change. Detailer feedback is important for program evaluation but is rarely systematically collected. The study's objective was to develop a measure capturing the detailer's perception of the effectiveness of an AD program. METHODS: A six-item measure with a five-level scale was initially developed from the literature review and expert panel consultation. Item constructs were usefulness, acceptability, feasibility, relevance, effectiveness of communication, and readiness to change. The measure was piloted, refined, and tested during an opioid-focused AD program that included two visits. The instrument structure was evaluated using exploratory factor analysis, measure reliability was assessed using item-item correlation (rho), corrected item-total correlation, Cronbach alpha (α), and item response theory. RESULTS: The initial six-item instrument demonstrated unidimensionality. The Cronbach α for the measure was 0.74 (visit 1) and 0.79 (visit 2); one item (relevance) was redundant (α = 0.73 and 0.79 when deleted) and therefore dropped. Items related to usefulness, acceptability, and readiness to change displayed high item-item correlation (rho ≥ 0.50) and contributed the most information and seemed to operate as a single scale (ie, "likelihood to change") based on item response theory analysis. Items related to feasibility and communication were slightly different constructs and should be reported separately. DISCUSSION: The five-item detailer assessment of visit effectiveness (the "DAVE") instrument provides a standardized approach to assess AD. Further study of its validity and broader use in other programs and educational outreach activities is encouraged.

Practice change intentions after academic detailing align with subsequent opioid prescribing.

OBJECTIVE: Self-reported behavior change is used to evaluate the effectiveness of educational outreach interventions delivered to clinicians, such as academic detailing (AD). However, self-reported changes in behavior are often not corroborated with data on actual behavior change. To assess alignment between self-reported practice change intentions and actual opioid prescribing behavior among primary care clinicians after an AD intervention. METHODS: We used a difference-in-differences approach to compare pre-post changes in opioid prescribing using data from the Illinois Prescription Monitoring Program. An opioid-focused AD intervention was delivered to primary care clinicians from a large health system in the Chicago metropolitan area from June 2018 to August 2018. Immediately after the AD intervention, clinicians were administered a single-item self-reported practice change measure. Clinicians were categorized into 2 groups on the basis of their responses: (1) intention to change and (2) no-to-moderate intention to change. Outcomes were mean total opioid prescriptions and high-dose opioid prescriptions (≥ 90 morphine milligram equivalents) per clinician per month. Repeated measures linear regression models were used to compare changes in opioid prescribing outcomes between the 2 groups in the 6 months before and after the AD intervention. RESULTS: A total of 149 clinicians were included for analysis. An intention to change was reported by 72 clinicians and no-to-moderate intention to change was reported by 77 clinicians. In the 6 months after the AD intervention, there were 1.48 (95% CI -2.48 to -0.47) fewer total opioid prescriptions and 0.50 (-0.69 to -0.31) fewer high-dose opioid prescriptions per clinician per month in the intention to change group than in the no-to-moderate intention to change group. CONCLUSION: This study showed considerable alignment between self-reported practice change intentions and actual changes in opioid prescribing behavior. Future opioid-focused educational outreach interventions should consider using standardized single-item practice change measures as an immediate indicator of future behavior change.

Identification of barriers to safe opioid prescribing in primary care: a qualitative analysis of field notes collected through academic detailing.

BACKGROUND: Understanding barriers to safe opioid prescribing in primary care is critical amid the epidemic of prescription opioid abuse, misuse, and overdose in the US. Educational outreach strategies, such as academic detailing (AD), provide a forum for identification of barriers to, and strategies to facilitate, safe opioid prescribing in primary care. AIM: To identify barriers to safe opioid prescribing among primary care providers (PCPs) through AD. DESIGN AND SETTING: Qualitative analysis of data was collected through an existing AD intervention to improve safe opioid prescribing in primary care. The AD intervention was delivered from June 2018 to August 2018 to licensed PCPs with prescriptive authority within a large independent health system in the metropolitan Chicagoland area. METHOD: The AD intervention involved visits by trained detailers to PCPs who contemporaneously documented details from each visit via field notes. Using qualitative analysis, field notes were analysed to identify recurring themes related to opioid prescribing barriers. RESULTS: Detailer-entered field notes from 186 AD visits with PCPs were analysed. Barriers to safe opioid prescribing were organised into six themes: 1) gaps in knowledge; 2) lack of prescription monitoring programme (PMP) utilisation; 3) patient pressures to prescribe opioids; 4) insurance coverage policies; 5) provider beliefs; and 6) health system pain management practices. CONCLUSION: Barriers to safe opioid prescribing in primary care, identified through AD visits among this large group of PCPs, support the need for continued efforts to enhance pain-management education, maximise PMP utilisation, and increase access to, and affordability of, non-opioid treatments.

Estimating the Impact of Food and Drug Administration's Unapproved Drug Initiative on Drug Prices and Sales.

BACKGROUND: The 2006 FDA's Unapproved Drug Initiative (UDI) aimed to improve safety and public health by decreasing the availability of drug products that never obtained FDA approval (unapproved drug products) in the market and incentivizing manufacturers to emphasize that these products must obtain FDA approval. The objective of this study was to measure changes in the prices, sales, and quantities sold of drug products approved under the FDA-UDI. METHODS: Drug products that obtained voluntary approval under FDA-UDI from 2006 to 2015 were identified and trends in prices, sales, and units sold were analyzed using the IQVIA National Sales Perspective database. RESULTS: Eleven drug products were included in the final analysis. Relative to baseline levels 2 years before approval, a steep increase in price and sales was observed 2 years postapproval for all except 2 of the drug categories-with median percent change of 245% (range: -37% to 9618%) for price and 238% (range: -4% to 6707%) for sales. Substantial variance was observed in the changes in units sold. CONCLUSION: A marked increase was seen in postapproval prices and sales for the vast majority of drug products approved in the FDA-UDI with mixed results in changes in units sold. In addition to increased information on safety, the policy's impact on postapproval drug prices and associated effects on units sold should be considered in assessing the policy, especially when substantial price increases and decreases in units sold may negatively impact health.

Mediation analyses of socioeconomic factors determining racial differences in the treatment of diffuse large B-cell lymphoma in a cohort of older adults.

Despite near universal health coverage under Medicare, racial disparities persist in the treatment of diffuse large B-cell lymphoma (DLBCL) among older patients in the United States. Studies evaluating DLBCL outcomes often treat socioeconomic status (SES) measures as confounders, potentially introducing biases when SES factors are mediators of disparities in cancer treatment.To examine differences in DLBCL treatment, we performed causal mediation analyses of SES measures, including: metropolitan statistical area (MSA) of residence; census-tract poverty level; and private Medicare supplementation using the Surveillance, Epidemiology and End Results-Medicare linked database between 2001 and 2011. In this retrospective cohort study of DLBCL patients ages 66+ years, we conducted a series of multivariable logistic regression analyses estimating odds ratios (OR) and 95% confidence intervals (CI) relating chemo- and/or immuno-therapy treatment and each SES measure, comparing non-Hispanic (NH)-black, Hispanic/Latino, and Asian/Pacific Islander (API) to NH-white patients.Compared to NH-white patients, racial/ethnic minority patients had lower odds of receiving chemo- and/or immuno-therapy treatment (NH-black: OR 0.84, 95% CI 0.65, 1.08; API: OR 0.80, 95% CI 0.64, 1.01; Hispanic/Latino: OR 0.78, 95% CI 0.64, 0.96) and higher odds of lacking private Medicare supplementation and residence within an urban MSA and poor census tracts. Adjustment for SES measures as confounders nullified observed racial differences. In causal mediation analyses, between 31% and 38% of race/ethnicity differences were mediated by having private Medicare supplementation.Providing equitable access to Medicare supplementation may reduce disparities in receipt of chemo- and/or immuno-therapy treatment in older DLBCL patients.