Risk of acute pancreatitis among new users of empagliflozin compared to sulfonylureas in patients with type 2 diabetes: A post-authorization safety study.

PURPOSE: This study was undertaken to evaluate the potential risk of acute pancreatitis with empagliflozin in patients with type 2 diabetes (T2D) newly initiating empagliflozin. METHODS: Data from two large US claims databases were analyzed in an observational study of patients with T2D receiving metformin who were newly prescribed empagliflozin versus sulfonylurea (SU). Because dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have been associated with the risk of acute pancreatitis in some studies, patients on these agents were excluded. Using pooled analyses of data from the two databases (2014-2021), patients initiating empagliflozin were matched 1:1 within database to patients initiating SU using propensity scores (PS) that incorporated relevant demographic and clinical characteristics. Prespecified sensitivity analyses were performed for design parameters. RESULTS: The analyses identified 72 661 new users of empagliflozin and 422 018 new users of SUs, with both patient groups on concurrent metformin therapy. Baseline characteristics within treatment groups appeared to be similar across the 72 621 matched pairs. After mean follow-up of ~6 months, incidence rates of acute pancreatitis in the pooled matched cohort were 10.30 (95% confidence interval [CI] 9.29-11.39) events per 1000 patient-years (PY) for empagliflozin and 11.65 (95% CI 10.59-12.77) events per 1000 PY for SUs. On a background of metformin, patients newly initiating empagliflozin did not have an increased risk of acute pancreatitis compared with those initiating an SU (pooled PS matched hazard ratio 0.88 [0.76-1.02]) across 75621.42 PY of follow-up. CONCLUSIONS: The results of this voluntary post-approval safety study provide additional evidence that the use of empagliflozin for the treatment of T2D is not associated with an increased risk of acute pancreatitis.

Clarifying the causal contrast: An empirical example applying the prevalent new user study design.

PURPOSE: The prevalent new user design extends the active comparator new user design to include patients switching to a treatment of interest from a comparator. We examined the impact of adding "switchers" to incident new users on the estimated hazard ratio (HR) of hospitalized heart failure. METHODS: Using MarketScan claims data (2000-2014), we estimated HRs of hospitalized heart failure between patients initiating GLP-1 receptor agonists (GLP-1 RA) and sulfonylureas (SU). We considered three estimands: (1) the effect of incident new use; (2) the effect of switching; and (3) the effect of incident new use or switching, combining the two population. We used time-conditional propensity scores (TCPS) and time-stratified standardized morbidity ratio (SMR) weighting to adjust for confounding. RESULTS: We identified 76 179 GLP-1 RA new users, of which 12% were direct switchers (within 30 days) from SU. Among incident new users, GLP-1 RA was protective against heart failure (adjHRSMR = 0.74 [0.69, 0.80]). Among switchers, GLP-1 RA was not protective (adjHRSMR = 0.99 [0.83, 1.18]). Results in the combined population were largely driven by the incident new users, with GLP-1 RA having a protective effect (adjHRSMR = 0.77 [0.72, 0.83]). Results using TCPS were consistent with those estimated using SMR weighting. CONCLUSIONS: When analyses were conducted only among incident new users, GLP-1 RA had a protective effect. However, among switchers from SU to GLP-1 RA, the effect estimates substantially shifted toward the null. Combining patients with varying treatment histories can result in poor confounding control and camouflage important heterogeneity.

Current Practices and Challenges When Submitting Patient Experience Data for Regulatory Decisions by the US Food and Drug Administration: An Industry Survey.

OBJECTIVES: To understand industry practices and challenges when submitting patient experience data (PED) for regulatory decisions by the US Food and Drug Administration (FDA). METHODS: A two-part online survey related to collection, submission, and use of PED by FDA in regulatory decision-making (part 1) and a best-worst exercise for prioritizing potential PED initiatives (part 2) was completed by industry and contract research organization (CRO) members with ≥ 2 years of recent experience with patient-reported outcome (PRO), natural history study (NHS), or patient preference (PP) data; and direct experience with FDA filings including PED. RESULTS: A total of 50 eligible respondents (84% industry) completed part 1 of the survey, among which 46 completed part 2. Respondents mostly had PRO (86%) and PP (50%) experience. All indicated that FDA meetings should have a standing agenda item to discuss PED. Most (78%) reported meetings should occur before pivotal trials. A common challenge was justifying inclusion without knowing if and how data will be used. Most agreed that FDA and industry should co-develop the PED table in the FDA clinical review (74%), and the table should report reason(s) for not using PED (96%) in regulatory decision-making. Most important efforts to advance PED use in decision-making were a dedicated meeting pathway and expanded FDA guidance (51% each). CONCLUSIONS: FDA has policy targets expanding PED use, but challenges remain regarding pathways for PED submission and transparency in regulatory decision-making. Alignment on the use of existing meeting opportunities to discuss PED, co-development of the PED table, and expanded guidance are encouraged.

Characterizing Imbalance in the Tails of the Propensity Score Distribution.

Understanding characteristics of patients with propensity scores in the tails of the propensity score (PS) distribution has relevance for inverse-probability-of-treatment-weighted and PS-based estimation in observational studies. Here we outline a method for identifying variables most responsible for extreme propensity scores. The approach is illustrated in 3 scenarios: 1) a plasmode simulation of adult patients in the National Ambulatory Medical Care Survey (2011-2015) and 2) timing of dexamethasone initiation and 3) timing of remdesivir initiation in patients hospitalized for coronavirus disease 2019 from February 2020 through January 2021. PS models were fitted using relevant baseline covariates, and tails of the PS distribution were defined using asymmetric first and 99th percentiles. After fitting of the PS model in each original data set, values of each key covariate were permuted and model-agnostic variable importance measures were examined. Visualization and variable importance techniques were helpful in identifying variables most responsible for extreme propensity scores and may help identify individual characteristics that might make patients inappropriate for inclusion in a study (e.g., off-label use). Subsetting or restricting the study sample based on variables identified using this approach may help investigators avoid the need for trimming or overlap weights in studies.

Can Weight of Evidence, Quantitative Bias, and Bounding Methods Evaluate Robustness of Real-world Evidence for Regulator and Health Technology Assessment Decisions on Medical Interventions?

PURPOSE: High-quality evidence is crucial for health care intervention decision-making. These decisions frequently use nonrandomized data, which can be more vulnerable to biases than randomized trials. Accordingly, methods to quantify biases and weigh available evidence could elucidate the robustness of findings, giving regulators more confidence in making approval and reimbursement decisions. METHODS: We conducted an integrative literature review to identify methods for determining probability of causation, evaluating weight of evidence, and conducting quantitative bias analysis as related to health care interventions. Eligible studies were published from 2012 to 2021, applicable to pharmacoepidemiology, and presented a method that met our objective. FINDINGS: Twenty-two eligible studies were classified into 4 categories: (1) quantitative bias analysis; (2) weight of evidence methods; (3) Bayesian networks; and (4) miscellaneous. All of the methods have strengths, limitations, and situations in which they are more well suited than others. Some methods seem to lend themselves more to applications of health care evidence on medical interventions than others. IMPLICATIONS: To provide robust evidence for and improve confidence in regulatory or reimbursement decisions, we recommend applying multiple methods to triangulate associations of medical interventions, accounting for biases in different ways. This approach could lead to well-defined robustness assessments of study findings and appropriate science-driven decisions by regulators and payers for public health.

Strategy for Generating Blinded Evidence for Single-Arm Trials with External Controls Using Expert Review of Home Video.

INTRODUCTION: Neurodegenerative diseases cause developmental delays and loss of milestones in infants and children. However, scalable outcome measures that quantify features meaningful to parents/caregivers (P/CGs) and have regulatory precedence are lacking for assessing the effectiveness of treatments in clinical trials of neurodegenerative disorders. To address this gap, we developed an innovative, blinded strategy for single-arm trials with external controls using expert panel review of home video. METHOD: We identified meaningful, observable, and objective developmental milestones from iterative interviews with P/CGs and clinical experts. Subsequently, we standardized video recording procedures and instructions to ensure consistency in how P/CGs solicited each activity. In practice, videos would be graded by an expert panel blinded to treatment. To ensure blinding and quality control, video recordings from interim time points would be randomly interspersed. We conducted a pilot study and a pretest of grading to test feasibility and improve the final strategy. RESULTS: The five P/CGs participating in the pilot study found the instructions clear, selected activities important and reflective of their children's abilities, and recordings at-home preferrable to in-clinic assessments. The three grading experts found the videos easy to grade and the milestones clinically meaningful. CONCLUSION: Our standardized strategy enables expert panel grading of developmental milestone achievements using at-home recordings, blinded to treatment and post-baseline time points. This rigorous and objective scoring system has broad applicability in various disease contexts, with or without external controls. Moreover, our strategy facilitates flexible, continued data collection and the videos can be archived for future analyses.

Assessment of Codispensing Patterns of Mirabegron and Prespecified CYP2D6 Substrates in Patients with Overactive Bladder.

BACKGROUND: Patients with overactive bladder (OAB) experience sudden, intense urges to urinate, which may include urge urinary incontinence and nocturia. Pharmacotherapy includes ß3-adrenergic receptor agonists such as mirabegron; however, mirabegron contains a label warning for cytochrome P450 (CYP) 2D6 inhibition, making coadministration with CYP2D6 substrates require monitoring and dose adjustment to avoid unintended increases in substrate concentration. OBJECTIVE: To understand the codispensing patterns of mirabegron among patients using ten predefined CYP2D6 substrates with and before mirabegron dispensing. METHODS: This retrospective claims database analysis used the IQVIA PharMetrics® Plus Database to assess codispensing of mirabegron with ten predefined CYP2D6 substrate groups identified on the basis of medications most frequently prescribed in the United States, those with high susceptibility to CYP2D6 inhibition, and those with evidence for exposure-related toxicity. Patients had to be ≥ 18 years old before initiation of the CYP2D6 substrate episode that overlapped with mirabegron. The cohort entry period was November 2012 to September 2019, and the overall study period was 1 January 2011 to 30 September 2019. Comparisons of patient profiles at dispensing were made between time periods with and before mirabegron use in the same patient. Descriptive statistics were used to assess the number of exposure episodes, total duration of exposure, and median duration of exposure of CYP2D6 substrate dispensing with and before mirabegron. RESULTS: CYP2D6 substrate exposure periods totaling ≥ 9000 person-months were available before overlapping exposure to mirabegron for all ten CYP2D6 substrate cohorts. Median codispensing duration for chronically administered CYP2D6 substrates was 62 (interquartile range [IQR] 91) days for citalopram/escitalopram, 71 (105) days for duloxetine/venlafaxine, and 75 (115) days for metoprolol/carvedilol; median codispensing duration for acutely administered CYP2D6 substrates was 15 (33) days for tramadol and 9 (18) days for hydrocodone. CONCLUSIONS: In this claims database analysis, the dispensing patterns of CYP2D6 substrates with mirabegron displayed frequent overlapping of exposure. Thus, a need exists to better understand the outcomes experienced by patients with OAB who are at increased risk for drug‒drug interactions when taking multiple CYP2D6 substrates concurrently with a CYP2D6 inhibitor.

CYP2D6 Substrate Dispensing Among Patients Dispensed Mirabegron: An Administrative Claims Analysis.

BACKGROUND: Overactive bladder (OAB) is characterized by the presence of bothersome urinary symptoms. Pharmacologic treatment options for OAB include anticholinergics and ß3-adrenergic agonists. Use of ß3-adrenergic agonists may result in similar treatment efficacy with a decreased side effect profile compared with anticholinergics because high anticholinergic burden is associated with cardiovascular and neurologic side effects. However, the ß3-adrenergic agonist mirabegron, one of two approved drugs within this class, is a moderate cytochrome P450 (CYP) 2D6 inhibitor, and coadministration of drugs that are CYP2D6 substrates with mirabegron may lead to adverse drug effects. OBJECTIVE: The aim of this study was to quantify how often CYP2D6 substrates were dispensed in patients receiving mirabegron among adults of any age and among those ≥ 65 years of age. METHODS: In this retrospective descriptive analysis, a deidentified administrative claims database in the United States, IQVIA PharMetrics® Plus, was used to identify dispensing claims for CYP2D6 substrates and mirabegron from November 2012 to September 2019. Prevalence of CYP2D6 substrate dispensing was assessed in patients dispensed mirabegron among all adults ≥ 18 years old and additionally among a cohort of those ≥ 65 years old. Patient baseline profiles at the time of mirabegron and CYP2D6 substrate codispensing and at the time of mirabegron dispensing were compared. CYP2D6 substrates were categorized as those with the potential for increased risk of QT prolongation, with anticholinergic properties, with narrow therapeutic index (NTI), contraindicated or having a black box warning when used with CYP2D6 inhibitors, or used for depression or other psychiatric disease. Dispensing data and patient profiles were summarized descriptively. RESULTS: Overall, 68.5% of adults ≥ 18 years old dispensed mirabegron had overlapping dispensings for one or more CYP2D6 substrate; 60.6% and 53.6% had overlapping dispensings for CYP2D6 substrates with anticholinergic properties or risk of QT prolongation, respectively. CYP2D6 substrates with NTI, contraindicated with CYP2D6 inhibitors, or for psychiatric use were codispensed in 17.7%, 16.6%, and 38.0% of adult mirabegron users, respectively. Mirabegron users receiving one or more concurrent CYP2D6 substrate were more likely to be older, have more comorbidities and baseline polypharmacy, and have increased healthcare resource utilization compared with those without concurrent CYP2D6 substrates. Commonly codispensed CYP2D6 substrates included hydrocodone, oxycodone, tramadol, metoprolol, and tamsulosin. Findings were similar for patients in the older cohort (≥ 65 years old), with 72.1% receiving overlapping CYP2D6 substrates. CONCLUSIONS: Codispensing of CYP2D6 substrates, especially those with anticholinergic properties or risk of QT prolongation, was common among adults and older adults receiving mirabegron. Results highlight the need for improved awareness of CYP2D6 substrate prescribing among patients receiving pharmacologic treatment for OAB that inhibits the CYP2D6 pathway.

Pain and Fatigue Improvements in Patients Treated with Repository Corticotropin Injection Across Five Indications: A Narrative Review.

Repository corticotropin injection (RCI; Acthar® Gel) is approved by the US Food and Drug Administration (FDA) for use in 19 indications, including for the treatment of selected patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), symptomatic sarcoidosis, uveitis, and keratitis. Despite treatment with disease-modifying antirheumatic drugs, many patients with RA, SLE, and other chronic inflammatory rheumatic diseases continue to be affected by severe pain and fatigue, indicating a need for other therapies. To examine the clinical data regarding the impact of RCI treatment on pain and fatigue in selected populations, this review included English-language peer-reviewed publications of clinical trials of any size and cohort studies with more than 10 patients that included pain and/or fatigue based on patient-reported outcomes (PROs) and/or physician-assessed measures in adults following treatment with RCI for RA, SLE, symptomatic sarcoidosis, uveitis, or keratitis. Literature searches identified eight studies that met these criteria. Four studies (reported in five publications) were in patients with RA or SLE, two in patients with sarcoidosis, one in patients with uveitis, and one in patients with noninfectious keratitis. Across the different types of studies assessed (clinical trials, chart reviews, real-world evidence), the results were consistent with respect to the impact of RCI treatment on improving pain and fatigue. As summarized in this review, data from patient- and physician-reported outcome measures in eight studies demonstrate that, in addition to improving more traditional efficacy measures, RCI may also improve pain and fatigue in patients with RA, SLE, symptomatic sarcoidosis, uveitis, and noninfectious keratitis.

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are chronic autoimmune diseases. Clinical studies of drugs for these diseases do not often ask patients how they feel after treatment. Despite treatment, many people with these diseases have pain and feel tired. Repository corticotropin injection (RCI) is a prescription drug for patients with RA, SLE, and other chronic immune diseases. We reviewed the results of published studies with data on pain and fatigue from patients treated with RCI. Four studies were in patients with RA or SLE. Two studies were in patients with symptomatic sarcoidosis. One study was in patients with uveitis. One study was in patients with noninfectious keratitis. These eight studies show that adding RCI to standard treatment lowers pain and fatigue in some patients. It would be helpful to measure pain and fatigue in future clinical studies of drugs for patients with chronic immune diseases.

Alternative analytic and matching approaches for the prevalent new-user design: A simulation study.

PURPOSE: To describe the creation of prevalent new user (PNU) cohorts and compare the relative bias and computational efficiency of several alternative analytic and matching approaches in PNU studies. METHODS: In a simulated cohort, we estimated the effect of a treatment of interest vs a comparator among those who switched to the treatment of interest using the originally proposed time-conditional propensity score (TCPS) matching, standardized morbidity ratio weighting (SMRW), disease risk scores (DRS), and several alternative propensity score matching approaches. For each analytic method, we compared the average RR (across 2000 replicates) to the known risk ratio (RR) of 1.00. RESULTS: SMRW and DRS yielded unbiased results (RR = 0.998 and 0.997, respectively). TCPS matching with replacement was also unbiased (RR = 0.999). TCPS matching without replacement was unbiased when matches were identified starting with patients with the shortest treatment history as initially proposed (RR = 0.999), but it resulted in very slight bias (RR = 0.983) when starting with patients with the longest treatment history. Similarly, creating a match pool without replacement starting with patients with the shortest treatment history yielded an unbiased estimate (RR = 0.997), but matching with the longest treatment history first resulted in substantial bias (RR = 0.903). The most biased strategy was matching after selecting one random comparator observation per individual that continued on the comparator (RR = 0.802). CONCLUSIONS: Multiple analytic methods can estimate treatment effects without bias in a PNU cohort. Still, researchers should be wary of introducing bias when selecting controls for complex matching strategies beyond the initially proposed TCPS.

Treatment patterns and burden of myelosuppression for patients with small cell lung cancer: A SEER-medicare study.

PURPOSE: To depict the treatment journey for patients with small cell lung cancer (SCLC) and evaluate health care resource utilization (HCRU) associated with myelosuppression, a complication induced by chemotherapy or chemotherapy plus radiation therapy. PATIENTS AND METHODS: This was a descriptive, retrospective study of patients with SCLC aged ≥65 years, identified from linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data curated between January 2012 and December 2015. Treatment types (chemotherapy, radiation therapy, surgery) were classified as first, second, or third line, depending on the temporal sequence in which regimens were prescribed. For each year, the proportions of patients completing 4- or 6-cycle chemotherapy regimens, with hospital admissions associated with myelosuppression, or who used granulocyte colony-stimulating factors (G-CSFs), blood/platelet transfusions, or erythropoiesis-stimulating agents (ESAs), were calculated. RESULTS: Chemotherapy was administered as initial treatment in 7,807/11,907 (65.6%) patients whose treatment journey was recorded. Approximately one-third (n = 3,985) subsequently received radiation therapy. In total, 5,791 (57.8%) patients completed the guideline-recommended 4-6 cycles of chemotherapy. Among all chemotherapy-treated patients, 10,370 (74.3%) experienced ≥1 inpatient admission associated with myelosuppression (anemia, 7,366 [52.8%]; neutropenia, 4,642 [33.3%]; thrombocytopenia, 2,375 [17.0%]; pancytopenia, 1,983 [14.2%]). Supportive care interventions included G-CSF (6,756 [48.4%] patients), ESAs (1,534 [11.0%]), and transfusions (3,674 [26.3%]). CONCLUSION: Chemotherapy remains a cornerstone of care for patients with SCLC. Slightly over half of patients completed the recommended number of cycles, underscoring the frailty of patients and aggressiveness of SCLC. HCRU associated with myelosuppression was prominent, suggesting a substantial burden on older patients with SCLC.

Risk of bias in non-randomized observational studies assessing the relationship between proton-pump inhibitors and adverse kidney outcomes: a systematic review.

BACKGROUND: Proton-pump inhibitors (PPIs) are widely prescribed as acid-suppression therapy. Some observational studies suggest that long-term use of PPIs is potentially associated with certain adverse kidney outcomes. We conducted a systematic literature review to assess potential bias in non-randomized studies reporting on putative associations between PPIs and adverse kidney outcomes (acute kidney injury, acute interstitial nephritis, chronic interstitial nephritis, acute tubular necrosis, chronic kidney disease, and end-stage renal disease). METHODS: We searched the medical literature within 10 years of 17 December 2020. Pre-specified criteria guided identification of relevant English language articles for assessment. Risk of bias on an outcome-specific basis was evaluated using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool by two independent reviewers. RESULTS: Of 620 initially identified records, 26 studies met a priori eligibility criteria and underwent risk of bias assessment. Nineteen studies were judged as having a moderate risk of bias for reported adverse kidney outcomes, while six studies were judged as having a serious risk of bias (mainly due to inadequate control of confounders and selection bias). We were unable to determine the overall risk of bias in two studies (one of which was assessed as having a moderate risk of bias for a different adverse kidney outcome) due to insufficient information presented. Effect estimates for PPIs in relation to adverse kidney outcomes varied widely (0.24-7.34) but associations mostly showed increased risk. CONCLUSION: Using ROBINS-I, we found that non-randomized observational studies suggesting kidney harm by PPIs have moderate to serious risk of bias, making it challenging to establish causality. Additional high-quality, real-world evidence among generalizable populations are needed to better understand the relation between PPI treatment and acute and chronic kidney outcomes, accounting for the effects of varying durations of PPI treatment, self-treatment with over-the-counter PPIs, and potential critical confounders.

Interpretation of the Meaningfulness of Symptom Reduction with Vibegron in Patients with Overactive Bladder: Analyses from EMPOWUR.

INTRODUCTION: Reductions in bothersome symptoms of overactive bladder (OAB) demonstrate improvement in clinical trials, but patient perception of meaningfulness of such improvement is lacking. In the 12-week phase 3 EMPOWUR trial, vibegron significantly reduced average daily number of micturitions, urgency episodes, and urge urinary incontinence (UUI) episodes vs placebo (P < 0.01 each). This analysis assessed meaningfulness of reductions in clinical endpoints observed in EMPOWUR using patient perception of improvement. METHODS: An anchor-based approach using Patient Global Impression of Change (PGI-C) applied to phase 2 data allowed predefining phase 3 responder definitions. To confirm in phase 3, median change from baseline at week 12 in average daily number of micturitions, urgency episodes, and UUI episodes was generated for each PGI-C category and pooled across treatments. Based on predefined meaningful responder definitions, percentages of patients achieving ≥ 15% reduction in micturitions (post hoc), ≥ 50% reduction in urgency episodes (predefined), and ≥ 75% (predefined) and ≥ 90% (post hoc) reduction in UUI episodes were determined for patients receiving vibegron or placebo. RESULTS: Across treatments, for micturitions, urgency episodes, and UUI episodes, median change from baseline to week 12 increased with greater subjective improvement based on PGI-C scores, and median reductions pooled across treatment groups were higher than the responder definitions that patients perceived as improved. Significantly more patients receiving vibegron vs placebo achieved ≥ 15% reduction in micturitions (56.3% vs 44.6%, respectively), ≥ 50% reduction in urgency episodes (39.5% vs 32.8%), ≥ 75% reduction in UUI episodes (49.3% vs 32.8%), and ≥ 90% reduction in UUI episodes (35.2% vs 23.5%) at week 12 (P < 0.05 each). CONCLUSION: Significantly more patients treated with vibegron vs placebo in EMPOWUR achieved meaningful reductions in micturitions, urgency episodes, and UUI episodes that were associated with patient-perceived improvement. Results of these analyses support the meaningfulness of reductions in clinical endpoints observed in the 12-week EMPOWUR trial. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier, NCT03492281.

Efficacy of Vibegron and Mirabegron for Overactive Bladder: A Systematic Literature Review and Indirect Treatment Comparison.

BACKGROUND: In the absence of head-to-head trials, we performed an indirect treatment comparison of the ß3-adrenergic agonists vibegron and mirabegron in the treatment of overactive bladder (OAB). METHODS: PubMed, Embase, and Cochrane Library were searched for articles related to phase 3, double-blind, controlled trials of vibegron 75 mg and mirabegron 25/50 mg in patients with OAB. Efficacy outcomes included change from baseline at weeks 4, 12, and 52 in mean daily number of total urinary incontinence episodes and micturitions and mean volume voided/micturition. Effect size was computed as placebo-subtracted change from baseline (weeks 4, 12) or active control (tolterodine)-subtracted change from baseline (week 52) for each treatment group. Adverse events (AEs) are presented descriptively. RESULTS: After removal of duplicates, 49 records were identified, and after screening 9 met inclusion criteria for analysis. Vibegron showed significantly greater reduction in mean daily number of total incontinence episodes than mirabegron 25 mg at week 4, mirabegron 50 mg (weeks 4, 52), and tolterodine (weeks 4, 12) (P < 0.05, each) and significantly greater improvement in volume voided versus mirabegron 25 mg (week 12), mirabegron 50 mg (weeks 12, 52), and tolterodine (week 4) (P < 0.05, each). Confidence intervals of point estimates overlapped zero for all other comparisons of vibegron and mirabegron (25 or 50 mg) or tolterodine, indicating no significant differences between treatments for these time/endpoints. Urinary tract infection, hypertension, and dry mouth were the most commonly occurring AEs for vibegron, mirabegron, and tolterodine, respectively, in the short-term trials; hypertension was the most commonly occurring AE with all three treatments in the long-term trials. CONCLUSIONS: Vibegron was associated with significant improvement in total incontinence episodes versus mirabegron at 4 and 52 weeks and volume voided at 12 and 52 weeks. Improvement in micturitions was similar between vibegron and mirabegron or tolterodine. Incidence of AEs was generally comparable between vibegron and mirabegron.

Cancer Patients' Perspectives and Experiences of Chemotherapy-Induced Myelosuppression and Its Impact on Daily Life.

PURPOSE: To evaluate which side effects of chemotherapy are considered most burdensome by patients with cancer, identify which health care professionals pay most attention to symptoms associated with chemotherapy-induced myelosuppression (CIM) from the patient perspective, and capture the "patient voice" describing how CIM impacts their daily lives. PARTICIPANTS AND METHODS: Online survey of participants with breast, lung, or colorectal cancer who had received chemotherapy within the past 12 months and experienced ≥1 episode of CIM in the past year. Participants were asked to answer close-ended questions and provide qualitative responses to: "In your own words, please describe how side effects from myelosuppression have impacted your life." RESULTS: Among 301 survey participants, fatigue was the most frequently reported side effect of chemotherapy; 55% of participants rated fatigue as highly bothersome (9 or 10 on a 1-10 scale of "bothersomeness"). Participants rated symptoms associated with CIM, including fatigue, weakened immune system (infections), bleeding and/or bruising, and shortness of breath, as being as bothersome as other side effects of chemotherapy, including alopecia, neuropathy, and nausea/vomiting. Overall, 24-43% of participants thought that CIM and its symptoms had a negative impact on their daily lives, including their ability to complete tasks at home and work, and to socialize. Qualitative responses supported these findings; participants highlighted that CIM-related symptoms, particularly fatigue and fear of infections, affected their ability to be physically active, complete work, or continue meaningful relationships with friends and family. CONCLUSION: Participants described a real-world impact of CIM that often isolates them from family and friends, and means that they are unable to work or perform tasks of daily living. Using measures that help patients to recognize and communicate the signs and symptoms of CIM might increase the likelihood of maintaining daily lives as close to normal as possible, during and after chemotherapy treatment.

Demonstrating that Real World Evidence Is Fit-For-Purpose to Support Labeling: Parallels to Patient Reported Outcomes in the Pursuit of Labeling Claims.

INTRODUCTION: In December 2021, U.S. Food & Drug Administration (FDA) will issue guidance on the use of real-world evidence (RWE) to support new indications or expanded product labeling. While difficult to foresee what FDA will require, learnings can be gleaned from previous paradigm shifts at FDA, such as for patient reported outcomes (PROs) in 2006-2009. METHODS: We contrast published requirements for justifying PROs as fit-for-purpose for a specific labeling claim with a potential approach to justify RWE as fit-for-purpose to support expanded labeling or a new indication. RESULTS: PRO labeling claims require a PRO Evidence Dossier that includes: specific wording of claim, clinical trial hypothesis structure and endpoint model, and justification that the PRO is relevant and meaningful to patients in the target population (content validity) with adequate psychometric properties. FDA's 2018 RWE Framework outlined critical considerations for using RWE to support regulatory decisions, including data quality, relevancy, provenance, and transparency. Strong parallels exist between the evidence required to justify that PROs are fit-for-purpose to support specific labeling claims and evidence to justify RWE as fit-for-purpose for specific research questions and labeling. Early discussion with FDA is encouraged. CONCLUSION: Drawing on parallels with use of PROs in labeling, RWE for regulatory purposes should be evaluated within the context of specific labeling or indication, specific study design and analysis plans, and the data attributes of data source. Sponsors seeking a new indication or labeling expansion based on RWE should justify that a specific data source and specific study design are fit-for-purpose.

Increased risk of incident dementia following use of anticholinergic agents: A systematic literature review and meta-analysis.

BACKGROUND/RATIONALE: Long-term treatment with anticholinergic agents may increase the risk of cognitive impairment or dementia. This systematic literature review and meta-analysis aimed to assess the impact of ≥3 months of exposure to anticholinergics as a class on the risk of dementia, mild cognitive impairment, and change in cognitive function. The impact of anticholinergic agents specifically used to treat overactive bladder was also evaluated. MATERIALS AND METHODS: A systematic literature review was conducted to identify English language articles evaluating the impact of anticholinergic use for ≥3 months on dementia or cognitive function in adult patients. Databases searched included PubMed, Embase, and the Cochrane Library. Meta-analyses were conducted using random-effects models; 95% confidence intervals (CIs) and 95% prediction intervals (PIs) were reported. RESULTS: A total of 2122 records were identified. Out of those, 21 studies underwent qualitative synthesis and 6 reported endpoints relevant for inclusion in a meta-analysis assessing the risk of incident dementia. The overall rate ratio for incident dementia was 1.46 (95% CI: 1.17-1.81; 95% PI: 0.70-3.04; n = 6). The risk of incident dementia increased with increasing exposure (n = 3). In addition, two studies from the meta-analysis reported an increased risk of dementia with ≥3 months of use of bladder antimuscarinics (adjusted odds ratios ranged from 1.21 to 1.65, depending on exposure category). CONCLUSION: Anticholinergic use for ≥3 months increased the risk of dementia on average by an estimated 46% versus nonuse. This relationship was consistent in studies assessing overactive bladder medications. The risk of developing dementia should be carefully considered in the context of potential benefit before prescribing anticholinergics.

Using propensity scores to estimate effects of treatment initiation decisions: State of the science.

Confounding can cause substantial bias in nonexperimental studies that aim to estimate causal effects. Propensity score methods allow researchers to reduce bias from measured confounding by summarizing the distributions of many measured confounders in a single score based on the probability of receiving treatment. This score can then be used to mitigate imbalances in the distributions of these measured confounders between those who received the treatment of interest and those in the comparator population, resulting in less biased treatment effect estimates. This methodology was formalized by Rosenbaum and Rubin in 1983 and, since then, has been used increasingly often across a wide variety of scientific disciplines. In this review article, we provide an overview of propensity scores in the context of real-world evidence generation with a focus on their use in the setting of single treatment decisions, that is, choosing between two therapeutic options. We describe five aspects of propensity score analysis: alignment with the potential outcomes framework, implications for study design, estimation procedures, implementation options, and reporting. We add context to these concepts by highlighting how the types of comparator used, the implementation method, and balance assessment techniques have changed over time. Finally, we discuss evolving applications of propensity scores.

Evaluating the Feasibility of Electronic Health Records and Claims Data Sources for Specific Research Purposes.

Data collected in real-world clinical settings are increasingly being used to evaluate therapeutic options. While in its infancy for research assessing effectiveness, especially comparative effectiveness in the regulatory environment, electronic health records (EHR) and administrative insurance claims data are used extensively by both manufacturers and regulators to evaluate post-marketing safety of products in the real world. The feasibility of using these data for analysis in a research study depends on the specific research question and the availability, quality and relevance of the collected data to address the scientific question. It is unlikely that any specific database could be 'qualified' for use across all research questions, even within a specific therapeutic area, due to dependence of feasibility on the elements of the specific research question. This paper describes considerations for determining whether EHR or claims data can be used for specific research purposes. A new structured approach for assessing the feasibility of these data in research is proposed. The framework builds on and considers whether each element of the PICOTS framework for well-structured research questions is adequately captured to allow for viable reliance on EHR and claims data for that specific scientific question. Practical examples and discussion of the limitations of RWD for research are given along with approaches for interpretation of analyses using RWD.