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The FDA is preparing guidance about using real-world evidence (RWE) to support decisions about product effectiveness. Several ongoing efforts aim to replicate randomized clinical trial (RCT) results using RWE with the intent of identifying circumstances and methods that provide valid evidence of drug effects. Lack of agreement may not be due to faulty methods but rather to the challenges with emulating RCTs, differences in healthcare settings and patient populations, differences in effect measures and data analysis, bias, and/or the efficacy–effectiveness gap. In fact, for some decisions, RWE may lead to better understanding of how treatments work in usual care settings than a more constrained view from RCTs. Efforts to reconcile the role and opportunities for generating complementary evidence from RWE and RCTs will advance regulatory science.

IMPORTANCE: There is increasing interest in performing comparative effectiveness analyses in large observational databases, yet these analyses must adjust for treatment selection issues. OBJECTIVES: To conduct comparative safety and efficacy analyses of prasugrel vs clopidogrel bisulfate after percutaneous coronary intervention and to evaluate inverse probability of treatment weighting (a propensity score method) and instrumental variable methods. DESIGN, SETTING, AND PARTICIPANTS: This study used data from the Treatment With Adenosine Diphosphate Receptor Inhibitors–Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) study. Included in the study were patients undergoing percutaneous coronary intervention for myocardial infarction, 26.0% of whom received prasugrel. The study dates were April 4, 2010, to October 31, 2012. EXPOSURES: Choice of initial antiplatelet agent (prasugrel or clopidogrel). MAIN OUTCOMES AND MEASURES: Safety and efficacy outcomes included 1-year composite major adverse cardiovascular events, moderate to severe bleeding, and stent thrombosis. Hospitalizations for pneumonia, bone fractures, and planned percutaneous coronary intervention were used as the falsification end points. RESULTS: The study cohort comprised 11 784 participants (mean [SD] age, 60.0 [11.6] years, and 28.0% were female). Using inverse probability of treatment weighting adjustment, prasugrel and clopidogrel had similar major adverse cardiovascular events (hazard ratio [HR], 0.98; 95% CI, 0.83-1.16) and bleeding outcomes (1.18; 0.77-1.80), but prasugrel had a lower rate of stent thrombosis (0.51; 0.31-0.85). Using instrumental variable methods, prasugrel use was associated with a lower rate of the major adverse cardiovascular event end point (HR, 0.68; 95% CI, 0.47-1.00) but nonsignificant differences in the rates of bleeding (0.95; 0.41-2.08) and stent thrombosis (0.67; 0.16-2.00). There was no significant treatment difference noted in any of the falsification end-point rates when analyses were performed using inverse probability of treatment weighting, although the bone fracture end point approached statistical significance. Nevertheless, a lower rate of pneumonia-related hospitalizations was noted in the prasugrel-treated patients when analyses were performed using instrumental variable methods. CONCLUSIONS AND RELEVANCE: Conclusions regarding the safety and efficacy of antiplatelet therapy varied depending on analytic technique, and none were concordant with the results from randomized trials. In addition, both statistical strategies demonstrated concerning associations when tested in the falsification analyses. A high level of scrutiny and careful attention to assumptions and validity are required when interpreting complex analyses of observational data.

AbstractObjective:To develop and apply a longitudinal model that adjusts for pre-treatment covariates to examine the trajectory of healthcare costs in duloxetine patients with major depressive disorder (MDD).Methods:Retrospective healthcare cost data from Thomson Reuters Marketscan® Database included 10,987 patients with MDD, aged 18–64, receiving duloxetine at low (<60 mg/day), standard (60 mg/day), or high (>60 mg/day) initial doses. A linear mixed-effects model for repeated measures used dose, month, and dosemonth as fixed effects and patient (dose) as a random effect, and adjusted for demographics, comorbidities, body system disorders, and prior medication history. Model goodness-of-fit was evaluated with R2. Rates of change (slopes) were estimated from the fitted model and differences in the cost trajectory among dosing cohorts were tested using the F-test. Bootstrapping and propensity score (PS) stratification were conducted to provide sensitivity analyses.Results:Main effects and covariates were all significant (p < 0.05). Adjustment by pre-treatment covariates greatly improved the model fit (R2  0.43). The model revealed a significant increase in healthcare costs in the 6 months preceding and a significant decrease in the 6 months following duloxetine initiation for each initial dose cohort and the overall cohort (p < 0.05). In both the pre- and post-treatment periods, the high initial-dose cohort had higher healthcare costs than standard or low initial-dose cohorts (p < 0.05). Bootstrapping and PS stratification confirmed these test results.Limitations:The analyses performed here were based on non-randomized, observational data, and thus subject to potential biases due to unmeasured confounding.Conclusions:Longitudinal models, compared with conventional mean-based methods, provide better opportunities to assess changes in cost trajectory patterns around the time of changes in medical treatment. In insured patients with MDD started on duloxetine, healthcare costs increased before duloxetine initiation, perhaps signaling a clinical deterioration that led to a change in treatment strategy. Healthcare costs then decreased following duloxetine initiation.

AbstractObjective:Little is known about early discontinuation of duloxetine therapy or the effect that initial dose has on discontinuation in patients with major depressive disorder (MDD).Methods:Data from a private payer insurance claim database included 6132 patients with MDD who started duloxetine between 7/1/2005 and 6/30/2006, had no prescription for duloxetine in the previous 3 months, and were enrolled for 12 months before and after initiation. Chi-square tests, t-tests, and logistic regression were used to compare demographic, clinical, and healthcare cost data stratified by length of continuation. Early discontinuation was defined as continuation ≤30 days. Healthcare costs, persistence, and adherence were compared between patients with suboptimal initial dose (<40 mg/day) and those with recommended initial dose (40–60 mg/day).Results:Discontinuation rates were 16.8% at ≤30 days, 16.7% at 31–90 days, 14.9% at 91–180 days, and 51.6% at >180 days. Suboptimal initial dose, younger age, male gender, prior benzodiazepine use, insomnia, psychiatric disorders, infectious diseases, digestive disorders, genitourinary disorders, and injury/poisoning increased the likelihood of early discontinuation (Odds ratios [ORs]: 1.18–2.16), while recent use of SSRIs or venlafaxine XR decreased the likelihood (ORs: 0.67–0.68). Compared with patients who persisted with therapy for >180 days, patients who discontinued early had more hospital admissions, longer hospital stays, and more ER visits during the 1-year follow-up (all p-values <0.01). Patients with an initial dose <40 mg/day had shorter persistence (p < 0.001) and lower rates of adherence (p < 0.001) compared with patients with an initial dose of 40–60 mg/day.Limitations:Limitations of this study were those of all analyses based on data from insurance claim databases.Conclusions:Early discontinuation was associated with increased healthcare utilization. Demographic and clinical predictors of early discontinuation were identified that may help target care for at-risk patients. Beginning therapy within the recommended dose range may improve persistence.

AbstractObjectiveTo examine healthcare cost patterns prior to and following duloxetine initiation in patients with major depressive disorder (MDD), focusing on patients initiated at or titrated to high doses.Research design and methodsRetrospective analysis of 10,987 outpatients, aged 18–64 years, who were enrolled in health insurance for 6 months preceding and 12 months following duloxetine initiation.Outcome measuresRepeated measures and pre–post analyses were used to examine healthcare cost trajectories before and after initiation of low- (<60 mg/day), standard- (60 mg/day), and high-dose (>60 mg/day) duloxetine therapy. Decision tree analysis was used to identify patient characteristics that might explain heterogeneity in economic outcomes following titration to high-dose therapy.ResultsLow-, standard-, and high-dose duloxetine were initiated for 29.6%, 60.9%, and 9.5% of patients, respectively. Within 6 months, 13.7% of patients had dose increases to > 60 mg/day. Regardless of dose, total costs increased prior to and decreased following initiation of treatment. The High Initial Dose Cohort had higher costs both prior to and throughout treatment compared to the other two cohorts. Following escalation to > 60 mg/day, higher medication costs were balanced by lower inpatient costs. Titration to high-dose therapy was cost-beneficial for patients with histories of a mental disorder in addition to MDD and higher prior medical costs.LimitationsConclusions are limited by a lack of supporting clinical information and may not apply to patients who are not privately insured.ConclusionsIn data taken from insured patients with MDD who were started on duloxetine in a clinical setting, healthcare costs increased prior to and decreased following initiation of therapy. Compared to patients initiated at low- and standard-doses, costs were greater prior to and following initiation for patients initiated at high doses. Increases in pharmacy costs associated with escalation to high-dose therapy were offset by reduced inpatient expenses.

To develop an adult self-report instrument for provisional diagnosis of four common mental disorders in primary care patients.

Adherence and persistence with medication therapy are important in the management of major depressive disorder. This study examined the association between initial prescription dosage of duloxetine and its adherence and persistence. In a large commercial managed-care claims database, 6132 patients with major depressive disorder were initiated on duloxetine between 1 July 2005 and 30 June 2006 at low dose (<60 mgday, n1989), mid dose (60 mgday, n3733), or high dose (>60 mgday, n410). Adherence was defined as medication possession ratio more than or equal to 0.8, and persistence was defined as the length of therapy without exceeding a 15-day gap. Over a 6-month period after duloxetine initiation, mid-dose initiated patients had a higher adherence rate (42.2) than low-dose (35.6, P<0.001) or high-dose initiated patients (36.1, P<0.001). Mid-dose duloxetine-initiated patients stayed significantly longer with the medication (107.3 days) compared with low-dose (95.8 days, P<0.01) or high-dose patients (95.4 days, P<0.01). After adjustment for baseline demographics, comorbid conditions, and prior medications, mid-dose initiated patients remained to have better adherence and longer persistence than low-dose or high-dose initiators. The findings suggest that patients initiated with a dose of 60 mgday of duloxetine seem to be more adherent to and persistent with the medication than those initiated with less or more than 60 mgday.

Objective: Numerous investigations have examined the efficacy of pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD) in children. However, relatively few studies have addressed the impact of treatment on long-term subjective, psychosocial outcomes, such as health-related quality of life (HRQL). This study examines the long-term effects of pharmacological treatment with atomoxetine on HRQL in children and adolescents with ADHD.Methods: Participants included 6- to 17-year-old children and adolescents (n = 912) with ADHD enrolled in a 24-month, multicenter, open-label trial of atomoxetine. Outcomes included clinician ratings of ADHD, parent ratings of ADHD, and a widely used measure of HRQL (The Child Health Questionnaire (CHQ)). Treatment response rates were calculated based on a CHQ improvement of at least 1 standard error of measurement.Results: Significant improvements in HRQL were found following both acute and long-term treatment for psychosocial but not physical health. Of participants who completed treatment (n = 312 or 34.2% of those enrolled), 81% responded to acute treatment and 78% responded to long-term treatment. Improvements noted after acute treatment were maintained during long-term treatment with the majority of participants (86%) continuing to respond to treatment.Conclusions: Atomoxetine is associated with improvements in HRQL, and the improvements are generally stable over time.

The 1-week single-blind placebo lead-in has long been a standard in double-blind psychopharmacology clinical trials. Although a lead-in period is often necessary (e.g., to receive laboratory results before randomization), some authors have demonstrated that the standard single-blind placebo lead-in’s performance was similar to having a lead-in in which placebo was not administered. The single-blind placebo lead-in did not decrease postrandomization placebo response, nor did it increase drug–placebo differences. To eliminate a higher percentage of placebo responders before randomization and to reduce potential biases in baseline ratings, the authors designed and implemented two depression studies with a double-blind variable placebo lead-in period. In these designs, both the patients and personnel at the investigative sites were blinded to the length of the placebo lead-in period and the start of the active treatment period. Approximately 28 of the patients in the double-blind placebo lead-in studies met criteria to be placebo lead-in responders, as compared with fewer than 10 from two single-blind placebo lead-in studies conducted in a similar time frame. Although all patients continued in the study (including placebo lead-in responders), the primary efficacy analysis prospectively excluded double-blind placebo lead-in responders. Analysis of postrandomization changes revealed that double-blind placebo lead-in responders, even when continuing to receive placebo treatment, maintained their response. At the study endpoint, these placebo lead-in responders had significantly lower severity scores than their counterparts who were not lead-in responders. The prospective removal of lead-in responders thus resulted in an increase in mean endpoint placebo group severity scores. This resulted in an increased drug–placebo treatment difference in one of the two studies but had no effect on the treatment difference in the other study.

Currently available antidepressants have a delayed onset of action and there is considerable interest in developing new products which exhibit a shorter time to response. Previous authors have suggested using a cure model to characterize the time to response for the combination of the patients who respond and the patients who do not respond. In this paper, we use the cure model and propose a Cramer–von Mises statistic to compare the time to response distributions for patients who respond to therapy. The asymptotic null distribution of the statistic is derived. A bootstap procedure is also proposed for sample sizes typical in antidepressant clinical trials. Results of the simulation study suggest that for common designs and sample sizes used in such trials, the statistic has reasonable size and power properties as long as censoring is moderate. Copyright © 2000 John Wiley & Sons, Ltd.

Currently available antidepressants have a delayed onset of action and there is considerable interest in developing new products which exhibit a shorter time to response. Previous authors have suggested using a cure model to characterize the time to response for the combination of the patients who respond and the patients who do not respond. In this paper, we use the cure model and propose a Cramer–von Mises statistic to compare the time to response distributions for patients who respond to therapy. The asymptotic null distribution of the statistic is derived. A bootstap procedure is also proposed for sample sizes typical in antidepressant clinical trials. Results of the simulation study suggest that for common designs and sample sizes used in such trials, the statistic has reasonable size and power properties as long as censoring is moderate. Copyright © 2000 John Wiley & Sons, Ltd.

Aim:To predict optimal treatments maximizing overall survival (OS) and time to treatment discontinuation (TTD) for patients with metastatic breast cancer (MBC) using machine learning methods on electronic health records. Patients/methods:Adult females with HR+/HER2- MBC on first- or second-line systemic therapy were eligible. Random survival forest (RSF) models were used to predict optimal regimen classes for individual patients and each line of therapy based on baseline characteristics. Results:RSF models suggested greater use of CDK4 & 6 inhibitor-based therapies may maximize OS and TTD. RSF-predicted optimal treatments demonstrated longer OS and TTD compared with nonoptimal treatments across line of therapy (hazard ratios = 0.44∼0.79). Conclusion:RSF may help inform optimal treatment choices and improve outcomes for patients with HR+/HER2- MBC.