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Background: Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative (Randomized, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology) uses a structured process to design RWE studies emulating randomized, controlled trials (RCTs) and compare results. We report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications. Methods: We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion and exclusion criteria, selected primary end points, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 preexposure confounders. All study measures were prospectively defined and protocols registered before hazard ratios and 95% CIs were computed. Success criteria for the primary analysis were prespecified for each replication. Results: Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a hazard ratio estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of Conclusions: Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs. Registration: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922.

Summary Background The risk of serious infection is a major concern when prescribing a disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. Little evidence exists with regard to serious infection risk associated with tofacitinib, a targeted synthetic (ts)DMARD, compared with biologic DMARDs (bDMARDs) among patients with rheumatoid arthritis. We compared the risk of serious infection in patients with rheumatoid arthritis initiating tofacitinib versus one of the seven bDMARDs. Methods In this multidatabase cohort study, we identified eight mutually exclusive groups of patients with rheumatoid arthritis initiating tofacitinib or one of the seven bDMARDs using US public (Medicare 20012–15) and private (Optum Clinformatics 2012–18 and IBM MarketScan 2012–17) health insurance programmes. Eligible patients were aged 18 years or older, and had one inpatient visit or two or more outpatient visits (7–365 days apart) for rheumatoid arthritis using International Classification of Diseases 9th and 10th revision codes. The primary outcome was a composite endpoint of admission to hospital for serious infection including bacterial, viral, or opportunistic infection based on the inpatient principal diagnosis code. Secondary outcomes were individual types of serious infections and herpes zoster. We adjusted for more than 60 potential confounders through propensity score-based inverse probability treatment weighting in each database. Database-specific adjusted hazard ratios (aHRs) were combined using a fixed-effects meta-analysis. Findings We identified 130 718 patients with rheumatoid arthritis across the three databases. During 100 790 person-years of follow-up, 3140 serious infections occurred (crude incidence rate per 100 person-years 3·12, 95% CI 3·01–3·23). The aHR for serious infection associated with tofacitinib was 1·41 (95% CI 1·15–1·73) versus etanercept, 1·20 (0·97–1·49) versus abatacept, 1·23 (0·94–1·62) versus golimumab, and 1·17 (0·89–1·53) versus tocilizumab. The serious infection risk with tofacitinib was similar to adalimumab (1·06, 0·87–1·30) and certolizumab (1·02, 0·80–1·29), and was lower than infliximab (0·81, 0·65–1·00). Tofacitinib was associated with a 2-fold higher risk of herpes zoster versus all bDMARDs. Interpretation This study found potential differences between tofacitinib and several bDMARDs in the risk of admission to hospital for serious infection, as well as herpes zoster, in patients with rheumatoid arthritis. These results contribute to the evolving understanding of the overall risk-benefit profile of tofacitinib. Funding Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Harvard Medical School, Harvard University, MA, USA.

Aims Medicines regulators issue post-market safety warnings to advise of newly uncovered risks, but with mixed impacts. We aimed to identify factors influencing the use of regulatory warnings by primary care and specialist physicians in the US and Australia. Methods Semi-structured qualitative interviews were carried out with 40 primary care physicians, endocrinologists and other generalist specialists in Boston (USA) and Australia. Coding and analysis were performed inductively and iteratively to identify and examine key factors. Analysis centred around four areas: physicians' awareness of drug safety information, preferred information sources, opinion-forming and sharing of information with patients. Results Uncertainty, trust and clinical authority emerged as factors influencing use of advisories. Although regulators were trusted as authoritative institutions, they appeared to lack clinical authority, and physicians validated regulatory information against other trusted sources including evidence, expert opinion and experience. Specialists became aware of drug safety issues through specialised literature, using evidence and clinical consensus to form opinions. Primary care physicians, fielding high volumes of information, relied on convenient, accessible information sources including the media and the "clinical grapevine" for awareness, and on clinical colleagues, specialists and experience for interpretation. Communicating risk to patients was complicated by uncertainty; physicians tailored information to patients' health literacy and information needs. US physicians were more aware of their national regulator's post-market safety role than Australian physicians of theirs. Conclusion Drug safety warnings may not be optimally received or used. Regulators should consider strategies that increase trust, clinical relevance and accessibility, and address physicians' needs in communicating risk to patients.

Background Empagliflozin (EMPA) reduced the risk of hospitalization for heart failure (HHF) (HR 0.65; 95% CI 0.50- 0.85) as demonstrated in the EMPA-REG OUTCOME trial in adults with type 2 diabetes (T2D) and established CV disease. However, the impact of EMPA treatment initiation on healthcare resource utilization (HCRU) in routine care in patients with history of heart failure (HF) or without history of HF remains unexplored. Purpose To compare HCRU among EMPA and dipeptidyl peptidase-4 inhibitor (DPP4i) initiators with and without HF history at time of treatment initiation. Methods We analyzed HCRU in the first two years after marketing of EMPA as part of EMPRISE, a non-interventional study on the comparative effectiveness, safety and HCRU of EMPA for T2D patients in routine care in two US commercial and Medicare claims datasets (08/2014–09/2016). We identified a 1:1 propensity-score-matched cohort of T2D patients ≥18 years initiating either EMPA or a DPP4i with and without baseline HF, and assessed the balance at baseline (period of 365 days) on ≥140 covariates including clinical, HCRU, and cost-related covariates using absolute standardized differences. We compared the risk of first all-cause hospitalization, risk of first HHF, risk of first emergency department (ED) visit, hospital length of stay (LOS), HF-related LOS, number of hospital admissions, HF-related hospital admissions, office visits, and ED visits in EMPA and DDP4i initiators. Results After propensity score matching, we identified 2,050 pairs with HF and 15,428 pairs without HF in the three datasets with mean follow-up of 5.2 and 5.4 months, respectively. All baseline characteristics were well balanced (with aSD Compared to DPP4i, the hazard ratio (HR) for first hospitalization was 0.68 (95% CI: 0.56, 0.83) for EMPA initiators with HF, and 0.89 (95% CI: 0.80, 1.00) for initiators without HF. Risk of HF-related hospitalization and ED visit was lower in EMPA initiators with prior HF [HR=0.53 (0.38, 0.74) and HR=0.73 (0.58, 0.93), respectively] and without prior HF [HR=0.45 (0.27, 0.73) and HR=0.82 (0.70, 0.95), respectively]. Compared to DPP4i initiators, EMPA initiators with and without baseline HF had lower number of all hospital admissions [Incidence rate ratio (IRR)= 0.59 (0.50, 0.70) and IRR= 0.78 (0.71, 0.85), respectively] and HF-related hospital admissions [IRR=0.49 (0.37, 0.65) and IRR=0.34 (0.22, 0.53), respectively]. In-hospital days and HF-related in-hospital days per member per year (PMPY) in patients with and without HF history initiating EMPA were lower than DDP4i (Table 1). Conclusions Results observed in this interim analysis of EMPRISE showed reduction in overall HCRU as well as HF-related HCRU in both patients with and without heart failure (HF) initiating EMPA compared to DDP4i initiators. Acknowledgement/Funding This study was supported by a research grant to the Brigham and Women's Hospital from Boehringer-Ingelheim.

EMPRISE studies the comparative effectiveness, safety and health care resource utilization of empagliflozin (EMPA) in Medicare and 2 U.S. commercial claims datasets (2014-2019). In this first analysis, we evaluated healthcare costs and medications burden associated with EMPA vs. dipeptidyl peptidase 4 inhibitors (DPP-4i) use in routine care patients with type 2 diabetes (T2D). We identified a 1:1 propensity-score-matched cohort of T2D patients ≥18 years initiating either EMPA or DPP-4i between 08/2014-09/2016. Total (inpatient, outpatient, pharmacy) cost and medication burden were compared for EMPA vs. DPP-4i. We identified 17,549 matched pairs with balanced baseline characteristics (Table 1) with mean follow-up of 5.4 months. Per member per year (PMPY) total cost was similar among EMPA vs. DDP4i initiators ($17,771 vs. $17,814; Diff= -$43, 95% CI: -1,380─1,295). Medical costs tended to be lower and pharmacy costs were higher in EMPA initiators. Distinct medication prescriptions were slightly lower among EMPA initiators [Incidence rate ratio 0.97, 95% CI: 0.96─0.98]. Results stratified by history of CV disease were consistent. Within the first two years of EMPRISE, we observed similar total cost, driven by trend towards lower medical and higher pharmacy costs, and lower medication burden in EMPA vs. DDP4i initiators. Disclosure A. Pawar: None. E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim International GmbH. A. Deruaz-Luyet: Employee; Self; Boehringer Ingelheim International GmbH. Employee; Spouse/Partner; Medtronic, Sanofi. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. A.V. Ustyugova: Employee; Self; Boehringer Ingelheim International GmbH. N. Gautam: None. L.G. Bessette: None. S. Schneeweiss: Consultant; Self; Aetion, WHISCON, LLC. M. Najafzadeh: Consultant; Self; Epigenomics. Funding Boehringer Ingelheim

Objective To evaluate the risk of first trimester exposure to prescription opioids for major congenital malformations, previously reported to be associated with such exposure. Design Population based cohort study. Setting Nationwide sample of publicly and commercially insured pregnant women linked to their liveborn infants, nested in the Medicaid Analytic eXtract (MAX, 2000-14) and the MarketScan Research Database (MarketScan, 2003-15). Participants 1 602 580 publicly insured (MAX) and 1 177 676 commercially insured (MarketScan) pregnant women with eligibility from at least three months before pregnancy to one month after delivery; infants with eligibility for at least three months after birth. Interventions Use of prescription opioids was ascertained by requiring two or more dispensations of any opioid during the first trimester. Main outcomes measures Major malformations overall, cardiac malformations overall, ventricular septal defect, secundum atrial septal defect/patent foramen ovale, neural tube defect, clubfoot, and oral cleft, defined based on validated algorithms. Propensity score stratification was used to adjust for potential confounders and/or proxies for confounders. Estimates from each database were combined using meta-analysis. Results 70 447 (4.4%) of 1 602 580 publicly insured and 12 454 (1.1%) of 1 177 676 commercially insured pregnant women had two or more dispensations of an opioid during the first trimester. Absolute risk of malformations overall was 41.0 (95% confidence interval 39.5 to 42.5) per 1000 pregnancies exposed to opioids versus 32.0 (31.7 to 32.3) per 1000 unexposed pregnancies in the MAX cohort, and 42.6 (39.0 to 46.1) and 37.3 (37.0 to 37.7) per 1000, respectively, in the MarketScan cohort. Pooled unadjusted relative risk estimates were raised for all outcomes but shifted substantially toward the null after adjustment; for malformations overall (relative risk 1.06, 95% confidence interval 1.02 to 1.10), cardiovascular malformations (1.09, 1.00 to 1.18), ventricular septal defect (1.07, 0.95 to 1.21), atrial septal defect/patent foramen ovale (1.04, 0.88 to 1.24), neural tube defect (0.82, 0.53 to 1.27), and clubfoot (1.06, 0.88 to 1.28). The relative risk for oral clefts remained raised after adjustment (1.21, 0.98 to 1.50), with a higher risk of cleft palate (1.62, 1.23 to 2.14). Conclusions Prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered, although a small increase in the risk of oral clefts associated with their use is possible.