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Increased interest in real-world evidence (RWE) for clinical and regulatory decision making and the need to evaluate long-term benefits and risks of pharmaceutical products raise the importance of understanding the use of external controls (ECs) for uncontrolled extensions of randomized controlled trials (RCTs). We searched clinicaltrials.gov from 2009 to 2019 for uncontrolled extensions and assessed the use of ECs in the trial protocol registry and PubMed. We present characteristics of identified uncontrolled extensions, their adoption of ECs, and a qualitative appraisal of published uncontrolled extensions with ECs according to good pharmacoepidemiologic practice. The number of uncontrolled extensions increased slightly across the study period, resulting in a total of 1,115 studies. Most originated from phase III RCTs (62.2%) and specified safety outcomes (61.9% among those with specified outcomes). Most uncontrolled extensions incorporated no control group with only 7 out of 1,115 (0.6%) employing ECs. For those studies with ECs, all involved treatments for rare conditions and assessment of effectiveness. Attempts to balance comparison groups varied from none mentioned to propensity score matching. We noted consistent deficiencies in outcome ascertainment methods and approaches to address attrition bias. The contrast of the large and growing number of uncontrolled extensions with the small number of studies that utilized ECs showed clear opportunities for enhancement in design, measurement, and analysis of uncontrolled extensions to allow causal inferences on long-term treatment effects. As extensions continue to expand within RWE regulatory frameworks, development of guidelines for use of EC with uncontrolled extensions is needed.

Purpose Clinical trials compare outcomes among patients receiving study treatment with comparators drawn from the same source. These internal controls are missing in single arm trials and from long‐term extensions (LTE) of trials including only the treatment arm. An external control group derived from a different setting is then required to assess safety or effectiveness. Methods We present examples of external control groups that demonstrate some of the issues that arise and make recommendations to address them through careful assessment of the data source fitness for use, design, and analysis steps. Results Inclusion and exclusion criteria and context that produce a trial population may result in trial patients with different clinical characteristics than are present in an external comparison group. If these differences affect the risk of outcomes, then a comparison of outcome occurrence will be confounded. Further, patients who continue into LTE may differ from those initially entering the trial due to treatment effects. Application of appropriate methods is needed to make valid inferences when such treatment or selection effects are present. Outcome measures in a trial may be ascertained and defined differently from what can be obtained in an external comparison group. Differences in sensitivity and specificity for identification or measurement of study outcomes leads to information bias that can also invalidate inferences. Conclusion This review concentrates on threats to the valid use of external control groups both in the scenarios of single arm trials and LTE of randomized controlled trials, along with methodological approaches to mitigate them.

ObjectiveTo provide current estimates of the number of patients with prevalent systemic lupus erythematosus (SLE) by major health insurance types in the US and describe patient characteristics. Four large US health insurance claims databases were analyzed to represent different types of insurance coverage, including private insurance, Medicaid, and Medicare Supplemental. ResultsOverall unadjusted SLE prevalence per 100,000 persons in the US ranged from 150.1 (private insurance) to 252.9 (Medicare Supplemental insurance). Extrapolating to the US civilian population in 2016, we estimated roughly 345,000 to 404,000 prevalent SLE patients with private/Medicare insurance, and 99,000 prevalent SLE patients with Medicaid insurance.Comorbidities, including renal failure/dialysis were commonly observed across multiple organ systems in SLE patients (8.4-21.1%). We estimated a larger number of prevalent SLE cases in the US civilian population than previous reports and observed extensive disease burden based on a 1-year cross-sectional analysis.

Thrombotic Thrombocytopenia after Ad26.COV2.S Vaccination — Manufacturer’s Response The manufacturer of the Ad26.COV2.S vaccine against Covid-19 comments on recent reports of thrombosis, including ...

Background There has been a more pronounced shift toward earlier, more aggressive therapies in Crohn’s disease than in ulcerative colitis (UC). The aim of this study was to describe the pre-biologic treatment and health care experience, including co-morbidities and overall health care utilization, for UC patients who initiated biologic therapies, in the 5 years prior to the initiation of the first biologic agent. Methods UC patients who initiated a biologic agent approved for UC between 9/15/2005 and 1/30/2018 were identified from the IBM® MarketScan® Commercial Database, a large US database. The date of the first recorded UC biologic exposure was defined as the index date, and ≥ 5 years of pre-index records were required to evaluate patients’ treatment, disease progression and overall health care utilization prior to initiating biologic agents. Results Among the 1891 eligible patients, treatment with oral corticosteroids, 5-aminosalicylates, and other non-biologic immunomodulators, all increased progressively across the 5 years prior to the index. From within year-five to within year-one prior to the index, the median duration of oral corticosteroid treatment increased from 34 to 88 days per year and the proportion of patients who experienced more extensive/pancolitis disease increased from 16 to 59%. Overall, the frequency of all-cause health care visits also increased. Conclusions Patients with UC experienced increasing morbidity and treatment burden in the 5 years prior to initiating biologic therapy. To achieve reduced corticosteroids in UC management, better risk stratification is needed to help identify patients for more timely biologic treatment.

Hana Müllerová,1 Sarah H Landis,1 Zaurbek Aisanov,2 Kourtney J Davis,3 Masakazu Ichinose,4 David M Mannino,5 Joe Maskell,1 Ana M Menezes,6 Thys van der Molen,7 Yeon-Mok Oh,8 Maggie Tabberer,9 MeiLan K Han10 1GSK, Worldwide Epidemiology, Uxbridge, UK; 2Pulmonology Research Institute, Moscow, Russia; 3GSK, Worldwide Epidemiology, Upper Providence, PA, USA; 4Tohoku University Graduate School of Medicine, Sendai, Japan; 5University of Kentucky College of Public Health, Lexington, KY, USA; 6Federal University of Pelotas, Pelotas, Brazil; 7University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 8University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; 9GSK, Value Evidence Outcomes, Uxbridge, UK; 10Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, MI, USA Background and aims: We used data from the Continuing to Confront COPD International Patient Survey to test the hypothesis that patients with COPD who report less engagement with their disease management are also more likely to report greater impact of the disease. Methods: This was a population-based, cross-sectional survey of 4,343 subjects aged ≥40years from 12 countries, fulfilling a case definition of COPD based on self-reported physician diagnosis or symptomatology. The impact of COPD was measured with COPD Assessment Test, modified Medical Research Council Dyspnea Scale, and hospital admissions and emergency department visits for COPD in the prior year. The 13-item Patient Activation Measure (PAM-13) instrument and the 8-item Morisky Medication Adherence Scale (MMAS-8) were used to measure patient disease engagement and medication adherence, respectively. Results: Twenty-eight percent of subjects reported being either disengaged or struggling with their disease (low engagement: PAM-13 levels 1 and 2), and 35% reported poor adherence (MMAS-8

Ana M Menezes,1 Sarah H Landis,2 MeiLan K Han,3 Hana Muellerova,2 Zaurbek Aisanov,4 Thys van der Molen,5 Yeon-Mok Oh,6 Masakazu Ichinose,7 David M Mannino,8 Kourtney J Davis9 1Federal University of Pelotas, Pelotas, Brazil; 2Worldwide Epidemiology, GlaxoSmithKline, Uxbridge, UK; 3Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, MI, USA; 4Pulmonology Research Institute, Moscow, Russia; 5University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 6University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; 7Tohoku University Graduate School of Medicine, Sendai, Japan; 8University of Kentucky College of Public Health, Lexington, KY, USA; 9Worldwide Epidemiology, GlaxoSmithKline, Wavre, Belgium Purpose: Using data from the Continuing to Confront COPD International Physician and Patient Surveys, this paper describes physicians’ attitudes and beliefs regarding chronic obstructive pulmonary disease (COPD) prognosis, and compares physician and patient perceptions with respect to COPD. Methods: In 12 countries worldwide, 4,343 patients with COPD were identified through systematic screening of population samples, and 1,307 physicians who regularly saw patients with COPD were sampled from in-country professional databases. Both patients and physicians completed surveys about their COPD knowledge, beliefs, and perceptions; physicians answered further questions about diagnostic methods and treatment choices for COPD. Results: Most physicians (79%) responded that the long-term health outlook for patients with COPD has improved over the past decade, largely attributed to the introduction of better medications. However, patient access to medication remains an issue in many countries, and some physicians (39%) and patients (46%) agreed/strongly agreed with the statement “there are no truly effective treatments for COPD”. There was strong concordance between physicians and patients regarding COPD management practices, including the use of spirometry (86% of physicians and 76% of patients reporting they used/had undergone a spirometry test) and smoking cessation counseling (76% of physicians reported they counseled their smoking patients at every clinic visit, and 71% of smoking patients stated that they had received counseling in the past year). However, the groups differed in their perception about the role of smoking in COPD, with 78% of physicians versus 38% of patients strongly agreeing with the statement “smoking is the cause of most cases of COPD”. Conclusion: The Continuing to Confront COPD International Surveys demonstrate that while physicians and patients largely agreed about COPD management practices and the need for more effective treatments for COPD, a gap exists about the causal role of smoking in COPD. Keywords: chronic obstructive pulmonary disease, physician survey, patient survey, beliefs, perceptions

Kourtney J Davis,1 Sarah H Landis,2 Yeon-Mok Oh,3 David M Mannino,4 MeiLan K Han,5 Thys van der Molen,6 Zaurbek Aisanov,7 Ana M Menezes,8 Masakazu Ichinose,9 Hana Muellerova11Worldwide Epidemiology, GlaxoSmithKline, Wavre, Belgium; 2Worldwide Epidemiology, GlaxoSmithKline, Uxbridge, UK; 3University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; 4University of Kentucky College of Public Health, Lexington, KY, USA; 5Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, MI, USA; 6University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 7Pulmonology Research Institute, Moscow, Russia; 8Federal University of Pelotas, Pelotas, Brazil; 9Tohoku University Graduate School of Medicine, Sendai, JapanAim: Utilizing data from the Continuing to Confront COPD (chronic obstructive pulmonary disease) International Physician Survey, this study aimed to describe physicians’ knowledge and application of the GOLD (Global initiative for chronic Obstructive Lung Disease) Global Strategy for the Diagnosis, Management and Prevention of COPD diagnosis and treatment recommendations and compare performance between primary care physicians (PCPs) and respiratory specialists.Materials and methods: Physicians from 12 countries were sampled from in-country professional databases; 1,307 physicians (PCP to respiratory specialist ratio three to one) who regularly consult with COPD, emphysema, or chronic bronchitis patients were interviewed online, by telephone or face to face. Physicians were questioned about COPD risk factors, prognosis, diagnosis, and treatment, including knowledge and application of the GOLD global strategy using patient scenarios.Results: Physicians reported using spirometry routinely (PCPs 82%, respiratory specialists 100%; P