Publications by authors named "Joseph S Ross"

474 Publications

Evaluation of Trials Comparing Single-Enantiomer Drugs to Their Racemic Precursors: A Systematic Review.

JAMA Netw Open 2021 May 3;4(5):e215731. Epub 2021 May 3.

Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut.

Importance: Chiral switching, a strategy in which drug manufacturers develop a single-enantiomer formulation of a drug to be substituted for a racemic formulation, allows manufacturers to maintain market exclusivity for drugs losing patent protection, even without demonstrating superior efficacy or safety.

Objective: To identify and characterize all randomized clinical trials (RCTs) directly comparing a Food and Drug Administration (FDA)-approved single-enantiomer drug against a previously approved racemic drug for 1 or more efficacy or safety end points.

Evidence Review: Drugs were identified using the Drugs@FDA database. Randomized clinical trials were identified using Ovid MEDLINE (1949 to October 22, 2019), Ovid Embase (1974 to October 22, 2019), Web of Science Core Collection (all years), ClinicalTrials.gov, and Cochrane Central Registry of Controlled Trials (CENTRAL, Wiley, Issue 8 of 12, October 22, 2019). Trials were characterized as favoring the single-enantiomer or racemic drugs based on whether the primary efficacy, secondary efficacy, and safety end points achieved each study's defined significance level (eg, P < .05). Trials were characterized as favoring neither drug if no statistically significant differences were reported for any end point or if both drugs were found to be superior for 1 or more separate end points.

Findings: Fifteen FDA-approved single-enantiomer drugs were identified with racemic precursors approved in the US or Europe. For 3 single-enantiomer racemic drug pairs, no RCTs directly comparing the drugs were identified. For the remaining 12 pairs, 185 RCTs comparing efficacy or safety of the drug pairs were identified, 124 (67.0%) of which studied 1 pair (levobupivacaine/bupivacaine). There were 179 RCTs directly comparing drug pairs using efficacy end points, of which 23 (12.8%) favored the single enantiomer based on primary efficacy end point results. There were 124 RCTs directly comparing drug pairs using safety end points, of which 17 (13.7%) favored the single-enantiomer drug. For 9 of the 15 single-enantiomer drugs (60.0%), no RCTs were identified providing evidence of improved efficacy, based on primary end point results, or safety as compared with their racemic precursors.

Conclusions And Relevance: The results of this systematic review suggest that most newly marketed FDA-approved single-enantiomer drugs are infrequently directly compared with their racemic precursors, and when compared, they are uncommonly found to provide improved efficacy or safety, despite their greater costs.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.5731DOI Listing
May 2021

Evaluation of Drug Trials in High-, Middle-, and Low-Income Countries and Local Commercial Availability of Newly Approved Drugs.

JAMA Netw Open 2021 May 3;4(5):e217075. Epub 2021 May 3.

Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Clinical research supporting US Food and Drug Administration (FDA) drug approvals is largely conducted outside the US.

Objective: To characterize where drugs were tested for FDA approval and to determine how commonly and quickly these drugs received marketing approval in the countries where they were tested, both overall and by country income level and geographical region.

Design, Setting, And Participants: This cross-sectional analysis of trials supporting FDA approval of novel drugs in 2012 and 2014, sponsored by large drug companies, did not involve human participants. The settings were the countries hosting trials supporting US drug approval. Data sources included Drugs@FDA, ClinicalTrials.gov, PubMed, Google Scholar, EMBASE, and drug regulatory agency websites. Data analysis was completed March through September 2020.

Main Outcomes And Measures: The primary outcomes were the proportion of drugs approved for marketing in the countries where they were tested for FDA approval within 1, 2, 3, 4, and 5 years of FDA approval and the proportion of countries contributing participants to trials supporting FDA approvals receiving market access to the drugs they helped test within 1, 2, 3, 4, and 5 years of FDA approval.

Results: In 2012 and 2014, the FDA approved 34 novel drugs sponsored by large companies, on the basis of a total of 898 trials, 563 of which had location information available. Each drug was tested in a median (interquartile range [IQR]) of 25 (18-37) unique countries, including a median (IQR) of 20 (13-25) high-income countries, 6 (4-11) upper-middle-income countries, and 1 (0-2) low-middle-income country. One drug was approved for marketing in all testing countries within 1 year of FDA approval and 15% (5 of 34 drugs) were approved in all testing countries within 5 years of FDA approval. Of the 70 countries contributing research participants for FDA drug approvals, 7% (5 countries) received market access to drugs they helped test within 1 year of FDA approval and 31% (22 countries) did so within 5 years. Access within 1 year occurred in 13% (5 of 39) of high-income countries, 0 of 22 upper-middle-income countries (0%), and 0 of 9 lower-middle-income countries (0%), whereas at 5 years access rates were 46% (18 of 39 countries), 9% (2 of 22 countries), and 22% (2 of 9 countries), respectively. Approvals were faster in high-income countries (median [IQR], 8 [0-11] months) than in upper-middle-income countries (median [IQR], 11 [5-29] months) or lower-middle-income countries (median [IQR], 17 [11-27] months) after FDA approval. Access was lowest in African countries.

Conclusions And Relevance: These findings suggest that substantial gaps exist between where FDA-approved drugs are tested and where they ultimately become available to patients, raising concerns about the equitable distribution of research benefits at the population level.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.7075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100865PMC
May 2021

Reporting of Study Participant Demographic Characteristics and Demographic Representation in Premarketing and Postmarketing Studies of Novel Cancer Therapeutics.

JAMA Netw Open 2021 Apr 1;4(4):e217063. Epub 2021 Apr 1.

Section of General Internal Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.

Importance: Adequate representation of demographic subgroups in premarketing and postmarketing clinical studies is necessary for understanding the safety and efficacy associated with novel cancer therapeutics.

Objective: To characterize and compare the reporting of demographic data and the representation of individuals by sex, age, and race in premarketing and postmarketing studies used by the Food and Drug Administration (FDA) to evaluate novel cancer therapeutics.

Design, Setting, And Participants: In this cross-sectional study, premarketing and postmarketing studies for novel cancer therapeutics approved by the FDA from 2012 through 2016 were identified. Study demographic information was abstracted from publicly available sources, and US cancer population demographic data was abstracted from US Cancer Statistics. Analyses were conducted from February 25 through September 21, 2020.

Main Outcomes And Measures: The percentages of trials reporting sex, age, and race/ethnicity were calculated, and participation to prevalence ratios (PPRs) were calculated by dividing the percentage of study participants in each demographic group by the percentage of the US cancer population in each group. PPRs were constructed for premarketing and postmarketing studies and by cancer type. Underrepresentation was defined as PPR less than 0.8.

Results: From 2012 through 2016, the FDA approved 45 cancer therapeutics. The study sample included 77 premarketing studies and 56 postmarketing studies. Postmarketing studies, compared with premarketing studies, were less likely to report patient sex (42 studies reporting [75.0%] vs 77 studies reporting [100%]; P < .001) and race (27 studies reporting [48.2%] vs 62 studies reporting [80.5%]; P < .001). Women were adequately represented in premarketing studies (mean [SD] PPR, 0.91; 95% CI, 0.90-0.91) and postmarketing studies (mean PPR, 1.00; 95% CI, 1.00-1.01). Although older adults and Black patients were underrepresented in premarketing studies (older adults: mean PPR, 0.73; 95% CI, 0.72-0.74; Black patients: mean PPR, 0.32; 95% CI, 0.31-0.32), these groups continued to be underrepresented in postmarketing studies (older adults: mean PPR, 0.75; 95% CI, 0.75-0.76; Black patients: mean PPR, 0.21; 95% CI, 0.21-0.21).

Conclusions And Relevance: This study found that older adults and Black patients were underrepresented in postmarketing studies of novel cancer therapeutics to a similar degree that they were underrepresented in premarketing studies. These findings suggest that postmarketing studies are not associated with improvements to gaps in demographic representation present at the time of FDA approval.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.7063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058642PMC
April 2021

US Food and Drug Administration utilization of postmarketing requirements and postmarketing commitments, 2009-2018.

Clin Trials 2021 Apr 16:17407745211005044. Epub 2021 Apr 16.

Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.

Background/aims: The US Food and Drug Administration outlines clinical studies as postmarketing requirements and commitments to be fulfilled following approval of new drugs and biologics ("therapeutics"). Regulators have increasingly emphasized lifecycle evaluation of approved therapeutics, and postmarketing studies are intended to advance our understanding of therapeutic safety and efficacy. However, little is known about the indications that clinical studies outlined in postmarketing requirements and commitments investigate, including whether they are intended to generate evidence for approved or other clinical indications. Therefore, we characterized US Food and Drug Administration postmarketing requirements and commitments for new therapeutics approved from 2009 to 2018.

Methods: We conducted a cross-sectional study of all novel therapeutics, including small-molecule drugs and biologics, receiving original US Food and Drug Administration approval from 2009 to 2018, using approval letters accessed through the Drug@FDA database. Outcomes included the number and characteristics of US Food and Drug Administration postmarketing requirements and commitments for new therapeutics at original approval, including the types of studies outlined, the indications to be investigated, and the clinical evidence to be generated.

Results: From 2009 to 2018, the US Food and Drug Administration approved 343 new therapeutics with 1978 postmarketing requirements and commitments. Overall, 750 (37.9%) postmarketing requirements and commitments outlined clinical studies. For 71 of 343 (20.7%) therapeutics, no postmarketing requirements or commitments for clinical studies were outlined, while at least 1 was outlined for 272 (79.3%; median 2 (interquartile range: 1-4)). Among these 272 therapeutics, the number of postmarketing requirements and commitments for clinical studies per therapeutic did not change from 2009 (median: 2 (interquartile range: 1-4)) to 2018 (median: 2 (interquartile range: 1-3)). Among the 750 postmarketing requirements and commitments for clinical studies, 448 (59.7%) outlined new prospective cohort studies, registries, or clinical trials, while the remainder outlined retrospective studies, secondary analyses, or completion of ongoing studies. Although 455 (60.7%) clinical studies investigated only original approved therapeutic indications, 123 (16.4%) enrolled from an expansion of the approved disease population and 61 (8.1%) investigated diseases unrelated to approved indications.

Conclusions: The US Food and Drug Administration approves most new therapeutics with at least 1 postmarketing requirement or commitment for a clinical study, and outlines investigations of safety or efficacy for both approved and unapproved indications. The median number of 2 clinical studies outlined has remained relatively constant over the last decade. Given increasing emphasis by the US Food and Drug Administration on faster approval and lifecycle evaluation of therapeutics, these findings suggest that more postmarketing requirements and commitments may be necessary to address gaps in the clinical evidence available for therapeutics at approval.
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http://dx.doi.org/10.1177/17407745211005044DOI Listing
April 2021

Misreporting of Results of Research in Psychiatry.

Schizophr Bull 2021 Apr 16. Epub 2021 Apr 16.

Stanley Medical Research Institute, Kensington, MD, USA.

Few studies address publication and outcome reporting biases of randomized controlled trials (RCTs) in psychiatry. The objective of this study was to determine publication and outcome reporting bias in RCTs funded by the Stanley Medical Research Institute (SMRI), a U.S. based, non-profit organization funding RCTs in schizophrenia and bipolar disorder. We identified all RCTs (n = 280) funded by SMRI between 2000 and 2011, and using non-public, final study reports and published manuscripts, we classified the results as positive or negative in terms of the drug compared to placebo. Design, outcome measures and statistical methods specified in the original protocol were compared to the published manuscript. Of 280 RCTs funded by SMRI between 2000 and 2011, at the time of this writing, three RCTs were ongoing and 39 were not performed. Among the 238 completed RCTs, 86 (36.1%) reported positive and 152 (63.9%) reported negative results: 86% (74/86) of those with positive findings were published in contrast to 53% (80/152) of those with negative findings (P < .001). In 70% of the manuscripts published, there were major discrepancies between the published manuscript and the original RCT protocol (change in the primary outcome measure or statistics, change in a number of patient groups, 25% or more reduction in sample size). We conclude that publication bias and outcome reporting bias is common in papers reporting RCTs in schizophrenia and bipolar disorder. These data have major implications regarding the validity of the reports of clinical trials published in the literature.
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http://dx.doi.org/10.1093/schbul/sbab040DOI Listing
April 2021

Covid-19, open science, and the CVD-COVID-UK initiative.

Authors:
Joseph S Ross

BMJ 2021 04 7;373:n898. Epub 2021 Apr 7.

Section of General Medicine Department of Internal Medicine, Yale University School of Medicine, PO box 208093, New Haven, CT 06520-8093, USA.

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http://dx.doi.org/10.1136/bmj.n898DOI Listing
April 2021

Leveraging Open Science to Accelerate Research.

N Engl J Med 2021 Apr 24;384(17):e61. Epub 2021 Mar 24.

From Lincoln College, University of Oxford, Oxford, United Kingdom (K.T.K.); Harvard Medical School and Harvard Business School, Boston (A.L.B.); the Section of General Internal Medicine (J.S.R.), the National Clinician Scholars Program (J.S.R.), and the Section of Cardiovascular Medicine (H.M.K.), the Department of Internal Medicine, Yale School of Medicine, the Department of Health Policy and Management, Yale School of Public Health (J.S.R., H.M.K.), and the Center for Outcomes Research and Evaluation, Yale New Haven Hospital (J.S.R., H.M.K.) - all in New Haven.

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http://dx.doi.org/10.1056/NEJMp2034518DOI Listing
April 2021

Medicare's New Device-Coverage Pathway - Breakthrough or Breakdown?

N Engl J Med 2021 Mar 10;384(12):e43. Epub 2021 Mar 10.

From the Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Boston (V.K.R.); the Section of General Medicine (J.S.R.), Yale School of Medicine (J.L.J.), New Haven, CT; and the Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco (S.S.D.).

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http://dx.doi.org/10.1056/NEJMp2101874DOI Listing
March 2021

U.S. Prescribing of On-and-Off-Label Medications for Alcohol Use Disorder in Outpatient Visits: NAMCS 2014 to 2016.

J Gen Intern Med 2021 Mar 5. Epub 2021 Mar 5.

Section of General Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1007/s11606-021-06668-xDOI Listing
March 2021

Effects of forced disruption in Medicaid managed care on children with asthma.

Health Serv Res 2021 Feb 23. Epub 2021 Feb 23.

Department of Health Policy and Management, Yale University School of Public Health, New Haven, Connecticut, USA.

Objective: To evaluate the effect of a forced disruption to Medicaid managed care plans and provider networks on health utilization and outcomes for children with persistent asthma.

Data Sources: Medicaid managed care administrative claims data from 2013 to 2016, obtained from a southeastern state.

Study Design: A difference-in-difference analysis compared patients' outpatient, inpatient, and emergency department (ED) utilization and receipt of recommended services before and after implementation of a statewide redistribution of patients among nine managed care plans.

Data Collection/extraction Methods: Enrollment data for children with asthma were linked to the administrative claims. Children were included if they had a diagnosis of persistent asthma in 2013 and if they were enrolled continuously throughout 2014-2016.

Principal Findings: Among the 28 537 children with asthma, 26% were forced to switch their managed care plan after the redistribution. Of these, 67% also switched their primary care provider (PCP). Relative to those who remained in their plan, disruption was associated with an additional 2.1 percentage-point decrease in the number of children who had an outpatient visit per quarter [95%CI -2.8, -1.3], from 71% to 66% (compared to plan stayers: 74% to 71%). Among children experiencing a change to their plan, there was overall a decrease in the proportion of children receiving an asthma-specific visit per quarter, but there was less of a decrease in children that also changed their PCP [1.6 percentage points, 95%CI 0.7, 2.5], from 9.7% to 8.3% (compared to those who did not switch their PCP: 12% to 8.6%). Indicators of asthma care quality and emergent care utilization were not significantly different between the two periods.

Conclusions: While there was a decrease in the number of outpatient visits associated with forced disruption of Medicaid managed care plans for children with persistent asthma, there were no consistent associations with worse asthma quality performance or higher emergent health care utilization.
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http://dx.doi.org/10.1111/1475-6773.13643DOI Listing
February 2021

Use of Mechanical Circulatory Support Devices Among Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock.

JAMA Netw Open 2021 02 1;4(2):e2037748. Epub 2021 Feb 1.

Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut.

Importance: Mechanical circulatory support (MCS) devices, including intravascular microaxial left ventricular assist devices (LVADs) and intra-aortic balloon pumps (IABPs), are used in patients who undergo percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) complicated by cardiogenic shock despite limited evidence of their clinical benefit.

Objective: To examine trends in the use of MCS devices among patients who underwent PCI for AMI with cardiogenic shock, hospital-level use variation, and factors associated with use.

Design, Setting, And Participants: This cross-sectional study used the CathPCI and Chest Pain-MI Registries of the American College of Cardiology National Cardiovascular Data Registry. Patients who underwent PCI for AMI complicated by cardiogenic shock between October 1, 2015, and December 31, 2017, were identified from both registries. Data were analyzed from October 2018 to August 2020.

Exposures: Therapies to provide hemodynamic support were categorized as intravascular microaxial LVAD, IABP, TandemHeart, extracorporeal membrane oxygenation, LVAD, other devices, combined IABP and intravascular microaxial LVAD, combined IABP and other device (defined as TandemHeart, extracorporeal membrane oxygenation, LVAD, or another MCS device), or medical therapy only.

Main Outcomes And Measures: Use of MCS devices overall and specific MCS devices, including intravascular microaxial LVAD, at both patient and hospital levels and variables associated with use.

Results: Among the 28 304 patients included in the study, the mean (SD) age was 65.4 (12.6) years and 18 968 were men (67.0%). The overall MCS device use was constant from the fourth quarter of 2015 to the fourth quarter of 2017, although use of intravascular microaxial LVADs significantly increased (from 4.1% to 9.8%; P < .001), whereas use of IABPs significantly decreased (from 34.8% to 30.0%; P < .001). A significant hospital-level variation in MCS device use was found. The median (interquartile range [IQR]) proportion of patients who received MCS devices was 42% (30%-54%), and the median proportion of patients who received intravascular microaxial LVADs was 1% (0%-10%). In multivariable analyses, cardiac arrest at first medical contact or during hospitalization (odds ratio [OR], 1.82; 95% CI, 1.58-2.09) and severe left main and/or proximal left anterior descending coronary artery stenosis (OR, 1.36; 95% CI, 1.20-1.54) were patient characteristics that were associated with higher odds of receiving intravascular microaxial LVADs only compared with IABPs only.

Conclusions And Relevance: This study found that, among patients who underwent PCI for AMI complicated by cardiogenic shock, overall use of MCS devices was constant, and a 2.5-fold increase in intravascular microaxial LVAD use was found along with a corresponding decrease in IABP use and a significant hospital-level variation in MCS device use. These trends were observed despite limited clinical trial evidence of improved outcomes associated with device use.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.37748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900859PMC
February 2021

Age-Related Trajectories of Cardiovascular Risk and Use of Aspirin and Statin Among U.S. Adults Aged 50 or Older, 2011-2018.

J Am Geriatr Soc 2021 Feb 17. Epub 2021 Feb 17.

Center on Aging, University of Connecticut Health, Farmington, Connecticut, USA.

Objectives: To examine age-related trajectories of cardiovascular risk and use of aspirin and statin among U.S. adults aged 50 or older.

Design: Repeated cross-sectional study using data from 2011 to 2018 National Health and Nutrition Examination Surveys.

Setting: Nationally representative health interview survey in the United States.

Participants: Non-institutionalized adults aged 50 years and older (n = 11,392 unweighted).

Measurements: Primary prevention was defined as the prevention of a first cardiovascular event including coronary heart disease, angina/angina pectoris, heart attack, or stroke, whereas secondary prevention was defined as those with a history of these clinical conditions. Medication use was determined by self-report; aspirin use included dose and frequency, and statin use included generic names, days of prescription fills, and indications. We examined linear trends between age and each medication use, after controlling for period, sex, and race/ethnicity.

Results: Prevalence of those eligible for primary prevention treatment increased with age from 31.8% in ages 50-54 to 52.0% in ages ≥75 (p < 0.001). Similarly, those eligible for secondary prevention treatment increased with age from 2.7% in ages 50-54 to 21.1% in ages ≥75 (p < 0.001). Low-dose daily aspirin use increased with age (p < 0.001), and 45.3% of adults aged ≥75 took low-dose aspirin daily for primary prevention. Statin use also increased with age (p < 0.001), and 56.4% of adults aged ≥75 had long-term statin use for secondary prevention.

Conclusion: While adults aged ≥75 do not benefit from the use of aspirin to prevent the first CVD, many continue to take aspirin on a regular basis. In spite of the clear benefit of statin use to prevent a subsequent CVD event, many older adults in this risk category are not taking a statin. Further education and guidance for both healthcare providers and older adults regarding the appropriate use of aspirin and statins to prevent CVD is needed.
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http://dx.doi.org/10.1111/jgs.17038DOI Listing
February 2021

Physician variation in the de-adoption of ineffective statin and fibrate therapy.

Health Serv Res 2021 Feb 10. Epub 2021 Feb 10.

University of Minnesota, Minneapolis, Minnesota, USA.

Objective: To describe physicians' variation in de-adopting concurrent statin and fibrate therapy for type 2 diabetic patients following a reversal in clinical evidence.

Data Sources: We analyzed 2007-2015 claims data from OptumLabs Data Warehouse, a longitudinal, real-world data asset with de-identified administrative claims and electronic health record data.

Study Design: We modeled fibrate use among Medicare Advantage and commercially insured type 2 diabetic statin users before and after the publication of the ACCORD lipid trial, which found statins and fibrates were no more effective than statins alone in reducing cardiovascular events among type 2 diabetic patients. We modeled fibrate use trends with physician random effects and physician characteristics such as age and specialty.

Data Extraction: We identified patient-year-quarters with one year of continuous insurance enrollment, type 2 diabetes diagnoses, and fibrate use. We designated the physician most responsible for patients' diabetes care based on evaluation and management visits and prescriptions of glucose-lowering drugs.

Principal Findings: Fibrate use increased by 0.12 percentage points per quarter among commercial patients (95% CI, 0.10 to 0.14) and 0.17 percentage points per quarter among Medicare Advantage patients (95% CI, 0.13 to 0.20) before the trial and then decreased by 0.16 percentage points per quarter among commercial patients (95% CI, -0.18 to -0.15) and 0.05 percentage points per quarter among Medicare Advantage patients (95% CI, -0.06 to -0.03) after the trial. However, 45% of physicians treating commercial patients and 48% of physicians treating Medicare Advantage patients had positive trends in prescribing following the trial. Physicians' characteristics did not explain their variation (pseudo R  = 0.000).

Conclusion: On average, physicians decreased fibrate prescribing following the ACCORD lipid trial. However, many physicians increased prescribing following the trial. Observable physician characteristics did not explain variations in prescribing. Future research should examine whether physicians vary similarly in other de-adoption settings.
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http://dx.doi.org/10.1111/1475-6773.13630DOI Listing
February 2021

Publishing at any cost: a cross-sectional study of the amount that medical researchers spend on open access publishing each year.

BMJ Open 2021 02 1;11(2):e047107. Epub 2021 Feb 1.

Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut, USA

Objective: To estimate the financial costs paid by individual medical researchers from meeting the article processing charges (APCs) levied by open access journals in 2019.

Design: Cross-sectional analysis.

Data Sources: Scopus was used to generate two random samples of researchers, the first with a senior author article indexed in the 'Medicine' subject area (general researchers) and the second with an article published in the ten highest-impact factor general clinical medicine journals (high-impact researchers) in 2019. For each researcher, Scopus was used to identify all first and senior author original research or review articles published in 2019. Data were obtained from Scopus, institutional profiles, Journal Citation Reports, publisher databases, the Directory of Open Access Journals, and individual journal websites.

Main Outcome Measures: Median APCs paid by general and high-impact researchers for all first and senior author research and review articles published in 2019.

Results: There were 241 general and 246 high-impact researchers identified as eligible for our study. In 2019, the general and high-impact researchers published a total of 914 (median 2, IQR 1-5) and 1471 (4, 2-8) first or senior author research or review articles, respectively. 42% (384/914) of the articles from the general researchers and 29% (428/1471) of the articles from the high-impact medical researchers were published in fully open access journals. The median total APCs paid by general researchers in 2019 was US$191 (US$0-US$2500) and the median total paid by high-impact researchers was US$2900 (US$0-US$5465); the maximum paid by a single researcher in total APCs was US$30115 and US$34676, respectively.

Conclusions: Medical researchers in 2019 were found to have paid between US$0 and US$34676 in total APCs. As journals with APCs become more common, it is important to continue to evaluate the potential cost to researchers, especially on individuals who may not have the funding or institutional resources to cover these costs.
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http://dx.doi.org/10.1136/bmjopen-2020-047107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852964PMC
February 2021

Comparison of Diabetes Medications Used by Adults With Commercial Insurance vs Medicare Advantage, 2016 to 2019.

JAMA Netw Open 2021 02 1;4(2):e2035792. Epub 2021 Feb 1.

Division of Health Care Policy and Research, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.

Importance: Glucagonlike peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and dipeptidyl peptidase-4 inhibitors (DPP-4i) are associated with low rates of hypoglycemia, and postmarketing trials of GLP-1RA and SGLT2i demonstrated that these medications improved cardiovascular and kidney outcomes.

Objective: To compare trends in initiation of treatment with GLP-1RA, SGLT2i, and DPP-4i by older adults with type 2 diabetes insured by Medicare Advantage vs commercial health plans.

Design, Setting, And Participants: This retrospective cohort study used administrative claims data from a deidentified database of commercially insured and Medicare Advantage beneficiaries. Adults aged 58 to 66 years with type 2 diabetes who filled any medication prescription to lower glucose levels from January 1, 2016, to December 31, 2019, were compared between groups.

Exposure: Enrollment in a Medicare Advantage or commercial health insurance plan.

Main Outcomes And Measures: The odds of initiating GLP-1RA, SGLT2i, and DPP-4i treatment were examined for Medicare Advantage vs commercial insurance beneficiaries using 3 separate logistic regression models adjusted for year and demographic and clinical factors. These models were used to calculate adjusted annual rates of medication initiation by health plan.

Results: A total of 382 574 adults with pharmacologically treated type 2 diabetes (52.9% men; mean [SD] age, 62.4 [2.7] years) were identified, including 172 180 Medicare Advantage and 210 394 commercial beneficiaries. From 2016 to 2019, adjusted rates of initiation of GLP-1RA, SGLT2i, and DPP-4i treatment increased among all beneficiaries, from 2.14% to 20.02% for GLP-1RA among commercial insurance beneficiaries and from 1.50% to 11.44% among Medicare Advantage beneficiaries; from 2.74% to 18.15% for SGLT2i among commercial insurance beneficiaries and from 1.57% to 8.51% among Medicare Advantage beneficiaries; and from 3.30% to 11.71% for DPP-4i among commercial insurance beneficiaries and from 2.44% to 7.68% among Medicare Advantage beneficiaries. Initiation rates for all 3 drug classes were consistently lower among Medicare Advantage than among commercial insurance beneficiaries. Within each calendar year, the odds of initiating GLP-1RA treatment ranged from 0.28 (95% CI, 0.26-0.29) to 0.70 (95% CI, 0.65-0.75) for Medicare Advantage and commercial insurance beneficiaries, respectively; SGLT2i, from 0.21 (95% CI, 0.20-0.22) to 0.57 (95% CI, 0.53-0.61), respectively; and DPP-4i, from 0.37 (95% CI, 0.34-0.39) to 0.73 (95% CI, 0.69-0.78), respectively (P < .001 for all). The odds of starting GLP-1RA and SGLT2i increased with income; for an income of $200 000 and higher vs less than $40 000, the odds ratio for GLP-1RA was 1.23 (95% CI, 1.15-1.32) and for SGLT2i was 1.16 (95% CI, 1.09-1.24).

Conclusions And Relevance: These findings suggest that Medicare Advantage beneficiaries may be less likely than commercially insured beneficiaries to be treated with newer medications to lower glucose levels, with greater disparities among lower-income patients. Better understanding of nonclinical factors contributing to treatment decisions and efforts to promote greater equity in diabetes management appear to be needed.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.35792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851726PMC
February 2021

To Expand the Evidence Base About Harms from Tests and Treatments.

J Gen Intern Med 2021 Jan 21. Epub 2021 Jan 21.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Rigorous evidence about the broad range of harms that might be experienced by a patient in the course of testing and treatment is sparse. We aimed to generate recommendations for how researchers might more comprehensively evaluate potential harms of healthcare interventions, to allow clinicians and patients to better include this evidence in clinical decision-making. We propose seven domains of harms of tests and treatments that are relevant to patients: (1) physical impairment, (2) psychological distress, (3) social disruption, (4) disruption in connection to healthcare, (5) labeling, (6) financial impact, and (7) treatment burden. These domains will include a range of severity of harms and variation in timing after testing or treatment, attributable to the service itself or a resulting care cascade. Although some new measures may be needed, diverse data and tools are available to allow the assessment of harms comprehensively across these domains. We encourage researchers to evaluate harms in sub-populations, since the harms experienced may differ importantly by demographics, social determinants, presence of comorbid illness, psychological state, and other characteristics. Regulators, funders, and editors might require either assessment or reporting of harms in each domain or require justification for inclusion and exclusion of different domains.
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http://dx.doi.org/10.1007/s11606-021-06597-9DOI Listing
January 2021

Reporting of substance use treatment quality in United States adult drug courts.

Int J Drug Policy 2021 Apr 11;90:103050. Epub 2020 Dec 11.

Section of General Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States; SEICHE Center, Yale School of Medicine, New Haven, CT,  United States.

Background: Adult drug courts are growing in popularity within the Unites States, but the quality of substance use treatment within drug court programs and the impact of drug courts on health and substance use treatment outcomes is largely unknown. We appraised the quality of United States adult drug court process evaluations and the inclusion of measures of substance use treatment quality.

Methods: We systematically reviewed the adult drug court evaluations between 2008 and 2018 in accordance with recommended strategies for systematic gray literature search. We appraised evaluation quality using the Evidence for Policy and Practice Information and Coordination Center tool for process evaluations. We extracted recommended measures of substance use treatment quality, including measures related to screening and monitoring, diagnosis, service availability, service utilization, and outcomes.

Results: Our search identified 112 evaluations. Process measures were included within 68 evaluations, 45% of which had poor data reliability. We found that less than 10% of evaluations reported substance use treatment quality measures related to service utilization, overdose, and mortality, while more than 75% contained criminal justice measures, including program graduation (completion of criminal justice proceedings) and participant recidivism.

Conclusions: We found low uptake of measures of substance use treatment quality. The absence of data call into question the ability of drug courts to stem harmful substance use related health outcomes.
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http://dx.doi.org/10.1016/j.drugpo.2020.103050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046712PMC
April 2021

Mandatory Registration and Results Reporting of Real-World Evidence Studies of FDA-Regulated Medical Products.

Mayo Clin Proc 2020 12 21;95(12):2609-2611. Epub 2020 Oct 21.

Section of General Internal Medicine and National Clinician Scholars Program, Yale School of Medicine, New Haven, CT; Department of Health Policy and Management, Yale School of Public Health, New Haven, CT; Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT.

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http://dx.doi.org/10.1016/j.mayocp.2020.04.013DOI Listing
December 2020

Submissions and Downloads of Preprints in the First Year of medRxiv.

JAMA 2020 11;324(18):1903-1905

Section of General Internal Medicine, Yale School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1001/jama.2020.17529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656287PMC
November 2020

Association Between Industry Payments to Physicians and Device Selection in ICD Implantation.

JAMA 2020 11;324(17):1755-1764

Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut.

Importance: Little is known about the association between industry payments and medical device selection.

Objective: To examine the association between payments from device manufacturers to physicians and device selection for patients undergoing first-time implantation of a cardioverter-defibrillator (ICD) or cardiac resynchronization therapy-defibrillator (CRT-D).

Design, Setting, And Participants: In this cross-sectional study, patients who received a first-time ICD or CRT-D device from any of the 4 major manufacturers (January 1, 2016-December 31, 2018) were identified. The data from the National Cardiovascular Data Registry ICD Registry was linked with the Open Payments Program's payment data. Patients were categorized into 4 groups (A, B, C, and D) corresponding to the manufacturer from which the physician who performed the implantation received the largest payment. For each patient group, the proportion of patients who received a device from the manufacturer that provided the largest payment to the physician who performed implantation was determined. Within each group, the absolute difference in proportional use of devices between the manufacturer that made the highest payment and the proportion of devices from the same manufacturer in the entire study cohort (expected prevalence) was calculated.

Exposures: Manufacturers' payments to physicians who performed an ICD or CRT-D implantation.

Main Outcomes And Measures: The primary outcome of the study was the manufacturer of the device used for the implantation.

Results: Over a 3-year period, 145 900 patients (median age, 65 years; 29.6% women) received ICD or CRT-D devices from the 4 manufacturers implanted by 4435 physicians at 1763 facilities. Among these physicians, 4152 (94%) received payments from device manufacturers ranging from $2 to $323 559 with a median payment of $1211 (interquartile range, $390-$3702). Between 38.5% and 54.7% of patients received devices from the manufacturers that had provided physicians with the largest payments. Patients were substantially more likely to receive devices made by the manufacturer that provided the largest payment to the physician who performed implantation than they were from each other individual manufacturer. The absolute differences in proportional use from the expected prevalence were 22.4% (95% CI, 21.9%-22.9%) for manufacturer A; 14.5% (95% CI, 14.0%-15.0%) for manufacturer B; 18.8% (95% CI, 18.2%-19.4%) for manufacturer C; and 30.6% (95% CI, 30.0%-31.2%) for manufacturer D.

Conclusions And Relevance: In this cross-sectional study, a large proportion of ICD or CRT-D implantations were performed by physicians who received payments from device manufacturers. Patients were more likely to receive ICD or CRT-D devices from the manufacturer that provided the highest total payment to the physician who performed an ICD or CRT-D implantation than each other manufacturer individually.
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http://dx.doi.org/10.1001/jama.2020.17436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610190PMC
November 2020

The Promise of Big Data and Digital Solutions in Building a Cardiovascular Learning System: Opportunities and Barriers.

Methodist Debakey Cardiovasc J 2020 Jul-Sep;16(3):212-219

YALE SCHOOL OF MEDICINE, NEW HAVEN, CONNECTICUT.

The learning health system is a conceptual model for continuous learning and knowledge generation rooted in the daily practice of medicine. While companies such as Google and Amazon use dynamic learning systems that learn iteratively through every customer interaction, this efficiency has not materialized on a comparable scale in health systems. An ideal learning health system would learn from every patient interaction to benefit the care for the next patient. Notable advances include the greater use of data generated in the course of clinical care, Common Data Models, and advanced analytics. However, many remaining barriers limit the most effective use of large and growing health care data assets. In this review, we explore the accomplishments, opportunities, and barriers to realizing the learning health system.
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http://dx.doi.org/10.14797/mdcj-16-3-212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587314PMC
November 2020

Transparency and Accountability of Medicaid Section 1115 Waiver Demonstration Programs Under the Affordable Care Act.

JAMA Netw Open 2020 10 1;3(10):e2022035. Epub 2020 Oct 1.

National Clinician Scholars Program, Department of Internal Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut.

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http://dx.doi.org/10.1001/jamanetworkopen.2020.22035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588940PMC
October 2020

Association between FDA and EMA expedited approval programs and therapeutic value of new medicines: retrospective cohort study.

BMJ 2020 10 7;371:m3434. Epub 2020 Oct 7.

Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Objective: To characterize the therapeutic value of new drugs approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) and the association between these ratings and regulatory approval through expedited programs.

Design: Retrospective cohort study.

Setting: New drugs approved by the FDA and EMA between 2007 and 2017, with follow-up through 1 April 2020.

Data Sources: Therapeutic value was measured using ratings of new drugs by five independent organizations (Prescrire and health authorities of Canada, France, Germany, and Italy).

Main Outcome Measures: Proportion of new drugs rated as having high therapeutic value; association between high therapeutic value rating and expedited status.

Results: From 2007 through 2017, the FDA and EMA approved 320 and 268 new drugs, respectively, of which 181 (57%) and 39 (15%) qualified for least one expedited program. Among 267 new drugs with a therapeutic value rating, 84 (31%) were rated as having high therapeutic value by at least one organization. Compared with non-expedited drugs, a greater proportion of expedited drugs were rated as having high therapeutic value among both FDA approvals (45% (69/153) 13% (15/114); P<0.001) and EMA approvals (67% (18/27) 27% (65/240); P<0.001). The sensitivity and specificity of expedited program for a drug being independently rated as having high therapeutic value were 82% (95% confidence interval 72% to 90%) and 54% (47% to 62%), respectively, for the FDA, compared with 25.3% (16.4% to 36.0%) and 90.2% (85.0% to 94.1%) for the EMA.

Conclusions: Less than a third of new drugs approved by the FDA and EMA over the past decade were rated as having high therapeutic value by at least one of five independent organizations. Although expedited drugs were more likely than non-expedited drugs to be highly rated, most expedited drugs approved by the FDA but not the EMA were rated as having low therapeutic value.
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http://dx.doi.org/10.1136/bmj.m3434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537471PMC
October 2020

Comparative Effectiveness and Safety of Oral Anticoagulants Across Kidney Function in Patients With Atrial Fibrillation.

Circ Cardiovasc Qual Outcomes 2020 10 5;13(10):e006515. Epub 2020 Oct 5.

Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery (X.Y., J.W.I., C.G.N., N.D.S., P.A.N.), and Department of Internal Medicine, Mayo Clinic, Rochester, MN.

Background: Patients with atrial fibrillation and severely decreased kidney function were excluded from the pivotal non-vitamin K antagonist oral anticoagulants (NOAC) trials, thereby raising questions about comparative safety and effectiveness in patients with reduced kidney function. The study aimed to compare oral anticoagulants across the range of kidney function in patients with atrial fibrillation.

Methods And Results: Using a US administrative claims database with linked laboratory data, 34 569 new users of oral anticoagulants with atrial fibrillation and estimated glomerular filtration rate ≥15 mL/(min·1.73 m) were identified between October 1, 2010 to November 29, 2017. The proportion of patients using NOACs declined with decreasing kidney function-73.5%, 69.6%, 65.4%, 59.5%, and 45.0% of the patients were prescribed a NOAC in estimated glomerular filtration rate ≥90, 60 to 90, 45 to 60, 30 to 45, 15 to 30 mL/min per 1.73 m groups, respectively. Stabilized inverse probability of treatment weighting was used to balance 4 treatment groups (apixaban, dabigatran, rivaroxaban, and warfarin) on 66 baseline characteristics. In comparison to warfarin, apixaban was associated with a lower risk of stroke (hazard ratio [HR], 0.57 [0.43-0.75]; <0.001), major bleeding (HR, 0.51 [0.44-0.61]; <0.001), and mortality (HR, 0.68 [0.56-0.83]; <0.001); dabigatran was associated with a similar risk of stroke but a lower risk of major bleeding (HR, 0.57 [0.43-0.75]; <0.001) and mortality (HR, 0.68 [0.48-0.98]; =0.04); rivaroxaban was associated with a lower risk of stroke (HR, 0.69 [0.51-0.94]; =0.02), major bleeding (HR, 0.84 [0.72-0.99]; =0.04), and mortality (HR, 0.73 [0.58-0.91]; =0.006). There was no significant interaction between treatment and estimated glomerular filtration rate categories for any outcome. When comparing one NOAC to another NOAC, there was no significant difference in mortality, but some differences existed for stroke or major bleeding. No relationship between treatments and falsification end points was found, suggesting no evidence for substantial residual confounding.

Conclusions: Relative to warfarin, NOACs are used less frequently as kidney function declines. However, NOACs appears to have similar or better comparative effectiveness and safety across the range of kidney function.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.006515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580213PMC
October 2020