Premarket Evidence and Postmarketing Requirements for Real-Time Oncology Review Indication Approvals.

This cross-sectional study evaluates the use of the US Food and Drug Administration's Real-Time Oncology Review (RTOR) program in confirming the effectiveness of cancer drugs.

Reporting of Demographics & Subgroup Analyses in Premarketing Studies of FDA Approved High-Risk Cardiovascular Devices, 2014-2022.

Background: Representation of diverse study populations in pivotal clinical trials for medical devices and subgroup analyses for demographic groups to explore differences in safety and effectiveness are essential to understanding the benefits and risks in diverse populations. The US Food and Drug Administration (FDA) has taken many steps to improve transparency and subgroup analyses over the past decade, but there has not been a recent evaluation of demographic reporting and subgroup analyses. Methods: We reviewed all FDA Premarket Approvals for high-risk cardiovascular devices from 2014 to 2022, focusing on pivotal studies supporting device approval. We abstracted detailed demographic data about the age, sex, race, ethnicity, and socioeconomic position of study participants. We also assessed the presence and results of subgroup analyses to understand the safety and effectiveness of devices across trial populations. Results: Analysis of 92 pivotal studies revealed that age and sex were reported in 96.7% of the studies, while race and ethnicity were reported in 71.7% and 58.7%, respectively. However, only 7.9% of studies explicitly detailed the participation of older adults (≥65 years) and no studies reported patients' socioeconomic position. Subgroup analyses by sex were conducted in 70.7% of studies, with 12.3% reporting significant differences. In contrast, analyses by race and ethnicity were performed in only 12.0% of the studies, with 9.1% reporting significant differences. Conclusion: Approximately one-third of pivotal studies for high-risk cardiovascular devices approved by the FDA from 2014 to 2022 did not report the race of study participants, nearly 40% did not report ethnicity, and more than 90% did not report the participation of older adults (≥65 years). Subgroup analyses were infrequently conducted by age or race and ethnicity. There is a need for better trial demographic reporting and conduct of subgroup analyses in premarketing studies to ensure the safety and effectiveness of medical devices for all patients.

A Public Option for Clinical Trials? Lessons from Convalescent Plasma.

The case of clinical trials for convalescent plasma during COVID-19 illustrates important lessons for realizing public sector approaches to biomedical research and development. These lessons, centering on mission, transparency, and spillover effects, can be translated to wider efforts to develop a "public option" for clinical trials.

RETRACTED PAPERS ORIGINATING FROM PAPER MILLS: A CROSS-SECTIONAL ANALYSIS OF REFERENCES AND CITATIONS.

OBJECTIVE: The aims of this study are: (1) to analyze the references cited by retracted papers originated from paper mills; (2) to analyze the citations received by retracted papers originated from paper mills; and (3) to analyze the potential relationships existing between paper mill papers, their references and their citations. STUDY DESIGN AND SETTING: Cross-sectional study. All original papers retracted in 2022 identified as having originated from paper mills and had been published at least 12 months before their retraction (hereinafter "source retracted papers") were included. The Retraction Watch database was used to identify the source retracted papers and Web of Science was used to identify the references contained within them and the citations received by them. We described the characteristics of the papers and journals. Additionally, two networks of source retracted papers mutually interconnected via their citations and references were built: one with only retracted references and retracted citations; and the other with all references and citations (retracted or unretracted). RESULTS: A total of 416 paper mill papers retracted in 2022 (sourced retracted papers) were identified, with a median of 1,247 (IQR, 907.75-1673.5) days between publication and retraction. Of all authors identified, 92.3% were affiliated with Chinese institutions. There were 14,411 references contained in the source retracted papers and 8,479 citations received by them; the median number of references and citations was 35 (29-40) and 16 (9-25), respectively. In total, 473 references and citations had also been retracted for being paper mill papers. Among the 416 sourced retracted papers, 169 (41.9%) and 178 (42.8%) were referenced or were cited by at least one retracted paper, the majority of which also originated from paper mills. The first network analysis, which included source retracted papers along with their retracted references and citations, found three clusters of 53, 48 and 44 retracted papers that were mutually interconnected. The second network analysis, with all references and citations (retracted or unretracted) identified a large cluster of 2,530 interconnected papers. CONCLUSION: Retracted papers originating from paper mills frequently reference and are cited by papers that are later retracted for having originated from paper mills, displaying interrelationships. Detecting these interrelationships can serve as an indicator for identifying potentially fraudulent publications.

Characterization of accelerated approval status, trial endpoints and results, and recommendations in guidelines for oncology drug treatments from the National Comprehensive Cancer Network: cross sectional study.

Objectives: To evaluate National Comprehensive Cancer Network (NCCN) guideline recommendations for oncology drug treatments that have been granted accelerated approval, and to determine whether recommendations are updated based on the results of confirmatory trials after approval and based on status updates from the US Food and Drug Administration (FDA). Design: Cross sectional study. Setting: US FDA and NCCN guidelines. Population: Oncology therapeutic indications (ie, specific oncological conditions for which the drug is recommended) that have been granted accelerated approval in 2009-18. Main outcome measures: NCCN guideline reporting of accelerated approval status and postapproval confirmatory trials, and guideline recommendation alignment with postapproval confirmatory trial results and FDA status updates. Results: 39 oncology drug treatments were granted accelerated approval for 62 oncological indications. Although all indications were recommended in NCCN guidelines, accelerated approval status was reported for 10 (16%) indications. At least one postapproval confirmatory trial was identified for all 62 indications, 33 (53%) of which confirmed benefit; among these indications, NCCN guidelines maintained the previous recommendation or strengthened the category of evidence for 27 (82%). Postapproval confirmatory trials failed to confirm benefit for 12 (19%) indications; among these indications, NCCN guidelines removed the previous recommendation or weakened the category of evidence for five (42%). NCCN guidelines reflected the FDA's decision to convert 30 (83%) of 36 indications from accelerated to traditional approval, of which 20 (67%) had guideline updates before the FDA's conversion decision. NCCN guidelines reflected the FDA's decision to withdraw seven (58%) of 12 indications from the market, of which four (57%) had guidelines updates before the FDA's withdrawal decision. Conclusions: NCCN guidelines always recommend drug treatments that have been granted accelerated approval for oncological indications, but do not provide information about their accelerated approval status, including surrogate endpoint use and status of postapproval confirmatory trials. NCCN guidelines consistently provide information on postapproval trial results confirming clinical benefit, but not on postapproval trials failing to confirm clinical benefit. NCCN guidelines more frequently update recommendation for indications converted to traditional approval than for those approvals that were withdrawn.

Intravascular Microaxial Left Ventricular Assist Device Manufacturer Payments to Cardiologists and Use of Devices.

This study examines whether payments from a left ventricular assist device manufacturer to cardiologists performing percutaneous coronary intervention were associated with any use of the devices.

Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments.

Importance: Surrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals. Objective: To systematically summarize the evidence from meta-analyses, systematic reviews and meta-analyses, and pooled analyses (hereafter, meta-analyses) of clinical trials examining the strength of association between treatment effects measured using surrogate markers and clinical outcomes in nononcologic chronic diseases. Data sources: The Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023. Study Selection: Three reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded. Data Extraction and Synthesis: Two reviewers extracted correlation coefficients, coefficients of determination, slopes, effect estimates, or results from meta-regression analyses between surrogate markers and clinical outcomes. Main Outcomes and Measures: Correlation coefficient or coefficient of determination, when reported, was classified as high strength (r ≥ 0.85 or R2 ≥ 0.72); primary findings were otherwise summarized. Results: Thirty-seven surrogate markers listed in FDA's table and used as primary end points in clinical trials across 32 unique nononcologic chronic diseases were included. For 22 (59%) surrogate markers (21 chronic diseases), no eligible meta-analysis was identified. For 15 (41%) surrogate markers (14 chronic diseases), at least 1 meta-analysis was identified, 54 in total (median per surrogate marker, 2.5; IQR, 1.3-6.0); among these, median number of trials and patients meta-analyzed was 18.5 (IQR, 12.0-43.0) and 90 056 (IQR, 20 109-170 014), respectively. The 54 meta-analyses reported 109 unique surrogate marker-clinical outcome pairs: 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates, or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically significant result. Conclusions and Relevance: Most surrogate markers used as primary end points in clinical trials to support FDA approval of drugs treating nononcologic chronic diseases lacked high-strength evidence of associations with clinical outcomes from published meta-analyses.

Industry Payments to US Physicians by Specialty and Product Type.

This study examines the distribution of payments within and across specialties and the medical products associated with the largest total payments.

Implications for Public Health Regulation if Chevron Deference Is Overturned.

This Viewpoint describes implications for medicine and public health if the US Supreme Court decides to overturn or narrow Chevron deference.

Association of Race and Ethnicity With Postoperative Gabapentinoid and Opioid Prescribing Trends for Older Adults.

BACKGROUND: Disparities in opioid prescribing by race/ethnicity have been described in many healthcare settings, with White patients being more likely to receive an opioid prescription than other races studied. As surgeons increase prescribing of nonopioid medications in response to the opioid epidemic, it is unknown whether postoperative prescribing disparities also exist for these medications, specifically gabapentinoids. METHODS: We conducted a retrospective cohort study using a 20% Medicare sample for 2013-2018. We included patients ≥66 years without prior gabapentinoid use who underwent one of 14 common surgical procedures. The primary outcome was the proportion of patients prescribed gabapentinoids at discharge among racial and ethnic groups. Secondary outcomes were days' supply of gabapentinoids, opioid prescribing at discharge, and oral morphine equivalent (OME) of opioid prescriptions. Trends over time were constructed by analyzing proportion of postoperative prescribing of gabapentinoids and opioids for each year. For trends by year by racial/ethnic groups, we ran a multivariable logistic regression with an interaction term of procedure year and racial/ethnic group. RESULTS: Of the 494,922 patients in the cohort (54% female, 86% White, 5% Black, 5% Hispanic, mean age 73.7 years), 3.7% received a new gabapentinoid prescription. Gabapentinoid prescribing increased over time for all groups and did not differ significantly among groups (P = 0.13). Opioid prescribing also increased, with higher proportion of prescribing to White patients than to Black and Hispanic patients in every year except 2014. CONCLUSIONS: We found no significant prescribing variation of gabapentinoids in the postoperative period between racial/ethnic groups. Importantly, we found that despite national attention to disparities in opioid prescribing, variation continues to persist in postoperative opioid prescribing, with a higher proportion of White patients being prescribed opioids, a difference that persisted over time.

Medicare Part B and Part D drug eligibility for center for Medicare and Medicaid Services price negotiation under the Inflation Reduction Act: estimates using 2016-2019 data.

Background: To reduce Medicare prescription drug expenditures, the 2022 Inflation Reduction Act (IRA) allows the Centers for Medicare & Medicaid Services (CMS) to directly negotiate with drug manufacturers on Medicare prices of high-expenditure drugs (≥$200m annual spending) which meet certain eligibility criteria. However, it is unclear what proportion of high-expenditure drugs covered by Medicare, and attributable annual drug spending, would typically be eligible for CMS negotiations in a given year. Methods: We used historical Medicare drug spending data to determine how many high-expenditure drugs, and attributable drug spending, would have been eligible for CMS negotiations had the IRA been in effect from 2016-2019, while also determining which of the IRA's eligibility criteria is most restrictive. Results: From 2016-2019, approximately one third (33.3% for Part B, 32.4% for Part D) of high-expenditure Medicare drugs would have been eligible for negotiation, with ineligible drugs accounting for 75.2% and 63.8% of spending on high-expenditure drugs in Medicare Part B and D, respectively. Most ineligible high-expenditure drugs were ineligible because they launched too recently. From 2016-2019, between 59 and 74 high-expenditure drugs were eligible per year, indicating that in some years there may not be enough eligible drugs for CMS to negotiate on the maximum number of drugs allowable by law. Conclusions: The IRA's current eligibility criteria may restrict CMS from being able to negotiate drug prices on approximately two-thirds of the high-expenditure drugs covered by Medicare and may not allow CMS to negotiate on the maximum number of drugs allowable by law. Congress could consider relaxing eligibility requirements for price negotiation, such as those pertaining to launch date recency, to ensure there are a sufficient number of high-expenditure drugs eligible for negotiation or make certain ineligible drugs contributing to significant annual Medicare spending eligible for negotiation on a case-by-case basis.

Comparison of industry payments to psychiatrists and psychiatric advanced practice clinicians in the USA, 2021: a cross-sectional study.

OBJECTIVES: To compare industry payment patterns among US psychiatrists and psychiatric advanced practice clinicians (APCs) and determine how scope of practice laws has influenced these patterns. DESIGN: Cross-sectional study. SETTING: This study used the publicly available US Centers for Medicare and Medicaid Services Sunshine Act Open Payment database and the National Plan and Provider Enumeration System (NPPES) database for the year 2021. PARTICIPANTS: All psychiatrists and psychiatric APCs (subdivided into nurse practitioners (NPs) and clinical nurse specialists (CNSs)) included in either database. PRIMARY AND SECONDARY OUTCOME MEASURES: Number and percentage of clinicians receiving industry payments and value of payments received. Total payments and number of transactions by type of payment, payment source and clinician type were also evaluated. RESULTS: A total of 85 053 psychiatric clinicians (61 011 psychiatrists (71.7%), 21 895 NPs (25.7%), 2147 CNSs (2.5%)) were reviewed; 16 240 (26.6%) psychiatrists received non-research payment from industry, compared with 10 802 (49.3%) NPs and 231 (10.7%) CNSs (p<0.001) for pairwise comparisons). Psychiatric NPs were significantly more likely to receive industry payments compared with psychiatrists (incidence rate ratio (IRR), 1.85 (95% CI 1.81 to 1.88); p<0.001)). Compared with psychiatrists, NPs were more likely to receive payments of > United States Dollars (US) $) 100 (33.9% vs 14.6%; IRR, 2.14 (2.08 to 2.20); p<0.001) and > US$ 1000 (5.3% vs 4.1%; IRR, 1.29 (1.20 to 1.38); p<0.001) but less likely to receive > US$ 10 000 (0.4% vs 1.0%; IRR, 0.39 (0.31 to 0.49); p<0.001). NPs in states with 'reduced' or 'restricted' scope of practice received more frequent payments (reduced: IRR, 1.22 (1.18 to 1.26); restricted: IRR, 1.26 (1.22 to 1.30), both p<0.001). CONCLUSIONS: Psychiatric NPs were nearly two times as likely to receive industry payments as psychiatrists, while psychiatric CNSs were less than half as likely to receive payment. Stricter scope of practice laws increases the likelihood of psychiatric NPs receiving payment, the opposite of what was found in a recent specialty agnostic study.

Published research on the human health implications of climate change between 2012 and 2021: cross sectional study.

Objective: To better understand the state of research on the effects of climate change on human health, including exposures, health conditions, populations, areas of the world studied, funding sources, and publication characteristics, with a focus on topics that are relevant for populations at risk. Design: Cross sectional study. Data sources: The National Institute of Environmental Health Sciences climate change and human health literature portal, a curated bibliographical database of global peer reviewed research and grey literature was searched. The database combines searches of multiple search engines including PubMed, Web of Science, and Google Scholar, and includes added-value expert tagging of climate change exposures and health impacts. Eligibility criteria: Inclusion criteria were peer reviewed, original research articles that investigated the health effects of climate change and were published in English from 2012 to 2021. After identification, a 10% random sample was selected to manually perform a detailed characterisation of research topics and publication information. Results: 10 325 original research articles were published between 2012 and 2021, and the number of articles increased by 23% annually. In a random sample of 1014 articles, several gaps were found in research topics that are particularly relevant to populations at risk, such as those in the global south (134 countries established through the United Nations Office for South-South Cooperation) (n=444; 43.8%), adults aged 65 years or older (n=195; 19.2%), and on topics related to human conflict and migration (n=25; 2.5%) and food and water quality and security (n=148; 14.6%). Additionally, fewer first authors were from the global south (n=349; 34.4%), which may partly explain why research focusing on these countries is disproportionally less. Conclusions: Although the body of research on the health effects of climate change has grown substantially over the past decade, including those with a focus on the global south, a disproportionate focus continues to be on countries in the global north and less at risk populations. Governments are the largest source of funding for such research, and governments, particularly in the global north, need to re-orient their climate and health research funding to support researchers in the global south and to be more inclusive of issues that are relevant to the global south.

Approval, Evidence, and "Off-Label" Device Utilization: The Patent Foramen Ovale Closure Story.

BACKGROUND: Following regulatory approval, medical devices may be used "off-label." Patent foramen ovale (PFO) closure is indicated to reduce recurrent stroke but has been proposed for other indications, including migraine, transient ischemic attack, and diving decompression illness. We sought to evaluate PFO closure rates and indications relative to the timing of regulatory approval and publication of key randomized trials. METHODS: We performed a retrospective cohort study using the OptumLabs Data Warehouse of US commercial insurance enrollees from 2006 to 2019. We quantified PFO closure among individuals with ≥2 years of preprocedure coverage to establish indications, classified hierarchically as stroke/systemic embolism, migraine, transient ischemia attack, or other. RESULTS: We identified 5315 patients undergoing PFO closure (51.8% female, 29.2%≥60 years old), which increased from 4.75 per 100 000 person-years in 2006 to 6.60 per 100 000 person-years in 2019. Patients aged ≥60 years accounted for 29.2% of closures. Procedure volumes corresponded weakly with supportive clinical publications and device approval. Among patients with PFO closure, 58.6% underwent closure for stroke/systemic embolism, 10.2% for transient ischemia attack, 8.8% for migraine, and 22.4% for other indications; 17.6% of patients had atrial fibrillation at baseline; and 11.9% developed atrial fibrillation postprocedure. Those aged ≥60 years and male were less likely to undergo closure for migraine than stroke/systemic embolism. CONCLUSIONS: From 2006 to 2019, PFO closure use was consistently low and corresponded weakly with clinical trial publications and regulatory status. Nearly half of patients underwent PFO closure for indications unapproved by the Food and Drug Administration. Regulators and payers should coordinate mechanisms to promote utilization for approved indications to ensure patient safety and should facilitate clinical trials for other possible indications.