Discrepancies in the results reported for multiple sclerosis clinical trials: A comparison between ClinicalTrials.gov and peer-reviewed journals.

OBJECTIVE: We aimed to compare the results of phase III and IV clinical trials examining drugs to treat multiple sclerosis (MS) registered at ClinicalTrials.gov to those published in peer-reviewed journals. METHODS: After identifying trials registered at ClinicalTrials.gov, consecutive searches were conducted in PubMed, EMBASE and Google Scholar for matching publications. Information regarding participants and efficacy and safety results was extracted and compared. The degree of consistency was classified as 'concordant', 'discrepant' or 'not comparable'. The Kaplan-Meier method was used to model time to reporting. RESULTS: In total, 65 trials were appraised. The median time from completion to reporting was shorter for ClinicalTrials.gov (16.4 vs 27.3 months; p = 0.010). Information availability was generally higher in journals except for serious adverse events (SAEs) (86.2% vs 100.0%, p = 0.029) and their description (78.2% vs 100.0%, p < 0.001). However, 45 trials had at least one reporting discrepancy (69.2%). Three studies omitted one or more primary outcomes in the matching journal publication. Regarding safety results, the lowest consistencies were found for causes of death (60.0%) and description of SAEs (27.9%). CONCLUSION: Consulting both ClinicalTrials.gov and journals increases the accessibility to MS clinical trial results. Some data were frequently missing or disagreed between sources, raising concerns about transparency and generalizability of results.

At-Home Testing for Survivors of Sexual Assault-Empowerment or Exploitation?

In this Viewpoint, the accuracy, usefulness, and marketing of at-home rape kits is explored.

Harnessing policy to promote inclusive medical product evidence: development of a reference standard and structured audit of clinical trial diversity policies.

Objective: To develop a reference standard based on US Food and Drug Administration and stakeholder guidance for pharmaceutical companies' policies on diversity in clinical trials and to assess these policies. Design: Development of a reference standard and structured audit for clinical trial diversity policies. Setting: 50 pharmaceutical companies selected from the top 500 by their market capitalizations in 2021 (the 25 largest companies and 25 non-large companies, randomly selected from the remaining 475 companies). Population: Data from pharmaceutical company websites and annual reports. Policy guidance from the Pharmaceutical Research and Manufacturers of America, International Federation of Pharmaceutical Manufacturers and Associations, Biotechnology Industry Organization, International Committee of Medical Journal Editors, the US Food and Drug Administration, European Medicines Agency, and World Health Organization, up to 15 May 2023. Main outcome measures: Multicomponent measure based on distinct themes derived from FDA and stakeholder guidance. Results: Reviewing FDA and stakeholder guidance identified 14 distinct themes recommended for improving diversity in clinical trials, which were built into a reference standard: (1) enrollment targets that reflect the prevalence of targeted conditions in populations, (2) broad eligibility criteria for trials, (3) diversity in the workforce, (4) identification and remedy of barriers to trial recruitment and retention, (5) incorporation of patient input into trial design, (6) health literacy, (7) multidimensional approaches to diversity, (8) sites with diverse providers and patient populations, (9) data collection after product approval, (10) diverse enrollment in every country where trials are conducted, (11) diverse enrollment should be a focus for all phases of clinical trials, not just later stage or pivotal trials, (12) varied trial design, (13) expanded access, and (14) public reporting of the personal characteristics of participants in trials. Applying this reference standard, 48% (24/50) of companies had no public policy on diversity in clinical trials; among those with policies, content varied widely. Large companies were more likely to have a public policy than non-large companies (21/25, 84% v 5/25, 20%, P<0.001). Large companies most frequently committed to using epidemiological based trial enrollment targets representing the prevalence of indicated conditions in various populations (n=15, 71%), dealing with barriers to trial recruitment (n=15, 71%), and improving patient awareness of trial opportunities (n=14, 67%). The location of the company was not associated with having a public diversity policy (P=0.17). The average company policy had five of the 14 commitments (36%, range 0-8) recommended in FDA and stakeholder guidance. Conclusions: The findings of the study showed that many pharmaceutical companies did not have public policies on diversity in clinical trials, although policies were more common in large than non-large companies. Policies that were publicly available varied widely and lacked important commitments recommended by stakeholder guidance. The results of the study suggest that corporate policies can be better leveraged to promote representation and fair inclusion in research, and implementation of FDA and stakeholder guidance.

Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies.

Importance: The US Food and Drug Administration (FDA) awards the breakthrough therapy designation to expedite development and review of therapeutics intended to treat serious conditions when preliminary clinical evidence demonstrates potential substantial improvement over existing therapies on clinically significant end points. Under the 21st Century Cures Act of 2016, the FDA is required to publish and routinely update a list of surrogate markers to provide industry sponsors with indication-specific information about end points that were or may be considered for approval. Therapeutics that are granted breakthrough therapy designation can receive accelerated or traditional approval; however, little is known about those approved through the latter pathway, where postmarketing confirmatory studies are typically not required, regardless of the end point used. Objective: To evaluate the primary end points used in premarket pivotal trials supporting FDA breakthrough therapy-designated approvals and to determine whether postmarketing studies confirming efficacy were required for approvals based on pivotal trials using surrogate markers as primary end points. Design, Setting, and Participants: This cross-sectional study used data from the Drugs@FDA database for all original breakthrough therapy-designated approvals from inception to December 31, 2023, in the US. The first designation was approved on November 1, 2013. Data analysis was performed in January 2024. Main Outcomes and Measures: Descriptive analyses were used to characterize the breakthrough therapy-designated indication approval pathways, the primary end points of pivotal efficacy trials, and their postmarketing requirements or commitments. Results: From 2013 to 2023, the FDA approved 157 original indications with breakthrough therapy designation. Of these, 52 (33%) were granted accelerated approval and 105 (67%) were granted traditional approval. All accelerated approvals were based on pivotal trials using surrogate markers as primary end points and had FDA-required postmarketing studies to confirm efficacy. Of these 52 indications, 51 (98%) were approved based on surrogate end points listed in the FDA table of surrogate end points for the same indication. Among traditional approvals, 61 (58%) were based on pivotal trials using surrogate markers as primary end points, of which 4 (7%) had FDA-required postmarketing studies to confirm efficacy and 39 (64%) were approved based on surrogate end points listed in the FDA table for the same indication. Conclusions and Relevance: In this cross-sectional study of original FDA breakthrough therapy-designated approvals from 2013 to 2023, trials supporting these approvals often used surrogate markers as primary end points (even when not approved via accelerated approval) and lacked FDA-required postmarketing studies to verify clinical benefit. These findings suggest that requiring postmarketing studies for breakthrough therapy-designated indications approved based on surrogate markers, regardless of approval pathway, may increase patient and clinician certainty of the expected clinical benefit.

Differential times of submission and approval of CFTR modulators for the treatment of Cystic Fibrosis in the United States and the European Union.

BACKGROUND: The objective of this study was to assess the differential times of submission and approval of CFTR modulators in the United States (US) and the European Union (EU). METHODS: By collecting publicly available data from the websites of the Food and Drug Administration and the European Medicines Agency, we quantified differential times in submission, review duration, and approvals of initial marketing authorization and variation of indications of CFTR modulators in the US and the EU by December 31, 2023. RESULTS: Applications regarding marketing of 4 CFTR modulators were submitted 103 (SD ±143) days later in the EU than in the US: 31 (SD ±39) days later for initial approval, and 124 (SD ±155) days for supplemental indications. The regulatory review process was completed in 181 days [IQR, 179 - 182] in the US and 325 days [IQR, 276 - 382] in the EU: 167 days [IQR, 102 - 232] in the US and 346 days [IQR, 302 - 400] in the EU for first approvals, 181 days [IQR, 181 - 182] in the US and 324 days [IQR, 264 - 382] in the EU for supplemental indication approvals. CFTR modulators were approved 267 (SD 143) days later in the EU than in the US: 220 (SD ±76) days for initial approval and 280 (SD ±157) days for supplemental indications. CONCLUSION: We found significant differences in times of submission and for approval of CFTR modulators between the US and EU, whereby initial approvals and subsequent indication approvals were always first granted in the US.

Use of Muscle Relaxants After Surgery in Traditional Medicare Part D Enrollees.

BACKGROUND: Surgeons have come under increased scrutiny for postoperative pain management, particularly for opioid prescribing. To decrease opioid use but still provide pain control, nonopioid medications such as muscle relaxants are being used, which can be harmful in older adults. However, the prevalence of muscle relaxant prescribing, trends in use over time, and risk of prolonged use are unknown. STUDY DESIGN: Using a 20% representative Medicare sample, we conducted a retrospective analysis of muscle relaxant prescribing to patients ≥ 65 years of age. We merged patient data from Medicare Carrier, MedPAR, and Outpatient Files with Medicare Part D for the years 2013-2018. A total of 14 surgical procedures were included to represent a wide range of anatomic regions and specialties. RESULTS: The study cohort included 543,929 patients. Of the cohort, 8111 (1.5%) received a new muscle relaxant prescription at discharge. Spine procedures accounted for 12% of all procedures but 56% of postoperative prescribing. Overall, the rate of prescribing increased over the time period (1.4-2.0%, p < 0.001), with increases in prescribing primarily in the spine (7-9.6%, p < 0.0001) and orthopedic procedure groups (0.9-1.4%, p < 0.0001). Of patients discharged with a new muscle relaxant prescription, 10.7% had prolonged use. CONCLUSIONS: The use of muscle relaxants in the postoperative period for older adults is low, but increasing over time, especially in ortho and spine procedures. While pain control after surgery is crucial, surgeons should carefully consider the risks of muscle relaxant use, especially for older adults who are at higher risk for medication-related problems.

Altmetric Attention Scores and Citations of Published Research With or Without Preprints.

This cross-sectional study assesses how frequently research articles published in the clinical journals with high impact factors are preprinted and whether preprinting is associated with changes in media attention and citation counts.

Unveiling the Adoption and Barriers of Telemedicine in US Hospitals: A Comprehensive Analysis (2017-2022).

BACKGROUND: Telemedicine has emerged as a vital healthcare delivery model, especially pronounced during the COVID-19 pandemic. Our study uniquely focuses on an institutional lens, examining US hospitals to offer targeted policy implications. OBJECTIVE: To investigate the trend in telemedicine adoption across US hospitals from 2017 to 2022 and analyze the institutional challenges they encounter, particularly in the realm of electronic health information exchange. DESIGN: Cross-sectional study leveraging data from the American Hospital Association's (AHA) annual surveys for the years 2017 to 2021 and the 2022 AHA IT Supplement Survey. SETTING: The study includes a national sample of US hospitals, covering a diverse range of hospital types including large, nonprofit, teaching, and system-affiliated institutions. PARTICIPANTS: US hospitals form the study's participants, with a substantial response rate to the surveys. MAIN MEASURES: Key metrics include the number of telemedicine patient encounters, percentage of hospitals offering telemedicine services, and institutional challenges to electronic health information exchange. KEY RESULTS: Telemedicine encounters saw a 75% increase, growing from approximately 111.4 million in 2020 to nearly 194.4 million in 2021. The percentage of hospitals offering at least one form of telemedicine service went from 46% in 2017 to 72% in 2021. Larger, nonprofit, and teaching hospitals were more prone to telehealth adoption, without notable urban-rural disparities. While over 90% of hospitals allow patients to view and download medical records, only 41% permit online data submission. Importantly, 25% of hospitals identified Certified Health IT Developers such as EHR vendor as frequent culprits in information blocking, with cost being the primary obstacle. CONCLUSIONS: The findings underscore the rapid yet uneven adoption of telemedicine services in U.S. hospitals. The results point to the need for comprehensive policy interventions to address the challenges identified and realize telemedicine's full potential in healthcare delivery and resilience.

Derivation of an Annualized Claims-Based Major Adverse Cardiovascular Event Estimator in Type 2 Diabetes.

Background: Major adverse cardiovascular events (MACE) are a leading cause of morbidity and mortality among adults with type 2 diabetes. Currently, available MACE prediction models have important limitations, including reliance on data that may not be routinely available, narrow focus on primary prevention, limited patient populations, and longtime horizons for risk prediction. Objectives: The purpose of this study was to derive and internally validate a claims-based prediction model for 1-year risk of MACE in type 2 diabetes. Methods: Using medical and pharmacy claims for adults with type 2 diabetes enrolled in commercial, Medicare Advantage, and Medicare fee-for-service plans between 2014 and 2021, we derived and internally validated the annualized claims-based MACE estimator (ACME) model to predict the risk of MACE (nonfatal acute myocardial infarction, nonfatal stroke, and all-cause mortality). The Cox proportional hazards model was composed of 30 covariates, including patient age, sex, comorbidities, and medications. Results: The study cohort comprised 6,623,526 adults with type 2 diabetes, mean age 68.1 ± 10.6 years, 49.8% women, and 73.0% Non-Hispanic White. ACME had a concordance index of 0.74 (validation index range: 0.739-0.741). The predicted 1-year risk of the study cohort ranged from 0.4% to 99.9%, with a median risk of 3.4% (IQR: 2.3%-6.5%). Conclusions: ACME was derived in a large usual care population, relies on routinely available data, and estimates short-term MACE risk. It can support population risk stratification at the health system and payer levels, participant identification for decentralized clinical trials of cardiovascular disease, and risk-stratified observational studies using real-world data.

Funding of evidence included within public comments submitted to inform Medicare national coverage determinations.

The Centers for Medicare & Medicaid Services (CMS) relies on public comments submitted in response to proposed national coverage determinations to assist the agency in determining the coverage of items and services for Medicare beneficiaries. In a cross-sectional study, we characterized the cited evidence and what funding supported the cited evidence submitted in public comments to CMS for all therapeutic medical device national coverage determinations finalized between June 2019 and June 2022. Of 681 public comments, 159 (23%) cited at least 1 identifiable published scientific journal article. Within these 159 public comments, 198 unique articles were cited, 170 (86%) of which included funding statements or author disclosures. Among these, 96 (56%) disclosed funding from manufacturers that would benefit from Medicare coverage and/or were written by author(s) who received funding from these manufacturers. In summary, most public commenters for national coverage determinations did not cite published scientific journal articles to support their positions. Among those who did, more than half of articles were directly funded by manufacturers that would benefit from coverage. Greater funding of independent, non-industry-supported research may help provide unbiased evaluations of benefits and harms to support Medicare coverage decisions.

Assessing Real-World Data From Electronic Health Records for Health Technology Assessment: The SUITABILITY Checklist: A Good Practices Report of an ISPOR Task Force.

This ISPOR Good Practices report provides a framework for assessing the suitability of electronic health records data for use in health technology assessments (HTAs). Although electronic health record (EHR) data can fill evidence gaps and improve decisions, several important limitations can affect its validity and relevance. The ISPOR framework includes 2 components: data delineation and data fitness for purpose. Data delineation provides a complete understanding of the data and an assessment of its trustworthiness by describing (1) data characteristics; (2) data provenance; and (3) data governance. Fitness for purpose comprises (1) data reliability items, ie, how accurate and complete the estimates are for answering the question at hand and (2) data relevance items, which assess how well the data are suited to answer the particular question from a decision-making perspective. The report includes a checklist specific to EHR data reporting: the ISPOR SUITABILITY Checklist. It also provides recommendations for HTA agencies and policy makers to improve the use of EHR-derived data over time. The report concludes with a discussion of limitations and future directions in the field, including the potential impact from the substantial and rapid advances in the diffusion and capabilities of large language models and generative artificial intelligence. The report's immediate audiences are HTA evidence developers and users. We anticipate that it will also be useful to other stakeholders, particularly regulators and manufacturers, in the future.

Effectiveness of glucose-lowering medications on cardiovascular outcomes in patients with type 2 diabetes at moderate cardiovascular risk.

Cardiovascular disease (CVD) is the leading cause of death among people with type 2 diabetes1-5, most of whom are at moderate CVD risk6, yet there is limited evidence on the preferred choice of glucose-lowering medication for CVD risk reduction in this population. Here, we report the results of a retrospective cohort study where data for US adults with type 2 diabetes and moderate risk for CVD are used to compare the risks of experiencing a major adverse cardiovascular event with initiation of glucagon-like peptide-1 receptor agonists (GLP-1RA; n = 44,188), sodium-glucose cotransporter 2 inhibitors (SGLT2i; n = 47,094), dipeptidyl peptidase-4 inhibitors (DPP4i; n = 84,315) and sulfonylureas (n = 210,679). Compared to DPP4i, GLP-1RA (hazard ratio (HR) 0.87; 95% confidence interval (CI) 0.82-0.93) and SGLT2i (HR 0.85; 95% CI 0.81-0.90) were associated with a lower risk of a major adverse cardiovascular event, whereas sulfonylureas were associated with a higher risk (HR 1.19; 95% CI 1.16-1.22). Thus, GLP-1RA and SGLT2i may be the preferred glucose-lowering agents for cardiovascular risk reduction in patients at moderate baseline risk for CVD. ClinicalTrials.gov registration: NCT05214573.

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.