Abstract Initial clinical studies of new medical technologies involve a complex balance of research participant benefits versus risks and costs of uncertainty when novel concepts are tested. The Food ...and Drug Administration Center for Devices and Radiological Health has recently introduced the Early Feasibility Study (EFS) Program for facilitating the conduct of these studies under the Investigational Device Exemption regulations. However, a systematic approach is needed to successfully implement this program while affording appropriate preservation of the rights and interests of patients. For this to succeed, a holistic reform of the clinical studies ecosystem for performing early-stage clinical research in the United States is necessary. The authors review the current landscape of the U.S. EFS and make recommendations for developing an efficient EFS process to meet the goal of improving access to early-stage, potentially beneficial medical devices in the United States.
Recent studies have produced inconsistent findings regarding the outcomes of the percutaneous microaxial left ventricular assist device (LVAD) during acute myocardial infarction with cardiogenic ...shock (AMICS).
To compare the percutaneous microaxial LVAD vs alternative treatments among patients presenting with AMICS using observational analyses of administrative data.
This comparative effectiveness research study used Medicare fee-for-service claims of patients admitted with AMICS undergoing percutaneous coronary intervention from October 1, 2015, through December 31, 2019. Treatment strategies were compared using (1) inverse probability of treatment weighting to estimate the effect of different baseline treatments in the overall population; (2) instrumental variable analysis to determine the effectiveness of the percutaneous microaxial LVAD among patients whose treatment was influenced by cross-sectional institutional practice patterns; (3) an instrumented difference-in-differences analysis to determine the effectiveness of treatment among patients whose treatment was influenced by longitudinal changes in institutional practice patterns; and (4) a grace period approach to determine the effectiveness of initiating the percutaneous microaxial LVAD within 2 days of percutaneous coronary intervention. Analysis took place between March 2021 and December 2022.
Percutaneous microaxial LVAD vs alternative treatments (including medical therapy and intra-aortic balloon pump).
Thirty-day all-cause mortality and readmissions.
Of 23 478 patients, 14 264 (60.8%) were male and the mean (SD) age was 73.9 (9.8) years. In the inverse probability of treatment weighting analysis and grace period approaches, treatment with percutaneous microaxial LVAD was associated with a higher risk-adjusted 30-day mortality (risk difference, 14.9%; 95% CI, 12.9%-17.0%). However, patients receiving the percutaneous microaxial LVAD had a higher frequency of factors associated with severe illness, suggesting possible confounding by measures of illness severity not available in the data. In the instrumental variable analysis, 30-day mortality was also higher with percutaneous microaxial LVAD, but patient and hospital characteristics differed across levels of the instrumental variable, suggesting possible confounding by unmeasured variables (risk difference, 13.5%; 95% CI, 3.9%-23.2%). In the instrumented difference-in-differences analysis, the association between the percutaneous microaxial LVAD and mortality was imprecise, and differences in trends in characteristics between hospitals with different percutaneous microaxial LVAD use suggested potential assumption violations.
In observational analyses comparing the percutaneous microaxial LVAD to alternative treatments among patients with AMICS, the percutaneous microaxial LVAD was associated with worse outcomes in some analyses, while in other analyses, the association was too imprecise to draw meaningful conclusions. However, the distribution of patient and institutional characteristics between treatment groups or groups defined by institutional differences in treatment use, including changes in use over time, combined with clinical knowledge of illness severity factors not captured in the data, suggested violations of key assumptions that are needed for valid causal inference with different observational analyses. Randomized clinical trials of mechanical support devices will allow valid comparisons across candidate treatment strategies and help resolve ongoing controversies.
The article by Conte et al. on behalf of the Society for Vascular Surgery (SVS) in this issue of the Journal of Vascular Surgery provides guidelines for improving the consistency and interpretability ...of clinical trials intended to evaluate treatment options for patients with critical limb ischemia (CLI). This article identifies a number of key challenges with conducting and comparing CLI trials, including the wide spectrum of clinical presentations that CLI encompasses, the use of disparate eligibility criteria and endpoint measurements, and logistical and economic considerations that can limit study initiation and completion. The authors propose definitions for a number of performance goals derived from historical surgical literature as a means of reducing the negative impact of these factors. The current editorial reviews aspects of this proposal from the perspective of the authors in terms of their understanding of the statutory obligations of the U.S. Food and Drug Administration (FDA) to regulate the marketing of cardiovascular devices based on valid scientific evidence.
The quality of clinical data submitted by manufacturers to support Food and Drug Administration cardiovascular device premarket approval (PMA) applications varies widely and formal quality assessment ...has not been previously performed. This study evaluated all original cardiovascular device PMAs with Food and Drug Administration decisions between January 1, 2000, and December 31, 2007, to assess the quality of clinical investigations submitted by manufacturers. Effectiveness and safety end points were judged high quality if they were clearly defined and associated with a specific time point for analysis. Subject accounting was high quality if 90% or greater of the original cohort was accounted for at study conclusion. In total, 88 cardiovascular device PMAs (77.3% permanent implants), 132 clinical studies, 37,328 study subjects (age 61.0 +/- 14.5 years, 33.9% women, 86.3% white), and 29,408 device recipients were analyzed. All PMAs contained clinical data. Primary effectiveness end points, primary safety end points, and subject accounting were deemed high quality in 81.8%, 60.2%, and 77.3% of pivotal studies, respectively. Key cardiovascular comorbidities (coronary artery disease 51.1%, diabetes 36.6%, hypertension 35.2%, heart failure 37.5%, tobacco use 31.8%) and race (14.8%) were infrequently reported, and studies rarely included patients younger than 18 years of age (10.2% of studies). Poorly defined safety and effectiveness end points, poor patient accounting, and incomplete collection of important patient comorbidities make device safety and effectiveness assessments more challenging. Women, pediatric, and nonwhite populations are underrepresented in premarket cardiovascular clinical trials. Manufacturers, regulators, and the clinical community should collaborate to address these study shortcomings to ensure that patients are treated with reliable, safe, and clinically useful medical devices.
Composite outcomes are commonly used in heart failure trials. The aim of this article is to discuss the advantages and disadvantages of composite outcomes and recommend guidelines for reporting them. ...Examples are used to illustrate key points.
A workshop jointly planned by the Heart Failure Society of America and the US Food and Drug Administration was convened in April 2004. One of the panel discussions concerned the use of composite outcomes in heart failure trials. With use of composite outcomes, event rates are higher and if it is reasonable to assume that the treatment effect is similar for each component of the composite outcome, sample size will be smaller than using one of the components as the primary end point. Composites end points are difficult to interpret if effects are not similar for all components or if the effect of treatment is primarily on a more common, less serious component of the composite. Composite outcomes typically only focus on the first occurring event. This can lead to a substantial loss of information in some trials. When composite end points are used, data collection for all components should continue until the end of the trial so that each component can be separately evaluated.
Composite end points should be used with caution. Additional research is need on optimally weighting components of composite outcomes and to better using the entire event history of patients in heart failure trials. Further analyses of completed trials could be useful in this respect.
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