High-risk Cardiovascular Devices Research Articles

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

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. 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. 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. 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.

Quality and transparency of evidence for implantable cardiovascular medical devices assessed by the CORE-MD consortium.

The European Union Medical Device Regulation 2017/745 challenges key stakeholders to follow transparent and rigorous approaches to the clinical evaluation of medical devices. The purpose of this study is a systematic evaluation of published clinical evidence underlying selected high-risk cardiovascular medical devices before and after market access in the European Union (CE-marking) between 2000 and 2021. Pre-specified strategies were applied to identify published studies of prospective design evaluating 71 high-risk cardiovascular devices in seven different classes (bioresorbable coronary scaffolds, left atrial appendage occlusion devices, transcatheter aortic valve implantation systems, transcatheter mitral valve repair/replacement systems, surgical aortic and mitral heart valves, leadless pacemakers, subcutaneous implantable cardioverter-defibrillator). The search time span covered 20 years (2000-21). Details of study design, patient population, intervention(s), and primary outcome(s) were summarized and assessed with respect to timing of the corresponding CE-mark approval. At least one prospective clinical trial was identified for 70% (50/71) of the pre-specified devices. Overall, 473 reports of 308 prospectively designed studies (enrolling 97 886 individuals) were deemed eligible, including 81% (251/308) prospective non-randomized clinical trials (66 186 individuals) and 19% (57/308) randomized clinical trials (31 700 individuals). Pre-registration of the study protocol was available in 49% (150/308) studies, and 16% (48/308) had a peer-reviewed publicly available protocol. Device-related adverse events were evaluated in 82% (253/308) of studies. An outcome adjudication process was reported in 39% (120/308) of the studies. Sample size was larger for randomized in comparison to non-randomized trials (median of 304 vs. 100 individuals, P < .001). No randomized clinical trial published before CE-mark approval for any of the devices was identified. Non-randomized clinical trials were predominantly published after the corresponding CE-mark approval of the device under evaluation (89%, 224/251). Sample sizes were smaller for studies published before (median of 31 individuals) than after (median of 135 individuals) CE-mark approval (P < .001). Clinical trials with larger sample sizes (>50 individuals) and those with longer recruitment periods were more likely to be published after CE-mark approval, and were more frequent during the period 2016-21. The quantity and quality of publicly available data from prospective clinical investigations across selected categories of cardiovascular devices, before and after CE approval during the period 2000-21, were deemed insufficient. The majority of studies was non-randomized, with increased risk of bias, and performed in small populations without provision of power calculations, and none of the reviewed devices had randomized trial results published prior to CE-mark certification.

US Food and Drug Administration Approval of High-risk Cardiovascular Devices for Use in Children and Adolescents, 1977-2021

This study uses data from US Food and Drug Administration (FDA) databases to quantify approval of high-risk cardiovascular devices for use in pediatric populations and assess the clinical evidence supporting the approvals.

US Food and Drug Administration–Mandated Postmarketing Studies for High-risk Cardiovascular Devices Approved 2015-2019

US Food and Drug Administration–Mandated Postmarketing Studies for High-risk Cardiovascular Devices Approved 2015-2019

Registration, publication, and outcome reporting among pivotal clinical trials that supported FDA approval of high-risk cardiovascular devices before and after FDAAA

BackgroundSelective registration, publication, and outcome reporting of clinical trials distort the primary clinical evidence that is available to patients and clinicians regarding the safety and efficacy of US Food and Drug Administration (FDA)-approved medical devices. The purpose of this study is to compare registration, publication, and outcome reporting among pivotal clinical trials that supported FDA approval of high-risk (class III) cardiovascular devices before and after the FDA Amendment Act (FDAAA) was enacted in 2007.MethodsUsing publicly available data from ClinicalTrials.gov, FDA summaries, and PubMed, we determined registration, publication, and reporting of findings for all pivotal clinical studies supporting FDA approval of new high-risk cardiovascular devices between 2005 and 2020, before and after FDAAA. For published studies, we compared both the primary efficacy outcome with the FDA’s Premarket Approval (PMA) primary efficacy outcome and the published interpretation of findings with the FDA reviewer’s interpretation (positive, equivocal, or negative).ResultsBetween 2005 and 2020, the FDA approved 156 high-risk cardiovascular devices on the basis of 165 pivotal trials, 48 (29%) of which were categorized as pre-FDAAA and 117 (71%) as post-FDAAA. Post-FDAAA, pivotal clinical trials were more likely to be registered (115 of 117 (98%) vs 24 of 48 (50%); p < 0.001), to report results (98 of 117 (87%) vs 7 of 48 (15%); p < 0.001) on ClinicalTrials.gov, and to be published (100 or 117 (85%) vs 28 of 48 (58%); p < 0.001) in peer-reviewed literature when compared to pre-FDAAA. Among published trials, rates of concordant primary efficacy outcome reporting were not significantly different between pre-FDAAA trials and post-FDAAA trials (24 of 28 (86%) vs 96 of 100 (96%); p = 0.07), nor were rates of concordant trial interpretation (27 of 28 (96%) vs 93 of 100 (93%); p = 0.44).ConclusionsFDAAA was associated with increased registration, result reporting, and publication for trials supporting FDA approval of high-risk medical devices. Among published trials, rates of accurate primary efficacy outcome reporting and trial interpretation were high and no different post-FDAAA.

Abstract 17056: Food and Drug Administration Mandated Post-Market Studies for High Risk Cardiovascular Devices Approved 2015-2019

Introduction: The Food and Drug Administration (FDA) emphasizes a “life-cycle approach” to medical device regulation, in which the pre-approval process is expedited and more emphasis is placed on post-approval data in order to shorten patient access to new devices. The FDA can mandate post approval studies (PASs) for high-risk devices to augment pre-approval data. This study describes the characteristics of FDA-mandated PASs. Methods: We searched the FDA database for all PASs required for original high-risk cardiovascular devices approved from January 1, 2015 and December 31, 2019. Data elements abstracted for each PAS included: study type, presence of controls, blinding, total number of patients enrolled, study duration, and whether primary outcomes were surrogate or composite measures. We also checked the FDA website for any available interim data prior to study completion. Results: The FDA approved 71 high-risk cardiovascular devices and ordered a total of 68 PASs for 49 (69%) devices. Most PASs were prospective cohorts (n=47, 69.1%). The median study size was 250 patients (IQR 151-563) and median study duration was 5 years (IQR 3-5). Only 19 studies (28%) included active or historic controls, 12 studies (17.7%) were randomized, 5 studies (7.3%) were single-blinded, and none were double-blinded (Table). Twenty-two (32.4%) studies provided data before completion of study. Conclusion: Most PAS are not randomized, lack controls, contain small numbers of patients, and have composite or surrogate primary outcomes that may not be clinically relevant, despite their importance for generating long-term clinical data for high-risk cardiovascular devices. Interim data are often not available. Increased quality and availability of evidence related to PASs would better establish device safety, effectiveness, and appropriate use. Lastly, PAS data should be readily accessible to help clinicians and patients make well-informed decisions.

Assessment of Clinical Trial Evidence for High-Risk Cardiovascular Devices Approved Under the Food and Drug Administration Priority Review Program

This study uses publicly available FDA summaries to analyze the quality of evidence in pivotal studies that support cardiovascular premarket device approval under FDA priority review from 2007 to 2017.

Abstract 280: Strength of Clinical Trial Evidence for High-Risk Cardiovascular Devices Approved Through Food and Drug Administration (FDA) Priority Review

Importance: There is increasing emphasis on getting medical devices to market more quickly by use of priority review pathways, promoted in recent US Food &amp; Drug Administration (FDA) guidance documents and the 21 st Century Cures Act of 2016. Objective: To evaluate the impact of priority review pathways for high-risk cardiovascular devices by analyzing the quality and characteristics of premarket clinical studies in support of their approval and the frequency of postmarket recalls. Design and Setting: Descriptive study of premarket clinical studies supporting all high-risk cardiovascular devices approved via the priority review premarket approval (PMA) pathway between January 1, 2005 and June 15, 2017. Exposure: Priority Review PMA Main Outcome(s) and Measure(s): For all clinical studies which supported priority review PMAs we analyzed: number of patients enrolled, number of patients analyzed for each primary endpoint, demographic information, randomization, blinding, use and type of controls, use of training patients, number and location of study sites, and time of FDA review to approval. We also determined if a post hoc analysis was conducted. We counted all Class 1 and Class 2 recalls and examined FDA expert device panel recommendations. Results: There were 16 priority review cardiovascular devices approved, with mean 1.4 (SD 0.6, range 1-3) pivotal studies per device. Eleven of 16 (69%) were approved based on a single pivotal study. Of 23 pivotal studies, ten (43%) were randomized, 3 (13%) were single-blinded, and none were double-blinded. Twelve (52%) used a noninferiority primary endpoint hypothesis for at least one endpoint and 18 (78%) used a surrogate endpoint. Of the 11 votes on device effectiveness by FDA expert panels, 6 (55%) voted devices were effective. There were a total of 18 Class 1 and 2 recalls for 7 of these devices. Conclusions and Relevance: Most priority review pathway high-risk cardiovascular devices are approved without a randomized or blinded trial. Noninferiority design and use of surrogate endpoints are common. These devices are frequently subject to recalls.

Off-label Use of High-Risk Cardiovascular Devices

Off-label Use of High-Risk Cardiovascular Devices

Review times and adverse events for cardiovascular devices.

Shorter regulatory review times for high-risk cardiovascular devices correlate with the likelihood of reports of adverse events.

Publication of Clinical Studies Supporting FDA Premarket Approval for High-Risk Cardiovascular Devices Between 2011 and 2013: A Cross-sectional Study.

Publication of Clinical Studies Supporting FDA Premarket Approval for High-Risk Cardiovascular Devices Between 2011 and 2013: A Cross-sectional Study.

Abstract 17021: Association Between Regulatory Review Times and Adverse Event Reports in New Cardiovascular Devices

Introduction: The Food and Drug Administration (FDA) approves new high-risk medical devices after reviews of safety and effectiveness data gathered in clinical trials. Some have advocated for shorter review times to encourage innovation. We evaluated whether regulatory review time and product novelty predict adverse events involving high-risk cardiovascular devices. Methods: All high-risk cardiovascular devices approved between 2000-2009, grouped by FDA-assigned product codes were linked to regulatory review data and adverse events reported in the FDA’s Manufacturer and User Facility Device Experience database over the four years following FDA approval. Adverse events were classified according to severity, and linear probability / logistic regression models evaluated whether regulatory review times or product novelty predicted adverse event reporting. Results: Regulatory review times for 106 devices averaged 14.6 (SD: 9.77) months. Only 48/106 (45%) of devices in 28 product codes had at least 1 reported adverse event (mean: 182, range: 1-2706), yielding a total of 8,721 adverse event reports. Shorter regulatory review times were associated with a higher probability of any adverse event, as well as a higher probability of patient injury/death: a one standard deviation decrease in regulatory review time was associated with a 13.7% absolute/30.4% relative increase in risk of any adverse event reporting (95% CI: 6.8-20.5, p&lt;0.001), a 9.8% absolute/39.1% relative increase in absolute risk of adverse events involving serious injury or death (95% CI: 2.0-17.6, p=0.02), and a 9.8% absolute/39.1% relative increase in probability of being in the top quartile of the count of total adverse events involving injury or death (95% CI: 2.0-18.6, p=0.02). Controlling for review time, novelty of a product was not predictive of the presence or frequency of adverse event reports. Conclusion: High-risk cardiovascular devices with shorter FDA reviews were associated with a higher probability of any reported adverse events, of events involving serious injury or death, and were more likely to be among those with the highest number of adverse event reports of injury or death. These data should inform current proposals aimed at expediting the review of high-risk devices.

Regulatory science: Trust and transparency in clinical trials of medical devices.

Regulatory approval of high-risk cardiovascular devices is on the basis of clinical studies submitted with a premarket approval application. Failure to publish many of these studies in peer-reviewed literature, and major discrepancies between premarket approval submissions and those studies that are published, raise important questions for clinicians and other stakeholders.

Selective reporting in trials of high risk cardiovascular devices: cross sectional comparison between premarket approval summaries and published reports

Objective To investigate characteristics of clinical trials and results on safety and effectiveness reported in US Food and Drug Administration (FDA) documents for recently approved high risk cardiovascular devices compared...

Most Important Outcomes Research Papers on Cardiovascular Disease in Women

Cardiovascular disease (CVD) in women has been historically understudied. For many years, heart disease had been thought to be primarily a “man’s disease.” Consequently, women have been significantly under-represented in longitudinal studies of disease history and in clinical trials. High-quality data from women at the extremes of age, with multiple co-morbidities, and from racial and ethnic minorities have been particularly rare. In order to increase awareness of cardiovascular prevention among women, in 1999 the American Heart Association (AHA) published its first women-specific clinical recommendations for the prevention of CVD.1 In 2004, the AHA and multiple other collaborating organizations subsequently sponsored “Evidence-Based Guidelines for Cardiovascular Disease Prevention in Women,” which underwent updates in 2007 and 2011. As a result of these and other related initiatives, the rate of public awareness of CVD as the leading cause of death among US women has increased from 30% in 1997 to 54% in 2009.2 CVD-associated death among US women has declined significantly over this time period.3,4 Yet substantial work still needs to be done to improve women’s cardiovascular health. CVD remains the number one killer among women.4 As the obesity epidemic continues, we are actually finding increases in coronary heart disease (CHD) death among young women 35 to 54 years of age.2 Morbidity and mortality from stroke and hypertension remain high.4 In addition, substantial outcomes disparities continue for women from racial and ethnic minorities.4 We have therefore dedicated our topic summaries in this issue of Circulation: Cardiovascular Quality and Outcomes to CVD in women. We have included only those studies where authors provided a convincing a priori reason to study a particular disease process or clinical intervention in women and reported primary endpoints that were sex-specific. We have included articles on the representation of women …

Rethinking medical device regulation

Rethinking medical device regulation

Abstract 140: Majority of High-Risk Cardiovascular Device Studies Do Not Include Comparative Efficacy Data at the Time of FDA Approval

Introduction Comparative effectiveness data is important in informing regulatory and treatment decisions with information on the clinical significance of the measured outcomes. There is increasing utilization and significance of cardiovascular devices in the United States, thus it is important to know the comparative efficacy of novel cardiovascular devices at the time they receive Food and Drug Administration (FDA) approval. Hypothesis We assessed the hypothesis that clinical trials results submitted to the FDA for approval of novel, high-risk cardiovascular devices often provide comparative efficacy data. Methods Comparative efficacy was defined as the presence of an active control. For all high-risk cardiovascular devices approved by the FDA from 2000 through 2011, we extracted information on comparative efficacy data from Summaries of Safety and Effectiveness Data (Summary) which include study data used to justify FDA approval. All identified studies were examined to determine if they relied upon active controls, historical controls, objective performance criteria, or if they had no control. The proportion of studies containing comparative efficacy data was calculated and cross-tabulated by approval year and device class. A multivariate logistic model was used to assess trends over time and the Kruskal-Wallis test was used to examine differences between device sub-types. Results We examined 114 Summaries which contained 340 cardiovascular device studies. Of these studies, 140 (41%) contained an active control. Historical controls 48 (14%) and objective performance 83 (24%) criteria were commonly used. Sixty-nine (20%) of the studies were single-arm studies without controls. In our Summary-level analysis, 74 (65%) devices had an active control in at least one supporting study. Approval year was not significantly associated with type of control arm after controlling for device type in our multivariate logistic analysis. Use of comparative efficacy data was significantly associated with device type. Use ranged from 15/19 (79%) of hemostasis devices to 0/3 (0%) of ventricular assist devices. Conclusions A minority of studies for the highest risk cardiovascular devices approved by the FDA since 2000 included comparative efficacy data through the use of an active comparator arm. Increasing use of active controls would help to better inform regulatory and treatment decisions at the point of FDA approval.

Evaluating Sex Differences in Medical Device Clinical Trials

THE SAFETY AND EFFECTIVENESS OF MEDICAL TREATments can differ in men and women for many reasons related to different epidemiologic characteristics, physiology, and body size. In general, women have higher bleeding rates and procedural morbidity and mortality than men, which means that their risk/benefit ratios for many implanted medical devices can differ from men. Therefore, sex-specific safety and effectiveness data are necessary for informed patient decision making. In 2008, the US Food and Drug Administration (FDA) convened 2 workshops on this topic that included multiple stakeholders— patient groups, medical device industry representatives, academia, and government officials. In December 2011, the FDA released a draft guidance informed by these workshops, entitled “Evaluation of Sex Differences in Medical Device Clinical Studies.” This document discusses the underrepresentation of women in medical device clinical trials and provides recommendations for increasing enrollment of women and performing sex-specific analyses. A 90-day public comment period began on December 19, 2011. The FDA draft guidance document provides a number of helpful guidelines to support adequate enrollment of women in clinical trials. For studies that have not yet been completed, the draft guidance recommends keeping enrollment open until a prespecified number of women are enrolled. Following this recommendation so that women are enrolled in proportion to disease prevalence would do the most to ensure sufficient data about the effect of a medical device on women. The draft guidance document also recommends that outcomes data be analyzed by sex. By not limiting its guidance to new studies, the FDA is indicating that it hopes changes will occur more immediately. This approach is laudable; the difference between men and women in terms of effectiveness and safety of medical devices has long been understudied. The recommendations in this draft guidance may help ensure safe and effective use of medical devices in both sexes. However, the notation on this guidance stating that it “Contains Nonbinding Recommendations” raises the fundamental question of whether these important guidelines will be followed. This is not a new question. In 1994, FDA issued a “Gender Bias” directive stating that FDA Summaries of Safety and Effectiveness Data, which are released on premarket approval for all high-risk medical devices, should examine clinical trial data for differences in safety and efficacy by sex. However, an examination of compliance with this directive found that it is routinely ignored. Among 78 high-risk cardiovascular devices approved during the years 2000 through 2007, the overall patient population in these studies was 67% men with no increase in the enrollment of women over time, although women make up 46% of all patients with cardiovascular disease. The analyses by sex specified in the 1994 FDA directive occurred in only 41% of studies (51/123). When these analyses were completed, 26% (12/47) identified some difference in device safety or effectiveness by sex. In 28% of device studies (34/123), no sex distribution of the patient population was stated. As a result, clinically important sex-specific differences related to use of many medical devices are unknown. For example, the implantable cardioverter-defibrillator (ICD), a device shown to be lifesaving in selected populations, is commonly implanted in men and women. At the time of device approval, there were gaps in the data because of very low enrollment of women in the pivotal studies. In 2003 the Medicare Coverage and Advisory Committee was convened pursuant to a manufacturer’s request for expanded Medicare coverage of ICDs for primary prevention (which was granted). During the meeting, when asked why there were so few women in the pivotal Multicenter Automatic Defibrillator Implantation Trial II, the trial’s principal investigator stated, “we are contemplating a trial in the

TCT-395: Study Modifications and Primary Endpoint Reinterpretations Prior to FDA Approval of High-Risk Cardiovascular Devices

TCT-395: Study Modifications and Primary Endpoint Reinterpretations Prior to FDA Approval of High-Risk Cardiovascular Devices

Gender Bias in Studies for Food and Drug Administration Premarket Approval of Cardiovascular Devices

Cardiovascular devices can have different safety and effectiveness profiles in men and women. The type and quality of sex-specific data reviewed by the Food and Drug Administration (FDA) before approval of these devices are unknown. We performed a systematic review of the demographics, comments on gender bias, and analysis of results by sex for 78 high-risk cardiovascular devices that received premarket approval by the FDA between 2000 and 2007. FDA summaries of evidence did not report sex of enrollees in 34 (28%) of 123 studies. For studies reporting sex distribution, the study populations were, on average, 67% men. There was no increase in the enrollment of women over time. Explanations for the relatively low percentage of women often stated that the trials reflected either underlying disease distribution or referral rates for similar procedures or that the sex distribution reflected similar or previous trials. Forty-one percent of studies included a gender bias comment or analysis, and 12 (26%) of 47 of these analyses identified some difference in device safety or effectiveness by sex. There is a lack of sex-specific safety and effectiveness data for high-risk cardiovascular devices before FDA approval. The justifications for this lack of evidence may perpetuate the status quo. More rigorous FDA requirements for sex-specific data before device approval could present an opportunity to improve cardiovascular outcomes.