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

Background Selective 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. Methods Using 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). Results Between 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). Conclusions FDAAA 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.

The effects of non-Newtonian blood modeling and pulsatility on hemodynamics in the food and drug administration’s benchmark nozzle model

BACKGROUND: Computational fluid dynamics (CFD) is an important tool for predicting cardiovascular device performance. The FDA developed a benchmark nozzle model in which experimental and CFD data were compared, however, the studies were limited by steady flows and Newtonian models. OBJECTIVE: Newtonian and non-Newtonian blood models will be compared under steady and pulsatile flows to evaluate their influence on hemodynamics in the FDA nozzle. METHODS: CFD simulations were validated against the FDA data for steady flow with a Newtonian model. Further simulations were performed using Newtonian and non-Newtonian models under both steady and pulsatile flows. RESULTS: CFD results were within the experimental standard deviations at nearly all locations and Reynolds numbers. The model differences were most evident at Re = 500, in the recirculation regions, and during diastole. The non-Newtonian model predicted blunter upstream velocity profiles, higher velocities in the throat, and differences in the recirculation flow patterns. The non-Newtonian model also predicted a greater pressure drop at Re = 500 with minimal differences observed at higher Reynolds numbers. CONCLUSIONS: An improved modeling framework and validation procedure were used to further investigate hemodynamics in geometries relevant to cardiovascular devices and found that accounting for blood’s non-Newtonian and pulsatile behavior can lead to large differences in predictions in hemodynamic parameters.

Systematic morphological characterization of sub-visible particles generated from cardiovascular devices using dynamic image analysis

The assessment of particulate matter generated during a simulated use is requested by international standards for approval of cardiovascular devices. The particle suspension was generated during a simulated use test procedure of a commercially available coronary stent delivery system and analyzed by Dynamic image analysis (DIA) using FlowCAM 8000. Four parameters were analyzed: the diameter, the aspect ratio value, the circularity and the intensity. The results revealed that 53% of the particles were larger than 25 μm. The particle shapes were inhomogeneous with a wide ranging aspect ratio of 0.03 to 0.95. Around 83% had an intensity value of more than 140 grey scales and appeared translucent.

In vitro biocompatibility testing of polymeric nanofiber scaffolds: fine-tuning for a better prediction of the in vivo behaviour

Biomaterial research efforts focus on the development of biomaterials that mimic the natural extracellular environment. In addition, different strategies are applied to render materials for blood-contacting devices nonthrombogenic through surface modifications that would suppress activation of platelets, coagulation and the complement system. A confluent thin layer of endothelial cells lines all blood vessels and produces factors responsible for inhibition of coagulation, thrombosis and neointimal hyperplasia. Thus, the ability to rapidly form a healthy endothelium upon implantation represents a desired property of biomaterials used for cardiovascular devices. In this study we used advanced in vitro methods to investigate the biocompatibility of a biodegradable and a permanent electrospun nanofiber fabric, poly-L-lactic acid and polycarbonate-based silicone elastomer respectively, with the focus on endothelialization and hemocompatibility.

A review of the bio-tribology of medical devices

Numerous medical devices have been applied for the treatment or alleviation of various diseases. Tribological issues widely exist in those medical devices and play vital roles in determining their performance and service life. In this review, the bio-tribological issues involved in commonly used medical devices are identified, including artificial joints, fracture fixation devices, skin-related devices, dental restoration devices, cardiovascular devices, and surgical instruments. The current understanding of the bio-tribological behavior and mechanism involved in those devices is summarized. Recent advances in the improvement of tribological properties are examined. Challenges and future developments for the prospective of bio-tribological performance are highlighted.

Registration, Publication, and Outcome Reporting among Pivotal Clinical Trials that Supported FDA Approval of High-Risk Medical Devices Before and After FDAAA

ABSTRACTBackgroundSelective registration, publication, and outcome reporting of clinical trials distorts the primary clinical evidence that is available to patients and clinicians regarding the safety and efficacy of 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) medical devices before and after the U.S. Food and Drug Administration (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 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 115 (85%) vs 7 of 24 (29%); 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, results 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.

Informed consent and compulsory medical device registries: ethics and opportunities

Many high-risk medical devices earn US marketing approval based on limited premarket clinical evaluation that leaves important questions unanswered. Rigorous postmarket surveillance includes registries that actively collect and maintain information defined by individual patient exposures to particular devices. Several prominent registries for cardiovascular devices require enrolment as a condition of reimbursement for the implant procedure, without informed consent. In this article, we focus on whether these registries, separate from their legal requirements, have an ethical obligation to obtain informed consent from enrolees, what is lost in not doing so, and the ways in which seeking and obtaining consent might strengthen postmarket surveillance in the USA.

Venous and Arterial Endothelial Cells from Human Umbilical Cords: Potential Cell Sources for Cardiovascular Research

Although cardiovascular devices are mostly implanted in arteries or to replace arteries, in vitro studies on implant endothelialization are commonly performed with human umbilical cord-derived venous endothelial cells (HUVEC). In light of considerable differences, both morphologically and functionally, between arterial and venous endothelial cells, we here compare HUVEC and human umbilical cord-derived arterial endothelial cells (HUAEC) regarding their equivalence as an endothelial cell in vitro model for cardiovascular research. No differences were found in either for the tested parameters. The metabolic activity and lactate dehydrogenase, an indicator for the membrane integrity, slightly decreased over seven days of cultivation upon normalization to the cell number. The amount of secreted nitrite and nitrate, as well as prostacyclin per cell, also decreased slightly over time. Thromboxane B2 was secreted in constant amounts per cell at all time points. The Von Willebrand factor remained mainly intracellularly up to seven days of cultivation. In contrast, collagen and laminin were secreted into the extracellular space with increasing cell density. Based on these results one might argue that both cell types are equally suited for cardiovascular research. However, future studies should investigate further cell functionalities, and whether arterial endothelial cells from implantation-relevant areas, such as coronary arteries in the heart, are superior to umbilical cord-derived endothelial cells.