The US Food and Drug Administration (FDA) and Centers for Medicare & Medicaid Services (CMS) have different statutory authorities; FDA evaluates safety and effectiveness for market authorization of medical devices while CMS determines whether coverage is "reasonable and necessary" for its beneficiaries. CMS has recently enacted policies automatically providing supplemental reimbursement for new, costly devices authorized after designation in FDA's Breakthrough Devices Program (BDP) and in June 2023 issued notice for a new Transitional Coverage for Emerging Technologies pathway, accelerating coverage for Breakthrough devices.
ABSTRACT Background Selective 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. 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 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 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). Conclusions FDAAA 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.
Chest wall restriction is a common outcome in patients with ankylosing spondylitis (AS). Pulmonary function testing (PFT9s) demonstrates a restrictive pattern of impairment. This impairment may be exacerbated when the subject is recumbent particularly when sleeping. It is not clear to what extent the specific FVC and FEV1 standing or lying values correlate with other commonly employed physical exam and functional outcome measures.We postulate that critical diminution of recumbent pulmonary function may have an adverse effect on sleep quality and functional outcome measures.
Objectives
To determine the utility of PFT testing in AS patients. To determine if FVC and FEV1 values in standing and recumbent postures correlate with other physical and functional outcome measures in AS patients.
Methods
48 consecutive patients with AS had routine history and physical exams including the EDASMI (Edmonton Ankylosing Spondylitis Metrology Index). Standard AS questionnaires were administered BASG, BASDAI, BASFI and Epworth Sleepiness Scale was used to determine degree of daytime sleepiness as a measure of sleep quality. PFT9s were performed in standing and recumbent posture. Statistical analysis was performed with SPSS software and included age, sex and smoking adjusted analysis of correlation of FVC standing, FVC lying, FVC difference between standing and lying (FVC delta), FEV 1 standing, FEV 1 lying and FEV1 difference between standing and lying (FEV1 delta).
Results
The population consisted of 15 women 10 of whom were smokers and 34 men 24 of whom were smokers. The mean age for the females was 50 years with a mean disease duration of 29.2 years. The mean age of the males was 51 years with a mean disease duration of 28.7 years. Mean BMI for the females was 29.4 and for the males 28.3. There is a statistically significant correlation in men between FVC and FEV1 with chest expansion, EDASMI, BASFI and BASDAI. Tragus to wall measurement also correlated with FVC measurements. These relationship were observed even when controlling for age and smoking history. FVC delta did not correlate with measurements of AS outcome or the Epworth Sleepiness Scale. BASFI correlates with the Epworth Sleepiness Scale. In the female cohort, FVC correlation with EDASMI almost reached statistical significance. The FVC in female smokers correlates with the age of onset and duration of disease. However, there was no correlation of FVC or FEV 1 with measurement of chest expansion, tragus to wall measurement, BASFI or BASDAI. The FVC delta did correlate with BASFI in females who have smoked. Correlation between FEV1 delta (but not FVC delta) with the Epworth Sleepiness Scale almost reached statistical significance in the female smoking group.
Conclusions
FVC and FEV1 are objective and reproducible measures of pulmonary function. In men, these correlated well with the standard physical examination measurements including chest expansion, tragus to wall measurement and the EDASMI. In turn all of these physical measurements correlated with the patient function as measured by BASFI and to a lesser extent BASDAI. Further study of this patient population is required to determine the utility of PFT testing as an independent outcome variable.
Extracellular vesicles (EVs) are lipid-based particles naturally released from cells and recognized as promising drug delivery vehicles for improving therapeutic outcomes.
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.
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Small extracellular vesicles (sEVs) have great promise as effective carriers for drug delivery. However, the challenges associated with the efficient production of sEVs hinder their clinical applications. Herein, we report a stimulative 3D culture platform for enhanced sEV production. The proposed platform consists of a piezoelectric nanofibrous scaffold (PES) coupled with acoustic stimulation to enhance sEV production of cells in a 3D biomimetic microenvironment. Combining cell stimulation with a 3D culture platform in this stimulative PES enables a 15.7-fold increase in the production rate per cell with minimal deviations in particle size and protein composition compared with standard 2D cultures. We find that the enhanced sEV production is attributable to the activation and upregulation of crucial sEV production steps through the synergistic effect of stimulation and the 3D microenvironment. Moreover, changes in cell morphology lead to cytoskeleton redistribution through cell-matrix interactions in the 3D cultures. This in turn facilitates intracellular EV trafficking, which impacts the production rate. Overall, our work provides a promising 3D cell culture platform based on piezoelectric biomaterials for enhanced sEV production. This platform is expected to accelerate the potential use of sEVs for drug delivery and broad biomedical applications.
