Estimated Cost of Developing a Therapeutic Complex Medical Device in the US.

Importance: The US medical device market is the world's largest, but estimates of the cost to bring a medical device to market are not available to help inform policy making and regulatory efforts to enhance device safety and innovation. Objective: To estimate the mean expected capitalized cost of developing a novel therapeutic complex medical device. Design, Setting, and Participants: In this economic evaluation, an analytical model of novel therapeutic complex medical device development using data from public and proprietary sources with coverage from 2000 through 2018 was used to estimate the cost, duration, and phase transition success probability associated with each stage of development. Data analysis was completed in September 2021. Exposures: Conduct of nonclinical and clinical studies; payment of FDA user fees for novel therapeutic complex medical devices. Main Outcomes and Measures: Mean development cost (in 2018 US dollars) incurred by developers for an FDA-approved novel therapeutic complex medical device, accounting for failures and cost of capital. Results: In this economic analysis, the mean development cost for a novel therapeutic complex medical device was $54 million (95% CI, $25 million-$200 million) excluding any postapproval studies that might be required. After accounting for the cost of failed studies and cost of capital, the mean capitalized cost of bringing a novel therapeutic complex medical device to the US market was $522 million (95% CI, $205 million-$3382 million). The key factors associated with this cost were the phase transition probabilities: 46.9% for nonclinical to feasibility study, 48.0% for feasibility to pivotal study, 75.7% pivotal study to FDA premarket approval submission, and 80.5% for FDA premarket approval submission to approval. The nonclinical development stage constituted the largest portion of overall cost at 85.0% with the FDA review stage with the highest phase transition probability accounting for only a small fraction at 0.5%. Conclusions and Relevance: In this economic evaluation study, the cost of therapeutic complex medical device development from proof of concept through postapproval stages was assessed accounting for the cost of failures and the cost of capital. Existing estimates did not account for all stages of development, capitalization, or failure costs, which this study suggests were substantial.

Risk Factors for Retinal Detachment: A Case-Control Study.

OBJECTIVE: The aim of this study was to investigate risk factors for retinal detachment or tear (RD/T), and follow up two studies that found increased risk from work-related heavy lifting. METHODS: We conducted a case-control study including 200 cases of RD/T and 415 controls. Participants completed a questionnaire covering general health, vision, and physical exertion. Multiple logistic regression and propensity score matching was used to control confounding and estimate independent effects. RESULTS: RD/T risk was increased by one lifting measure: current regular lifting of more than 30 lbs (>13.6 kg). In the population aged less than 65 years, the odds ratio comparing those with/without heavy lifting was 1.81, 95% confidence interval = 1.08 to 3.04. CONCLUSION: Occupational heavy lifting may represent a risk factor for RD/T, but further research is needed in populations with frequent heavy physical exertion to more precisely quantify the risk.

Chlorine exposure during a biological decontamination study in a mock subway tunnel.

The Underground Transport Restoration (UTR) Operational Technology Demonstration (OTD) was a full-scale field study focused on remediation of a subway system after contamination with a Bacillus anthracis (Ba) surrogate (Bacillus atrophaeus, subspecies globigii [Bg]). The study involved all aspects of subway system remediation following contamination with a biological surrogate, including characterization, clearance sampling, and waste management.[ 1 ] Personal exposure to chlorine gas was also monitored throughout the decontamination portion of the study. Process-based personal monitoring for chlorine was conducted using portable single gas monitors with chlorine sensors during Level A entry into the biologically-contaminated area (exclusion zone) during spraying operations. Additional monitoring was conducted during the mixing of pH-adjusted bleach solutions and waste item decontamination (immersion dunking). An analysis of variance was performed to compare process-based time-averaged chlorine exposure among the similar exposure groups. Chlorine exposure was highest for the Decon Sprayers, which was expected based on their proximity to the spray streams. Peak exposure levels (5-sec readings) ranged from 11 to at least 50 parts per million (ppm). It is likely that exposure exceeded 50 ppm, but this was the upper limit of measurement. Oversight personnel were farther away from the spray operation but still had significant peak chlorine exposures of 13-26 ppm. The rail cart operators had peak exposures of 13-19 ppm. Statistically significant differences were observed between time-weighted average exposure levels of Decon Sprayers and the other workers. Spraying of pH-adjusted bleach solution on subway tunnel surfaces for biological decontamination produced up to 50 ppm chlorine vapor in the air that far exceeded the occupational exposure limits of 0.5-1 ppm for chlorine, as well as the Immediately Dangerous to Life or Health limit of 10 ppm. Health and safety plans and operational activities must provide appropriate worker protection during such events where potential for chlorine overexposure has been demonstrated.

Environmental triggers of COPD symptoms: a case cross-over study.

INTRODUCTION: This study investigated the hypothesis that common environmental chemical exposures with known irritant or sensitising properties trigger exacerbations for patients with chronic obstructive pulmonary disease (COPD). METHODS: We conducted a case cross-over study in 168 patients with COPD who were members of a disease management group in central Massachusetts. Participants completed a baseline health survey and several short exposure surveys. Exposure surveys were administered by a nurse when a participant telephoned to report an exacerbation (case periods) and at a maximum of three randomly identified control periods when they were not experiencing an exacerbation. We compared exposures in the week preceding an exacerbation with exposures in normal (non-exacerbation) weeks. The questionnaire assessed short-term (1 week) home, community and workplace activities and exposures that may be associated with COPD exacerbation. RESULTS: Self-reported exercise was negatively associated with exacerbation (OR=0.59, 95% CI: 0.35 to 1.00). Among the environmental chemical exposures, car and truck exhaust (OR=4.36, 95% CI: 1.76 to 10.80) and use of scented laundry products (OR=2.69, 95% CI: 1.31 to 5.52) showed strong positive effects. Self-reported respiratory infections were strongly associated with exacerbation (OR=7.90, 95% CI 4.29 to 14.50). Variations in outdoor temperature were associated with COPD exacerbation risk (moderate versus cold temperature OR=1.95, 95% CI 1.09 to 3.49 and warm versus cold OR=0.43, 95% CI: 0.26 to 0.70). CONCLUSIONS: These results suggest that some environmental chemical exposures may play a role in triggering COPD exacerbations. If confirmed, they may provide useful guidance for patients with COPD to better manage their disease.

Outdoor Air Pollution and COPD-Related Emergency Department Visits, Hospital Admissions, and Mortality: A Meta-Analysis.

A systematic literature review was performed to identify all peer-reviewed literature quantifying the association between short-term exposures of particulate matter <2.5 microns (PM2.5), nitrogen dioxide (NO2), and sulfur dioxide (SO2) and COPD-related emergency department (ED) visits, hospital admissions (HA), and mortality. These results were then pooled for each pollutant through meta-analyses with a random effects model. Subgroup meta-analyses were explored to study the effects of selected lag/averaging times and health outcomes. A total of 37 studies satisfied our inclusion criteria, contributing to a total of approximately 1,115,000 COPD-related acute events (950,000 HAs, 80,000 EDs, and 130,000 deaths) to our meta-estimates. An increase in PM2.5 of 10 ug/m3 was associated with a 2.5% (95% CI: 1.6-3.4%) increased risk of COPD-related ED and HA, an increase of 10 ug/m3 in NO2 was associated with a 4.2% (2.5-6.0%) increase, and an increase of 10 ug/m3 in SO2 was associated with a 2.1% (0.7-3.5%) increase. The strength of these pooled effect estimates, however, varied depending on the selected lag/averaging time between exposure and outcome. Similar pooled effects were estimated for each pollutant and COPD-related mortality. These results suggest an ongoing threat to the health of COPD patients from both outdoor particulates and gaseous pollutants. Ambient outdoor concentrations of PM2.5, NO2, and SO2 were significantly and positively associated with both COPD-related morbidity and mortality.

Validation of the breathlessness, cough and sputum scale to predict COPD exacerbation.

The breathlessness, cough and sputum scale (BCSS) is a three-item questionnaire rating breathlessness, cough and sputum on a 5-point Likert scale from 0 (no symptoms) to 4 (severe symptoms). Researchers have explored the utility of this tool to quantify efficacy of treatment following a chronic obstructive pulmonary disease (COPD) exacerbation; however, little work has been done to investigate the ability of the BCSS to predict COPD exacerbation. As part of a prospective case-crossover study among a cohort of 168 COPD patients residing in central Massachusetts, patients were asked standard BCSS questions during exacerbation and randomly identified non-exacerbation (or healthy) weeks. We found that the BCSS was strongly associated with COPD exacerbation (OR=2.80, 95% CI=2.27-3.45) and that a BCSS sum score of 5.0 identified COPD exacerbation with 83% sensitivity and 68% specificity. These results may be useful in the clinical setting to expedite interventions of exacerbation.

Low level air pollution and exacerbation of existing copd: a case crossover analysis.

BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) contribute greatly to increased morbidity, mortality and diminished quality of life. Recent studies report moderately strong positive associations between exposures to several air pollutants and COPD-related emergency department (ED) visits and hospital admissions (HA). Studies that use clinically defined exacerbations rather than counting ED visits and HA may be more sensitive to environmental triggers like air pollution, but very few such studies exist. Participants in a COPD disease management group living in an area of low air pollution and who were followed closely for the earliest signs of an exacerbation provided an opportunity to study associations between air pollution and COPD exacerbation. METHODS: Associations between short term exposures to air pollutants, including sulfur dioxide (SO2), nitrogen dioxide (NO2), and particulate matter < 2.5 microns (PM2.5), and COPD exacerbation were assessed among 168 patients residing in central Massachusetts, a region with air pollution levels well below USEPA National Ambient Air Quality Standards (NAAQS). Case-crossover analyses and multivariate conditional logistic regression were used to estimate associations between 7-day average concentrations of each air pollutant, as measured at central site monitors, and COPD exacerbation experienced in the patients' homes during the period 2012-2013, while controlling for temperature and self-reported influenza. RESULTS: We found that short-term exposures to SO2 were associated with an increase in COPD exacerbation risk (odds ratio (OR) = 2.45, 95 % CI: 1.75-3.45 per 1 ppb increase) after adjustment for PM2.5. Short-term exposures to NO2 concentrations showed a weaker association, (OR = 1.17, 95 % CI: 1.05-1.30 per 1 ppb increase) after adjustment for PM2.5. An unexpectedly modest negative association was seen for short-term exposures to PM2.5. CONCLUSIONS: Despite living in an area with air pollution concentrations below current USEPA NAAQS, these COPD patients appeared to suffer increased risk of COPD exacerbation following short-term exposures to increased concentrations of SO2 and NO2. An unexpected negative association with PM2.5 may result from the complex air chemistry of low level PM in this region.

Metabotropic glutamate receptor 5 knockout reduces cognitive impairment and pathogenesis in a mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) pathology occurs in part as the result of excessive production of ß-amyloid (Aß). Metabotropic glutamate receptor 5 (mGluR5) is now considered a receptor for Aß and consequently contributes to pathogenic Aß signaling in AD. RESULTS: Genetic deletion of mGluR5 rescues the spatial learning deficits observed in APPswe/PS1ΔE9 AD mice. Moreover, both Aß oligomer formation and Aß plaque number are reduced in APPswe/PS1ΔE9 mice lacking mGluR5 expression. In addition to the observed increase in Aß oligomers and plaques in APPswe/PS1ΔE9 mice, we found that both mTOR phosphorylation and fragile X mental retardation protein (FMRP) expression were increased in these mice. Genetic deletion of mGluR5 reduced Aß oligomers, plaques, mTOR phosphorylation and FMRP expression in APPswe/PS1ΔE9 mice. CONCLUSIONS: Thus, we propose that Aß activation of mGluR5 appears to initiate a positive feedback loop resulting in increased Aß formation and AD pathology in APPswe/PS1ΔE9 mice via mechanism that is regulated by FMRP.

Metabotropic glutamate receptor 5 knockout promotes motor and biochemical alterations in a mouse model of Huntington's disease.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin protein, which promotes progressive neuronal cell loss, neurological symptoms and death. In the present study, we show that blockade of mGluR5 with MTEP promotes increased locomotor activity in both control (Hdh(Q20/Q20)) and mutant HD (Hdh(Q111/Q111)) mice. Although acute injection of MTEP increases locomotor activity in both control and mutant HD mice, locomotor activity is increased in only control mice, not mutant HD mice, following the genetic deletion of mGluR5. Interestingly, treatment of mGluR5 knockout mice with either D1 or D2 dopamine antagonists eliminates the increased locomotor activity of mGluR5 knockout mice. Amphetamine treatment increases locomotor activity in control mice, but not mGluR5 null mutant HD mice. However, the loss of mGluR5 expression improves rotarod performance and decreases the number of huntingtin intranuclear inclusions in mutant HD mice. These adaptations may be due to mutant huntingtin-dependent alterations in gene expression, as microarray studies have identified several genes that are altered in mutant, but not wild-type HD mice lacking mGluR5 expression. qPCR experiments confirm that the mRNA transcript levels of dynein heavy chain, dynactin 3 and dynein light chain-6 are altered following the genetic deletion of mGluR5 in mutant HD mice, as compared with wild-type mutant HD mice. Thus, our data suggest that mutant huntingtin protein and mGluR5 exhibit a functional interaction that may be important for HD-mediated alterations in locomotor behavior and the development of intranuclear inclusions.

The role of group orientation and descriptive norms on water conservation attitudes and behaviors.

Social norms have been shown to impact behaviors, but with mixed results. The theory of normative social behavior delineates factors that moderate the relationship between descriptive norms and behaviors, and it addresses the attributes of behaviors that make them susceptible to normative influence. This study tests whether group orientation moderates the impact of descriptive norms on water conservation attitudes and behavioral intentions. Findings indicate a consistent pattern of interactions for descriptive norms and group orientation on both attitudes and behavioral intent. Implications for normative theory and campaign design are addressed.