Why Evidence Generation Should Matter to Payers and How They Can Help.

Importance: The US leads the world in bringing new medical products to market, but the ability to generate evidence to inform clinical practice in postmarket settings needs improvement. Although a diverse group of stakeholders is working to improve postmarket evidence generation, the role of private payers has been underappreciated. Observations: Payers are crucial allies in improving evidence generation because better data would better inform coverage decisions, their policies and practices influence the conduct of care and research, and their claims data are a source of real-world evidence used in medical product evaluation. In addition, payers have a stake in improving evidence generation because the kinds of evidence needed to inform health care and coverage decisions are often not available when a product enters the market and may not be generated without their involvement. Here, we describe several key steps payers could take to improve evidence generation, including participating in efforts to reduce administrative and financial barriers to the conduct of clinical trials, directly incentivizing evidence generation on high-priority questions by funding potential cost-saving trials, increasing engagement with the medical products industry on evidentiary needs for coverage decisions, and improving usability of claims data by reducing data lags and routinely recording unique device identifiers. Broad payer engagement with US Food and Drug Administration recommendations regarding evidence generation will ensure that the opportunities to participate in clinical research are extended to all communities and that evidence needed to inform care is generated in trials and surveillance systems that reflect the clinical reality across the US. Conclusions and Relevance: Increasing payer involvement in evidence generation can benefit all participants in the medical innovation ecosystem. The importance of payers in these efforts will continue to grow in response to imperatives to increase integration of care and research, engage a diverse set of communities in clinical research, and move toward alternative payment models.

Don't Ask Us to Stop Cycling: A Surgical Perspective.

MINI ABSTRACT: In this surgical perspective, we argue that counseling avoidance of bicycle commuting is not the right approach to cycling injury prevention or to overall urban health. Instead, we propose surgeons should take a more holistic approach that includes mitigating individual risk factors as well as creating an equitable environment of safety.

Why Should the FDA Focus on Pragmatic Clinical Research?

This Viewpoint from the FDA discusses how pragmatic clinical research­assessment that uses real-world data, often in combination with research data, after initial marketing approval­can help in evaluation of new technologies, benefit research sites in underresourced settings, and better inform regulatory decisions and clinical practice.

Why some Patients Benefit from Participating in a Sham Surgery Trial.

OBJECTIVE: We analyze the ethics of sham surgical trials from a utilitarian perspective and explore whether patients can benefit from participating in these trials. BACKGROUND: Sham-controlled randomized trials are an essential tool to evaluate the risks and benefits of some surgical procedures. However, sham trials are controversial because they expose patients to the harms of a sham procedure without the possibility of benefit. We argue that ethical analyses of sham trials have focused only on the harms of sham surgery and neglected to account for the harms of the procedure being studied. METHODS: We develop a theoretical model to estimate the harms and benefits experienced by patients who enter a sham surgery trial, taking into account the harms and benefits of the sham and intervention. RESULTS: When the procedure in question is found to be ineffective, sham trials typically result in a net benefit to participants because some participants are only exposed to the harms of the sham procedure, which are much lower than the harms of the full procedure. When the procedure is found to be beneficial, the primary harm to patients who underwent the sham is not due to the sham itself but because they suffer a delay in receiving an effective intervention. CONCLUSIONS: Patients often benefit from participating in sham surgery trials because the harms of the sham procedure are lower than the harms of the full procedure, which may turn out to be ineffective. Our results call for re-thinking the ethics of sham surgery trials.

Opioid Prescribing Patterns Before Fatal Opioid Overdose.

INTRODUCTION: Although opioid prescribing has decreased since 2010, overdose deaths involving illicit opioids have continued to rise. This study explores prescribing patterns before fatal overdose of decedents who died of prescription and illicit opioid overdoses. METHODS: This retrospective cohort study was conducted in 2019 and included all 1,893 Illinois residents who died of an opioid-related overdose in 2016. Each decedent was linked to any existing Prescription Monitoring Program records, calculating weekly morphine milligram equivalents for 52 weeks before overdose. RESULTS: Among the 1,893 fatal opioid overdoses, 309 involved any prescription opioid and 1,461 involved illicit opioids without the involvement of prescription opioids. The death rate because of illicit opioids was 23/100,000 among black residents versus 10.5/100,000 among whites. During the last year of life, 76% of prescription opioid decedents filled any opioid prescription totaling 10.7 prescriptions per decedent, compared with 36% of illicit opioid decedents totaling 2.6 prescriptions per decedent. During the last week of life, 33% of prescription opioid decedents filled an opioid prescription totaling 0.42 prescriptions per decedent, compared with 4% of illicit opioid decedents totaling 0.05 prescriptions per decedent. CONCLUSIONS: Prescribing patterns alone may not be sufficient to identify patients who are at high risk for opioid overdose, especially for those using illicit opioids. Interventions aimed at reducing opioid overdoses should take into account different patterns of opioid prescribing associated with illicit and prescription opioid overdose deaths and be designed around the local characteristics of the opioid overdose epidemic.

Mutational load causes stochastic evolutionary outcomes in acute RNA viral infection.

Mutational load is known to be of importance for the evolution of RNA viruses, the combination of a high mutation rate and large population size leading to an accumulation of deleterious mutations. However, while the effects of mutational load on global viral populations have been considered, its quantitative effects at the within-host scale of infection are less well understood. We here show that even on the rapid timescale of acute disease, mutational load has an effect on within-host viral adaptation, reducing the effective selection acting upon beneficial variants by ∼10 per cent. Furthermore, mutational load induces considerable stochasticity in the pattern of evolution, causing a more than five-fold uncertainty in the effective fitness of a transmitted beneficial variant. Our work aims to bridge the gap between classic models from population genetic theory and the biology of viral infection. In an advance on some previous models of mutational load, we replace the assumption of a constant variant fitness cost with an experimentally-derived distribution of fitness effects. Expanding previous frameworks for evolutionary simulation, we introduce the Wright-Fisher model with continuous mutation, which describes a continuum of possible modes of replication within a cell. Our results advance our understanding of adaptation in the context of strong selection and a high mutation rate. Despite viral populations having large absolute sizes, critical events in viral adaptation, including antigenic drift and the onset of drug resistance, arise through stochastic evolutionary processes.

Health Care Utilization of Opioid Overdose Decedents with No Opioid Analgesic Prescription History.

Opioid overprescribing is a major driver of the current opioid overdose epidemic. However, annual opioid prescribing in the USA dropped from 782 to 640 morphine milligram equivalents per capita between 2010 and 2015, while opioid overdose deaths increased by 63%. To better understand the role of prescription opioids and health care utilization prior to opioid-related overdose, we analyzed the death records of decedents who died of an opioid overdose in Illinois in 2016 and linked to any existing controlled substance monitoring program (CSMP) and emergency department (ED) or hospital discharge records. We found that of the 1893 opioid-related overdoses, 573 (30.2%) decedents had not filled an opioid analgesic prescription within the 6 years prior to death. Decedents without an opioid prescription were more likely to be black (33.3% vs 20.2%, p < .001), Hispanic (16.3% vs 8.8%, p < .001), and Chicago residents (46.8% vs 25.6%, p < .001) than decedents with at least one filled opioid prescription. Decedents who did not fill an opioid prescription were less likely to die of an overdose involving prescribed opioids (7.3% vs 19.5%, p < .001) and more likely to fatally overdose on heroin (63% vs 50.4%, p < .001) or fentanyl/fentanyl analogues (50.3% vs 41.8%, p = .001). Between 2012 and the time of death, decedents without an opioid prescription had fewer emergency department admissions (2.5 ± 4.2 vs 10.6 ± 15.8, p < .001), were less likely to receive an opioid use disorder diagnosis (41.3% vs 47.5%, p = .052), and were less likely to be prescribed buprenorphine for opioid use disorder treatment (3.3% vs 8.6%, p < .001). Public health interventions have often focused on opioid prescribing and the use of CSMPs as the core preventive measures to address the opioid crisis. We identified a subset of individuals in Illinois who may not be impacted by such interventions. Additional research is needed to understand what strategies may be successful among high-risk populations that have limited opioid analgesic prescription history and low health care utilization.