Prescriber perceptions of boxed warnings: A qualitative study.

PURPOSE: To explore how boxed warning (BW) information fits within the context of prescribers' overall treatment decision-making and communication with patients. METHODS: In-depth interviews (N = 52) were conducted with primary care providers and specialists. Participants were presented with one of two prescribing scenarios: (1) estrogen vaginal inserts to treat vulvovaginal atrophy (VVA) associated with menopause; or (2) direct-acting antivirals (DAA) to treat chronic hepatitis C virus infection (HCV). The semi-structured interviews explored participants' treatment decision-making within the scenario, reactions to current prescribing information for a product within the FDA-approved drug class, as well as their perceptions of BWs generally. RESULTS: Across scenarios, providers described that the BW is only one of several factors that influence treatment decision-making. In the VVA scenario, symptom severity, family history, and experience with nonprescription drugs were raised as common factors that influence prescribing considerations; compared to comorbid infections, viral load, and HCV genotype in the HCV scenario. Perceptions of the DAA BW were generally positive or neutral, as many participants found the information important and appropriate. The VVA BW was viewed less favorably, with many participants stating the BW overstates the risk for this drug. CONCLUSIONS: Findings suggest that BWs are one of several factors that influence providers' treatment decisions, and BW influence largely depends on context. Providers across scenarios expressed notable differences in their perceptions of the risk information provided in the presented BWs; however, across scenarios participants expressed consideration of how patients may perceive the BW.

Reducing opioid use disorder and overdose deaths in the United States: A dynamic modeling analysis.

Opioid overdose deaths remain a major public health crisis. We used a system dynamics simulation model of the U.S. opioid-using population age 12 and older to explore the impacts of 11 strategies on the prevalence of opioid use disorder (OUD) and fatal opioid overdoses from 2022 to 2032. These strategies spanned opioid misuse and OUD prevention, buprenorphine capacity, recovery support, and overdose harm reduction. By 2032, three strategies saved the most lives: (i) reducing the risk of opioid overdose involving fentanyl use, which may be achieved through fentanyl-focused harm reduction services; (ii) increasing naloxone distribution to people who use opioids; and (iii) recovery support for people in remission, which reduced deaths by reducing OUD. Increasing buprenorphine providers' capacity to treat more people decreased fatal overdose, but only in the short term. Our analysis provides insight into the kinds of multifaceted approaches needed to save lives.

Modeling the evolution of the US opioid crisis for national policy development.

The opioid crisis is a major public health challenge in the United States, killing about 70,000 people in 2020 alone. Long delays and feedbacks between policy actions and their effects on drug-use behavior create dynamic complexity, complicating policy decision-making. In 2017, the National Academies of Sciences, Engineering, and Medicine called for a quantitative systems model to help understand and address this complexity and guide policy decisions. Here, we present SOURCE (Simulation of Opioid Use, Response, Consequences, and Effects), a dynamic simulation model developed in response to that charge. SOURCE tracks the US population aged ≥12 y through the stages of prescription and illicit opioid (e.g., heroin, illicit fentanyl) misuse and use disorder, addiction treatment, remission, and overdose death. Using data spanning from 1999 to 2020, we highlight how risks of drug use initiation and overdose have evolved in response to essential endogenous feedback mechanisms, including: 1) social influence on drug use initiation and escalation among people who use opioids; 2) risk perception and response based on overdose mortality, influencing potential new initiates; and 3) capacity limits on treatment engagement; as well as other drivers, such as 4) supply-side changes in prescription opioid and heroin availability; and 5) the competing influences of illicit fentanyl and overdose death prevention efforts. Our estimates yield a more nuanced understanding of the historical trajectory of the crisis, providing a basis for projecting future scenarios and informing policy planning.

FDA's Benefit-Risk Framework for Human Drugs and Biologics: Role in Benefit-Risk Assessment and Analysis of Use for Drug Approvals.

BACKGROUND: Structured, descriptive approaches are utilized by drug regulatory agencies to support and communicate approval decisions about human drugs and biologics. The US Food and Drug Administration (FDA) uses the Benefit-Risk Framework (BRF), which has been integrated into its drug review process. This paper reviews how FDA review teams have used the BRF to communicate approval decisions. METHODS: This paper (1) uses content analysis to systematically review the decision factors communicated by FDA review teams in all BRFs associated with novel drugs approved by FDA in 2017-2018 and (2) presents a case study about how the BRF was used for three drugs approved for HIV-1 in 2018-2019. RESULTS: The content analysis found most BRFs for novel drug approvals communicate what we call an "urgent" context and complicating decision factors around benefit and/or risk; the HIV-1 case study highlights the flexibility of the structured BRF tool. CONCLUSIONS: FDA's BRF provides a flexible mechanism for communicating important decision factors, allowing it to support the diversity of drug approval decisions made by FDA.

Data Needs in Opioid Systems Modeling: Challenges and Future Directions.

INTRODUCTION: The opioid crisis is a pervasive public health threat in the U.S. Simulation modeling approaches that integrate a systems perspective are used to understand the complexity of this crisis and analyze what policy interventions can best address it. However, limitations in currently available data sources can hamper the quantification of these models. METHODS: To understand and discuss data needs and challenges for opioid systems modeling, a meeting of federal partners, modeling teams, and data experts was held at the U.S. Food and Drug Administration in April 2019. This paper synthesizes the meeting discussions and interprets them in the context of ongoing simulation modeling work. RESULTS: The current landscape of national-level quantitative data sources of potential use in opioid systems modeling is identified, and significant issues within data sources are discussed. Major recommendations on how to improve data sources are to: maintain close collaboration among modeling teams, enhance data collection to better fit modeling needs, focus on bridging the most crucial information gaps, engage in direct and regular interaction between modelers and data experts, and gain a clearer definition of policymakers' research questions and policy goals. CONCLUSIONS: This article provides an important step in identifying and discussing data challenges in opioid research generally and opioid systems modeling specifically. It also identifies opportunities for systems modelers and government agencies to improve opioid systems models.

Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study.

BACKGROUND: The new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 210 000 deaths worldwide. However, little is known about the causes of death and the virus's pathologic features. OBJECTIVE: To validate and compare clinical findings with data from medical autopsy, virtual autopsy, and virologic tests. DESIGN: Prospective cohort study. SETTING: Autopsies performed at a single academic medical center, as mandated by the German federal state of Hamburg for patients dying with a polymerase chain reaction-confirmed diagnosis of COVID-19. PATIENTS: The first 12 consecutive COVID-19-positive deaths. MEASUREMENTS: Complete autopsy, including postmortem computed tomography and histopathologic and virologic analysis, was performed. Clinical data and medical course were evaluated. RESULTS: Median patient age was 73 years (range, 52 to 87 years), 75% of patients were male, and death occurred in the hospital (n = 10) or outpatient sector (n = 2). Coronary heart disease and asthma or chronic obstructive pulmonary disease were the most common comorbid conditions (50% and 25%, respectively). Autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients. Postmortem computed tomography revealed reticular infiltration of the lungs with severe bilateral, dense consolidation, whereas histomorphologically diffuse alveolar damage was seen in 8 patients. In all patients, SARS-CoV-2 RNA was detected in the lung at high concentrations; viremia in 6 of 10 and 5 of 12 patients demonstrated high viral RNA titers in the liver, kidney, or heart. LIMITATION: Limited sample size. CONCLUSION: The high incidence of thromboembolic events suggests an important role of COVID-19-induced coagulopathy. Further studies are needed to investigate the molecular mechanism and overall clinical incidence of COVID-19-related death, as well as possible therapeutic interventions to reduce it. PRIMARY FUNDING SOURCE: University Medical Center Hamburg-Eppendorf.

Development of failure scenarios for biosolids land application risk assessment.

Although deviations from standard guidance for land application of biosolids occur in practice, their importance is largely unknown. A list of such deviations (plausible failure scenarios) were identified at a workshop of industry, regulators, and academic professionals. Next, a survey of similar professionals was conducted to rank the plausible failure scenarios according to their severity, frequency, incentive to ignore control measures, gaps in existing control processes, public concern, and overall concern. Survey participants rated intentional dumping (unpermitted disposal) as the most severe of the failure scenarios, lack of worker protection as the most frequent scenario, and application of Class A biosolids that have failed to meet treatment standards as the scenario for which incentives to ignore control measures are highest. Failure of public access restrictions to application sites was the scenario for which existing controls were judged the weakest; application of biosolids too close to wells was ranked highest for public concern and for overall concern. Two scenarios for which existing controls were considered weaker, site restriction violations and animal contact leading to human exposure, were also rated as frequently occurring. Both scenarios are related in that they (1) involve inappropriate access to a site before the required time has elapsed, and (2) could be addressed through similar biosolids management measures.

A preliminary model of wheelchair service delivery.

OBJECTIVE: To integrate and expand on previously published models of wheelchair service delivery, and provide a preliminary framework for developing more comprehensive, descriptive models of wheelchair service delivery for adults with spinal cord injury within the U.S. health care system. DESIGN: Literature review and a qualitative analysis of in-depth interviews. SETTING: Not applicable. PARTICIPANTS: Ten academic, clinical, regulatory, and industry experts (Department of Veterans Affairs [VA] and non-VA) in wheelchair service delivery. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Interviewees were asked to discuss the full range of variables and stakeholders involved in wheelchair service delivery, and to limit their scope to the provision of primary subsequent or replacement chairs (not backup chairs) to adults within the United States. RESULTS: Most experts we interviewed stressed that clients who require a wheelchair play a central role in the wheelchair service delivery process. Providers (including clinicians, rehabilitation engineers, and rehabilitation counselors) are also critical stakeholders. More so than in other health care settings, suppliers play an integral role in the provision of wheelchairs to clients and may significantly influence the appropriateness of the wheelchair provided. Suppliers often have a direct role in wheelchair service delivery through their interactions with the clinician and/or client. This model also identified a number of system-level factors (including facility administration and standards, policies, and regulations) that influence wheelchair service delivery and ultimately the appropriateness of the wheelchair provided. CONCLUSIONS: We developed a detailed, descriptive model of wheelchair service delivery that integrates the delivery process and device outcomes, and includes the patient-level, provider-level, and system-level factors that may directly influence those processes and outcomes. We believe that this detailed model can help clinicians and researchers describe and consider the complexities of wheelchair service delivery. It can be used to identify factors that may be related to disparities in wheelchair service delivery and in the appropriateness of the wheelchair prescribed. Further, this model can help researchers and clinicians identify factors that may be related to disparities in wheelchair service delivery, and intervene to reduce such disparities.

The impact of over-the-counter availability of "Plan B" on teens' contraceptive decision making.

In ruling on the over-the-counter status (OTC) of the emergency contraceptive, "Plan B", the US Food and Drug Administration (FDA) questioned whether younger adolescent females could adequately self-select and self-medicate. That determination requires a judgment of fact, regarding how increased emergency contraceptive availability would affect adolescents' behavior, and a judgment of values, regarding the acceptability of different outcomes. We present a general approach to such problems, using analytical and empirical methods grounded in behavioral decision research. We illustrate it with findings from 30 in-depth interviews and follow-up surveys, with adolescent females aged 13-19 in the Pittsburgh area reporting how Plan B availability would affect three decisions (having sex, choosing contraceptives, using Plan B). Although the FDA expressed concern about younger teens using Plan B as their primary form of contraception, neither younger nor older teens revealed such an intention. However, teens preferred easier availability, should emergency contraceptive be needed. Incorporating an understanding of teens' decision-related perspectives can make such policies more predictable and transparent.