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.

The Integration of Clinical Trials With the Practice of Medicine: Repairing a House Divided.

Importance: Optimal health care delivery, both now and in the future, requires a continuous loop of knowledge generation, dissemination, and uptake on how best to provide care, not just determining what interventions work but also how best to ensure they are provided to those who need them. The randomized clinical trial (RCT) is the most rigorous instrument to determine what works in health care. However, major issues with both the clinical trials enterprise and the lack of integration of clinical trials with health care delivery compromise medicine's ability to best serve society. Observations: In most resource-rich countries, the clinical trials and health care delivery enterprises function as separate entities, with siloed goals, infrastructure, and incentives. Consequently, RCTs are often poorly relevant and responsive to the needs of patients and those responsible for care delivery. At the same time, health care delivery systems are often disengaged from clinical trials and fail to rapidly incorporate knowledge generated from RCTs into practice. Though longstanding, these issues are more pressing given the lessons learned from the COVID-19 pandemic, heightened awareness of the disproportionate impact of poor access to optimal care on vulnerable populations, and the unprecedented opportunity for improvement offered by the digital revolution in health care. Four major areas must be improved. First, especially in the US, greater clarity is required to ensure appropriate regulation and oversight of implementation science, quality improvement, embedded clinical trials, and learning health systems. Second, greater adoption is required of study designs that improve statistical and logistical efficiency and lower the burden on participants and clinicians, allowing trials to be smarter, safer, and faster. Third, RCTs could be considerably more responsive and efficient if they were better integrated with electronic health records. However, this advance first requires greater adoption of standards and processes designed to ensure health data are adequately reliable and accurate and capable of being transferred responsibly and efficiently across platforms and organizations. Fourth, tackling the problems described above requires alignment of stakeholders in the clinical trials and health care delivery enterprises through financial and nonfinancial incentives, which could be enabled by new legislation. Solutions exist for each of these problems, and there are examples of success for each, but there is a failure to implement at adequate scale. Conclusions and Relevance: The gulf between current care and that which could be delivered has arguably never been wider. A key contributor is that the 2 limbs of knowledge generation and implementation-the clinical trials and health care delivery enterprises-operate as a house divided. Better integration of these 2 worlds is key to accelerated improvement in health care delivery.

Is Vaccination Approaching a Dangerous Tipping Point?

This Viewpoint discusses declining vaccination rates in the US, specifically against COVID-19, and the ways in which clinicians and the Food and Drug Administration can counter the current large volume of vaccine misinformation.

Now is the time to fix the evidence generation system.

Despite enormous advances in biomedical science, corresponding improvements in health outcomes lag significantly. This is particularly true in the United States, where life expectancy trails far behind that of other high-income countries. In addition, substantial disparities in life expectancy and other health outcomes exist as a function of race, ethnicity, wealth, education, and geographic location. A major reformation of our national system for generating medical evidence-the clinical research enterprise-is needed to facilitate the translation of biomedical research into useful products and interventions. Currently, premarket systems for generating and evaluating evidence work reasonably well, but the postmarket phase is disaggregated and often fails to answer essential questions that must be addressed to provide optimal clinical care and public health interventions for all Americans. Solving these problems will require a focus on three key domains: (1) improving the integration of and access to high-quality data from traditional clinical trials, electronic health records, and personal devices and wearable sensors; (2) restructuring clinical research operations to support and incentivize the involvement of patients and frontline clinicians; and (3) articulating ethical constructs that enable responsible data sharing to support improved implementation. Finally, we must also address the systemic tendency to optimize individual components of the clinical research enterprise without considering the effects on the system as a whole. Overcoming suboptimization by creating incentives for integration and sharing will be essential to achieve more timely and equitable improvement in health outcomes.

Biological therapies need definitive randomized controlled clinical trials.

Adequate and well-controlled clinical trials remain critical tools for helping to bring benefit to patients in medical need.

The Need for a Smoking Cessation "Care Package".

This Viewpoint from leadership at the US Food and Drug Administration (FDA) proposes the creation of a comprehensive "care package" framework of resources to help maximize cessation of tobacco use, including components focused on strategies at the individual, health system, and population levels.

Over-the-counter Hearing Aids: From Research to Policy to Practice.

In this Viewpoint from officials at NIH and FDA, the authors discuss research collaborations between federal agencies and the private sector, using new regulations for over-the-counter hearing aids as an illustration.

Benefits of Streamlined Point-of-Care Trial Designs: Lessons Learned From the UK RECOVERY Study.

This Viewpoint discusses the benefits of streamlined point-of-care trial designs in clinical research, using lessons learned from the UK RECOVERY study of dexamethasone dosing for patients with COVID-19 and hypoxia.

General Anxiety Disorder-7 Questionnaire as a marker of low socioeconomic status and inequity.

BACKGROUND: The General Anxiety Disorder-7 (GAD-7) questionnaire is a standard tool used for screening and follow-up of patients with Generalized Anxiety Disorder (GAD). Although it is generally accepted that anxiety correlates with clinical and psychosocial stressors, precise quantitative data is limited on the relations among GAD-7, traditional biomarkers, and other measures of health. Further research is needed about how GAD-7 relates to race, ethnicity, and socioeconomic status (SES) as an assembly. We determined how multiple demographic and socioeconomic data correlate with the participants' GAD-7 results when compared with laboratory, physical function, clinical, and other biological markers. METHODS: The Project Baseline Health Study (BHS) is a prospective cohort of adults representing several populations in the USA. We analyzed a deeply phenotyped group of 2502 participants from that study. Measures of interest included: clinical markers or history of medical diagnoses; physical function markers including gait, grip strength, balance time, daily steps, and echocardiographic parameters; psychometric measurements; activities of daily living; socioeconomic characteristics; and laboratory results. RESULTS: Higher GAD-7 scores were associated with female sex, younger age, and Hispanic ethnicity. Measures of low SES were also associated with higher scores, including unemployment, income ≤$25,000, and ≤12 years of education. After adjustment for 158 demographic, clinical, laboratory, and symptom characteristics, unemployment and overall higher SES risk scores were highly correlated with anxiety scores. Protective factors included Black race and older age. LIMITATIONS: Correlations identified in this cross-sectional study cannot be used to infer causal relationships; further, we were not able to account for possible use of anxiety treatments by study participants. CONCLUSIONS: These findings highlight the importance of understanding anxiety as a biopsychosocial entity. Clinicians and provider organizations need to consider both the physical manifestations of the disorder and their patients' social determinants of health when considering treatment pathways and designing interventions.

The FDA and scientific priorities.

Earlier this year, when I was confirmed as the new commissioner of the US Food and Drug Administration (FDA), the world faced ongoing public health issues related to the pandemic and war in Ukraine, among other challenges. Most notably, the US is experiencing a flattening or decline in life expectancy compared with other high-income countries. As part of a wider effort to reverse this decline, relationships between FDA and the biomedical ecosystem should be reimagined to facilitate more effective translation of science into successful health interventions.

Association of left ventricular diastolic function with coronary artery calcium score: A Project Baseline Health Study.

BACKGROUND: Coronary artery calcium (CAC) and left ventricular diastolic dysfunction (LVDD) are strong predictors of cardiovascular events and share common risk factors. However, their independent association remains unclear. METHODS: In the Project Baseline Health Study (PBHS), 2082 participants underwent cardiac-gated, non-contrast chest computed tomography (CT) and echocardiography. The association between left ventricular (LV) diastolic function and CAC was assessed using multidimensional network and multivariable-adjusted regression analyses. Multivariable analysis was conducted on continuous LV diastolic parameters and categorical classification of LVDD and adjusted for traditional cardiometabolic risk factors. LVDD was defined using reference limits from a low-risk reference group without established cardiovascular disease, cardiovascular risk factors or evidence of CAC, (n â€‹= â€‹560). We also classified LVDD using the American Society of Echocardiography recommendations. RESULTS: The mean age of the participants was 51 â€‹± â€‹17 years with 56.6% female and 62.6% non-Hispanic White. Overall, 38.1% had hypertension; 13.7% had diabetes; and 39.9% had CAC >0. An intertwined network was observed between diastolic parameters, CAC score, age, LV mass index, and pulse pressure. In the multivariable-adjusted analysis, e', E/e', and LV mass index were independently associated with CAC after adjustment for traditional risk factors. For both e' and E/e', the effect size and statistical significance were higher across increasing CAC tertiles. Other independent correlates of e' and E/e' included age, female sex, Black race, height, weight, pulse pressure, hemoglobin A1C, and HDL cholesterol. The independent association with CAC was confirmed using categorical analysis of LVDD, which occurred in 554 participants (26.6%) using population-derived thresholds. CONCLUSION: In the PBHS study, the subclinical coronary atherosclerotic disease burden detected using CAC scoring was independently associated with diastolic function. GOV IDENTIFIER: NCT03154346.