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.

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.

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.

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.

Clinical Evidence Generation During a Pandemic: Lessons Learned for Sustaining Progress.

ABSTRACT: Because of significant adaptations forced by the COVID-19 pandemic, resultant changes within health care delivery and clinical research introduced the potential for evaluation of novel evidence generation approaches in oncology. On July 26 and 27, 2021, the National Academies of Science, Engineering, and Medicine, National Cancer Policy Forum hosted a virtual workshop entitled "Cancer Care and Cancer Research in the Context of the COVID-19 Pandemic: A Workshop on Lessons Learned." This workshop examined changes in cancer care and cancer research that occurred in response to the COVID-19 pandemic and considered lessons learned from that experience. The goal was to identify what changes could improve the delivery of high-quality cancer care and the conduct of cancer clinical trials in the postpandemic era, with an emphasis on health equity. How can we sustain the valuable lessons learned that might accelerate progress and enhance clinical evidence generation for patients and clinicians? In this overview, we discuss ways in which the COVID-19 experience has catalyzed research efficiencies as well as fostered a broader array of trial design and research methods that may facilitate improved cancer drug development during the pandemic and beyond.

Biological and clinical correlates of the patient health questionnaire-9: exploratory cross-sectional analyses of the baseline health study.

OBJECTIVES: We assessed the relationship between the Patient Health Questionnaire-9 (PHQ-9) at intake and other measurements intended to assess biological factors, markers of disease and health status. DESIGN, SETTING AND PARTICIPANTS: We performed a cross-sectional analysis of 2365 participants from the Baseline Health Study, a prospective cohort of adults selected to represent major demographic groups in the USA. Participants underwent deep phenotyping on demographic, clinical, laboratory, functional and imaging findings. IMPORTANCE: Despite extensive research on the clinical implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and other measures of health and disease; we sought to better understand this relationship. INTERVENTIONS: None. MAIN OUTCOMES AND MEASURES: Cross-sectional measures of medical illnesses, gait, balance strength, activities of daily living, imaging and laboratory tests. RESULTS: Compared with lower PHQ-9 scores, higher scores were associated with female sex (46.9%-66.7%), younger participants (53.6-42.4 years) and compromised physical status (higher resting heart rates (65 vs 75 bpm), larger body mass index (26.5-30 kg/m2), greater waist circumference (91-96.5 cm)) and chronic conditions, including gastro-oesophageal reflux disease (13.2%-24.7%) and asthma (9.5%-20.4%) (p<0.0001). Increasing PHQ-9 score was associated with a higher frequency of comorbidities (migraines (6%-20.4%)) and active symptoms (leg cramps (6.4%-24.7%), mood change (1.2%-47.3%), lack of energy (1.2%-57%)) (p<0.0001). After adjustment for relevant demographic, socioeconomic, behavioural and medical characteristics, we found that memory change, tension, shortness of breath and indicators of musculoskeletal symptoms (backache and neck pain) are related to higher PHQ-9 scores (p<0.0001). CONCLUSIONS: Our study highlights how: (1) even subthreshold depressive symptoms (measured by PHQ-9) may be indicative of several individual- and population-level concerns that demand more attention; and (2) depression should be considered a comorbidity in common disease. TRIAL REGISTRATION NUMBER: NCT03154346.

Importance of Social Determinants in Screening for Depression.

IMPORTANCE: The most common screening tool for depression is the Patient Health Questionnaire-9 (PHQ-9). Despite extensive research on the clinical and behavioral implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and social determinants of health and disease. OBJECTIVE: To assess the relationship between the PHQ-9 at intake and other measurements intended to assess social determinants of health. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses of 2502 participants from the Baseline Health Study (BHS), a prospective cohort of adults selected to represent major demographic groups in the US; participants underwent deep phenotyping on demographic, socioeconomic, clinical, laboratory, functional, and imaging findings. INTERVENTIONS: None. MAIN OUTCOMES AND MEASURES: Cross-sectional measures of clinical and socioeconomic status (SES). RESULTS: In addition to a host of clinical and biological factors, higher PHQ-9 scores were associated with female sex, younger participants, people of color, and Hispanic ethnicity. Multiple measures of low SES, including less education, being unmarried, not currently working, and lack of insurance, were also associated with higher PHQ-9 scores across the entire spectrum of PHQ-9 scores. A summative score of SES, which was the 6th most predictive factor, was associated with higher PHQ-9 score after adjusting for 150 clinical, lab testing, and symptomatic characteristics. CONCLUSIONS AND RELEVANCE: Our findings underscore that depression should be considered a comorbidity when social determinants of health are addressed, and both elements should be considered when designing appropriate interventions.