Faculty Bibliography

Convalescent plasma is an investigational product, not approved by the Food and Drug Administration for any use, that has been administered for the prevention and treatment of epidemic infections, including Ebola and most recently COVID-19. On 3 April 2020, Food and Drug Administration authorized an Expanded Access Program for treatment use of convalescent plasma in hospitalized COVID-19 patients, with Mayo Clinic as the coordinating site for this nationwide effort. Expanded Access, historically referred to as ''compassionate use,'' is a regulatory pathway that allows patients to use an investigational product outside of a clinical trial when four conditions are met: the patient has a life-threatening or serious disease, no comparable or satisfactory alternative treatment options are available, clinical trial enrollment is not possible, and non-trial use does not pose a threat to timely clinical development. Food and Drug Administration can authorize Expanded Access through requests for single patients, intermediate-size patient populations, and widespread treatment programs. The convalescent plasma Expanded Access Program was the largest in US history, leading to infusion of more than 94,000 patients. In comparison, the largest prior Expanded Access Programs-for lamivudine (HIV) and gefitinib (cancer)-each provided unapproved drugs to approximately 30,000 patients outside of clinical trials. Expanded Access Programs of this size are unusual and dwarf most clinical trials. However, Expanded Access Programs are intended for treatment, not research. Therefore, even when they involve sizable patient populations, they lack features of rigorous trial design, including control groups and randomization. Nevertheless, Expanded Access Program data have been considered pivotal by both the Food and Drug Administration and European Medicines Agency, often in the context of rare disease and the collection of safety data, and it was primarily the convalescent plasma Expanded Access Program data that led Food and Drug Administration to issue an emergency use authorization for that product. Although Expanded Access Programs are by regulation not supposed to hinder clinical trials, large Expanded Access Programs can create circular challenges, as when a lack of trial opportunities makes an Expanded Access Program an important pathway for initial access to an investigational product, but then the Expanded Access Program becomes a barrier to launching new trials. In this session, we will discuss the statistical, ethical, and regulatory issues that arise in the context of Expanded Access Programs, using the convalescent plasma Expanded Access Program as a case study in contrast to clinical trials, with a focus on issues arising in the context of a global pandemic. We will first discuss biostatistical considerations for extracting realworld evidence from Expanded Access Program data, as well as the role of these data in supplementing results from clinical trials. We will also consider the perspective of the patient in deciding whether to enroll in an Expanded Access Program versus clinical trial, including the opportunity for personal benefit or harm, potential for participation to impact the greater good, and the patient understanding of an unproven investigational treatment. Then, we will address the gatekeeping role of clinicians, institutions, and regulators, to ensure that Expanded Access Programs do not interfere with clinical trials. Finally, we will address patient pathways for accessing investigational drugs, especially in the context of a global pandemic, and the capacity for collecting rigorous data via these mechanisms, while prioritizing rigorous trials

BACKGROUND:Intensive glycemic control is of unclear benefit and carries increased risk for older adults with diabetes. The American Geriatrics Society's (AGS) Choosing Wisely (CW) guideline promotes less aggressive glycemic targets and reduction in pharmacologic therapy for older adults with type II diabetes. Meanwhile, behavioral economic (BE) approaches offer promise in influencing hard-to-change behavior, and previous studies have shown the benefits of using electronic health record (EHR) technology to encourage guideline adherence. OBJECTIVE:This study aimed to develop and pilot test an intervention that leverages BE with EHR technology to promote appropriate diabetes management in older adults. DESIGN/METHODS:A pilot study within the New York University Langone Health (NYULH) EHR and Epic system to deliver BE-inspired nudges at five NYULH clinics at varying time points from July 12, 2018, through October 31, 2019. PARTICIPANTS/METHODS:Clinicians across five practices in the NYULH system whose patients were older adults (age 76 and older) with type II diabetes. INTERVENTIONS/METHODS:A BE-EHR module comprising six nudges was developed through a series of design workshops, interviews, user-testing sessions, and clinic visits. BE principles utilized in the nudges include framing, social norming, accountable justification, defaults, affirmation, and gamification. MAIN MEASURES/METHODS:Patient-level CW compliance. KEY RESULTS/RESULTS:CW compliance increased 5.1% from a 16-week interval at baseline to a 16-week interval post intervention. From February 14 to June 5, 2018 (prior to the first nudge launch in Vanguard clinics), CW compliance for 1278 patients was mean (95% CI)-16.1% (14.1%, 18.1%). From July 3 to October 22, 2019 (after BE-EHR module launch at all five clinics), CW compliance for 680 patients was 21.2% (18.1%, 24.3%). CONCLUSIONS:The BE-EHR module shows promise for promoting the AGS CW guideline and improving diabetes management in older adults. A randomized controlled trial will commence to test the effectiveness of the intervention across 66 NYULH clinics. NIH TRIAL REGISTRY NUMBER/UNASSIGNED:NCT03409523.

SARS-CoV-2 poses a public health threat for which therapeutic agents are urgently needed. Herein, we report that high-throughput microfluidic screening of antigen-specific B-cells led to the identification of LY-CoV555, a potent anti-spike neutralizing antibody from a convalescent COVID-19 patient. Biochemical, structural, and functional characterization revealed high-affinity binding to the receptor-binding domain, ACE2 binding inhibition, and potent neutralizing activity. In a rhesus macaque challenge model, prophylaxis doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract. These data demonstrate that high-throughput screening can lead to the identification of a potent antiviral antibody that protects against SARS-CoV-2 infection.

Changing physician behaviors is difficult. Electronic health record (EHR) clinical decision support (CDS) offers an opportunity to promote guideline adherence. Behavioral economics (BE) has shown success as an approach to supporting evidence-based decision-making with little additional cognitive burden. We applied a user-centered approach to incorporate BE "nudges" into a CDS module in two "vanguard" sites utilizing: (1) semi-structured interviews with key informants (n = 8); (2) a design thinking workshop; and (3) semi-structured group interviews with clinicians. In the 133 day development phase at two clinics, the navigator section fired 299 times for 27 unique clinicians. The inbasket refill alert fired 124 times for 22 clinicians. Fifteen prescriptions for metformin were written by 11 clinicians. Our user-centered approach yielded a BE-driven CDS module with relatively high utilization by clinicians. Next steps include the addition of two modules and continued tracking of utilization, and assessment of clinical impact of the module.

BACKGROUND:In theory, efficient design of randomized controlled trials (RCTs) involves randomization algorithms that control baseline variable imbalance efficiently, and corresponding analysis involves pre-specified adjustment for baseline covariates. This review sought to explore techniques for handling potentially influential baseline variables in both the design and analysis phase of RCTs. METHODS:We searched PubMed for articles indexed "randomized controlled trial", published in the NEJM, JAMA, BMJ, or Lancet for two time periods: 2009 and 2014 (before and after updated CONSORT guidelines). Upon screening (343), 298 articles underwent full review and data abstraction. RESULTS:Typical articles reported on superiority (86%), multicenter (92%), two-armed (79%) trials; 81% of trials involved covariates in the allocation and 84% presented adjusted analysis results. The majority reported a stratified block method (69%) of allocation, and of the trials reporting adjusted analyses, 91% were pre-specified. Trials published in 2014 were more likely to report adjusted analyses (87% vs. 79%, p = 0.0100) and more likely to pre-specify adjustment in analyses (95% vs. 85%, p = 0.0045). Studies initiated in later years (2010 or later) were less likely to use an adaptive method of randomization (p = 0.0066; 7% of those beginning in 2010 or later vs. 31% of those starting before 2000) but more likely to report a pre-specified adjusted analysis (p = 0.0029; 97% for those initiated in 2010 or later vs. 69% of those started before 2000). CONCLUSION/CONCLUSIONS:While optimal reporting procedures and pre-specification of adjusted analyses for RCTs tend to be progressively more prevalent over time, we see the opposite effect on reported use of covariate-adaptive randomization methods.

To disseminate lessons learned from the implementation experience of a public-private sector partnership, we describe a comprehensive HIV/AIDS program including 5-year survival outcomes for individuals who initiated antiretroviral therapy (ART) treatment in Togo from 2010 to 2015. A retrospective case study analysis was conducted from a cohort of patients receiving ART at an HIV/AIDS care clinic in Kara Region, Togo. Kaplan-Meier curves with Log rank tests were used to compare estimated survival curves by demographic and clinical characteristics. Associations were described between survival probability and age, gender, World Health Organization (WHO) disease stage, and timing of ART initiation. Cox proportional hazard model was used to determine predictors of mortality. After approximately five-years since ART initiation (1780 days), there were 114 deaths, with a survival probability of 75.3% (95% CI: 70.3-80.6%). Participants with advanced WHO disease stage were more likely at risk of death relative to patients categorized as WHO Stage 1, with Stage 4 approximately 9 times more likely (aHR 9.22, 95% CI 4.29-19.84). Our study suggests that delivering comprehensive HIV care through a private-public partnership may serve as a model to expand and improve HIV/AIDS care as well as high quality primary care.

Recent work has quantified the geometric parameters of individual rat vibrissae (whiskers) and developed equations that describe how these parameters vary as a function of row and column position across the array. This characterization included a detailed quantification of whisker base diameter and arc length as well as the geometry of the whisker medulla. The present study now uses these equations for whisker geometry to quantify several properties of the whisker that govern its mechanical behavior. We first show that the average density of a whisker is lower in its proximal region than in its distal region. This density variation appears to be largely attributable to the presence of the whisker cuticle rather than the medulla. The density variation has very little effect on the center of mass of the whisker. We next show that the presence of the medulla decreases the deflection of the whisker under its own weight and also decreases its mass moment of inertia while sacrificing <1% stiffness at the whisker base compared with a solid whisker. Finally, we quantify two dimensionless parameters across the array. First, the deflection-to-length ratio decreases from caudal to rostral: caudal whiskers are longer but deflect more under their own weight. Second, the nondimensionalized radius of gyration is approximately constant across the array, which may simplify control of whisking by the intrinsic muscles. We anticipate that future work will exploit the mechanical properties computed in the present study to improve simulations of the mechanosensory signals associated with vibrissotactile exploratory behavior. NEW & NOTEWORTHY The mechanical signals transmitted by a whisker depend critically on its geometry. We used measurements of whisker geometry and mass to quantify the center of mass, mass moment of inertia, radius of gyration, and deflection under gravity of the whisker. We describe how variations in these quantities across the array could enhance sensing behaviors while reducing energy costs and simplifying whisking control. Most importantly, we provide derivations for these quantities for use in future simulation work.

Background/UNASSIGNED:Current guidelines recommend less aggressive target hemoglobin A1c (HbA1c) levels based on older age and lower life expectancy for older adults with diabetes. The effectiveness of electronic health record (EHR) clinical decision support (CDS) in promoting guideline adherence is undermined by alert fatigue and poor workflow integration. Integrating behavioral economics (BE) and CDS tools is a novel approach to improving adherence to guidelines while minimizing clinician burden. Methods/UNASSIGNED: = 8), (2) a 2-h, design-thinking workshop to derive and refine initial module ideas, and (3) semi-structured group interviews at each site with clinic leaders and clinicians to elicit feedback on three proposed nudge module components (navigator section, inbasket refill protocol, medication preference list). Detailed field notes will be summarized by module idea and usability theme for rapid iteration. Frequency of firing and user action taken will be assessed in the first month of implementation via EHR reporting to confirm that module components and related reporting are working as expected as well as assess utilization. To assess the utilization and feasibility of the new tools and generate estimates of clinician compliance with the Choosing Wisely guideline for diabetes management in older adults, a 6-month, single-arm pilot study of the BE-EHR module will be conducted in six outpatient primary care clinics. Discussion/UNASSIGNED:We hypothesize that a low burden, user-centered approach to design will yield a BE-driven, CDS module with relatively high utilization by clinicians. The resulting module will establish a platform for exploring the ability of BE concepts embedded within the EHR to affect guideline adherence for other use cases.