PCORI Health Care Horizon Scanning System: Horizon Scanning COVID-19 Supplement Status Report Volume 2, Issue 2

Prepared for: Patient-Centered Outcomes Research Institute 1828 L St, NW, Suite 900 Washington, DC 20036

Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12

Prepared by: ECRI 5200 Butler Pike Plymouth Meeting, PA 19462

Investigators: Randy Hulshizer, MA, MS Jennifer De Lurio, MS Marcus Lynch, PhD, MBA Brian Wilkinson, MA Damian Carlson, MS Christian Cuevas, PhD Andrea Druga, MSPAS, PA-C Misha Mehta, MS Prital Patel, MPH Donna Beales, MLIS Eloise DeHaan, BS Eileen Erinoff, MSLIS Madison Kimball, MS Maria Middleton, MPH Melinda Rossi, BA Rosemary Walker, MLIS Andrew Furman, MD, MMM, FACEP

March 2021

Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System COVID-19 Supplement, operated by ECRI under contract to PCORI, Washington, DC (Contract No. MSA- HORIZSCAN-ECRI-ENG-2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI.

An innovation that potentially meets inclusion criteria might not appear in this report simply because the Horizon Scanning System has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual COVID-19 Supplement. Inclusion or absence of innovations in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions.

A representative from PCORI served as a contracting officer’s technical representative and provided input during the implementation of the Horizon Scanning System. PCORI does not directly participate in horizon scanning or assessing leads or topics and did not provide opinions regarding the potential impact of interventions.

Financial Disclosure Statement None of the individuals compiling this information has any affiliations or financial involvement that conflict with the material presented in this report.

Public Domain Notice This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated.

All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of PCORI or its Board of Governors. This publication was developed through a contract to support PCORI’s work. Questions or comments may be sent to PCORI at [email protected] or by mail to 1828 L St, NW, Suite 900, Washington, DC 20036. ©2021 Patient-Centered Outcomes Research Institute. For more information see www.pcori.org.

Suggested citation: Hulshizer R, De Lurio J, Lynch M, et al. PCORI Health Care Horizon Scanning System: Horizon Scanning COVID-19 Supplement Status Report: Volume 2, Issue 2. Patient-Centered Outcomes Research Institute; March 2021. Prepared by ECRI under Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12.

HORIZON SCANNING SUPPLEMENT STATUS REPORT ● MARCH 2021 i

Preface Horizon scanning is a systematic process that serves as an early warning system to inform decision makers about possible future opportunities and threats. Health care horizon scanning identifies technologies, innovations, and trends with potential to cause future shifts or disruptions—positive or negative—in areas such as access to care, care delivery processes, care settings, costs of care, current treatment models or paradigms, health disparities, health care infrastructure, public health, and patient health outcomes. The PCORI Health Care Horizon Scanning System (HCHSS) conducts horizon scanning to better inform its patient-centered outcomes research investments. Initially, PCORI defined the HCHSS project scope to focus on interventions with high potential for disruption in the United States in 5 priority areas: Alzheimer’s disease and other dementias, cancer, cardiovascular diseases, mental and behavioral health conditions, and rare diseases. In addition, the system captures high-level disruptive trends across all clinical areas, which may lead PCORI to expand the project scope to include other priority areas in the future. In early 2020, the COVID-19 pandemic created a fast-moving, widespread public health crisis. In May 2020, PCORI expanded its HCHSS to elucidate the landscape of potentially impactful applications for COVID-19. The HCHSS COVID-19 Supplement scans for, identifies, monitors, and reports on emerging and available COVID-19-related treatments, diagnostics, preventive measures, management strategies, and systems changes with potential for high impact to patient outcomes—for individuals and populations—in the United States in the next 12 months. The HCHSS COVID-19 Supplement produces 3 main outputs. Status Reports (every 4 months) briefly list and describe all COVID-19-related topics identified, monitored, and recently archived. High Impact Reports (every 4 months) highlight those topics that ECRI internal stakeholders (eg, physicians, nurses, allied health professionals, public health professionals, first responders, health systems experts, clinical engineers, researchers, business and finance professionals, information technology professionals) have identified as having potential for high impact relative to COVID-19 in the United States. Biweekly COVID-19 Scans provide ECRI Horizon Scanning with a vehicle to inform PCORI in a timely manner of important topics of interest identified during ongoing scanning and topic identification or through the ECRI stakeholder survey process. For more information about the HCHSS COVID-19 Supplement outputs or the COVID-19- specific horizon scanning process, see the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual COVID-19 Supplement. We welcome comments on this document. Send comments by mail to Patient-Centered Outcomes Research Institute, 1828 L St, NW, Suite 900, Washington, DC 20036, or by email to [email protected].

HORIZON SCANNING SUPPLEMENT STATUS REPORT ● MARCH 2021 ii Contents

Introduction ...... 1 Section 1. Devices: 9 Topics ...... 5 Table 1.1. Topics Added Since Last Status Report: 1 Topic ...... 5 Table 1.2. Currently Monitored Topics: 8 Topics ...... 6 Section 2. Identifiable Risk Factors and Prognostic Indicators: 3 Topics ...... 14 Table 2.1. Topics Added Since Last Status Report: 3 Topics...... 14 Section 3. Screening and Diagnostics: 24 Topics ...... 17 Table 3.1. Topics Added Since Last Status Report: 9 Topics...... 17 Table 3.2. Currently Monitored Topics: 13 Topics ...... 26 Table 3.3. Recently Archived Topics: 2 Topics ...... 39 Section 4. Systems and Management: 25 Topics ...... 41 Table 4.1. Topics Added Since Last Status Report: 11 Topics...... 41 Table 4.2. Currently Monitored Topics: 11 Topics ...... 52 Table 4.3. Recently Archived Topics: 3 Topics ...... 61 Section 5. Treatments: 33 Topics ...... 63 Table 5.1. Topics Added Since Last Status Report: 8 Topics...... 63 Table 5.2. Currently Monitored Topics: 21 Topics ...... 71 Table 5.3. Recently Archived Topics: 4 Topics ...... 87 Section 6. Vaccines and Prophylaxis: 9 Topics ...... 89 Table 6.1. Topics Added Since Last Status Report: 4 Topics ...... 89 Table 6.2. Currently Monitored Topics: 5 Topics ...... 93 Appendix. Abbreviations and Acronyms ...... 98

HORIZON SCANNING SUPPLEMENT STATUS REPORT ● MARCH 2021 iii

Introduction

The PCORI Health Care Horizon Scanning System (HCHSS) COVID-19 Supplement scans for, identifies, monitors, and reports on emerging and available COVID-19-related treatments, diagnostics, preventive measures, management strategies, and systems changes with high potential to impact patient outcomes—for individuals and populations—in the United States within the next 12 months. COVID-19 Supplement Status Reports The PCORI HCHSS COVID-19 Supplement produces Status Reports every 4 months. The reports summarize key data elements for all COVID-19 topics monitored in the system and, if applicable, recently archived topics (typically those archived since the last Status Report). This Status Report is organized into 6 sections titled as follows: (1) Devices, (2) Identifiable Risk Factors and Prognostic Indicators, (3) Screening and Diagnostics, (4) Systems and Management, (5) Treatments, and (6) Vaccines and Prophylaxis. An appendix lists the abbreviations and acronyms used in the report. Each of the 6 sections can contain 1 to 3 tables, depending on the topics included in that section: (1) topics added since the last Status Report, (2) currently monitored topics, and (3) recently archived topics. If no topics fall into a given category (ie, added, monitored, archived), then no table will be included for that category in that section. Tables for newly added and currently monitored topics summarize information by row in the following columns: Title, Description, Possible areas of impact, and Possible future impacts. Tables of archived topics summarize information by row in the following columns: Title, Description, and Archive reason. Within each table, topics are sorted alphabetically by title. ECRI Horizon Scanning has selected the topics included in this report as those with potential for impact relative to COVID-19 in the United States within the next 12 months. All views presented are preliminary and based on readily available information at the time of writing. Because these topics are rapidly developing, the accuracy of this information cannot be guaranteed after the date listed on this publication. Information presented in the Possible areas of impact and Possible future impacts columns solely represent prospective views of ECRI Horizon Scanning and have typically not been vetted by other stakeholders. These statements represent an ECRI Horizon Scanning analyst’s initial perspectives on a topic’s possible impacts. Analysts have been instructed, in the absence of hard data, to consider a topic’s possible areas of impact and possible future impacts in light of the developer’s claims (ie, if the product does what the developer purports, where it might have impact, and what its possible future impacts might be). Therefore, information presented in the Possible areas of impact and Possible future impacts columns should be considered prospective and may be updated, amended, or deleted when new information becomes available or after stakeholder review. No information in this report should be construed as an endorsement or rejection of any product listed herein. Topics initially added to the system for monitoring may be archived after review of new data or after stakeholder review (see COVID-19 Supplement Horizon Scanning Process Overview: Monitoring, Updating, and Archiving Topics) when it appears that the topic does not have high impact potential relative to COVID-19 in the United States in the next 12 months. An archived

HORIZON SCANNING SUPPLEMENT STATUS REPORT ● MARCH 2021 1

topic may reenter the system at a later date if new information comes to light suggesting that the topic has high impact potential. COVID-19 Supplement Horizon Scanning Process Overview The PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual COVID-19 Supplement (hereafter referred to as the Protocol) details the criteria we use to select topics. We briefly describe our process below.

Scanning, Lead Selection, and Topic Identification Scanners (ie, medical librarians and research assistants) collect COVID-19-related information leads from broad scanning and enter them into a leads database, categorize them according to content area (ie, devices, identifiable risk factors and prognostic indicators, screening and diagnostics, systems and management, treatments, and vaccines and prophylaxis) and subcategory, and link them, if applicable, to existing topics in the COVID-19 topics database. A research assistant assigns each lead to a horizon scanning analyst for review. Analysts review leads to discover potential topics. If a topic meets inclusion criteria, the analyst creates a new record in the COVID-19 topics database and enters a title and a description of the topic, possible areas of impact, and possible future impacts, which constitute the analyst’s rationale for proposing the topic. This information represents the analyst’s initial impressions of the topic prior to vetting it with other stakeholders and should be considered prospective. When populating the Possible areas of impact column, the analyst selects from the following terms (criteria for selection are listed after each term), based on her or his understanding of the currently available evidence, or, in the absence of hard evidence, his or her theoretical extrapolation based on the developer’s claims: • Patient outcomes: This topic might impact health outcomes for an individual patient. • Population health: This topic might impact health outcomes across a group of individuals (eg, ethnicity, socioeconomic status, geographic area of residence, age). This is distinct from individual patient outcomes in that a particular intervention might impact individuals differently than it might impact populations (eg, a vaccine might carry certain risks to certain individuals but provide overall benefit to a population or populations). • Clinician and/or caregiver safety: This topic might impact, positively or negatively, the safety of a clinician or caregiver. • Health care delivery and process: This topic might impact the way health care is delivered to patients. • Health care disparities: This topic might increase or decrease health care disparities (ie, differences in the burden of disease or access to health care between different groups or populations). • Health care costs: This topic might substantially increase or decrease costs of care for patients, payers (ie, insurers), or health care providers. Each proposed topic is rapidly reviewed and voted on for inclusion by a preselected 3- member panel of PCORI HCHSS senior team members. A majority vote includes or excludes a topic accordingly. All included topics are reported in the Status Report. Each included topic undergoes content review and is then activated as a summary for the stakeholder survey process.

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Stakeholder Review Process Topics are posted to an online bulletin board visible to a preselected panel of about 50 internal ECRI expert stakeholders (eg, physicians, nurses, allied health professionals, public health professionals, first responders, health systems experts, clinical engineers, researchers, business and finance professionals, information technology professionals). As topics are posted, stakeholders review them and complete an accompanying survey, which elucidates the stakeholder’s perspective on the topic’s potential for impact relative to the COVID-19 pandemic in the United States. The survey first prompts the stakeholder to indicate areas of potential impact, rating each area on a scale of 1 (no impact) to 4 (high impact). It then asks the stakeholder to rate the topic’s overall impact potential, timing of the impact, and likelihood of the impact on the same 1-to-4 scale. Finally, the stakeholder is asked to provide a brief written rationale explaining her or his selections and ratings. When a topic has received at least 5 completed surveys, it is eligible to be considered for inclusion in a High Impact Report (see below); however, the questionnaire function remains active for all topics until the High Impact Report selection process begins, allowing each member of the expert panel to comment on each topic as time permits.

High-Impact Report Topic Selection Every 4 months, all currently monitored topics that have received at least 5 completed stakeholder surveys are considered for inclusion in the High Impact Report. The purpose of the selection process is to identify topics that stakeholders have deemed to have potential for high impact relative to COVID-19 in the United States. Generally, topics that stakeholders agree have a moderately high to high overall impact potential and are likely to cause impact within the next 12 months in the United States are selected for inclusion. However, stakeholder comments must generally support conclusions suggested by ratings. For topics with borderline ratings, high variance, or questionable comments, a brief review and vote by a preselected 3-member panel of senior horizon scanning team members determines inclusion or exclusion. A majority affirmative vote selects the topic for inclusion. See the Protocol for a detailed explanation of how we select topics for inclusion in the High Impact Report.

Monitoring, Updating, and Archiving Topics Scanners use keywords and controlled vocabulary terms to monitor and search resources. When possible, scanners create automated alerts to capture new topic-specific information on an ongoing basis. These monitoring activities can trigger a change in topic status, depending on what has occurred. Analysts update topics as new information arises to ensure that the content is current. When a topic is updated, stakeholders who have commented on the topic are alerted to review the new information and revise or update their survey ratings and rationales, if desired. An included topic may be archived when new information overwhelmingly suggests that the topic is unlikely to cause significant impact relative to the COVID-19 pandemic in the United States in the next 12 months. Reasons may include one or more of the following: • Stakeholder ratings and comments strongly suggest that the topic does not have high impact potential. • New data do not support the developer’s claims relative to COVID-19.

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• Development has ceased or stalled. • The development timeline has shifted, and the product is no longer likely to be available within the next 12 months. Reporting Period Summary The PCORI HCHSS COVID-19 Supplement began operating in May 2020. As of February 22, 2021, review of about 4200 information leads had led to the identification and selection of more than 200 COVID-19-related topics. After subjecting the potential topics to our inclusion criteria and nomination process, 103 topics have been selected and are being actively monitored in the system, or were being monitored but have been archived within the past 3 months. These 103 topics, included in this Status Report, are distributed across the 6 content areas as follows (also see Figure 1): • Devices: 9 topics (9%) • Identifiable risk factors and prognostic indicators: 3 topics (3%) • Screening and diagnostics: 24 topics (23%) • Systems and management: 25 topics (24%) • Treatments: 33 topics (32%) • Vaccines and prophylaxis: 9 topics (9%)

Figure 1. Percentage of Topics by Content Area

HORIZON SCANNING SUPPLEMENT STATUS REPORT ● MARCH 2021 4

Section 1. Devices: 9 Topics

Table 1.1. Topics Added Since Last Status Report: 1 Topic

Title Description Possible areas of impact Possible future impacts

Mask-worn test strips to Recent COVID-19 surges despite precautions highlight a need to Population health Might improve COVID-19 detection in detect COVID-19 infection enhance detection of coronavirus infection, especially among high-risk populations by Clinician and/or caregiver vulnerable populations in low-resource settings. University of recommending additional laboratory safety California at San Diego researchers are developing disposable test testing, when appropriate strips to detect SARS-CoV-2 in breath or saliva. The adhesive strips are Might provide reassurance for high- designed to be placed on the front of a user’s mask (ie, surgical, risk populations by adding another cloth, or N95 respirator). At the end of a shift or mask change, the user safety tool squeezes the attached blister pack to release nanoparticles onto the testing strip; the nanoparticles change color if SARS-CoV-2 proteases Might help lower costs by are present. Developers describe the test strips as an early warning to avoiding laboratory testing of indicate a need for, not a replacement for, more conventional COVID- asymptomatic persons unlikely to 19 testing. They estimate the test strips could be easily mass produced have COVID-19, especially when local for a few cents each with roll-to-roll manufacturing. Developers test availability is limited suggest the test strips might be most useful in high-risk settings, such as group homes, prisons, dialysis clinics, and homeless shelters. Researchers are developing the test strip through a grant from the National Institutes of Health’s (NIH’s) Rapid Acceleration of Diagnostics Radical (RADx-rad) program for COVID-19.

SECTION 1. DEVICES 5

Table 1.2. Currently Monitored Topics: 8 Topics

Title Description Possible areas of impact Possible future impacts

Decontamination Depleted supplies of N95 respirators for health care personnel have Clinician and/or caregiver Might reduce shortages of N95 systems for prompted manufacturers to seek FDA Emergency Use Authorization (EUA) safety respirators for health care personnel reprocessing of single- for systems intended to decontaminate N95 respirators designed for single Health care delivery and Might cost less than disposing of use N95 respirators use, allowing them to be reused safely. A systematic review found few process single-use respirators and purchasing recent studies have assessed the safety and effectiveness of N95 respirator new respirators at inflated costs decontamination, and most studies have examined the use of ultraviolet Health care costs during supply shortages radiation for decontamination. As of February 16, 2021, FDA had granted 14 EUAs for the use of N95 respirator decontamination systems during the Might raise safety concerns among COVID-19 outbreak. These systems typically employ vapor hydrogen health care personnel if subsequent peroxide or steam for decontamination of compatible N95 respirators that issues with respirator reprocessing may be contaminated with SARS-CoV-2 or other pathogenic arise microorganisms. Most systems with EUAs are authorized for decontaminating N95 respirators for single-person use for 2 to 20 (clearly marked) decontamination cycles. In most cases, health care facilities ship used respirators to a manufacturer site for decontamination via special handling and shipping procedures. N95 respirators that contain cellulose material are incompatible with those decontamination systems that have EUAs thus far. Another system has EUA for bioburden reduction (ie, not decontamination) of up to 99.9% of viral particles on single-use N95 respirators.

SECTION 1. DEVICES 6

Title Description Possible areas of impact Possible future impacts

External laser therapy Pneumonia in patients with COVID-19 can severely damage lung tissue. Patient outcomes Might improve patient outcomes by for treating COVID-19 Researchers at Lowell General Hospital (Lowell, Massachusetts) speeding resolution of COVID-19 Clinician and/or caregiver pneumonia suggest that external pulsed infrared lasers directed at the lungs may help pneumonia safety resolve COVID-19 pneumonia. The treatment, dubbed Might reduce costs if patients can be photobiomodulation, delivers low-level laser energy to the lungs through Health care delivery and discharged sooner the back, with the patient lying face down. The treatment purportedly process starts a cascade of molecular reactions that improve cellular function and Might expose more health care staff to Health care costs promote natural healing. The research team reported that one of the first infection risk if bedside lasers require patients treated in a pilot study showed improved oxygenation, reduced specially trained personnel to operate inflammatory markers, and resolved ground-glass opacity on chest x-ray. Physicians applied the laser energy for 14 minutes to each lung once daily for 4 consecutive days, in addition to standard inpatient medical care. Immediately after treatment, the patient had improved exercise capacity; he was discharged 2 days later on minimal supplemental oxygen. Two days after discharge, physicians began weaning the patient to room air. The bedside laser system is cleared by FDA for delivering topical heat to temporarily relieve stiffness and pain in muscles or joints due to arthritis or muscle spasm, typically in the lower back and hips.

SECTION 1. DEVICES 7

Title Description Possible areas of impact Possible future impacts

Extracorporeal blood Early available data suggest that a major contributor to poor outcomes in Patient outcomes Might improve patient outcomes by filtration to treat patients with COVID-19 is a cytokine storm, an overly aggressive immune avoiding or lessening severity of Health care delivery and COVID-19 response that can damage healthy tissue. Removing inflammatory cytokine storm process mediators from patients through an external blood filtering circuit has Might require additional staff been proposed to lessen or prevent the cytokine storm. As of February 16, experienced with extracorporeal blood 2021, FDA had granted Emergency Use Authorization (EUA) to 4 filtration procedures manufacturers of extracorporeal blood filtration devices for use during the COVID-19 pandemic. When used with appropriate systems (eg, apheresis Might increase treatment complexity systems, continuous renal replacement therapy systems), these devices and necessitate additional patient purportedly remove inflammatory cytokines and, depending on the monitoring to quickly identify specific filter, pathogens from patients’ blood. Extracorporeal blood hematologic complications filtration increases the risk of several complications, including bleeding, blood clots (thrombosis), air embolism, destruction of red blood cells (hemolysis), infection, low blood pressure (hypotension), and unintentional removal of other blood substances (eg, vitamins, minerals, proteins, medications).

SECTION 1. DEVICES 8

Title Description Possible areas of impact Possible future impacts

Isolation bags for safe Computed tomography (CT) scans can be used in alternative diagnostics Population health Might increase the number of patients CT imaging in or to guide the management of COVID-19 complications. However, who receive a chest CT scan in a timely Clinician and/or caregiver suspected COVID-19 protecting patients and staff requires lengthy cleaning procedures manner safety cases between patients to decontaminate equipment and rooms. A team led by Might reduce staff exposure to National Institutes of Health (NIH) researchers has developed Health care delivery and coronavirus by better isolating patients an inexpensive bag intended to safely isolate patients during CT scans. The process during imaging disposable bag is made from translucent (ie, almost clear) Health care costs plastic commonly used to protect patients and surgical equipment in other Might reduce maintenance and health care settings. The bag covers the patient’s head and chest. The bag procedural costs if patient isolation has an integrated N95 filter patch and is secured at the waist with a bags can safely avoid the need for disposable belt. The patient wears an N95 respirator or surgical mask to some more intensive disinfection block respiratory droplets and a hat with a visor to keep the bag off the procedures between imaging patients face. Patients receive oxygen through a supply line connected to the bag’s Might cause some facilities to reduce input nozzle. Researchers estimate that use of the isolation bag might cleaning requirements below allow about 14 times more patients per day to undergo CT on a single recommended standards scanner in a hospital emergency department. However, the addition of another protective device on top of personal protective equipment (PPE) Might cause anxiety in patients who does not eliminate the recommendation for cleaning as part of standard already have difficulty breathing infection control.

SECTION 1. DEVICES 9

Title Description Possible areas of impact Possible future impacts

Negative-pressure Negative-pressure rooms can contain the spread of airborne pathogens, Clinician and/or caregiver Might increase the availability of tents to limit airborne but COVID-19 case volume can overload this resource. Portable negative- safety negative-pressure environments to transmission of pressure tents might reduce the need for negative-pressure rooms, enhance protection for frontline health Health care delivery and coronavirus decrease airborne transmission risk to health care providers, and increase care providers process patient throughput. Compact tents are placed over the patient’s head and Might reduce treatment costs of shoulders. Larger designs enclose the entire patient bed. Tents are Health care costs providing negative-pressure constructed of either clear rigid plastic or clear soft plastic over a reusable environments compared with standard frame. Providers reach patients through hand-access ports or slits in the negative-pressure rooms walls. A vacuum hose connected to the hospital air-evacuation system creates a negative-pressure environment. As of February 17, 2021, FDA had granted Emergency Use Authorization (EUA) for 6 negative-pressure tents—4 compact tents and 2 whole-bed tents—to enhance personal barrier protection for providers during airway management, medical procedures, or transport of patients with COVID-19. Further, on August 20, 2020, FDA revoked an umbrella EUA issued on May 1, 2020, that authorized the use of protective barrier enclosures without negative pressure when treating patients with confirmed or suspected COVID- 19. FDA cited recent research of simulated intubations using passive barriers, suggesting they might not reduce and could increase provider exposure to airborne particles. FDA recommended using only negative- pressure protective barrier enclosures with EUA.

SECTION 1. DEVICES 10

Title Description Possible areas of impact Possible future impacts

Nickel foam air filter to According to the US Environmental Protection Agency (EPA), indoor air is Patient outcomes Might increase safety of indoor spaces reduce the risk of about 2 to 100 times more polluted than outdoor air because of the by reducing circulation of airborne Population health coronavirus continuous circulation of particulates and bioaerosols (airborne particles of coronavirus, potentially reducing risk of transmission microbial, animal, or plant origin) within indoor spaces. With the reopening Clinician and/or caregiver transmission in businesses, schools, of schools and businesses during the COVID-19 pandemic, new methods safety and other enclosed environments of improving indoor air quality are needed. Researchers at the University of Health care costs Might increase risk of COVID-19 Houston and collaborators developed an air filter intended to remove transmission if people stop following airborne biothreats, including coronavirus. The proposed use of the filter is public health guidance (eg, social in air handling systems for central air conditioning units; however, distancing) owing to installation of researchers envision other uses, such as mobile personal air-purification these air filters devices to yield clean personal air space. The filter uses a nickel foam material that allows air to pass through its pores and is electrically conductive so that it can be heated up to 250°C. To maximize the energy efficiency of indoor air conditioning systems, the air filtration technology is heated internally, allowing minimal heat to escape to rooms. Tests conducted with this heated air filter found that 99.8% of coronavirus was effectively killed in a single pass. As of February 18, 2021, manufacturer Integrated Viral Protection (Houston, Texas) reported its air filtration systems had already been installed in elementary schools in Texas and Florida; colleges, hospitals, restaurants, and gyms in Texas; and commercial office buildings in Delaware.

SECTION 1. DEVICES 11

Title Description Possible areas of impact Possible future impacts

Reusable silicone Shortages of N95 respirators can increase the risk of COVID-19 infection Clinician and/or caregiver Might help alleviate shortages of respirators to protect for frontline personnel. Massachusetts Institute of Technology (Cambridge) safety single-use N95 respirators for health against COVID-19 researchers have designed a reusable filtering facepiece respirator as an care providers and emergency services Health care costs infection alternative to single-use N95 respirators. The new silicone-based design responders during surges in COVID-19 purportedly can be mass produced at a relatively low cost with standard cases injection molding manufacturing. The reusable mask—a tight-fitting, Might allow simpler reprocessing of elastomeric respirator with a bidirectional filter—can be sterilized and used respirators compared with that of reused multiple times while retaining its elasticity. The single-use filter conventional single-use N95 inserts are replaced during decontamination reprocessing. Based on early respirators, which must meet certain user feedback, researchers redesigned the device, now called eligibility requirements for safe the transparent, elastomeric, adaptable, long-lasting (TEAL) respirator, to decontamination and reuse improve fit and increase visibility of the user’s mouth and facial expressions. In an evaluation of TEAL respirators among 47 physicians, Might help reduce personal protective nurses, and technicians, users rated the following parameters as good equipment (PPE) supply costs if to excellent: fit, 90%; breathability, 77.5%; and ease of filter exchange, 95%. reusable respirators can be mass Respirators retained elasticity and fit after multiple decontamination produced with standard manufacturing methods, including 100 cycles of autoclaving, microwaving, ultraviolet techniques light, 100% isopropyl alcohol, and 8.25% bleach. Further, 60% of users preferred the TEAL device over conventional respirators, and 35% had no preference. Researchers anticipate receiving Emergency Use Authorization (EUA) from FDA for the TEAL respirator. However, FDA had not granted EUA for the TEAL respirator as of February 18, 2021.

SECTION 1. DEVICES 12

Title Description Possible areas of impact Possible future impacts

Transvenous phrenic Prolonged mechanical ventilation can cause diaphragm muscle atrophy, Patient outcomes Might improve patient outcomes by nerve stimulation to making ventilator weaning difficult. The Lungpacer Diaphragm Pacing increasing successful ventilator Health care delivery and improve ventilator Therapy System is intended to reduce diaphragm atrophy by stimulating weaning attempts process weaning the phrenic nerves, which control breathing with the diaphragm. Physicians Might increase procedural costs for temporarily insert a single-use, multielectrode catheter into the left Health care costs disposable catheters and system subclavian vein at the left shoulder and advance it adjacent to the left and control unit/pulse generators right phrenic nerves within the upper chest. Clinicians modulate electrical stimulation though the system’s portable pulse generator and control unit. Might moderately reduce overall In May 2016, FDA granted Lungpacer Medical, Inc (Vancouver, British treatment costs by preventing Columbia, Canada), Expedited Access Pathway (now Breakthrough incidence of ventilator weaning failures Therapy) designation for the Lungpacer to treat patients unable to wean Might increase the need for specialist from ventilators. On April 14, 2020, FDA granted the developer Emergency staff experienced in placing indwelling Use Authorization (EUA) to assist in weaning patients deemed at high risk intravenous catheters, which might also of weaning failure during the COVID-19 pandemic. The Lungpacer is to be increase exposure risk and the need for used for no longer than 30 days. In a clinical trial of patients on mechanical personal protective equipment (PPE) ventilation for general indications for more than 4 days with 2 failed weaning attempts, patients receive 120 total daily stimulation repetitions, Might increase patient monitoring delivered in 2 daily sessions, for an unspecified duration. requirements during temporary electrode catheter placement

SECTION 1. DEVICES 13

Section 2. Identifiable Risk Factors and Prognostic Indicators: 3 Topics

Table 2.1. Topics Added Since Last Status Report: 3 Topics

Title Description Possible areas of impact Possible future impacts

Artificial intelligence Early identification of COVID-19 patients who may develop critical illness is Patient outcomes Might assist health care professionals (AI)–based assessment of great importance and may aid in delivering proper treatment and with making better treatment Population health of clinical data to optimizing hospital resources. AI algorithms based on assessment of decisions determine COVID-19 patient clinical data are now being used to assist with determining which Clinician and/or caregiver Might help manage the surge of prognosis patients may need intensive critical care. On May 26, 2020, FDA granted safety patients requiring ventilators and Emergency Use Authorization (EUA) for the CLEWICU system (CLEW Health care delivery and alleviate the burden on health care Medical, San Francisco, California), which assesses electronic health record process professionals and facilities data to assist with the early identification of patients who are likely to be diagnosed with respiratory failure or hemodynamic instability, which are Health care costs Might help inform future triage common complications associated with COVID-19. Additionally, existing paradigms AI-based predictive analytics systems are being used to assess patients Might lead to inappropriate care in with COVID-19. AlgoMarkers software by Medial EarlySign (Aurora, cases of misclassification by the California) uses patient data from vital signs, laboratory test results, algorithm smoking history, and other medical history to help clinicians detect patients at increased risk of developing COVID-19 complications. The Deterioration Index by EPIC (Verona, Wisconsin) analyzes patients’ data and calculates a risk score on a scale from 0 to 100, with a higher number signaling elevated concern that the patient’s condition is deteriorating.

SECTION 2. IDENTIFIABLE RISK FACTORS AND PROGNOSTIC INDICATORS 14

Title Description Possible areas of impact Possible future impacts

Interleukin 6 (IL-6) Some COVID-19 patients have relatively mild symptoms, whereas others Patient outcomes Might streamline the triage of patients levels as a prognostic develop severe disease. Additionally, the clinical course of patients based on the potential need Population health factor in COVID-19 hospitalized for COVID-19 is variable, and patients may deteriorate rapidly for mechanical ventilation patients to respiratory failure, requiring ventilation and intensive care unit Clinician and/or caregiver Might reduce overall costs by admission. Research suggests that IL-6 levels might be a potential safety improving utilization of hospital biomarker of predicting severe COVID-19. Elevated IL-6 levels have been Health care delivery and resources associated with cytokine-mediated lung damage that can result in severe process respiratory distress in COVID-19 patients. Results from a clinical study Might improve understanding of the conducted in hospitalized patients suggested that IL-6 levels above 80 Health care disparities pathogenesis of COVID-19 pg/mL are indicative of a high risk of respiratory failure. FDA has granted Health care costs the Roche Diagnostics (Basel, Switzerland) Elecsys IL-6 test, the Siemens Healthcare (Malvern, Pennsylvania) ADVIA Centaur IL6 assay, and the Beckman Coulter (Brea, California) Access IL-6 assay Emergency Use Authorization (EUA) to help identify patients with confirmed COVID-19 who are at risk of intubation and mechanical ventilation. IL-6 testing is also available through multiple clinical laboratories (eg, ARUP Laboratories, LabCorp, Quest Diagnostics).

SECTION 2. IDENTIFIABLE RISK FACTORS AND PROGNOSTIC INDICATORS 15

Title Description Possible areas of impact Possible future impacts

SSRI use as a disease- An observational study found that selective serotonin reuptake inhibitor Patient outcomes Might reduce burden and costs modifying risk factor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) use might associated with intubation Population health for COVID-19 be associated with a lower risk of death or intubation in patients with Might improve understanding of COVID-19. A time-to-event analysis compared 460 patients with COVID-19 Health care delivery and COVID-19’s pathogenesis who received antidepressants during hospitalization with 6885 adult process inpatients without antidepressant exposure and found that treatment with escitalopram, fluoxetine, or venlafaxine was associated with lower risk of intubation or death. Fluoxetine has been shown to inhibit replication of SARS-CoV-2 in laboratory studies. In addition, fluoxetine is thought to decrease the expression of interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha, 2 inflammatory cytokines known to worsen COVID-19 disease progression. Two ongoing US clinical trials are investigating the use of SSRIs in treating COVID-19: an 1100-patient trial of fluvoxamine to prevent serious complications and a 2000-patient trial of fluoxetine to reduce intubation and death. Results from the preliminary, randomized, 152-patient fluvoxamine trial showed that patients receiving fluvoxamine had a lower likelihood of clinical deterioration than did patients taking placebo.

SECTION 2. IDENTIFIABLE RISK FACTORS AND PROGNOSTIC INDICATORS 16

Section 3. Screening and Diagnostics: 24 Topics

Table 3.1. Topics Added Since Last Status Report: 9 Topics

Title Description Possible areas of impact Possible future impacts

College and university College and university COVID-19 testing programs offered by third parties Patient outcomes Might help faculty, staff, and students SARS-CoV-2 testing (eg, Quest Diagnostics; Laboratory Corporation of America Holdings feel safe about returning to colleges or Population health programs to prevent [LabCorp]; Bio-Reference Laboratories, Inc; Color Genomics, Inc; Walgreens universities COVID-19 spread Co; CVS Health) are intended to limit coronavirus spread and boost Health care disparities Might catch COVID-19 cases on among returning student confidence about returning to campuses. Schools implementing a Health care costs campus early and help quickly students testing program may give all returning students, faculty, and staff a suppress spread of the virus COVID-19 molecular test along with an antibody test at the beginning of the school year, with several levels of surveillance throughout the year. Might create supply shortages via This approach will help schools assess a baseline for their community, frequent testing in large campus understand the prevalence of the virus on campus, and make decisions populations about quarantine and other distance measures for the population Might cause the virus to initially spread returning to campus. Some programs (eg, Quest Diagnostics, LabCorp) undetected if test results yield a high provide self-collection kits to avoid overwhelming health centers and rate of false negatives clinical laboratories. Upon receiving samples, central laboratories have test results available through an online platform in about 2 to 5 days. Some Might increase the rate of false- programs (eg, Return Ready by CVS Health, Test and Protect by negative test results if students using a Walgreens) may also offer point-of-care (POC) testing that provides same- self-collection kit do not acquire a day test results. College and university testing programs have the potential proper specimen with detectable virus to detect COVID-19 cases early and prevent coronavirus from spreading among students.

SECTION 3. SCREENING AND DIAGNOSTICS 17

Title Description Possible areas of impact Possible future impacts

Clustered regularly CRISPR–based assays are an alternative to standard-of-care (SoC) reverse Patient outcomes Might deliver comparable test results interspaced short transcription polymerase chain reaction (RT-PCR) assays for diagnosing quicker than do RT-PCR-based assays Population health palindromic repeats COVID-19 via detection of coronavirus nucleic acids. CRISPR-based assays Might decrease costs by allowing (CRISPR)–based assays can purportedly detect SARS-CoV-2 nucleic acids within an hour in a Health care disparities laboratories to process hundreds of to diagnose COVID-19 highly specific way. These assays employ a loop-mediated isothermal Health care costs patient samples per day amplification (LAMP) reaction to increase target nucleic acid copy number. The products of this amplification reaction are exposed to an RNA-guided Might increase the rate of false- nuclease (eg, Cas12a, Cas13a) that becomes activated only in the presence negative test results if the assays do of viral nucleic acids. If activated, the nuclease cleaves a reporter nucleic not detect very low levels of viral acid. Depending on the reporter technology used, reporter cleavage is nucleic acids measured by a fluorimeter or lateral flow assay. FDA has granted Might create disparities for patients Emergency Use Authorization (EUA) to several CRISPR-based assays (eg, who do not have access to health SARS-CoV-2 DETECTR kit, Sherlock CRISPR SARS-CoV-2 kit) for use in centers and laboratories that offer Certified Laboratory Improvement Amendments of 1988 (CLIA)–certified CRISPR-based testing laboratories. Two studies comparing CRISPR-based assays with an RT-PCR test in 378 upper respiratory tract and 154 nasopharyngeal samples reported a concordance ranging between 94.9% and 100%. Rapid CRISPR- based diagnostic tests are also being developed for use in the point-of- care (POC) and/or consumer use settings. Preliminary work on one such rapid test has shown it to detect viral nucleic acids as accurately as an EUA CRISPR test.

SECTION 3. SCREENING AND DIAGNOSTICS 18

Title Description Possible areas of impact Possible future impacts

Ellume over-the- The Ellume COVID-19 Home Test (Ellume, Ltd) is the first over-the-counter Patient outcomes Might reduce risk of transmission of counter and at-home coronavirus test granted Emergency Use Authorization (EUA) for use in the SARS-CoV-2 to medical staff and other Population health assay to diagnose home setting by FDA. It is a low-complexity, portable lateral flow patients by identifying infected and COVID-19 immunoassay containing fluorescent nanoparticles that detect nucleocapsid Clinician and/or caregiver uninfected individuals from home on antigens of SARS-CoV-2 in self-collected swabs from the upper-middle part safety the same day they are tested of the nasal cavity. The Ellume test is intended for use in individuals aged 2 Health care delivery and Might be more affordable and years or older regardless of symptoms or other epidemiologic reasons to process convenient compared with tests suspect SARS-CoV-2 infection. The Ellume test includes sample-processing performed in central laboratories fluid, a nasal swab, a sample-collecting dropper, and a single-use analyzer. Health care disparities The analyzer connects with an app on a smartphone to provide step-by-step Might increase the rate of false- video instructions and automatically receive test results. The app can share negative test results if the assay does results with providers to enable optimal patient care and with health not detect very low levels of viral authorities to help monitor COVID-19 cases. The manufacturer claims that nucleocapsid proteins each $30 Ellume test yields laboratory-quality results in about 20 minutes. Might create disparities in regions EUA was based on a simulated home-use clinical study that compared the where at-home test kits are not Ellume test with an EUA reverse transcription polymerase chain reaction (RT- available PCR) assay in 198 midturbinate nasal samples from symptomatic and asymptomatic individuals. The Ellume test had a sensitivity of 95% and a Might lead to increased numbers of specificity of 97%. false-positive test results if over-the- counter use is widespread among individuals at low risk of infection

SECTION 3. SCREENING AND DIAGNOSTICS 19

Title Description Possible areas of impact Possible future impacts

Employee SARS-CoV-2 Employee COVID-19 testing programs offered by third parties (eg, Quest Patient outcomes Might help employees feel safe about testing programs to Diagnostics; Laboratory Corporation of America Holdings [LabCorp]; Bio- returning to their workplace Population health reopen businesses Reference Laboratories, Inc; Color Genomics, Inc; Walgreens Co; CVS Might catch COVID-19 cases in the Health) are intended to limit novel coronavirus spread in the workplace Health care disparities workplace early and thus help quickly and boost confidence that employees can return to a safe work Health care costs suppress spread of the virus environment. Testing programs emphasize operating under simple, streamlined conditions intended to catch COVID-19 cases early and Might create disparities in regions prevent disease spread. COVID-19 testing programs might incorporate less where employee testing programs are reliable screening methods, including health questionnaires and not available temperature screening, or more reliable screening methods, such as Might cause the virus to initially spread nucleic acid testing, either at the employer site or offsite using an at-home undetected if test results yield high self-collection kit. Pilot programs (eg, Quest Diagnostics, LabCorp) use numbers of false negatives tests performed at central laboratories that provide results through an online platform within 2 to 5 days. Some programs (eg, Return Ready by Might create supply shortages via CVS Health, Test and Protect by Walgreens) also offer point-of-care (POC) frequent testing in large corporate testing that provides same-day test results. In addition to testing services, populations programs such as Test & Protect offer employers clinical guidance to Might be difficult to triage employees provide a safe working environment. The Centers for Disease Control and if it takes days for test results to Prevention (CDC) also offers detailed guidance on how to implement novel become available coronavirus testing in non–health care workplaces.

SECTION 3. SCREENING AND DIAGNOSTICS 20

Title Description Possible areas of impact Possible future impacts

Existing FDA- In December 2020, a genetic variant of SARS-CoV-2 with higher Patient outcomes Might help identify patients infected authorized nucleic transmissibility, B.1.1.7, was identified in the United Kingdom. It has with B.1.1.7 and other emerging strains Population health acid–based tests with subsequently been detected in countries around the world. Eight of the 17 of coronavirus potential to help mutations accumulated in B.1.1.7 occur in the spike protein–encoding S Health care delivery and Might help suppress spread of the identify the SARS- gene. Two of these mutations raise potential health concerns: N501Y process B.1.1.7 strain of coronavirus by CoV-2 B.1.1.7 variant might increase infectivity and 69-70del might help the strain evade Health care disparities informing infected individuals of the immune responses. Only sequencing can detect B.1.1.7, but no tests have need to self-isolate been specifically developed to detect B.1.1.7. FDA has identified 2 Health care costs authorized nucleic acid–based tests (NATs; Linea COVID-19 and TaqPath Might provide a more rapid and cost- COVID-19) with the potential to identify possible B.1.1.7 infections for effective means of identifying potential subsequent sequencing. The S gene mutations in B.1.1.7 lead to loss of an B1.1.7 infections compared with more S gene signal from these tests. However, because the tests assess multiple extensive genetic sequencing viral genes, they are still capable of producing positive signals from other Might create disparities for patients viral sequences and can appropriately detect SARS-CoV-2. This pattern of who do not live near health centers results (negative for S gene, positive for other genes) might serve as an with capabilities and certifications to early indicator of a potential B.1.1.7 infection. However, because variants offer these tests affecting S gene amplification are not unique to B.1.1.7, follow-up testing by more extensive genetic sequencing is required to confirm the presence Might increase costs associated with of B.1.1.7. subsequent testing by sequencing

SECTION 3. SCREENING AND DIAGNOSTICS 21

Title Description Possible areas of impact Possible future impacts

Multigene expression Asymptomatic and presymptomatic individuals infected with SARS-CoV-2 Patient outcomes Might help identify asymptomatic and tests to predict are highly contagious and difficult to identify. According to a study presymptomatic individuals infected Population health COVID-19 before examining the false-negative rates of SARS-CoV-2-specific reverse with SARS-CoV-2 more effectively symptom onset transcription polymerase chain reaction (RT-PCR) assays in people exposed Health care delivery and compared with diagnostic tests to COVID-19, false-negative results are more likely the earlier individuals process Might aid in guiding public health are tested before symptom onset. Multigene assays that measure changes Health care disparities interventions such as contract tracing, in host gene expression in the presence of an infectious agent, such as isolation, and follow-up testing SARS-CoV-2, might help identify these populations. Predigen, Inc, is Health care costs developing HR-PreV, a blood-based, 36-gene RT-PCR assay intended to Might improve health outcomes by detect the presence of respiratory viral infections earlier than a viral- managing and treating patients before specific diagnostic test. Using an algorithm based on the expression they manifest symptoms associated patterns of immune response genes, HR-PreV purportedly assesses an with COVID-19 individual’s risk of having been infected with a respiratory virus (eg, Might lead to unnecessary anxiety for adenovirus, coronavirus, influenza virus, respiratory syncytial virus, patients who would not develop active rhinovirus) before symptom onset. The test might help direct early clinical COVID-19 management or contribute to contact tracing efforts and quarantine of potentially infectious asymptomatic individuals. In collaboration with Might increase overall costs associated Predigen, Biomeme, Inc, is developing a 27-gene assay for use in a point- with testing of-care (POC) setting that can assess the risk of a viral infection within an Might create disparities for patients hour. who do not live near health centers with capabilities and certifications to offer multigene expression testing

SECTION 3. SCREENING AND DIAGNOSTICS 22

Title Description Possible areas of impact Possible future impacts

POC antigen assays to Central laboratory–based reverse transcription polymerase chain reaction Patient outcomes Might allow health centers to diagnose diagnose (RT-PCR) testing remains the standard of care for diagnosing COVID-19. COVID-19 soon after a symptomatic Population health COVID-19 However, the turnaround time required for these tests limits their potential patient arrives to quickly inform patient management decisions regarding treatment Health care delivery and Might help triage infected and and/or isolation. Point-of-care (POC) antigen tests are lateral flow process uninfected patients on the same day immunoassays that use labeled antibodies to detect coronavirus proteins Health care disparities they are tested (typically nucleocapsid protein) from nasal or nasopharyngeal swabs. POC antigen tests are designed to diagnose COVID-19 without the need for Health care costs Might be more affordable compared complicated devices so that untrained individuals can use them in with tests performed in central temporary screening facilities, physician office laboratories, and urgent laboratories care and long-term nursing facilities. FDA has granted Emergency Use Might increase the rate of false- Authorization (EUA) to several POC antigen tests (eg, BD Veritor System, negative test results if assays do not BinaxNow COVID-19, Sofia SARS Antigen), including both tests that detect very low levels of viral require a dedicated instrument for test interpretation and tests that can be nucleocapsid proteins read visually. Because POC antigen tests deliver results within minutes and cost as little as $5 per test, they might be more affordable than RT-PCR- Might create disparities for patients if based testing for rapidly identifying and isolating infected patients to the tests are not broadly available in all reduce further COVID-19 spread. However, antigen tests are limited by health centers their low sensitivity. A systematic review analyzed 5 studies evaluating antigen tests in 943 samples. The tests had an average sensitivity of 56.2% and an average specificity of 99.5%. Another study evaluating 3 antigen tests reported sensitivities ranging from 22.9% to 71.4%.

SECTION 3. SCREENING AND DIAGNOSTICS 23

Title Description Possible areas of impact Possible future impacts

POC nucleic acid– Central laboratory–based reverse transcription polymerase chain reaction Patient outcomes Might allow health centers to diagnose based assays to (RT-PCR) testing remains the standard of care for diagnosing COVID-19. COVID-19 soon after a symptomatic Population health diagnose COVID-19 However, the turnaround time required for these tests limits their potential patient arrives to quickly inform patient management decisions regarding treatment Health care delivery and Might help triage infected and and/or isolation. Point-of-care (POC) nucleic acid–based tests (NATs) are process uninfected patients on the same day an alternative test modality designed to diagnose COVID-19 without the Health care disparities they are tested need for complicated devices so that untrained individuals can use them in nonlaboratory settings. POC NATs deliver results within 15 to 30 minutes Health care costs Might be more affordable compared after sampling rather than hours or days for central laboratory–based with tests performed in central testing; therefore, they might play an important role in quickly identifying laboratories and isolating infected patients to reduce further COVID-19 spread. Four Might increase the rate of false- POC NATs (Accula SARS-Cov-2 Test, Cue COVID-19 Test, ID NOW COVID- negative test results if assays do not 19, Xpert Xpress SARS-CoV-2 Test) based on one of several processes (eg, detect very low levels of viral nucleic isothermal amplification, RT-PCR) have received Emergency Use acids Authorization (EUA) from FDA for detecting SARS-CoV-2. However, POC NATs have some limitations, including the need for sample processing Might create disparities for patients if steps, low sensitivity, and the need for dedicated hardware to process the the tests are not broadly available in all tests. A systematic review analyzed 11 studies evaluating POC NATs in health centers 2255 samples. The tests had an average sensitivity of 95.2% and an average specificity of 98.9%, but depending on the test, sensitivity ranged from 68% to 100%.

SECTION 3. SCREENING AND DIAGNOSTICS 24 Title Description Possible areas of impact Possible future impacts

Serology test kits for FDA has granted Emergency Use Authorization (EUA) to 4 serology test Patient outcomes Might help assess the adaptive quantitative detection kits for the qualitative and semiquantitative detection of SARS-CoV-2 humoral immune response to the Population health of SARS-CoV-2 antibodies in serum and plasma (Atellica IM SARS-CoV-2 IgG, Siemens SARS-CoV-2 spike protein antibodies Healthcare; ADVIA Centaur SARS-CoV-2 IgG, Siemens Healthcare; Kantaro Health care delivery and Might allow the detection and Semi-Quantitative SARS-CoV-2 IgG Antibody Kit, Kantaro Biosciences; process quantification of antibodies against and Elecsys Anti-SARS-CoV-2 S, Roche). These assays are intended for use Health care disparities SARS-CoV-2, thus aiding in identifying as an aid in identifying individuals with an adaptive immune response to potential convalescent plasma donors SARS-CoV-2, indicating recent or prior infection. Use of the tests is Health care costs restricted to laboratories certified under the Clinical Laboratory Might be used to assess the efficacy of Improvement Amendments of 1988 (CLIA) to perform moderate- or high- vaccine candidates in generating complexity tests. Quantitative detection of SARS-CoV-2 antibodies may aid neutralizing antibodies in determining eligibility for convalescent plasma donation, ascertaining Might be used to ease social distancing the course of antibodies over time, or assessing patient response to directives vaccination. However, it is unknown how long antibodies persist or whether the presence of antibodies confers protective immunity, and the Might misinform public health policies EUAs for these tests state that results should not be interpreted as an if they are based on erroneous test indication of the degree of immunity or protection from reinfection. results

SECTION 3. SCREENING AND DIAGNOSTICS 25 Table 3.2. Currently Monitored Topics: 13 Topics

Title Description Possible areas of impact Possible future impacts

3D-printed An early impediment to the widespread availability of COVID-19 testing Population health Might improve testing availability by nasopharyngeal swabs was a lack of testing accessories, including nasopharyngeal swabs to alleviating shortages of some testing Health care costs for COVID-19 testing collect patient samples. To help alleviate shortages, a consortium of accessories researchers, health care providers, and manufacturers collaborated to Might reduce costs for testing supplies develop nasopharyngeal swabs comparable to commercially available if more manufacturers are swabs that could be produced in high volumes using 3D printing. The supplying nasopharyngeal swabs consortium developed 4 prototypes and tested them for noninferiority against commercially available control swabs. Ultimately, investigators preferred one prototype over the other 3 and the control swab. The consortium developed the validated prototype in 22 days. The 3D-printed, FDA-registered test swabs with validated equivalent efficacy are available for order from manufacturers participating in the consortium. University of California, Los Angeles, researchers compared the 3D-printed swabs with conventional nasopharyngeal swabs in patients who underwent COVID-19 testing. Researchers found 3D-printed swabs performed comparably to conventional swabs and recommended that laboratories strongly consider their use during pandemic-related supply shortages. University of South Florida (Tampa) researchers developed 3D-printed swabs that performed as well as commercial swabs in multicenter validation testing and have provided the design and clinical data to hospitals, clinics, and licensed medical device companies around the world at no cost.

SECTION 3. SCREENING AND DIAGNOSTICS 26

Title Description Possible areas of impact Possible future impacts

Accula SARS-CoV-2 The Accula SARS-CoV-2 test is a reverse transcription polymerase chain Patient outcomes Might allow health centers to diagnose POC test to diagnose reaction (RT-PCR) assay developed by Mesa Biotech, Inc (San Diego, COVID-19 soon after a symptomatic Population health COVID-19 California), as a point-of-care (POC) COVID-19 test. It is intended for use in patient arrives temporary screening facilities, physician office laboratories, urgent care Health care delivery and Might help triage infected and facilities, and long-term nursing facilities. The Accula system consists of a process uninfected patients on the same day single-use cassette that contains the reagents needed to amplify viral Health care costs they are tested nucleic acids. A sample from a nasopharyngeal swab is added into the cassette, which is then placed in the Accula dock. The dock is a palm-sized Might be more affordable compared device that controls reaction temperatures, timing, and fluid movement with tests performed in central within the cassette. At the end of the reaction, results indicating whether laboratories viral nucleic acids have been detected in the patient sample are displayed Might increase the rate of false- on the side of the cassette. The Accula system purportedly yields negative test results if the assay does laboratory-quality results in about 30 minutes and is intended to not detect very low levels of viral complement central laboratories, where most current testing is performed. nucleic acids In March 2020, FDA granted the Accula SARS-CoV-2 test Emergency Use Authorization (EUA). A published study evaluated Accula SARS-CoV-2’s Might not be broadly available in all performance in 100 nasopharyngeal samples previously tested by an EUA health centers RT-PCR assay. Accula SARS-CoV-2 had a sensitivity of 68%, a specificity of 100%, and an overall percentage agreement of 84%.

SECTION 3. SCREENING AND DIAGNOSTICS 27

Title Description Possible areas of impact Possible future impacts

Assure COVID-19 The Assure COVID-19 IgG/IgM Rapid Test Device from Azure Biotech, Inc Patient outcomes Might enable more timely and IgG/IgM Rapid Test (Hangzhou, China), is a rapid lateral flow chromatographic immunoassay convenient results for individuals who Population health Device POC test to for use as a point-of-care (POC) fingerstick test for COVID-19. The test want to know if they have been detect SARS-CoV-2 qualitatively detects and differentiates IgM and IgG antibodies against the Health care delivery and previously infected with SARS-CoV-2 antibodies SARS-CoV-2 nucleocapsid protein and spike protein in human venous process Might aid in identifying plasma donors whole blood, serum, plasma, or fingerstick whole blood. Although the Health care disparities by allowing the detection of SARS- Emergency Use Authorization (EUA) issued in July 2020 originally limited CoV-2 antibodies this test to Clinical Laboratory Improvement Amendments of 1988 (CLIA)– Health care costs certified laboratories, the EUA has been reissued to authorize the test for Might misinform public health POC use in patient care settings such as doctors’ offices, hospitals, urgent decisions if they are based on false test care centers, and emergency departments. The test consists of individually results packed test devices, disposable pipettes, a buffer, a sterile safety lancet, alcohol prep pads, and optional materials such as external negative and positive controls, which are available upon request. A blood specimen is added to the well of the test device, followed by the buffer. Once the blue line on the device changes to red, results can be read at 15 minutes. Colored lines appear in the IgG and IgM test regions to signify the detection of antibodies. The Assure test has a specificity of 99.04%; the sensitivity of the test early after infection has not been determined. The Assure test is the first FDA-authorized COVID-19 POC serology test and is available by prescription only.

SECTION 3. SCREENING AND DIAGNOSTICS 28

Title Description Possible areas of impact Possible future impacts

BinaxNOW COVID-19 BinaxNOW COVID-19 Ag Card (BinaxNOW) is a lateral flow antigen Patient outcomes Might allow health centers to diagnose Ag Card POC antigen immunoassay developed by Abbott Diagnostics Scarborough as a point-of COVID-19 soon after a patient arrives Population health test to diagnose care (POC) test. BinaxNOW consists of a single-use card containing color- Might help triage infected and COVID-19 labeled antibodies that detect the coronavirus’s nucleocapsid protein, Health care delivery and uninfected patients on the same day which is detectable during the first 7 days of symptom onset. A patient’s process they are tested nasal swab is inserted into a small test card along with an extraction Health care disparities reagent that exposes the viral nucleocapsid. Test results are read on the Might be more affordable compared card like a pregnancy test, with one line indicating a negative result and 2 Health care costs with tests performed in central lines indicating a positive result. Results can be sent to a mobile device laboratories app (NAVICA), which can be used as a temporary digital health pass that is Might increase the rate of false- renewed each time an individual is tested. The manufacturer claims that negative test results if the assay does each $5 BinaxNOW card yields results in about 15 minutes. In August 2020, not detect very low levels of viral FDA granted BinaxNOW Emergency Use Authorization (EUA) based on a nucleocapsid proteins study that compared BinaxNOW with an EUA reverse transcription polymerase chain reaction (RT-PCR) assay in 102 nasal samples. BinaxNOW had a sensitivity of 97.1% and a specificity of 98.5%. A similar study comparing BinaxNOW and RT-PCR in 878 nasal samples reported a sensitivity of 93.3% and a specificity of 99.8%.

SECTION 3. SCREENING AND DIAGNOSTICS 29

Title Description Possible areas of impact Possible future impacts

COVID-19 at-home The COVID-19 at-home self-collection test kit consists of a nasal cotton Patient outcomes Might reduce the risk of patients self-collection kits swab or saliva collection tube, a biohazard specimen bag, and an overnight transmitting SARS-CoV-2 to medical Population health shipping envelope. The kit permits at-home collection of a sample staff and other patients appropriate to perform a SARS-CoV-2 nucleic acid–based test (NAT) for Clinician and/or caregiver Might reduce the need for PPE in individuals with COVID-19 symptoms or for those who have had possible safety testing departments exposure to the virus. The self-collection kit purportedly reduces the risk of Health care delivery and infected individuals transmitting the virus to others. Because the test kit Might increase testing in people with process does not require a health care worker to collect a nasal or saliva specimen, barriers to care it might also reduce the demand for personal protective equipment (PPE). Health care disparities Might increase the rate of false- On average, nasal swab self-collection kits cost about $115 each and saliva negative test results if the patient does collection kits cost between about $10 and $100 each. Out-of-pocket costs not acquire a proper specimen with may be waived for individuals deemed eligible by a survey or reimbursed detectable virus at the discretion of the patient’s health insurance. FDA has granted Emergency Use Authorization (EUA) to the COVID-19 self-collection test kit Might limit whether the sample is (Laboratory Corporation of America Holdings), COVID-19 test home safely shipped to a testing facility, collection kit (EverlyWell, Inc), Oragene Dx OGD-510 kit (DNA Genotek, Inc) because the kit is shipped by regular and SDNA-1000 Saliva Collection Device (Spectrum Solutions, LLC). mail and not by a laboratory courier service

SECTION 3. SCREENING AND DIAGNOSTICS 30

Title Description Possible areas of impact Possible future impacts

Dual POC nucleic acid Because symptoms for coronavirus and influenza virus infection can be Patient outcomes Might enable health centers to assays to diagnose similar, clinicians must be able to differentiate between the 2 to properly determine whether respiratory Population health COVID-19 and manage patients. Dual reverse transcription polymerase chain reaction symptoms are caused by coronavirus influenza (RT-PCR) assays have been developed to diagnose COVID-19 and Health care delivery and or influenza virus soon after a patient influenza. FDA has granted Emergency Use Authorization (EUA) to cobas process arrives SARS-CoV-2 & Influenza A/B Nucleic Acid Test (Roche Molecular Systems, Health care disparities Might help triage infected and Inc) and Xpert Xpress SARS-CoV-2/Flu/RSV (Cepheid, Inc). These assays are uninfected patients on the same day intended for use in point-of-care (POC) settings, including temporary Health care costs they are tested screening facilities, physician office laboratories, urgent care, and long- term nursing facilities. A patient’s nasal or nasopharyngeal sample is Might cost less to perform a single loaded into a single-use cartridge or tube that contains the reagents assay that detects both viruses needed for nucleic acid extraction, amplification, and detection of compared with performing 2 separate coronavirus and influenza virus. The cartridge or tube is placed in an tests analyzer that controls the reaction and reports whether viral nucleic acids Might increase the rate of false- have been detected. The manufacturers claim that their assays require a negative test results if the assay does small sample volume and minimal hands-on time to yield accurate results not detect very low levels of viral in less than an hour. Two multicenter studies compared Xpert Xpress nucleic acids SARS-CoV-2 (similar accuracy to the multipanel) with several standard-of- care (SoC) RT-PCR tests in 483 nasopharyngeal and 88 upper respiratory Might create disparities for patients tract samples and reported a positive percentage agreement (PPA) of who do not live near health centers 99.5% to 100% and a negative percentage agreement (NPA) of 95.8% to with capabilities and certifications to 100%. In 357 nasopharyngeal samples, the dual cobas test had a PPA of offer dual RT-PCR tests 100% and an NPA of 97.4% compared with an SoC RT-PCR test.

SECTION 3. SCREENING AND DIAGNOSTICS 31

Title Description Possible areas of impact Possible future impacts

Lucira COVID-19 All- The Lucira COVID-19 All-In-One-Test Kit (Lucira Health, Inc) is the first Patient outcomes Might reduce the risk of patients In-One Test Kit at- coronavirus test granted EUA for use in the home setting by FDA. It is a transmitting SARS-CoV-2 to medical Population health home assay to low-complexity, portable loop-mediated isothermal amplification (LAMP) staff and other patients by triaging diagnose COVID-19 assay that amplifies and detects viral nucleic acids. A health care provider Clinician and/or caregiver infected and uninfected individuals prescribes the test for home use in patients aged 14 years or older who are safety from home on the same day they are suspected of having COVID-19. The test is also intended for use in point- tested Health care delivery and of-care (POC) settings, including temporary screening facilities, physician process Might be more affordable and offices, laboratories, urgent care, and long-term nursing facilities. The convenient compared with tests Lucira COVID-19 test includes a single-use, battery-operated testing unit, a Health care disparities performed in central laboratories nasal swab, a sample vial, and a plastic disposal bag. According to Lucira Health, the test requires a small sample volume to yield laboratory-quality Might increase the rate of false- results in about 30 minutes and is expected to cost about $50 per kit. negative test results if the assay does Patients who test positive are recommended to self-quarantine and follow not detect very low levels of viral up with their health care provider. The Lucira COVID-19 package insert nucleic acids claims that its performance was evaluated in 51 samples also tested with Might create disparities in regions an FDA-authorized coronavirus test. Compared with this reference where at-home test kits are not standard, Lucira COVID-19 showed a positive percentage agreement (PPA) available of 94% and a negative percentage agreement (NPA) of 98%.

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Title Description Possible areas of impact Possible future impacts

Next-generation Central laboratory–based reverse transcription polymerase chain reaction Patient outcomes Might aid in diagnosing COVID-19 in sequencing assays to (RT-PCR) testing remains the standard of care for diagnosing COVID-19. symptomatic individuals and allow Population health diagnose COVID-19 However, a backlog of samples limits the tests’ potential to quickly inform laboratories to process thousands of patient management decisions about treatment and/or isolation. Next- Health care delivery and patient samples per day generation sequencing (NGS) assays are an alternative test modality that process Might allow health agencies to track offers high throughput, enabling 2000 to 3000 samples to be processed in Health care disparities the spread of coronavirus within about 12 hours, with accuracy comparable to that of RT-PCR tests. NGS infectious epicenters and identify assays employ deep sequencing (ie, a genetic sequencing technique that Health care costs emerging variants requires only a very small nucleic acid sample) and computational methods to detect nucleic acids of SARS-CoV-2. Tests can amplify and detect Might be more expensive compared sequences from the whole viral genome (ie, a string of about 30 000 with standard nucleic acid and antigen nucleic acids), several genomic regions, or individual genes (eg, S gene tests performed in central laboratories encoding the spike protein). FDA has granted Emergency Use and in point-of-care (POC) settings Authorization (EUA) to ClearDx SARS-CoV-2 Test, COVIDseq, Guardant-19, Might create disparities for patients and Helix COVID-19 NGS to diagnose COVID-19. These assays may be who do not live near health centers performed only at Clinical Laboratory Improvement Amendments of 1988 with capabilities and certifications to (CLIA)–certified laboratories, including central laboratories and some offer NGS testing laboratories at hospitals, research institutions, and academic institutions. NGS assays might also be used in epidemiology studies to track the spread of SARS-CoV-2 or identify emerging SARS-CoV-2 variants.

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Title Description Possible areas of impact Possible future impacts

Population-wide The COVID-19 pandemic has caused substantial public health and Patient outcomes Might inform actual infection rates and antibody testing to economic crises, which makes testing for the prevalence of more accurately track the spread of Population health quantify coronavirus coronavirus infection—as well as potential immunity—critical to measuring coronavirus infection rates the spread of the disease. Medicare beneficiaries who may be at greater Clinician and/or caregiver Might misinform public health risk of serious COVID-19 can receive an antibody test at no cost. Testing safety guidance ifthe employed serology tests for coronavirus-specific antibodies in the blood of individuals has the Health care delivery and generate high levels of false positives potential to identify those who have been exposed to the virus, process or false negatives regardless of whether they developed symptoms, and widespread serosurveys have the potential to provide data on the extent of COVID- Health care disparities Might misrepresent true infection rates 19 spread. The Centers for Disease Control and Prevention (CDC) is by depending on blood donors, who Health care costs conducting a countrywide COVID-19 study that will test blood samples of are disproportionately healthy and up to 325 000 donors in 25 selected cities over the course of 18 months. A may not be the ideal population to nonprofit blood service provider, Vitalant, will be partnering with the CDC evaluate the spread and the National Institutes of Health (NIH) to collect samples for of coronavirus infection this serologic study. Those who have received a COVID-19 vaccine are ineligible to give convalescent plasma; however, they may donate blood or platelets. The NIH also launched a similar study of 15 000 participants with no known coronavirus infection or exposure. The NIH is collecting blood samples from employee volunteers at its Bethesda campus and using at- home blood collection kits developed by Neoteryx (Torrance, California) for other volunteers.

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Title Description Possible areas of impact Possible future impacts

QIAstat-Dx Respiratory The QIAstat-Dx Respiratory SARS-CoV-2 Panel (Qiagen, N.V.) is a Patient outcomes Might enable health centers to SARS-CoV-2 Panel test polymerase chain reaction (PCR) assay intended to diagnose COVID-19 diagnose COVID-19 soon after a Population health to diagnose COVID-19 and differentiate it from 20 other causes of respiratory infection. The panel patient arrives and determine whether consists of a single-use cartridge that includes all reagents needed for Health care delivery and symptoms are caused by SARS-CoV-2 nucleic acid extraction, nucleic acid amplification, and detection of 3 process or a different infectious agent bacteria and 18 viruses (or their subtypes), including SARS-CoV-2, that Health care disparities Might help triage infected and cause respiratory symptoms. A nasopharyngeal swab sample is added into uninfected patients on the same day the cassette, which is then placed in the QIAstat-Dx Analyzer 1.0. At the Health care costs they are tested end of the reaction, results indicating whether pathogen nucleic acids have been detected in the sample are displayed on the analyzer’s screen. The Might cost less to perform a single panel purportedly requires a small sample volume and minimal hands-on assay that detects several infectious time, and the results are available in about 1 hour. In March 2020, FDA agents than it costs to perform several granted the QIAstat-Dx Respiratory SARS-CoV-2 Panel Emergency Use separate tests Authorization (EUA) for use in Clinical Laboratory Improvement Might increase the rate of false- Amendments of 1988 (CLIA)–certified laboratories. A published study negative test results if the assay does evaluated the performance of the panel for detecting SARS-CoV-2 in 69 not detect very low levels of nucleic samples previously tested by a reverse transcription polymerase chain acids from different infectious agents reaction (RT-PCR) test recommended by the World Health Organization (WHO). QIAstat-Dx had a sensitivity of 100%, a specificity of 93%, and an Might create disparities for patients overall percentage agreement of 97%. who do not live near health centers with capabilities and certifications to offer the test

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Title Description Possible areas of impact Possible future impacts

Rapid POC breath test A rapid breath test to detect COVID-19 in a few minutes in persons with or Patient outcomes Might enable more rapid POC testing to detect without symptoms could make high-volume testing more practical in large in public areas, such as airports or Population health COVID-19 public spaces such as airports, sports arenas, or theaters. Several businesses, to facilitate economic diagnostic firms and health systems are reportedly in early development or Health care costs reopening clinical testing of point-of-care (POC) tests to detect COVID-19 in breath Might help slow the spread of COVID- samples. Common designs feature a handheld or desk-mounted analyzer 19 if more asymptomatic carriers are unit and single-use cartridges into which patients breathe to deliver a identified sooner sample. Tests are intended to analyze breath samples using various diagnostic approaches, including terahertz spectroscopy to measure Might improve consumer confidence in coronavirus-specific electroacoustic properties, gas chromatography-ion public health efforts through simple, mobility spectrometry to detect COVID-19–specific metabolic rapid, and effective POC testing profiles, identification of coronavirus-specific biomarkers, and detection of viral nucleic acid or protein. Developers include Canary Health Technologies (Cleveland, Ohio); Indiana University (Indianapolis) ; Mercy Health (Janesville, Wisconsin)/RJ Lee Group, Inc (Monroeville, Pennsylvania); Ben-Gurion University (Beer-Sheva, Israel); Technion-Israel Institute of Technology (Haifa, Israel); Breathomix (Leiden, The Netherlands); and Exhalation Medical Technology (Cambridge, England, United Kingdom) . Cost estimates for tests in development vary widely, from about $2 up to $50 each, not including the diagnostic consoles/analyzer units. As of February 18, 2021, no rapid POC breath tests for COVID-19 had received Emergency Use Authorization (EUA) from FDA.

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Title Description Possible areas of impact Possible future impacts

Saliva-based nucleic Saliva-based nucleic acid assays use a process known as reverse Patient outcomes Might reduce the risk of patients acid assays to transcription polymerase chain reaction (RT-PCR) to detect nucleic acids of transmitting SARS-CoV-2 to medical Population health diagnose COVID-19 SARS-CoV-2 in a saliva sample. Compared with nasopharyngeal swab staff and other patients if sample sampling, which is considered the standard of care, saliva sampling is less Clinician and/or caregiver collection is performed at home, and invasive and less costly, and it can be performed at home or at a health safety might help triage infected and center without the supervision of a health care worker. Some saliva-based uninfected patients Health care delivery and assays have been validated to use minimally processed saliva samples, process Might decrease costs associated with obviating the need for a nucleic acid extraction step, which might save sample collection and ease the burden time and testing supplies. Results from 2 systematic reviews suggest that Health care disparities at testing sites with limited personal saliva-based tests yield similar outcomes to nasopharyngeal swab–based Health care costs protective equipment (PPE) and testing tests for detecting viral nucleic acids. Two published studies comparing supplies COVID-19 positivity on paired saliva samples and nasopharyngeal swabs tested by RT-PCR reported that saliva samples had an overall agreement of Might increase the rate of false- between 94% and 99% for detecting coronavirus nucleic acids when negative test results if assays testing compared with simultaneously collected nasopharyngeal swabs. FDA has saliva do not detect viral nucleic acids granted Emergency Use Authorization (EUA) to several saliva-based assays, at all stages of infection such as Advanta Dx SARS-CoV-2, Clarifi COVID-19, DxTerity SARS-CoV-2, Might create disparities for patients SalivaDirect, and Wren COVID-19, for use in Clinical Laboratory who do not live near health centers Improvement Amendments of 1988 (CLIA)–certified laboratories to with capabilities and certifications to diagnose COVID-19. offer saliva-based testing

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Title Description Possible areas of impact Possible future impacts

Sofia 2 SARS Antigen The Sofia 2 SARS Antigen Fluorescent Immunoassay (FIA; Quidel Corp) is a Patient outcomes Might allow health centers to diagnose FIA POC test to SARS-CoV-2 antigen detection assay intended for point-of-care (POC) use COVID-19 soon after a patient arrives Population health diagnose COVID-19 in settings such as temporary screening facilities, ambulatory care centers, Might help triage infected and and long-term nursing facilities. The Sofia 2 is a cassette-based lateral flow Health care delivery and uninfected patients on the same day immunoassay that uses antibodies to detect the nucleocapsid protein from process they are tested SARS-CoV (severe acute respiratory syndrome–associated coronavirus) and Health care costs SARS-CoV-2. After a nasal or nasopharyngeal swab is treated with a Might be more affordable compared solution that exposes the viral nucleocapsid, the sample is added to the with tests performed in central cassette and placed in the Sofia analyzer. The analyzer reads the cassette laboratories and reports whether viral antigen was detected in the patient sample. Sofia Might not be broadly available in all 2 purportedly requires a small sample volume and minimal hands-on time, health centers and the results are available in about 10 minutes. In May 2020, FDA granted Emergency Use Authorization (EUA) to Sofia 2, the first of 7 Might increase the rate of false- antigen tests to receive EUA. A published study compared Sofia 2’s negative test results if the assay does performance for detecting SARS-CoV-2 with that of an EUA reverse not detect very low levels of viral transcription polymerase chain reaction (RT-PCR) assay in 346 nucleocapsid proteins nasopharyngeal samples. Sofia 2 had a sensitivity of 77.0%, a specificity of 99.6%, and an overall agreement of 95.7%.

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Table 3.3. Recently Archived Topics: 2 Topics

Title Description Archive reason(s) based on data review and/or stakeholder ratings and comments

Artificial intelligence blood The COVID-19 resurgence across the United States has put substantial demand on Stakeholders reviewing this topic thought the test analysis to rule out hospital laboratories for polymerase chain reaction (PCR) testing. University of effectiveness of this approach was doubtful at COVID-19 Vermont (Burlington) researchers have developed and validated AI-COVID, a machine this early stage, given the low specificity of 59%. learning tool that purportedly could rule out COVID-19 using only standard blood Stakeholders thought this artificial intelligence tests routinely ordered in the emergency department, potentially allowing risk stratification approach was unlikely to replace standard PCR of patients to reduce COVID-19 PCR test burden. Researchers theorized that SARS-CoV- testing in the near future, suggesting minimal 2 might display characteristic patterns that machine learning methods could identify disruption. However, further research of its in results from comprehensive metabolic panel and complete blood count with potential should continue. differential laboratory tests. The team trained the model using blood tests from 2183 PCR- confirmed COVID-19 cases collected at 42 hospitals during the pandemic and negative controls from 10 000 patients at the same hospitals before the pandemic. They conducted an external validation study using 1020 PCR-confirmed cases at 23 hospitals and 171 734 prepandemic negative controls. Using a model-generated risk score cutoff of 2.0 (out of 100), the model had a 92.6% sensitivity (true-positive rate) and 59.9% specificity (true- negative rate). At the 2.0 cutoff, the negative predictive values (probability that a negative screening test result is truly negative) at COVID-19 disease prevalence rates of 1%, 10%, and 20% were 99.9%, 98.6%, and 97%, respectively. Biocogniv, Inc (South Burlington, Vermont), is commercializing AI-COVID.

SECTION 3. SCREENING AND DIAGNOSTICS 39

Title Description Archive reason(s) based on data review and/or stakeholder ratings and comments

cPass SARS-CoV-2 test to The cPass SARS-CoV-2 neutralization antibody detection kit developed by GenScript detects Stakeholders reviewing this topic agreed that the detect neutralizing antibodies capable of blocking infection with SARS-CoV-2 (ie, neutralizing antibodies) in cPass test is one of many available tests that has antibodies against human serum or plasma using an enzyme-linked immunosorbent assay (ELISA)–based test. the ability to detect neutralizing antibodies for SARS-CoV-2 The test assay purportedly mimics the binding interaction between the virus and host cell COVID-19, making it incremental and unlikely to receptor, which allows neutralizing antibody activity to be detected in patient samples. If cause large disruption in the current landscape. neutralizing antibodies are present in the sample, they will block the interaction between the 2 key components of the test kit, a recombinant subunit of the coronavirus spike surface protein and a recombinant form of the human angiotensin-converting enzyme 2 (ACE2) receptor protein. Detecting the presence of neutralizing antibodies might help identify individuals with an adaptive immune response to COVID-19 that indicates prior infection. By specifically detecting neutralizing antibodies, the test might provide a more biologically relevant assessment of an individual’s antibody levels compared with typical serology tests that detect antibodies against SARS-CoV-2 without regard for neutralizing activity. However, the level of neutralizing antibodies needed to prevent COVID-19 is still unknown. In November 2020, FDA granted cPass SARS-CoV-2 Emergency Use Authorization (EUA). Use of the cPass SARS-CoV-2 test is limited to laboratories certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) to perform high-complexity tests. The cPass kit has a sensitivity of 93.8% and a specificity of 99.4%.

SECTION 3. SCREENING AND DIAGNOSTICS 40

Section 4. Systems and Management: 25 Topics

Table 4.1. Topics Added Since Last Status Report: 11 Topics

Title Description Possible areas of impact Possible future impacts

COVID-19 Testing The gradual emergence of more choices for COVID-19 testing and Population health Might help schools safely reopen and Impact Calculator pandemic mitigation can make it difficult for organizations to select their stay open for in-person learning, based Health care disparities best options given their respective circumstances and on local circumstances resources. Researchers at Massachusetts General Hospital (Boston) and Health care costs Might help local businesses plan to Massachusetts Institute of Technology (Cambridge) developed the COVID- stay open or modify operations in 19 Testing Impact Calculator to give schools and businesses clear guidance response to changing conditions and on testing and risk-reduction measures to help them remain open safely. disease prevalence The National Institutes of Health funded the research project as part of its Rapid Acceleration of Diagnostics (RADx) Tech program. The modeling Might simplify institutions’ COVID-19 tool purportedly incorporates the latest testing and prevention safety planning efforts by providing a strategies to visually demonstrate how using masks, contact tracing, standardized modeling tool limiting unmasked social gatherings, and performing coronavirus testing Might help institutions preserve can help organizations minimize the spread of COVID-19 in their limited resources by avoiding environments. Users input details about their site, and the calculator unnecessary testing or mitigation provides customized surveillance testing scenarios using models of 4 efforts different onsite and laboratory-based COVID-19 testing methods. The modeling tool calculates the number of persons to test daily and the estimated weekly cost for each testing method.

SECTION 4. SYSTEMS AND MANAGEMENT 41

Title Description Possible areas of impact Possible future impacts

Emotional PPE Project The Emotional PPE Project is a nonprofit organization that began shortly Patient outcomes Might decrease the mental health to facilitate health care after the onset of the COVID-19 pandemic. Its purpose is to connect health burden on health care workers and Population health worker access to care workers whose mental health has been impacted by the COVID-19 help reduce burnout as they continue mental health services crisis with licensed mental health professionals for services at no cost. Clinician and/or caregiver to work during the COVID-19 Mental health professionals sign up on the project website to safety pandemic volunteer their services. After license verification, these professionals Health care delivery and Might decrease the burden on the appear in a database on the website. Health care workers are able to process health care system for mental health search by their state in the database to find mental health professionals services, especially considering mental and their contact information. Sessions are conducted via telehealth and health care provider shortages under the liability and malpractice insurance already held by the nationwide provider. The Emotional PPE Project intentionally left the definition of health care worker vague, considering the mental health impact Might reduce stigma surrounding the that COVID-19 has had on many professions and populations, and they mental health effects of the COVID-19 leave it up to the mental health providers to choose which and how many pandemic clients they take on. Hundreds of providers are available through The Emotional PPE Project, including clinical psychologists, licensed professional counselors, marriage and family therapists, neuropsychologists, psychiatrists, and social workers.

SECTION 4. SYSTEMS AND MANAGEMENT 42

Title Description Possible areas of impact Possible future impacts

Mobile health clinics As the COVID-19 pandemic continues, many underserved and rural Patient outcomes Might increase access to COVID-19 to increase access to communities as well as COVID-19 hot spots around the United States still testing in underserved hot spots and Population health COVID-19 health face challenges surrounding access to testing and treatment. An estimated rural communities services 2000 mobile clinics, customized motor vehicles that travel to communities Clinician and/or caregiver Might lead to faster implementation of to provide health care, are active in the United States and may be able to safety testing initiatives in hot spots and rural help meet needs for COVID-19 health services. In addition to the existing Health care delivery and communities mobile clinic infrastructure, various companies are offering mobile clinics. process For example, Aardvark Mobile Health vehicles, from Aardvark Mobile Might lead to long wait times if the Tours, LLC (Conshohocken, Pennsylvania), are mobile health trucks that are Health care disparities testing site is overwhelmed equipped with proper positive and negative air pressure and the ability to Health care costs become Certified Laboratory Improvement Amendments of 1988 (CLIA) certified up to biosafety level 2. The vehicles can be used for rapid testing, vaccinations, and health screenings. The trucks have a self-contained space with air conditioning and heating that takes 15 minutes to set up. The easily sterilized areas and partitions, which separate the nurses conducting the tests from the individuals receiving them, help maintain the safety of all involved. Two to 4 testing windows allow for nurses to administer up to 400 tests a day, similar to drive-through testing facilities, which are inaccessible to people who rely on public transportation. The Aardvark trucks can be bought or rented. The company supplies an experienced driver, maintenance, insurance, logistics management, and a program manager to give states or companies the ability to maintain focus on testing, vaccinations, and screenings.

SECTION 4. SYSTEMS AND MANAGEMENT 43

Title Description Possible areas of impact Possible future impacts

Pediatric-specific risk At the beginning of the COVID-19 pandemic, most hospitals canceled Patient outcomes Might assist surgeons in making better scoring systems to all elective surgeries, owing to the increased risk of patient and health care treatment decisions Clinician and/or caregiver prioritize surgical worker exposure to COVID-19, possible complications following surgical safety Might help manage the surge of procedures procedures, and limited availability of hospital resources (eg, personal patients requiring hospital protective equipment [PPE], personnel). This led to a backlog of surgical Health care delivery and resources and alleviate the burden on cases, leaving many patients waiting to receive treatment. To help manage process hospital staff and facilities this backlog, health systems developed multiple scoring tools to rank and triage elective surgeries in adults. More recently, these risk scoring systems Might lack accuracy due to the limited have been adapted to specifically address the pediatric population. availability of data on the impact By including risk factors specific to children (eg, less than 6 months of age, of comorbidities on SARS-CoV-2 presence of congenital heart defects), excluding risk factors not relevant to infection in pediatric patients children, and adjusting for the different effects of SARS-CoV-2 infection in children, these scoring systems are purportedly better suited to guide when to proceed with elective surgical procedures in pediatric patients. Examples of pediatric-specific scoring systems include the pediatric surgical wait priority score (pSWAPS), which calculates a risk score using resource-related, patient-related, and case urgency factors, and the pediatric medically necessary, time-sensitive (pMeNTS) system, which calculates a risk score using procedure-, disease-, and patient- specific factors. These systems are designed to be adaptable to the changing resource environment during the various phases of the COVID- 19 pandemic.

SECTION 4. SYSTEMS AND MANAGEMENT 44

Title Description Possible areas of impact Possible future impacts

Phone applications to The availability of multiple COVID-19 vaccines has led to a need for large Population health Might increase public knowledge manage COVID-19 public vaccine education campaigns, monitoring of vaccine effectiveness, about COVID-19 vaccines Health care delivery and vaccine and ways to schedule appointments and report side effects. Several apps process Might help maintain compliance to communications and are in development to help government agencies and health care COVID-19 vaccine dosing schedules scheduling professionals manage the communication and scheduling of COVID-19 Other vaccination. The Centers for Disease Control and Prevention (CDC) is Might cause public distrust providing vaccine recipients access to V-Safe, a smartphone app that uses surrounding health data confidentiality text messages and web surveys to keep track of any side effects experienced by patients who have received a COVID-19 vaccine. Additionally, the app can notify patients when it is time to go back for a second dose. Information provided by users remains confidential and private. GetWellNetwork (Bethesda, Maryland) has developed an app for LifeBridge Health (a regional health system in the Baltimore, Maryland, metropolitan area) to support vaccine distribution, education, and guidance. The app delivers patient communications through phones, smartwatches, and computers and allows users to schedule vaccination appointments, report side effects, learn more about the vaccines, and get reminders about second doses. The app also sends users reminders to remain engaged in protective measures even after receiving their vaccinations.

SECTION 4. SYSTEMS AND MANAGEMENT 45

Title Description Possible areas of impact Possible future impacts

Recharge rooms to Recharge rooms are spaces designed for rest and rejuvenation. The Patient outcomes Might significantly improve mental reduce stress in Abilities Research Center at the Icahn School of Medicine at Mount health and overall quality of life in Population health frontline health care Sinai, in collaboration with Studio Elsewhere, has created nature- frontline health care workers workers inspired recharge rooms for frontline health care workers during the Might positively impact the health care COVID-19 pandemic. Decorated with artificial plants and relaxing furniture, organization in ways such as reducing the rooms provide a multisensory experience consisting of employee turnover due to burnout and soothing nature scenes projected on a wall, relaxing music paired building resiliency within the with nature sounds, and calming scents diffused into the air. The rooms organization as a whole are intended to alleviate the stress that contributes to attention fatigue, burnout, and moral injury experienced by frontline health care Might improve population health workers. The researchers found that health care workers who spent a outcomes if health care workers single 15-minute stay in one of their recharge rooms experienced an provide better-quality care as a result average 60% decline in self-reported stress levels, and the rooms garnered a net promoter score of 99.3%. Studio Elsewhere is continuing research, development, and piloting of their recharge rooms, and is interested in connecting with organizations looking to implement them. Some hospitals are creating their own version of recharge rooms (eg, Baptist Health Hardin).

SECTION 4. SYSTEMS AND MANAGEMENT 46

Title Description Possible areas of impact Possible future impacts

SMART Health Cards Traditionally, individuals who are vaccinated are issued a written card that Population health Might streamline public health to provide digital includes protected health information (eg, name, date of birth), guidance and reopening procedures Health care delivery and COVID-19 which vaccine product they received, and when the next dose is due. process Might increase socioeconomic immunization records Several phone apps are also in development that are intended to help disparities by permitting only people people maintain a digital record of their vaccination status to Health care disparities with an immunity advantage to return facilitate return to work, school, and travel. A recently formed coalition of to work and/or travel health and technology industry leaders called the Vaccination Credential Initiative (VCI) aims to develop a secure, verifiable method Might make it more convenient for to digitize vaccination cards. The SMART Health people to store their immunization Cardsinitiative would provide individuals with access to their COVID-19 credentials vaccination records as well as laboratory results via digital wallet apps such Might raise privacy concerns around as Apple Wallet or Google Pay. Users can add their vaccine and laboratory sharing protected health information records by linking the app directly to laboratory or health care provider websites. By obtaining results directly from the provider, SMART Health Cards purportedly provide a verifiable source of vaccination status and/or laboratory test results. Users can then share information from their digital card with third parties seeking verification of immunization status or test results. Sharing of data might be facilitated through a platform such as CommonPass. For people without smartphones, the VCI is developing an option for a PDF or paper printout of a QR code containing verifiable credentials aligned with Fast Healthcare Interoperability Resources standards.

SECTION 4. SYSTEMS AND MANAGEMENT 47

Title Description Possible areas of impact Possible future impacts

Support phone lines Health care worker–directed support phone lines staffed by volunteer Patient outcomes Might decrease the mental health to alleviate emotional mental health professionals, such as Physician Support burden on health care workers and Population health burden on health care Line (nationwide), Curbside Nevada, and Tennessee COVID-19 Emotional help reduce burnout as they continue workers Support Line, are intended to offer free, confidential support to health care Clinician and/or caregiver to work during the COVID-19 workers during the ongoing COVID-19 pandemic. Health care workers safety pandemic have experienced a large mental health burden during the pandemic and Might decrease the burden on the may be at increased risk for mental health challenges. Support phone lines health care system for mental health allow health care workers to call in to discuss their work and services personal stressors with a peer who is specially trained in mental health care and has shared experiences of the profession. The phone lines Might reduce stigma in the medical are intended to normalize the pursuit of mental wellness in the medical community surrounding seeking menta community, offer free and confidential support that is easily accessible, l health care and express empathy to and promote unity within the medical Might promote unity within the community. Callers might also be referred to resources online or within the medical community and protect community for additional support. against ongoing moral injury

SECTION 4. SYSTEMS AND MANAGEMENT 48

Title Description Possible areas of impact Possible future impacts

Surveillance programs In December 2020, two genetic variants of SARS-CoV-2 with higher Population health Might help identify individuals infected to identify and follow transmissibility were identified in the United Kingdom (variant B.1.1.7) and with an emerging variant and lead to Health care disparities the spread of South Africa (variant B.1.351) . They have subsequently been detected in subsequent isolation and contact emerging SARS-CoV-2 countries around the world. Although B.1.1.7 and B.1.351 do not seem to Health care costs tracing variants increase disease severity, the variants might be more transmissible Might help detect an emerging SARS- compared with the previously dominant variant and, thus, lead to an CoV-2 variant in a community and put increase of COVID-19-related deaths. Moreover, available vaccines might systems in place to quickly suppress offer less-than-robust protection against variants such as B.1.351, which spread of the virus contains at least one mutation found in a region of the spike protein that serves as a key target for neutralizing antibodies. Surveillance programs Might create disparities in regions are needed to support a public health response to these emerging where surveillance programs are not variants. This will require expanded testing and genomic sequencing to available identify where variants are starting to spread, followed by contact tracing and quarantine programs to decrease transmission. With support from the Centers for Disease Control and Prevention (CDC), the genomic sequencing companies Illumina and Helix will expand the national surveillance infrastructure to track the emergence and prevalence of new variants. The CDC has also partnered with clinical laboratories, national laboratories, state and local health departments, and universities to ramp up sequencing-based surveillance and contact tracing.

SECTION 4. SYSTEMS AND MANAGEMENT 49

Title Description Possible areas of impact Possible future impacts

Temporary field Many organizations have established temporary field hospitals to help Patient outcomes Might improve survival outcomes by hospitals to increase manage the overflow of patients diagnosed with COVID-19 who do allowing patients to receive Clinician and/or caregiver capacity during the not require intensive care unit (ICU)–level care. These nontraditional appropriate care in a timely manner safety COVID-19 pandemic facilities have been set up to care for COVID-19 patients through various Might increase access to critical care phases of this pandemic and have reemerged during the recent surge in Health care delivery and resources to manage the second surge COVID-19 cases. Field hospitals have been set up inside large medical process of COVID-19 cases, especially in areas tents in parks and parking lots, and inside convention centers or large with limited critical care resources halls. Recent examples include the Worcester field hospital, run by University of Massachusetts Memorial Health Care, where patients wear Might ease the burden on medical staff a portable device on their finger that provides their vital signs to the health overwhelmed by patients diagnosed care team for routine monitoring. Tent-style field hospitals have also with COVID-19 been constructed in hard-hit areas of Los Angeles and North Carolina to care for non-ICU COVID-19 patients. These facilities are equipped with standard hospital equipment (eg, heart rate monitors, IV stands, supplemental oxygen) for patient monitoring and treatment. Some field hospitals have implemented rapid response teams to quickly identify, assess, and resuscitate rapidly worsening patients and transport them to an ICU. A potential benefit of field hospitals is that patients are less confined than they would be in traditional settings and can socialize with other COVID-19 patients while they recover. The long-term economic impacts (ie, coverage of operating costs, health care costs) of running these temporary hospitals remain unclear.

SECTION 4. SYSTEMS AND MANAGEMENT 50

Title Description Possible areas of impact Possible future impacts

Waived insurance To facilitate patient access to mental health services, numerous Patient outcomes Might improve individual and copayments, health insurance companies have waived mental health visit copayments, population mental health and quality Health care disparities coinsurance, and coinsurance, and/or deductibles temporarily during the ongoing COVID-19 of life deductibles to pandemic. The pandemic has negatively impacted the mental health of Health care costs Might reduce health disparities by facilitate patient millions of Americans. It has contributed to increased stress and social removing cost barriers to mental health access to mental isolation; increased rates of anxiety, depression, substance use, and services health services suicidality; worsening of preexisting conditions (eg, obsessive-compulsive disorder); and increased mental health–related emergency department Might reduce stigma surrounding visits among children. Additionally, a recent study found that patients with mental health conditions no psychiatric history had roughly a 1 in 5 chance of being diagnosed with Might increase health care costs for a mental health disorder (such as anxiety, depression, or insomnia) within 3 insurance companies in the short term months of being diagnosed with COVID-19. Amid increased telehealth but decrease mental health costs in the usage during the pandemic, a study found that behavioral health visits long term were a main driver of the increase.

SECTION 4. SYSTEMS AND MANAGEMENT 51 Table 4.2. Currently Monitored Topics: 11 Topics

Title Description Possible areas of impact Possible future impacts

3D-printed face The rapid influx of patients with COVID-19 infection substantially depleted Clinician and/or caregiver Might alleviate face shield shortages shields to protect many health care facilities’ supplies of personal protective equipment (PPE) safety for frontline health care personnel against COVID-19 for staff. Competition among hospitals for limited vendor supplies of PPE Might reduce supply costs if face infection has resulted in dramatically rising prices, prompting some academic shields can be 3D printed locally medical centers to redirect their in-house 3D printing capabilities to address PPE shortages. At several centers, including the University of Washington and Mississippi State University, engineers and health care personnel have collaborated to rapidly shift their 3D printing capacity to produce protective face shields for frontline staff. In some cases, collaborative teams have produced face shields that a facility’s personnel prefer to commercially available shields, using modifications based on personal needs and feedback from local staff.

Artificial intelligence Early identification of patients with COVID-19 who may develop critical Patient outcomes Might assist health care professionals (AI)–assisted illness is of great importance and may aid in delivering proper treatment with making better treatment Population health radiographic image and optimizing the use of hospital resources. AI algorithms based on decisions assessment for assessment of patient clinical data are now being used to assist with Clinician and/or caregiver Might help manage the surge of determining determining which patients may need intensive critical care. On February 3, safety patients requiring ventilators and COVID-19 prognosis 2021, CLEWICU system (CLEW Medical, Wilmington, Delaware) received Health care delivery and alleviate the burden on health care FDA 510k clearance following an Emergency Use Authorization (EUA) for process professionals and facilities assessment of electronic health record data to assist with early identification of patients who are likely to be diagnosed with respiratory Health care costs Might help inform future triage failure or hemodynamic instability, which are common complications paradigms associated with COVID-19. Additionally, existing AI-based predictive Might lead to inappropriate care in analytics systems are being used to assess patients with COVID- cases of misclassification by the 19. AlgoMarkers software by Medial EarlySign (Aurora, California) uses algorithm patient data from vital signs, laboratory test results, smoking history, and other medical history to help clinicians detect patients at increased risk of developing COVID-19 complications. The Deterioration Index by EPIC (Verona, Wisconsin) analyzes patients’ data and calculates a risk score on a scale from 0 to 100, with a higher number signaling elevated concern that the patient’s condition is deteriorating.

SECTION 4. SYSTEMS AND MANAGEMENT 52

Title Description Possible areas of impact Possible future impacts

Contact tracing Software developers have created contact tracing tools to inform Patient outcomes Might help governments and health software systems to governments and public health agencies about coronavirus spread. Apple agencies develop policies to reduce the Population health mitigate epidemic and Google have launched smartphone-based exposure notification spread of COVID-19 scenarios systems to track physical distance between people. Users can report a Health care delivery and Might increase privacy concerns, COVID-19 diagnosis to allow contact tracing by alerting users whose process especially for COVID-19-positive users devices have come near an infected person’s device. Additionally, public Health care disparities health systems can be granted access to the data to give potentially Might lead to poor population health exposed users advice on next steps. Many state governments have outcomes due to targeted advertising implemented proximity exposure tracing systems to track person-to- and mistaken self-diagnoses person transmission and transmission zones in their states. However, media reports suggest these systems are widely available in fewer than half of US states, and relatively few people have activated the tools where they are available, thus limiting their effectiveness. The Centers for Disease Control and Prevention (CDC) has noted several system limitations, including the potential to identify many false-positive contacts and increase workload for public health personnel, data and privacy issues, and the need for widespread software adoption to enable proximity tracking. The CDC has created the COVIDTracer and COVIDTracer Advanced spreadsheet-based tools to allow state and local public health officials and policymakers to compare the effectiveness and requirements of 3 user-defined contact tracing and monitoring strategies.

SECTION 4. SYSTEMS AND MANAGEMENT 53

Title Description Possible areas of impact Possible future impacts

COVID-19 Vaccine Early supplies of COVID-19 vaccines are limited. To help with orderly and Population health Might help local officials fairly Allocation Planner equitable early distribution of coronavirus vaccines, researchers at Ariadne distribute COVID-19 vaccines to the Clinician and/or caregiver Labs and the Surgo Foundation developed the COVID-19 Vaccine highest-priority populations by safety Allocation Planner. It is intended to help state and county decision makers providing a more standardized distribute early vaccines to the 13 priority populations identified Health care delivery and approach in the Framework for Equitable Allocation of COVID-19 Vaccine process Might improve transparency of the guidelines, created by the National Academies of Sciences, Engineering, early vaccine distribution process, and Medicine (NASEM). The planning tool purportedly lets users obtain increasing public acceptance of estimates of the size of high-priority populations in their respective distribution plans geographic regions and consider other factors, such as community vulnerability, to assign relative weights to groups when determining which Might provide a framework for fair groups should have highest priority. The allocation planner also helps distribution of COVID-19 vaccines users estimate the number of vaccine doses available and the percentage among the wider population after of vaccine coverage achievable under different scenarios. In a highest-priority groups receive related report that has not yet undergone peer review, Massachusetts vaccines Institute of Technology (Cambridge) researchers developed a computational model suggesting that optimized COVID-19 vaccine allocation could reduce US deaths by 10% to 25%, or 10 000 to 20 000 deaths, over 3 months.

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Title Description Possible areas of impact Possible future impacts

Drive-through The COVID-19 pandemic has shifted a substantial amount of health care to Patient outcomes Might reduce potential exposure to prenatal care model to the telehealth setting. However, some assessments that are part of routine COVID-19 infection for both the Population health reduce COVID-19 prenatal care still require direct interaction between patients and health patient and health care staff exposure care providers. To provide access to prenatal care while limiting COVID-19 Clinician and/or caregiver Might reduce patient anxiety due to exposure risk for obstetric providers and patients, investigators at Baylor safety continuation of planned prenatal visits College of Medicine (Houston, Texas) developed a drive-through prenatal Health care delivery and that cannot be completed using care model in which pregnant women remain in their cars while being process telehealth visits assessed by health care providers. Services such as blood pressure measurement, fetal heart rate assessment, and select ultrasound Health care disparities Might reduce costs for the patient due assessments are provided during drive-through appointments. The to reduced health care utilization Health care costs developers claim that the availability of these professional interactions Might offer convenient, timely prenatal might reduce patient anxiety related to having fewer prenatal clinic visits care for patients who have inadequate and could ease pandemic-related fears related to potential exposure internet access or limited computer within the clinic. The program uses equipment and disposables common literacy for telehealth visits to obstetric clinics in the United States. The investigators estimate that a drive-through prenatal care model might reduce the number of in-person Might lead to long wait times if the clinic visits by 33% per patient compared with standard prenatal care drive-through test center is modalities. overwhelmed

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Title Description Possible areas of impact Possible future impacts

Machine learning to COVID-19 has had significant social, political, economic, and public health Patient outcomes Might help predict changes in national- predict the spread of impacts globally. The Centers for Disease Control and Prevention (CDC) and state-level spread of coronavirus Population health COVID-19 has partnered with several universities to develop machine learning Might inform public health agencies to models to forecast national- and state-level changes in infection rates and Clinician and/or caregiver establish appropriate reopening deaths due to COVID-19. The UCLA-SuEIR model, developed at the safety procedures University of California, Los Angeles, purportedly infers the spread of Health care delivery and infection while accounting for underlying epidemic dynamics, making it a Might reduce overall health care costs process more comprehensive prediction model. California Institute of Technology by predicting possible resurgence in researchers developed a deep-learning model to predict COVID-19 Health care disparities cases earlier compared with other deaths at the county level with a 2-week forecast window. The DeepCOVID models, thereby helping with Health care costs model is trained on Google and Unacast human mobility data to yield emergency preparedness accurate forecasts of COVID-19 spread to purportedly quantify the effects of government interventions such as lock-downs and reopenings. The COVID-19 Outbreak Detection Tool detects recent outbreaks in US counties and predicts how fast an outbreak could spread within a given county by estimating the doubling time of COVID-19 cases. The COVID-19 Pandemic Vulnerability Index visually synthesizes county- level vulnerability indicators to allow local health authorities to compare them in regional, state, and national contexts and to support local decision making.

Multidose vials to Drug developers are quickly advancing coronavirus vaccine candidates Population health Might improve understanding of strengthen vial supply through clinical trials and, in parallel, readying manufacturing to prepare supply chain management and help Health care delivery and chain during COVID- for deployment if their candidate proves to be safe and effective. A recent prepare for future public health process 19 news brief highlighted a shortage of the medical-grade glass vials emergencies needed to distribute vaccines. A shortage of these glass vials or syringes Health care disparities Might change standards for quality and could create access issues for millions of people. Currently, to conserve manufacturing throughput of glass supply, the industry has decided to use 10-milliliter vials that pharmaceutical packaging are capable of holding 8 to 15 doses of coronavirus vaccine. Corning, Inc, will receive funding from the Biomedical Advanced Research and Might increase COVID-19 vaccine Development Authority (BARDA) to accelerate the manufacturing of glass access, potentially accelerating herd vials for COVID-19 vaccines and treatments. immunity

Might increase risks of iatrogenic illness due to cross-contamination

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Title Description Possible areas of impact Possible future impacts

Pandemic response In August 2020, the Centers for Disease Control and Prevention (CDC) Patient outcomes Might improve mental health strategies to mitigate urged a public health response to increase intervention and prevention outcomes for those directly and Population health mental health effects efforts for mental health conditions in the wake of COVID-19. Pandemic indirectly affected by COVID-19 of the COVID-19 response strategies specifically designed to address mental health issues Health care delivery and Might improve interdisciplinary pandemic might lessen the many negative mental health effects associated with the process collaboration and institutional current COVID-19 pandemic. These structured frameworks are intended to Health care disparities cohesion mobilize and optimize health care delivery to meet public health needs during a pandemic. To address mental health demands during the COVID- Health care costs Might revolutionize the mental health 19 pandemic, a recently published behavioral health pandemic response care delivery system if implemented strategy proposed actionable steps related to 6 pandemic phases. processes are adapted sustainably Examples of action steps include identifying and training crisis leadership Might decrease the stigma of mental teams, designing psychologically informed prevention and education health disorders campaigns and programs, training future behavioral health specialists for public health crisis response, developing flexible and scalable behavioral Might increase health disparities for health services, advancing behavioral health research, and ameliorating individuals living in rural areas, who health disparities and discrimination through outreach and raising cannot readily access mental health awareness. Caring Communities is one such initiative to implement a resources, or decrease health behavioral health response strategy during the COVID-19 pandemic, using disparities through efforts aimed a team of more than 100 psychologists, psychiatrists, transdisciplinary specifically to do so physicians, social workers, interdisciplinary trainees, and staff with expertise in web design and operations. A disaster psychiatry team mobilized by Massachusetts General Hospital in April 2020 follows a psychological first aid framework and aims to help the especially vulnerable homeless population.

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Title Description Possible areas of impact Possible future impacts

Post-COVID-19 Many hospitals across America are setting up post-COVID-19 recovery Patient outcomes Might improve management of long- recovery programs programs to accommodate the growing need for continued care in long term COVID-19 symptoms Population health haulers (ie, patients experiencing long-term side effects from COVID-19). Might help increase knowledge of Some long haulers have an increased risk of long-term health problems Health care delivery and long-term COVID-19 effects because of permanent damage to their lungs, heart, kidneys, and brain. process Even with no detectable damage to these organs, some patients still report Might increase health care costs if lingering and debilitating symptoms months after clearing the infection. clinic visits are not covered by Ongoing post-COVID-19 medical, psychological, and rehabilitation insurance programs may help ensure a full recovery from COVID-19. Patients who Might create long wait times and have cleared the viral infection but are still experiencing symptoms can go limited clinic access due to lack of to these postinfection programs with or without a referral, where they will programs in many areas and increased be screened to identify their clinical needs and establish a therapeutic demand for services plan. The programs consist of multidisciplinary teams comprising primary care physicians, pulmonologists, neurologists, mental health professionals, physical/occupational/speech therapists, and others. Some recovery programs address specific areas such as neurological effects, long-term symptoms in pediatric populations, or respiratory recovery. Some programs have implemented new therapeutic approaches to accommodate the precautions needed to minimize the risk of viral spread, such as negative-pressure rooms for patients in need of inpatient rehabilitation and isolation, as well as therapy via telemedicine.

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Title Description Possible areas of impact Possible future impacts

Statewide patient load The Arizona Department of Health Services (ADHS) has launched a Patient outcomes Might optimize interfacility transfer of management during statewide patient load balancing system (ie, surge line) to help with patients during COVID-19 or similar Population health the COVID-19 transferring patients between facilities during the COVID-19 emergency situations pandemic pandemic. ADHS hopes that the system will help accommodate potential Clinician and/or caregiver Might assist health care staff with surges in the number of COVID-19 cases, which have led some hospitals to safety effective time management by cancel or postpone elective procedures. The Arizona Surge Line is a 24/7 Health care delivery and reducing their call time to find the right toll-free call line for health care providers. For each call, a surge line process level of care for their patients transfer agent reviews critical care availability for each hospital in the state and transfers the call to the appropriate destination, thereby assisting with Health care disparities Might improve patient survival interfacility transfer of patients with presumed or confirmed COVID-19 or outcomes by enabling them to Health care costs transfer of patients to post–acute care facilities. It can assist with effectively receive appropriate care in a timely distributing new staffing placements from out of state. The surge line may manner also provide clinical consultation if a transfer is declined or delayed. Other Might enhance government policies states (eg, Illinois, Minnesota, Oregon) have created similar statewide hubs and public health emergency guidance with real-time visibility into bed and ventilator availability across health care systems. As of December 2020, the Arizona Surge Line has transferred more than 4000 COVID-19 cases to higher levels of care across more than 130 hospitals. A 4-month satisfaction survey suggested that the program successfully expedited transferring patients with COVID-19, load-balanced patients across Arizona hospitals, improved patient outcomes, and safeguarded the state’s health care system. These efforts might encourage other states to create similar statewide hubs with real-time visibility into bed capacity and the availability of ventilators across all facilities and health care systems.

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Title Description Possible areas of impact Possible future impacts

Vaccine Safety V-SAFE is a smartphone-based active surveillance program to measure Patient outcomes Might allow earlier detection of Assessment for COVID-19 vaccine safety. The Centers for Disease Control and Prevention vaccine-related adverse events Population health Essential Workers (CDC) developed V-SAFE to measure vaccine safety among health care Might permit earlier intervention or (V-SAFE) staff, essential workers, and others expected to be among the first vaccine Clinician and/or caregiver mitigation to reduce adverse event recipients. V-SAFE will use text-to-web and email-to-web surveys to safety risks conduct health checks in up to 20 million (or more) COVID-19 vaccine recipients during the early months of a vaccination program. CDC Might increase wider public vaccine will monitor subjects’ health after vaccination via text or email daily for acceptance if vaccines are perceived as the first week and weekly for the next 6 weeks. The CDC will actively safe and effective telephone all subjects who report a clinically important adverse event Might serve as a surveillance model for during a V-SAFE health check and file a Vaccine Adverse Event Reporting use in future pandemics and System (VAERS) report, if appropriate. The CDC states it has validated text vaccination efforts messaging as an effective method of vaccine safety monitoring. V-SAFE will purportedly let the CDC estimate rates of local and systemic immune response (ie, reactogenicity) and rates of vaccine-related adverse events. Further, V-SAFE will purportedly let the CDC compare coronavirus vaccine adverse event rates with background population rates and known rates for other vaccinations (eg, influenza).

SECTION 4. SYSTEMS AND MANAGEMENT 60 Table 4.3. Recently Archived Topics: 3 Topics

Title Description Archive reason(s) based on data review and/or stakeholder ratings and comments

Machine learning algorithm As areas across the United States face surges in COVID-19 cases, machine learning might be This machine learning approach could be useful to predict spikes in a predictive tool to anticipate spikes in COVID-19 hospital admissions. Northwell Health has for forecasting and improving allocation of COVID-19 cases developed a predictive tool that mines user data patterns from its website to anticipate health care supplies and resources; however, it is spikes in cases at its hospitals. The source code, which is to be made available for other unlikely to replace any current procedures in health systems, collects 15 different indicators and uses a machine learning algorithm to hospitals. Further research is needed to ensure recognize patterns in website traffic, including emergency department wait time searches that use of website traffic data is accurate and physician page clicks. The algorithm then generates a rolling 2-week forecast that enough to be widely employed by hospitals Northwell reports reflects caseload to date and might be able to help clinical teams prepare nationwide. for future surges. The data for Northwell Health’s algorithm were obtained from a high- traffic website (more than 20 million page views between March and September 2020) serving a collection of hospitals, outpatient facilities, and urgent care centers concentrated in the New York City metropolitan area.

Mental health applications During the COVID-19 pandemic, rates of mental health conditions (most commonly anxiety Mental health apps are unlikely to be as effective to alleviate mental health and depression), substance abuse, and suicidal ideation have been markedly as seeking mental health care from a trained effects of COVID-19 elevated. Despite increased use of telehealth and waived mental health visit copays by professional and are not a replacement for that select insurance companies, issues surrounding provider shortages and patient access to care. Their uptake is likely to be limited for some care contribute to an ongoing unmet need in mental health care. Mental health apps might by access to a smart device, and, unless a health help mitigate these needs by providing psychological support at home and when professional recommends particular apps, it convenient, and often at no direct cost to users. The apps offer a variety of tools, such as might be overwhelming to choose apps among guided meditation, mood and symptom tracking, cognitive reframing, and referral to the hundreds available. Some mental health additional resources. A variety of new mental health apps have been created in the wake of conditions might make it less likely a person will the COVID-19 pandemic. In particular, apps have been developed for use by vulnerable seek support in an app. For example, patients populations, including health care workers and veterans. Additionally, patients with who have major depressive disorder often preexisting mental health conditions have turned to apps when outpatient treatment groups struggle with motivation, which is necessary to were canceled. A few apps, including the popular meditation apps Headspace and Ten download and then engage with an app. Percent Happier, have started offering free access to health care workers and other essential workers.

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Title Description Archive reason(s) based on data review and/or stakeholder ratings and comments

Public-private partnerships As of September 2020, only one treatment had received Emergency Use Authorization (EUA) Coordinated efforts between public and private to fast track COVID-19 from FDA to treat COVID-19, and no FDA-approved vaccines were available to prevent sectors have helped optimize data collection and treatment and vaccine infection with SARS-CoV-2. The National Institutes of Health (NIH) is leading a public-private conduct of clinical trials; however, stakeholders development partnership called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) were concerned that political bias might that aims to identify, improve, and accelerate the development of promising treatments and influence scientific research. Directing finances to vaccines for COVID-19. Government agencies, nonprofit organizations, and fast track a clinical trial without substantial data biopharmaceutical companies will work together to contribute to the 4 identified fast-track could impact population health outcomes. areas: developing a collaborative, streamlined forum to identify preclinical treatments; Moreover, many uninsured patients do not have accelerating clinical testing of promising vaccines and treatments; improving clinical trial resources to pay for the latest COVID-19 capacity and effectiveness; and accelerating the evaluation of vaccine candidates to enable treatments, which increases disparities in the rapid authorization or approval. The NIH and National Institute of Allergy and Infectious population. Diseases (NIAID) created the COVID-19 Prevention Trials Network (COVPN) to advance these efforts by facilitating the participation of individuals as volunteers in clinical trials. COVPN is part of Operation Warp Speed, which aimed to deliver substantial quantities of a safe, effective vaccine by January 2021.

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Section 5. Treatments: 33 Topics

Table 5.1. Topics Added Since Last Status Report: 8 Topics

Title Description Possible areas of impact Possible future impacts

Aviptadil (Zyesami, Aviptadil (Zyesami, formerly RLF-100; Relief Therapeutics and Neuro Rx, Patient outcomes Might reduce risk of progression to formerly RLF-100) to Inc) is a synthetic version of human vasoactive intestinal peptide (VIP). It is acute respiratory distress syndrome Population health treat COVID-19 being investigated as an intravenous treatment for patients with critical (ARDS) in patients who have nonacute COVID-19 (ie, respiratory failure) in a phase 2/3 clinical trial and through Health care costs lung injury, shorten mechanical an expanded access protocol (EAP). Additionally, an inhaled (nebulized) ventilation time, and increase survival formulation is being investigated in patients with moderate to severe in patients who have ARDS COVID-19 in a phase 2/3 clinical trial. According to the developer, Might reduce health complications and aviptadil inhibits novel coronavirus replication, prevents the formation of risk for long-term sequelae inflammatory proteins (ie, cytokines), reduces lung cell death, and increases production of surfactant (a secreted mixture of phospholipids Might improve population health and proteins important for lung function). Top-line efficacy data reported outcomes if mechanical ventilator in October 2020 from a case-control study of patients enrolled in the shortages are minimized and burden EAP suggested aviptadil might increase survival; 21 patients treated with on the health care system is decreased aviptadil had an 80% survival rate at 60 days compared with only 17% in Might reduce health care costs if 24 control patients treated in the same setting. Initial data reported in length of hospitalization is shortened February 2021 from the phase 2/3 trial in patients with critical disease or fewer intensive care resources are suggested aviptadil shortened length of hospitalization: patients receiving needed high-flow nasal cannula (HFNC) therapy or mechanical ventilation were discharged a median of 5 days earlier, and when only patients receiving HFNC were considered, discharge was a median of 11 days earlier. NeuroRx submitted a request for Emergency Use Authorization (EUA) to FDA in September 2020 for the use of aviptadil in patients with critical COVID-19 and respiratory failure who have exhausted all approved treatments. In December 2020, FDA declined to grant the EUA but said it will continue to work with the developer and review additional data as they become available. Aviptadil to treat COVID-19 previously received FDA Fast Track designation.

SECTION 5. TREATMENTS 63

Title Description Possible areas of impact Possible future impacts

Colchicine to treat Colchicine is an oral drug approved by FDA to treat gout and familial Patient outcomes Might improve patient health COVID-19 Mediterranean fever. It is being investigated as a repurposed treatment for outcomes and increase survival Population health COVID-19 because of its immunomodulatory, anti-inflammatory, and Note: The topic had Might improve overall health and antiviral properties. Preliminary data from patients with COVID-19 treated Health care costs previously been quality of life by reducing health with colchicine suggested improved time to clinical deterioration, earlier archived but was complications and risk of long- discharge from the hospital, and lower rates of mortality and reinstated because of term sequelae intubation compared with standard-of-care (SoC) treatment. More positive data from the recently, in January 2021, the Montreal Heart Institute (MHI) reported data Might improve population health Montreal Heart from the phase 3 COLCORONA trial; in more than 4000 outcomes if the burden on the health Institute’s nonhospitalized patients who had received a diagnosis of COVID-19, care system is reduced with fewer COLCORONA study. colchicine reduced the risk of death or hospitalization by 21% compared hospitalizations and decreased need with placebo, a result that approached statistical significance. Additionally, for intensive care resources among patients with polymerase chain reaction (PCR)–confirmed COVID- Might reduce health care costs 19, colchicine reduced hospitalizations by 25%, the need for mechanical associated with hospitalization and ventilation by 50%, and deaths by 44% compared with placebo. MHI intensive care resources, especially as a stated colchicine could be the first effective oral drug for use in relatively cheap drug that is currently nonhospitalized patients with COVID-19. Two additional clinical trials widely available in the US health care involving colchicine (one phase 3 and one phase 2) are ongoing in the system United States in both inpatient and outpatient settings. Based on trial dosing information and colchicine pricing information, one treatment course of colchicine to treat COVID-19 costs approximately $80 to $150.

SECTION 5. TREATMENTS 64

Title Description Possible areas of impact Possible future impacts

Dexamethasone to Dexamethasone is an orally or intravenously administered corticosteroid Patient outcomes Might improve patient health treat severe that has become a standard-of-care (SoC) treatment in patients with outcomes and increase survival Population health COVID-19 severe or critical COVID-19. The National Institutes of Health (NIH) COVID- Might reduce the burden on the health 19 treatment guidelines recommend the use of dexamethasone in Health care costs care system and the risk of mechanical hospitalized patients with various disease severity levels, including ventilator shortages patients requiring increasing amounts of supplemental oxygen; patients requiring high-flow oxygen or noninvasive ventilation; and patients Might decrease health care costs requiring mechanical ventilation or extracorporeal membrane oxygenation. associated with hospitalization and The World Health Organization (WHO) similarly recommends the use of intensive care resources, especially dexamethasone in patients with severe or critical COVID-19. These because dexamethasone is a widely guidelines were based on findings from multiple trials. Data from the available, inexpensive drug 6425-patient phase 2/3 RECOVERY trial found that dexamethasone Might improve understanding of significantly lowered 28-day mortality among those who were receiving hyperinflammation in COVID-19 and either invasive mechanical ventilation or oxygen alone, but not among the role of anti-inflammatory drugs those who were not receiving respiratory support. A meta-analysis in treatment performed by the WHO before publication of the RECOVERY data showed that systemic corticosteroids in those critically ill with COVID-19 were associated with a lower 28-day all-cause mortality in 1703 patients across 7 randomized trials. In addition, several clinical trials of dexamethasone are ongoing (eg, phase 3 ACCT-4 trial, phase 4 trial). Based on available trial dosing information and dexamethasone pricing, a course of COVID-19 treatment with dexamethasone is likely to cost between $9 and $21 per patient.

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Title Description Possible areas of impact Possible future impacts

Monoclonal Cellular entry of SARS-CoV-2 depends on an interaction between the viral Patient outcomes Might improve health outcomes by antibodies targeting surface spike protein and cell surface protein angiotensin-converting reducing mechanical ventilation time Population health SARS-CoV-2 spike enzyme 2 (ACE2). Therefore, monoclonal antibodies targeting the spike and increasing survival in patients with protein receptor protein receptor-binding domain (RBD) may interfere with this interaction. Health care costs acute respiratory distress binding domain for Two anti–spike protein RBD antibody-based treatments (bamlanivimab syndrome (ARDS) treating [LY-CoV555] and casirivimab/imdevimab [REGN-COV2]) recently received Might improve overall health and nonhospitalized Emergency Use Authorization (EUA) from FDA for treating mild to quality of life by reducing related patients with moderate COVID-19 in patients who are at high risk for progressing to health complications and risk for long- COVID-19 severe COVID-19 or hospitalization. The EUA for bamlanivimab was based term sequelae on results of the randomized, double-blind BLAZE-1 trial, which showed that 1 of 3 dose levels of bamlanivimab reduced viral load at day 11 and Might improve population health that the treatment reduced the percentage of patients who had a COVID- outcomes if mechanical ventilator 19-related hospitalization or emergency department visit compared with shortages are minimized placebo (1.6% versus 6.3%, respectively). Results have also been released Might reduce health care costs if on the use of bamlanivimab in combination with a second antibody length of hospitalization is reduced (etesevimab [LY-CoV016]), which demonstrated a significant reduction and fewer intensive care resources are in hospitalization and mortality. Following these results, FDA gave EUA for needed; however, costs might increase the administration of bamlanivimab with etesevimab for treating recently if these expensive drugs are used diagnosed patients with mild to moderate COVID-19 who are aged 12 inappropriately. Therefore, a need years and older and are at high risk for progression to severe disease. The exists for clear physician and pharmacy EUA for casirivimab/imdevimab was based on a phase 2/3 trial that found oversight of use in only the appropriate that, compared with placebo, treatment resulted in a reduction of COVID- patient populations. 19-related medical visits by 57% through day 29 and a higher average daily change in viral load through day 7 in patients with high viral load.

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Title Description Possible areas of impact Possible future impacts

Peginterferon lambda- Peginterferon lambda-1A (Lambda; Eiger Biopharmaceuticals) is a long- Patient outcomes Might prevent progression to severe 1A (Lambda) for acting form of interferon lambda (IFNλ) that might be able to limit initial COVID-19 Health care costs treating mild to SARS-CoV-2 infection by activating the innate immune response to the Might result in resolution of hypoxia moderate COVID-19 virus. In response to viral infection, IFNλ is induced at a low viral burden and targets type 3 interferon (IFN) receptors to stimulate immune Might result in a faster time to patient responses that are important for the development of host hospital discharge protection. Additionally, Lambda may moderate the development of the Might cause adverse events related to cytokine storm associated with severe COVID-19. Instead of being immune response stimulation proinflammatory like type 1 IFNs, IFNλ is tissue protective and anti- inflammatory, potentially leading to the prevention of massive tissue damage in the lungs of COVID-19 patients, which is thought to be caused by aberrant hyperinflammatory responses. A phase 2 randomized study in 60 patients in home isolation with uncomplicated COVID-19 found that a single subcutaneous injection of Lambda resulted in accelerated viral decline and a greater proportion of patients with viral clearance by day 7 compared with placebo. However, another phase 2 study of Lambda found that it did not reduce time to cessation of viral shedding or symptom duration in COVID-19 outpatients. Lambda is currently being evaluated in 4 investigator-sponsored phase 2 studies in COVID-19 patients, with estimated completion dates in 2021.

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Title Description Possible areas of impact Possible future impacts

Prophylactic Coagulopathy is a common complication of COVID-19 and may lead to Patient outcomes Might improve patient health rivaroxaban increased rates of venous thromboembolic events, such as deep vein outcomes and increase survival Population health anticoagulation for thrombosis (DVT) and pulmonary embolism (PE), in affected patients. Might improve population health nonhospitalized Additionally, extensive microvascular thrombosis in the lungs has been Health care delivery and outcomes by reducing the burden on patients with observed in autopsies of COVID-19 patients, suggesting a potential role of process the health care system COVID-19 coagulopathy in the pathogenesis of the disease. While guidelines from Health care disparities both the American Society of Hematology and the American College of Might improve understanding of Chest Physicians recommend that all patients hospitalized with COVID-19 Health care costs coagulopathy in cases of severe receive anticoagulant thromboprophylaxis (typically using subcutaneously COVID-19 and the role of injected heparin), anticoagulation is not routinely prescribed to anticoagulant treatment nonhospitalized patients with COVID-19. Rivaroxaban is an FDA-approved Might increase health care disparities anticoagulant intended to prevent venous thromboembolic events and to due to the cost of the treatment treat and prevent recurrence of DVT and PE. The orally administered small- molecule drug binds directly to free and clot-bound factor Xa to block the Might increase risk of bleeding events amplification of the coagulation cascade, thereby preventing thrombus formation. A phase 3 randomized controlled trial (RCT) is ongoing in 4000 COVID-19 outpatients to investigate the role of rivaroxaban in reducing venous thromboembolism, all-cause hospitalization, and all-cause mortality. The study has an estimated completion date of March 3, 2021. Given at a dose of 10 mg a day for 35 days, the cost of a full course of rivaroxaban for treating COVID-19 would be about $547.89.

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Title Description Possible areas of impact Possible future impacts

Remdesivir (Veklury) Remdesivir (Veklury; Gilead Sciences, Inc) is an intravenously administered Patient outcomes Might reduce COVID-19 course length to treat patients antiviral adenosine analogue prodrug that purportedly inhibits the and severity Population health hospitalized with replication of SARS-CoV-2. Remdesivir became the first FDA-approved Might improve population health if the COVID-19 treatment for COVID-19 on October 22, 2020. It is indicated for use in Health care costs burden on the health care system is hospitalized patients aged 12 years or older weighing at least 40 kg. FDA reduced also revised its previous Emergency Use Authorization (EUA) for remdesivir to include children younger than the age of 12 weighing enough to receive Might reduce health care costs related the drug intravenously (3.5 kg). The approval was based on data from 3 to hospitalization and intensive care randomized clinical trials that suggested remdesivir significantly resources reduced time to recovery and increased odds of clinical improvement. No Might improve understanding of randomized trial of remdesivir has demonstrated a statistically significant antiviral treatments for COVID-19 effect on mortality, including the World Health Organization (WHO)– sponsored SOLIDARITY study. The developer expects that remdesivir will be effective against the newly identified SARS-CoV-2 variants B.1.1.7 and B.1.351 and is working on confirming its efficacy. Current guidelines on the use of remdesivir are conflicting. National Institutes of Health (NIH) guidelines recommend the use of remdesivir in hospitalized patients who require supplemental oxygen but not in less severely affected patients or patients requiring mechanical ventilation. The WHO recommends against its use in patients with COVID-19 regardless of disease severity. The cost of remdesivir to the US government is $2340, and the list price is $3120 per 5-day treatment course.

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Title Description Possible areas of impact Possible future impacts

rNAPc2 (AB201) for The inflammatory response that results from coronavirus infection often Patient outcomes Might shorten time to recovery for treating COVID-19 leads to life-threatening complications such as acute respiratory distress COVID-19 patients Population health syndrome (ARDS) and thrombotic events. rNAPC2 (AB201) is a small Might prevent COVID-19 disease recombinant protein under development by ARCA biopharma as a Health care delivery and progression and/or mortality treatment for RNA virus–associated diseases such as COVID-19. rNAPc2 process selectively inhibits tissue factor (TF), a protein that plays a central role in Might cause adverse events related to Health care disparities the activation of the coagulation cascade. Patients with COVID-19 have anticoagulant or anti-inflammatory been observed to exhibit elevated TF levels, which may be associated with properties disease severity and mortality. The treatment purportedly acts through Might have undiscovered adverse anticoagulant, anti-inflammatory, and antiviral mechanisms to prevent effects if made available through serious complications because of inappropriate activation of the an accelerated approval process coagulation system and other parts of the immune response. An ongoing phase 2/3 randomized trial is evaluating the ability of rNAPc2 to shorten time to recovery compared with heparin in 100 hospitalized patients with COVID-19, with estimated completion on April 30, 2021. rNAPc2 was given Fast Track designation by FDA as a potential COVID-19 treatment in November 2020.

SECTION 5. TREATMENTS 70 Table 5.2. Currently Monitored Topics: 21 Topics

Title Description Possible areas of impact Possible future impacts

Anakinra (Kineret) for Anakinra (Kineret) is an interleukin-1 receptor antagonist approved by FDA Patient outcomes Might improve health outcomes by treating COVID-19 for treating rheumatoid arthritis and cryopyrin-associated periodic reducing mechanical ventilation time Population health with acute respiratory syndromes. It is also under study for treating COVID-19. Some patients and increasing survival in patients with distress syndrome and with COVID-19 develop a maladaptive inflammatory response that can Health care costs acute respiratory distress syndrome hyperinflammation lead to acute lung injury and respiratory insufficiency. Anakinra acts as a (ARDS) competitive antagonist of the cytokine receptor IL-1R1, which drives Might improve overall health and proinflammatory signaling. A study of patients with severe COVID-19- quality of life by reducing related related bilateral pneumonia reported that 25% of patients (n = 52) who health complications and risk for long- received anakinra (200 mg/day on days 1 to 3, 100 mg/day on days 4 to term sequelae 10) required mechanical ventilation or died compared with 73% of patients (n = 44) in a historical control group. A randomized controlled trial Might improve population health (CORIMUNO-ANA) in France found that anakinra did not improve outcomes if mechanical ventilator outcomes in patients with mild to moderate COVID-19 pneumonia. shortages are minimized Multiple studies involving anakinra for treating patients with COVID-19 are Might reduce health care costs related registered at the National Library of Medicine trial registry. However, to length of hospitalization and enrollment in a large French trial (ANACONDA) was suspended after intensive care resources needed excess mortality was observed in patients who received anakinra.

ANG-3777 to treat Some patients with COVID-19 experience severe respiratory distress and Patient outcomes Might improve health outcomes and patients hospitalized multiple organ failure due to the direct effects of viral infection and quality of life by preventing or with COVID-19 indirect effects associated with the body’s response to the virus. ANG-3777 reducing the risk of acute lung and pneumonia is an investigational hepatocyte growth factor (HGF) mimetic that might kidney injury due to COVID-19 mitigate or prevent acute lung or kidney injury caused by COVID-19. HGF pneumonia is purportedly essential for activating the c-Met cascade in response to Might reduce burden on the health acute organ injury, which promotes tissue and organ repair. ANG-3777 was care system by reducing demand on developed to have a longer half-life (3 hours) than that of HGF (less than 5 mechanical ventilators and dialysis minutes) and is being administered as a daily intravenous infusion for 4 devices as well as hospitalization days in clinical trials. A phase 2 randomized trial is comparing ANG-3777 length of stay with placebo in patients (n = 100) hospitalized in Brazil with severe COVID- 19 pneumonia and receiving standard-of-care (SoC) treatment. The primary end point of this trial is the proportion of patients free of the requirement for mechanical ventilation or renal replacement therapy, and primary completion was anticipated in October 2020. If successful, the company plans to conduct clinical trials in the United States.

SECTION 5. TREATMENTS 71

Title Description Possible areas of impact Possible future impacts

Anti-interleukin-6 Some patients with COVID-19 experience an inflammatory condition Patient outcomes Might improve health outcomes by monoclonal antibodies leading to pulmonary dysfunction and cardiovascular events thought to reducing mechanical ventilation time Population health for treating patients contribute to COVID-19-related death. Investigators are studying whether and increasing survival in patients with hospitalized with anti-IL-6 monoclonal antibodies can treat COVID-19 by inhibiting the IL- Health care costs acute respiratory distress severe COVID-19 1/IL-6 pathway thought to be a key driver of this inflammation. Multiple Might improve overall health and trials of commercially available (eg, sarilumab, siltuximab, tocilizumab) and quality of life by reducing related investigational (eg, clazakizumab, levilimab, sirukumab) IL-6 pathway– health complications and risk for long- targeting antibodies are ongoing. Data have been reported from multiple term sequelae randomized controlled trials (RCTs) of tocilizumab for treating patients with COVID-19, including 2020P001159, CORIMUNO-TOCI, COVACTA, Might improve population health EMPACTA, REMAP-CAP, and RCT-TCZ-COVID-19. These trials have outcomes if mechanical ventilator produced variable results and, as of November 2020, NIH COVID-19 shortages are minimized treatment guidelines recommended against the use of tocilizumab outside Might reduce health care costs due of a clinical trial. Roche continues to study tocilizumab in a phase 3 trial in to length of hospitalization or fewer combination with remdesivir. Regarding sarilumab, Sanofi and Regeneron intensive care resources needed have reported that both a US-based trial and an international trial failed to meet their primary end points, and the companies indicated that they have no plans for future trials of sarilumab in COVID-19. However, positive preliminary data on siltuximab for treating patients with COVID-19 were reported in a preprint.

SECTION 5. TREATMENTS 72

Title Description Possible areas of impact Possible future impacts

Auxora to treat severe Auxora (CalciMedica, Inc, San Diego, California) is an investigational, Patient outcomes Might improve patient health COVID-19-associated intravenously administered inhibitor of the calcium release–activated outcomes by decreasing risk of Population health pneumonia calcium (CRAC) channel; it is in clinical development to treat severe thromboembolic COVID-19-related pneumonia. Auxora might protect the cells lining the Health care disparities complications, shortening recovery lungs against damage, increase oxygen saturation, and prevent the release time, and minimizing need for invasive of cytokines (proinflammatory proteins) thought to contribute to mechanical ventilation hyperinflammation and respiratory disease severity in COVID-19. Initial Might improve population health clinical trial data reported in February 2021 suggested Auxora is effective outcomes by decreasing the burden on in lowering blood levels of D-dimer, a key marker of clotting and the health care system inflammation, which is correlated with disease severity and risk of mortality in patients with COVID-19. Data published August 14, 2020, from an open- Might improve understanding of label, randomized portion of an ongoing developer-sponsored phase 2 mitigating hyperinflammation to treat trial showed that patients with severe or critical COVID-19 given Auxora in COVID-19 addition to standard-of-care (SoC) treatment (20 patients) had a median Might increase health disparities if time to recovery of 5 days and a mechanical ventilation rate of 18% Auxora is available in only limited compared with patients receiving SoC treatment alone (10 patients), who quantities after authorization or had a median time to recovery of 12 days and a mechanical ventilation approval for clinical use rate of 50%. The developer began a second phase 2 trial in December 2020 investigating the use of Auxora in 400 patients with critical COVID-19. Its expected primary completion date is in May 2021.

CD24Fc (MK-7110) for CD24Fc (MK-7110) is an investigational recombinant fusion protein under Patient outcomes Might prevent COVID-19 disease treating severe development by OncoImmune and Merck to treat severe COVID-19. progression and/or mortality Health care costs COVID-19 CD24Fc purportedly modulates immune responses through multiple Might decrease the need for and/or mechanisms. First, it purportedly acts as an agonist of Siglec 10, a receptor duration of mechanical ventilation that dampens host immune responses. Second, CD24Fc purportedly binds and blocks the activity of danger-associated molecular patterns, molecules Might cause adverse events related to that can initiate and perpetuate inflammatory responses. CD24Fc is immunomodulation in phase 3 development, and a randomized, placebo-controlled trial studying the safety and efficacy of CD24Fc in 243 hospitalized patients with severe or critical COVID-19 was completed in October 2020. In this trial, patients received CD24Fc or placebo at day 1 and were evaluated for 29 days. Preliminary data from 203 hospitalized participants with COVID- 19 receiving standard care revealed that the addition of CD24Fc improved the likelihood of clinical recovery by 60% compared with placebo and decreased median time to recovery from 10 days to 6 days.

SECTION 5. TREATMENTS 73

Title Description Possible areas of impact Possible future impacts

Convalescent plasma Convalescent plasma (CP) is under study as a COVID-19 treatment based Patient outcomes Might improve health outcomes by for treating patients on the idea that it may contain high levels of coronavirus-neutralizing reducing mechanical ventilation time Population health hospitalized with antibodies that might confer passive immunity to the virus. To generate and increasing survival in patients with COVID-19 CP, plasma is collected from recovered COVID-19 patients by apheresis, Health care costs acute respiratory distress with each donation providing sufficient plasma to treat up to 4 patients of Might improve overall health and matching blood type. On August 23, 2020, FDA issued Emergency Use quality of life by reducing related Authorization (EUA) for CP to treat hospitalized patients with COVID-19, health complications and risk for long- based largely on experience with CP in an FDA expanded access program. term sequelae Among the first 35 322 patients treated in this program, the 7-day mortality rate of patients who received CP within 3 days of diagnosis was Might improve population health reported as 8.7% compared with 11.9% in patients who received CP 4 or outcomes if mechanical ventilator more days after diagnosis. A systematic review that included evidence shortages are minimized from 2 randomized controlled trials (RCTs) of 189 participants indicated Might reduce health care costs if that it remained uncertain whether CP decreases mortality. Since the last length of hospitalization is reduced update to that review, results of 2 additional RCTs (a 464-patient study in or fewer intensive care resources are India and a 333-patient study in Argentina) have been published. Both needed trials failed to demonstrate a difference in mortality between patients who received CP and patients who did not receive CP. An unphased randomized trial that enrolled 160 older adults within 72 hours of onset of mild COVID-19 symptoms found that high-titer CP reduced the relative risk of severe respiratory disease by 48%. FDA has revised the EUA, allowing only high-titer CP and limiting usage to hospitalized patients early in the disease course and to those with impaired humoral immunity.

SECTION 5. TREATMENTS 74

Title Description Possible areas of impact Possible future impacts

CYT107 for treating CYT107 (Revimmune, Inc, Bethesda, Maryland) is a recombinant Patient outcomes Might improve overall health and hospitalized patients therapeutic form of interleukin-7 (IL-7), a key cytokine involved in human quality of life by reducing related Health care costs with COVID-19-related T-cell survival and expansion. The factor purportedly can induce the health complications from lymphopenia proliferation of naïve T cells to help replenish immune cells lost during the immunosuppression course of COVID-19-related cytokine storms and sepsis. T-cell counts are Might reduce health care costs related dramatically reduced during COVID-19 infection, which studies have to length of hospitalization and use of shown has a negative correlation with patient survival. Results from a intensive care resources phase 2 clinical trial that studied IL-7’s ability to restore lymphocyte counts in sepsis patients showed that CYT107 reversed lymphopenia (low levels of lymphocytes) and improved immunity in patients with life-threatening sepsis. An ongoing phase 2 randomized trial (ILIAD-7) is studying the ability of CYT107 to improve clinical outcomes in lymphopenic patients with COVID-19, with an expected primary completion date of October 30, 2021. A total of 48 participants with COVID-19 and absolute lymphocyte counts of fewer than 1000 cells/mm3 are randomly assigned to twice- weekly intramuscular injections of CYT107 (10 μg/kg) or placebo for 3 weeks and checked for immune reconstitution and clinical improvement.

Dociparstat for Dociparstat is a glycosaminoglycan derivative of heparin being Patient outcomes Might improve patient health treating COVID-19 investigated by Chimerix (Durham, North Carolina) as an intravenous outcomes and increase survival Population health treatment for COVID-19 in hospitalized adult patients. Hypercoagulability Might reduce the burden on the health is commonly observed in patients who have COVID-19 and is associated Health care costs care system and mechanical ventilator with worse outcomes. It might be partly due to damage to endothelial shortages cells from infection with SARS-CoV-2. Treatment with anticoagulants such as heparin has been linked to increased survival in patients who have Might decrease health costs associated severe COVID-19. Dociparstat, a derivative of heparin, purportedly reduces with hospitalization and intensive care excessive inflammation, immune cell infiltration, and hypercoagulability resources associated with poor outcomes in severe COVID-19. It can purportedly be Might improve understanding of given at larger doses without the same risk for bleeding as that of heparin. anticoagulation and anti-inflammatory Dociparstat is in a developer-sponsored phase 2/3 clinical trial that intends drugs in the treatment of COVID-19 to enroll more than 500 hospitalized adults who have COVID-19 and acute lung injury requiring supplemental oxygen or noninvasive ventilation. The trial had a primary completion date in February 2021.

SECTION 5. TREATMENTS 75

Title Description Possible areas of impact Possible future impacts

EIDD-2801 for treating EIDD-2801 (Ridgeback Biotherapeutics, Miami, Florida; and Merck, Patient outcomes Might improve patient health COVID-19 Kenilworth, New Jersey) is an antiviral drug being investigated to treat outcomes and increase survival Population health COVID-19. It is an orally bioavailable prodrug of EIDD-1931, a Might improve population health ribonucleoside analog developed to treat respiratory viruses. EIDD-2801 Health care delivery and outcomes if burden on the health care has demonstrated broad-spectrum anti–RNA virus activity in several process system is reduced animal models, including in ferrets, a member of the weasel genus, Health care costs which has been found to transmit the novel coronavirus efficiently. Like Might decrease health care costs remdesivir, another antiviral in development to treat COVID-19, EIDD-2801 associated with hospitalization and targets viral RNA polymerase to block successful viral RNA replication. intensive care resources Preclinical studies suggest that EIDD-2801 might have activity against viral Might provide more convenient dosing RNA polymerase with remdesivir resistance mutations. EIDD-2801 is taken compared with intravenous antivirals, by mouth, which might be more convenient compared with the which might help shift the treatment of intravenous route of remdesivir. Ongoing clinical trials of EIDD-2801 to COVID-19 to the home setting sooner treat COVID-19 include developer-sponsored phase 2 studies in outpatient and inpatient settings, which had primary completion dates expected in January and February 2021, respectively.

SECTION 5. TREATMENTS 76

Title Description Possible areas of impact Possible future impacts

GM-CSF-inhibiting Some patients with COVID-19 experience an inflammatory condition Patient outcomes Might improve health outcomes by monoclonal antibodies leading to pulmonary dysfunction and cardiovascular events thought to reducing mechanical ventilation time Population health for treating COVID-19 contribute to COVID-19-related death. Patients with COVID-19 exhibit and increasing survival in patients with elevated levels of various proinflammatory cytokines, including Health care costs acute respiratory distress granulocyte-macrophage colony-stimulating factor (GM-CSF), which is Might improve overall health and thought to play a key role. Several GM-CSF-inhibiting drugs are being quality of life by reducing related investigated as potential COVID-19 treatments, including gimsilumab, health complications and risk for long- lenzilumab, mavrilimumab, otilimab, and plonmarlimab (TJM2). A term sequelae nonrandomized trial reported that 13 non–mechanically ventilated patients with COVID-19 treated with mavrilimumab demonstrated decreased 28- Might improve population health day mortality (0% versus 27%), decreased time to clinical improvement outcomes if mechanical ventilator (median 8 days versus 19 days), and reduced rates of mechanical shortages are minimized ventilation (8% versus 35%) compared with a 26-patient matched Might reduce health care costs if cohort. Similarly, a nonrandomized trial reported that 12 patients length of hospitalization is reduced hospitalized with COVID-19 and treated with lenzilumab demonstrated and fewer intensive care resources are increased rates of clinical improvement (91.7% versus 81.5%) and needed decreased time to clinical improvement (5 days versus 11 days) compared with a 27-patient matched cohort. Multiple randomized controlled trials (RCTs) of GM-CSF-inhibiting monoclonal antibodies are ongoing, including trials of gimsilumab, lenzilumab, mavrilimumab, and plonmarlimab. Positive interim results from a randomized phase 3 trial indicated that lenzilumab treatment increased recoveries in patients hospitalized with COVID-19 by 37%. Humanigen indicated that it intended to file for Emergency Use Authorization (EUA) for lenzilumab in the first quarter of 2021, pending final trial results.

SECTION 5. TREATMENTS 77

Title Description Possible areas of impact Possible future impacts

Hyperimmune Coronavirus-specific hyperimmune immunoglobulin (H-IG) is a preparation Patient outcomes Might improve patient health immunoglobulin for of purified human immunoglobulins prepared from pooled plasma outcomes and increase survival Population health treatment of collected from a large number of patients who have recovered from Might improve population health COVID-19 infection with SARS-CoV-2. Neutralizing antibodies against coronavirus Health care delivery and outcomes by reducing the burden on present in H-IG might confer passive immunity to the virus and, therefore, process the health care system and reducing could be used as a potential treatment for patients with COVID-19. H-IG Health care disparities the risk of mechanical ventilator has several potential benefits compared with the use of convalescent shortages plasma from single donors, including dose standardization, improved shelf Health care costs life, and higher antibody concentrations. Higher antibody concentrations Might increase the cost of treating allow for lower transfusion volumes, which might protect against certain COVID-19, which could be partially infusion reactions (eg, transfusion-associated circulatory overload). offset by reductions in costs associated Multiple efforts to produce an H-IG product are under way, including with hospitalization and intensive care development programs by the COVIg-19 Plasma Alliance, Emergent resources BioSolutions (Rockville, Maryland), and Grifols SA (Barcelona, Spain). A phase 3 trial of H-IG plus remdesivir compared with placebo plus remdesivir is ongoing, with primary completion expected in July 2021.

Leronlimab for Some patients with COVID-19 experience an inflammatory condition leading Patient outcomes Might improve health outcomes by treating COVID-19 to pulmonary dysfunction and cardiovascular events thought to contribute reducing mechanical ventilation time Population health to COVID-19-related death. The CCL5 (RANTES)-CCR5 signaling axis might and increasing survival in patients with contribute to this hyperinflammatory response by promoting the chemotaxis Health care costs acute respiratory distress (homing and accumulation) of immune cells, thereby amplifying Might improve overall health and inflammatory responses. Leronlimab is an investigational monoclonal quality of life by reducing related antibody that purportedly acts as a C-C chemokine receptor type 5 (CCR5) health complications and risk for long- antagonist, inhibiting CCR5-mediated trafficking of proinflammatory term sequelae immune cells. A study of 10 patients treated with compassionate-care leronlimab found reductions in proinflammatory cytokines (eg, interleukin-6 Might improve population health [IL-6]) and coronavirus in the blood. Additionally, the developer (CytoDyn, outcomes if mechanical ventilator Inc) has announced preliminary data from a randomized phase 2 trial of shortages are minimized leronlimab in 84 patients with mild to moderate COVID-19. An additional Might reduce health care costs if randomized phase 2/3 trial in 390 patients with severe or critical COVID-19 length of hospitalization is reduced had an expected primary completion date in December 2020. Although and fewer intensive care resources are leronlimab is not commercially available, it is being developed as a potential needed treatment for patients with HIV. A Biologic License Application for that indication was submitted to FDA in April 2020; however, the company received a refuse-to-file letter from FDA in July 2020.

SECTION 5. TREATMENTS 78

Title Description Possible areas of impact Possible future impacts

Losartan for treating Losartan, an angiotensin II receptor blocker (ARB), is an FDA-approved Patient outcomes Might reduce illness severity and COVID-19 blood pressure medication being investigated to reduce lung injury and increase survival Population health disease progression in patients who have COVID-19 with or without Might improve population health underlying high blood pressure. ARBs are inhibitors of the renin- Health care disparities outcomes if burden on the health care angiotensin system (RAS), a complex hormone system that regulates blood Health care costs system is reduced pressure and fluid and electrolyte balance. SARS-CoV-2 is thought to disrupt the RAS (specifically through binding to angiotensin-converting Might reduce health care costs if enzyme 2 [ACE2] receptors for cellular entry) and increase inflammation, hospitalization can be avoided, contributing to the various renal, cardiovascular, and immune symptoms hospitalization length is shortened, or seen in COVID-19. Losartan blocks activation of a receptor in the RAS (ie, fewer intensive care resources are angiotensin II type 1) involved in stimulating fibrosis and inflammatory needed processes. It has been shown preclinically to reduce lung inflammation in Might improve understanding of the SARS-CoV (severe acute respiratory syndrome–associated coronavirus) role of the RAS in COVID-19 pathology infection and improve survival in avian influenza H5N1 infection. and ACEIs or ARBs as potential Investigators had concerns that RAS inhibitors might enhance the treatments infectivity of SARS-CoV-2 by increasing the number of cellular surface ACE2 receptors. Results of recent research, published in May 2020 and Might complicate care delivery and June 2020, have not observed that effect. Instead, a lower risk of all-cause adherence for patients with death in patients with hypertension and COVID-19 who take an ARB or hypertension angiotensin-converting enzyme inhibitor (ACEI), another RAS-inhibiting drug, was reported. Multiple ongoing clinical trials in the United States are investigating the use of losartan to treat COVID-19.

SECTION 5. TREATMENTS 79

Title Description Possible areas of impact Possible future impacts

Lowering testosterone Researchers at Columbia University Irving Medical Center report that Patient outcomes Might improve survival and other levels to treat lowering testosterone may reduce the severity or duration of COVID-19. patient health outcomes by reducing Population health coronavirus infection This research shows that SARS-CoV-2 can be prevented from entering the severity of illness human lung cells by interfering with lung cell expression of Health care delivery and Might reduce health care costs if transmembrane serine protease 2 (TMPRSS2), which is required for viral process length of hospitalization is shortened entry. Further, the research shows that androgenic and estrogenic Health care costs or fewer intensive care resources are compounds function as modulators of TMPRSS2 expression. Consequently, needed the US Department of Veterans Affairs launched a phase 2 clinical trial to evaluate the use of a prostate cancer drug, degarelix (sold as Firmagon), Might raise quality-of-life concerns which suppresses testosterone production, to treat hospitalized male based on adverse effects of hormone patients with COVID-19 who are not in intensive care, with primary therapy completion in July 2021. Female patients are not included in the trial Might increase treatment costs, because degarelix might increase the production of TMPRSS2 in females. depending on patients’ insurance More recently, researchers have postulated that, while lowering high levels coverage of testosterone might have protective effects in patients with COVID-19, testosterone levels that are too low might similarly pose risks.

SECTION 5. TREATMENTS 80

Title Description Possible areas of impact Possible future impacts

Machine learning to The coronavirus pandemic has prompted researchers to evaluate whether Population health Might expedite the search for identify drug artificial intelligence (AI) can identify therapeutic agents that might offer approved drugs that could benefit Health care costs candidates to treat benefit in treating COVID-19. Gates and Hamed (Norwich University, patients with COVID-19 if used off- COVID-19 Northfield, Vermont) developed the CovidX Network Algorithm to identify label drugs approved for other indications that might help treat COVID-19 (ie, Might expedite the search for drug repurposing drugs for off-label use). Kowalewski and Ray (University of candidates that could benefit patients California, Riverside) used machine learning techniques to predict drugs’ with COVID-19 effectiveness against COVID-19 from an analysis of 100 000 FDA-approved drugs and registered chemicals and approximately 14 million other Might provide a useful model for rapid commercially available chemicals. They propose that findings could discovery of potential drugs targeting identify FDA-approved drugs suitable for repurposing or short-term emerging pathogens in future approval and other agents that require longer-term study. Piplani et al pandemics identified 84 potential COVID-19 therapeutics among antiviral agents, including simeprevir, sofosbuvir, lopinavir, ritonavir, and remdesivir. Hsieh et al developed a deep graph neural network to identify promising repurposed drugs for treating COVID-19, in an article yet to undergo peer review. They assessed 3635 available drugs used to treat COVID-19, as identified in the Comparative Toxicogenomics Database. Their proposed pipeline prioritized azithromycin, atorvastatin, acetaminophen, and aspirin. They also identified promising drug combinations, including etoposide or mefloquine plus sirolimus, losartan plus ribavirin, and hydroxychloroquine plus melatonin.

SECTION 5. TREATMENTS 81

Title Description Possible areas of impact Possible future impacts

MultiStem for treating Patients with severe COVID-19 can develop acute respiratory distress Patient outcomes Might increase the number of COVID-19-induced syndrome (ARDS), a complication that is associated with a high likelihood ventilator-free days in patients with Health care costs ARDS of death. MultiStem is an investigational cell-based therapy under COVID-19-induced ARDS development by Athersys for the treatment of ARDS. The stem cell product Might reduce death related to COVID- is developed from multipotent adult progenitor cells obtained from the 19-induced ARDS bone marrow of healthy adult donors. These cells are multiplied in culture at the manufacturer’s facility and frozen for later use. The treatment can be Might cause adverse events related to administered without tissue-matching procedures or immunosuppressive cell therapy treatments and purportedly expresses a range of therapeutically relevant proteins and factors that have the potential to reduce inflammation. By decreasing peripheral immune responses to the initial injury, MultiStem purportedly results in less secondary tissue damage and allows for accelerated repair processes. A randomized, double-blind, exploratory clinical trial for treating ARDS found that patients given MultiStem had a lower death rate as well as more ventilator-free and intensive care unit (ICU)–free days compared with patients given placebo. MultiStem is the only cell therapy treatment for ARDS that has Fast Track and Regenerative Medicine Advanced Therapy (RMAT) designation from FDA. MultiStem is being evaluated in a phase 2/3 randomized, placebo-controlled safety and efficacy trial in 400 adults with COVID-19-related ARDS, with primary completion expected in September 2021.

SECTION 5. TREATMENTS 82

Title Description Possible areas of impact Possible future impacts

Nitazoxanide (NT-300) Nitazoxanide, an oral drug with broad-spectrum antiviral properties, is Patient outcomes Might reduce recovery time and risk of to treat mild to being developed as the extended-release formulation NT-300 (Romark progression to severe COVID-19 Population health moderate COVID-19 Laboratories LC) to treat mild to moderate COVID-19. In cell cultures in the Might decrease burden on the health laboratory, nitazoxanide has been found to inhibit the replication of Health care costs care system multiple coronaviruses, including SARS-CoV-2, SARS-CoV (severe acute respiratory syndrome–associated coronavirus), and MERS-CoV (Middle Might improve understanding of East respiratory syndrome caused by coronavirus), as well as other viruses, mitigating hyperinflammation to treat such as those that cause the flu and the common cold. In addition to COVID-19 inhibiting the replication of viruses, nitazoxanide purportedly suppresses Might result in cost savings if the drug the production of various proinflammatory proteins called cytokines. This cost is outweighed by potential health action might treat mild to moderate COVID-19 by moderating an care costs saved with better outcomes, overexaggerated inflammatory response to SARS-CoV-2 (ie, or result in higher costs if the drug is hyperinflammation), which is thought to contribute to severe disease and more expensive than potential health poor outcomes. NT-300 is being investigated in a developer-sponsored care costs saved phase 3 trial (n = 800) that had a primary completion date expected in February 2021. In clinical trials, NT-300 is administered by mouth twice daily for 5 days.

SECTION 5. TREATMENTS 83

Title Description Possible areas of impact Possible future impacts

Proteomics to identify Researchers at the University of California, San Francisco, have developed a Patient outcomes Might speed development of human protein targets protein interaction map for SARS-CoV-2. The map might facilitate new COVID-19 therapeutics from Health care costs for treating COVID-19 repurposing of drugs approved or in development for other indications. approved drugs The team identified 66 human proteins or host factor targets and 69 Might uncover potential compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 treatment targets for new therapeutic preclinical compounds) as potential treatment candidates. Researchers agents identified 2 drug classes with antiviral activity: messenger RNA (mRNA) translation inhibitors (including the investigational cancer drugs zotatifin and ternatin-4) and predicted regulators of the sigma-1 and sigma-2 receptors (including the hormone progesterone, antipsychotic drugs haloperidol and chlorpromazine, antianxiety drug siramesine, and antihistamines clemastine and cloperastine). Researchers suggest these agents could produce new COVID-19 treatments. Chinese Academy of Sciences researchers have created a publicly available web server to explore potential COVID-19 treatments. The web server has 2 goals: to predict protein targets for drugs or compounds observed in clinical or laboratory studies and to identify lead compounds against potential drug targets via molecular docking. University of Virginia (Charlottesville) researchers proposed a computational model to predict protein interactions between novel viruses and humans by using only protein sequence information, dramatically shortening the discovery process compared with conventional techniques.

SECTION 5. TREATMENTS 84

Title Description Possible areas of impact Possible future impacts

SPI-1005 to treat SPI-1005 (Sound Pharmaceuticals, Inc) is an investigational proprietary oral Patient outcomes Might reduce COVID-19 severity and moderate to severe formulation of the organoselenium compound ebselen that is purported progression through dual mechanism Health care delivery and COVID-19 to have anti-inflammatory and antiviral properties and is being of action of antiviral and anti- process investigated to treat moderate to severe COVID-19. Ebselen is a small- inflammatory effects molecule drug that mimics and induces glutathione peroxidase, an Health care costs Might decrease burden on the health antioxidant enzyme found in the inner ear, brain, lung, and kidney. It care system purportedly reduces lung inflammation by decreasing inflammatory oxidants and cytokines. Separately, a study published in April 2020 Might improve understanding of identified ebselen as an inhibitor of the SARS-CoV-2 main protease (Mpro), inhibiting coronavirus replication and an enzyme required to generate viral proteins essential for viral replication, activity and mitigating suggesting it has potential as a targeted antiviral treatment for COVID-19. hyperinflammation to treat COVID-19 Another study published in September 2020 by different researchers Might result in cost savings if the drug echoed computational findings that ebselen has promise against SARS- cost is outweighed by potential health CoV-2. Sound Pharmaceuticals is investigating the use of oral SPI-1005 to care costs saved with better outcomes, treat 120 adults who have moderate or severe COVID-19 in two phase 2 or result in higher costs if the drug is clinical trials with expected primary completion dates in April 2021. more expensive than potential health care costs saved

TD-0903 for treating TD-0903 (Theravance Biopharma, Dublin, Ireland) is an investigational Patient outcomes Might improve patient health acute lung injury in inhaled janus kinase (JAK) inhibitor intended to prevent the progression of outcomes and increase survival Population health COVID-19 acute lung injury to life-threatening acute respiratory distress syndrome Might improve population health (ARDS) in patients with COVID-19. ARDS in COVID-19 is thought to be Health care costs outcomes if it reduces the burden on caused, in part, by a rapid influx of inflammatory proteins called cytokines the health care system and decreases into the lungs (ie, cytokine storm). This causes severe inflammation and the risk of mechanical ventilator impaired oxygen exchange that can result in the need for mechanical shortages ventilation. Intervening early to block cytokine storm in COVID-19 pneumonia might be critical for survival. TD-0903 purportedly broadly Might decrease health costs associated inhibits the activity of JAKs that play a central role in cytokine signaling. It with hospitalization and intensive care is taken in a nebulized form to directly target hyperinflammation in the resources lungs and limit systemic suppression of the immune system. A phase 2 Might improve understanding of JAK study enrolling 222 hospitalized COVID-19 patients is ongoing. Primary inhibitors and/or inhibiting cytokine completion is expected in April 2021. storm in acute respiratory illnesses such as COVID-19

SECTION 5. TREATMENTS 85

Title Description Possible areas of impact Possible future impacts

Tranexamic acid for Tranexamic acid is a commercially available antifibrinolytic protease Patient outcomes Might improve patient health treating COVID-19 inhibitor that is being investigated to treat adults with COVID-19. outcomes and survival Health care delivery and Tranexamic acid, a synthetic analog of the amino acid lysine, inhibits the process Might improve population health conversion of plasminogen to the protease plasmin as well as the activity outcomes by reducing burden on the of plasmin itself. Elevated plasmin is a risk factor for COVID-19 Health care costs health care system susceptibility. Elevated plasmin is thought to induce a hyperfibrinolytic state and contribute to the development of acute respiratory distress Might decrease health care costs if syndrome (ARDS) in COVID-19 patients. Additionally, plasmin could cleave hospitalizations are reduced, the viral spike protein (a step required for viral entry) and, therefore, hospitalization lengths are shortened, elevated plasmin might increase the infectivity and virulence of SARS-CoV- and/or fewer intensive care resources 2. Tranexamic acid might increase the risk of local blood clot formation are needed per patient (thrombosis) when administered alone. Concomitant anticoagulation Might improve understanding of administration might mitigate this risk. Tranexamic acid is in two phase 2 antifibrinolytics used to treat trials for treating adults with COVID-19 in the outpatient setting and the COVID-19 non–intensive care inpatient setting. Additionally, a novel formulation of tranexamic acid, LB1148, is in phase 2 development for hospitalized patients who have COVID-19 with ARDS and lung dysfunction, and has an expected primary completion date in December 2021. Generic tranexamic acid costs as little as $26 for a 30-day supply (650-mg tablets) and is covered by Medicare.

SECTION 5. TREATMENTS 86 Table 5.3. Recently Archived Topics: 4 Topics

Title Description Archive reason(s) based on data review and/or stakeholder ratings and comments

Combination baricitinib and Baricitinib in combination with remdesivir received Emergency Use Authorization (EUA) from Stakeholders reviewing this topic thought that remdesivir to treat FDA on November 19, 2020, to treat hospitalized adults and children with COVID-19 who combination baricitinib and remdesivir is likely to COVID-19 require respiratory support. National Institutes of Health (NIH) COVID-19 treatment be incremental to remdesivir alone. Shortages in guidelines currently recommend its use when corticosteroids cannot be used. Baricitinib plus remdesivir might limit the clinical uptake of this remdesivir is the first combination therapy to receive EUA from FDA for COVID-19. combination therapy. It might be a worthwhile Baricitinib is an oral janus kinase (JAK) inhibitor that is FDA approved to treat moderate to treatment to bridge the gap until more effective severe rheumatoid arthritis. It is intended to reduce inflammation in COVID-19 by blocking a treatments and vaccines are approved and being proinflammatory signaling pathway. Remdesivir is an intravenous antiviral that was FDA widely used but is not likely to have large approved on October 22, 2020, to treat patients hospitalized with COVID-19. The EUA for disruption potential itself. the combination of baricitinib and remdesivir was issued based on data from the Adaptive COVID-19 Treatment Trial (ACTT-2), published December 11, 2020, which demonstrated that patients taking the drug combination, compared with remdesivir alone, experienced improved recovery time (7 versus 8 days, respectively), 30% higher chance for better clinical status at day 15, and decreased risk of death at day 28 (5.1% versus 7.8%). A phase 3 trial, ACTT-4, is ongoing. Based on available dosing information and pricing, up to 14 days of treatment with baricitinib costs about $2200. Based on prescribing information and pricing, up to 10 days of treatment with remdesivir costs about $6100. The cost of a single course of the combined regimen is therefore $8300.

Fenofibrate to treat Fenofibrate, an oral drug in the fibrate class, is FDA approved for lowering cholesterol Stakeholders reviewing this topic thought that, COVID-19 and triglycerides. It is being investigated as a treatment for COVID-19 because of its fat- although fenofibrate is a relatively inexpensive lowering effects. Although COVID-19 is not primarily a metabolic disease, controlling drug with an established safety profile and metabolic parameters (eg, lipids, glucose) is thought to be important for better health promising initial observational data, at this time outcomes in those infected with SARS-CoV-2. Additionally, SARS-CoV-2 infection is thought efficacy data are insufficient to suggest it might to disrupt cellular metabolism in a way that leads to excessive fat buildup, which enables have greater than a moderate impact on patient viral replication. Researchers at Hebrew University in Israel reported preliminary clinical outcomes. findings that patients with COVID-19 taking fibrates demonstrated improved time to recovery and zero mortality, and that patients taking medications that build fats showed greater lung damage and mortality. The researchers are investigating fenofibrate further in a phase 3 trial that has an expected primary completion date in April 2021. An ongoing phase 2 trial in the United States, sponsored by the University of Pennsylvania, has a primary completion date in August 2021. Fenofibrate is available as a generic. Based on available trial information and pricing, a treatment course with fenofibrate for COVID- 19 is estimated to cost $12.

SECTION 5. TREATMENTS 87

Title Description Archive reason(s) based on data review and/or stakeholder ratings and comments

Quellor (XPro1595) for Quellor (XPro1595) is a next-generation tumor necrosis factor (TNF) inhibitor thought to Stakeholders reviewing this topic thought that treating immune-mediated selectively neutralize only soluble TNF (sTNF). sTNF activates immune cells that contribute to the number of currently available COVID-19 complications of COVID-19 acute respiratory distress syndrome (ARDS) , a condition that often leads to the need for treatments, as well as the lack of safety and mechanical ventilation. Currently approved TNF inhibitors are nonselective, blocking both efficacy data for Quellor, portend a low impact sTNF and transmembrane TNF (tmTNF). tmTNF purportedly does not contribute to COVID- potential for this intervention. 19 but does contribute to normal immune function. Quellor purportedly decreases inflammation and inflammatory immune complications related to end–organ dysfunction in the lungs, kidneys, heart, and brain. The treatment purportedly does not cause immunosuppression that is seen in nonselective TNF inhibitors, and it might have beneficial effects in COVID-19 patients with immune-related complications. An ongoing phase 2/3 randomized, placebo-controlled trial is studying Quellor’s ability to prevent the need for mechanical ventilation in 366 patients hospitalized with pulmonary complications of COVID- 19. Patients will receive subcutaneously injected Quellor plus standard care, with a second dose of Quellor given a week later, or placebo and standard care. The trial had an estimated completion date of February 2021.

Recombinant plasma An investigational anti-inflammatory treatment, rhu-pGSN is under study for treating severe Stakeholders reviewing this topic agreed that gelsolin (rhu-pGSN) for COVID-19 pneumonia. Gelsolin is a naturally occurring protein that acts through multiple this treatment is being evaluated in a small trial treating COVID-19 mechanisms to modulate host inflammatory reactions and enhance immune clearance of and there are no data to support its success. pneumonia microbes and toxins. The protein is abundant in healthy individuals, but severe injury and Because the intervention is also unlikely to be infection deplete it, which may contribute to excessive inflammatory responses, organ used alone, its disruption potential is expected damage, and death. Gelsolin depletion has been associated with poor outcomes in COVID- to be an incremental change to current care. 19, and supplementing depleted levels of gelsolin with rhu-pGSN might help mitigate the debilitating effects of cytokine storm and severe inflammation seen in COVID-19 patients. A phase 2 randomized controlled trial (RCT) is evaluating rhu-pGSN compared with placebo in adults with COVID-19 pneumonia (n = 60), with primary completion expected in May 2021. Patients will be given 3 doses of rhu-pGSN, along with standard-of-care (SoC) treatment, to evaluate its efficacy (survival without organ failure on day 14), safety, and tolerability.

SECTION 5. TREATMENTS 88 Section 6. Vaccines and Prophylaxis: 9 Topics

Table 6.1. Topics Added Since Last Status Report: 4 Topics

Title Description Possible areas of impact Possible future impacts

CoVLP vaccine for CoVLP is a recombinant virus-like particle (VLP) Patient outcomes Might reduce coronavirus infection risk preventing vaccine being developed by Medicago and GSK against the novel and improve patient health outcomes Population health SARS-CoV-2 infection coronavirus. The vaccine mimics the shape and dimensions of the virus, Might reduce rates of severe infections displaying the SARS-CoV-2 spike protein on the surface of VLPs Clinician and/or caregiver and, thereby, reduce costs associated (assemblies of viral proteins that present antigens in a manner similar to safety with their treatment the native virus, but do not incorporate genetic material and, therefore, are Health care delivery and noninfectious). By presenting viral antigens in a manner similar to the virus, Might allow relaxation of social process VLPs purportedly elicit a balanced immune response that is both antibody distancing protocols and cell mediated. CoVLP is in a phase 2/3 randomized trial in 30 918 Health care disparities Might increase knowledge of the adults with an estimated completion of December 2021. Participants will Health care costs effectiveness of plant-based receive 2 doses of placebo or 3.75 µg of CoVLP with AS03 adjuvant given manufacturing technology 21 days apart. Results from a phase 1 randomized trial found that almost all of the patients receiving both doses of adjuvanted CoVLP developed Might have vaccine shortages, if neutralizing antibody responses that were 10- to 50-fold higher than levels effective, due to limited production seen in individuals recovering from COVID-19 infection. Pain at the capacity injection site, headache, and fatigue were the most common reactions, and most adverse events were mild to moderate and of short duration.

SECTION 6. VACCINES AND PROPHYLAXIS 89

Title Description Possible areas of impact Possible future impacts

JNJ-78436735 JNJ-78436735 (Ad26.COV2-S; Johnson & Johnson) is a recombinant, Patient outcomes Might reduce coronavirus infection risk (Ad26.COV2-S) attenuated adenovirus vector vaccine that is purported to generate a and improve patient health outcomes Population health vaccine for preventing strong immune response from a single dose without replicating (avoiding Might reduce the cost of treating coronavirus infection an active infection from the vaccine). The vector was modified to contain Clinician and/or caregiver severe infections the gene for the SARS-CoV-2 spike protein, which is expressed on the safety surface of SARS-CoV-2 and is responsible for viral fusion and entry. JNJ- Might relax social distancing protocols Health care delivery and 78436735 purportedly enters the cytosol of antigen-presenting cells and process Might not provide the level of induces the expression of viral spike protein, which can induce host protection hoped for due to the immune responses to prevent future infection. The vaccine is part of the Health care disparities accelerated approval process US government’s Operation Warp Speed. A company press release Health care costs announced that, in the randomized phase 3 ENSEMBLE trial enrolling Might have undiscovered adverse 44 325 volunteers, JNJ-78436735 was 66% effective at preventing events due to the accelerated approval moderate to severe disease and 85% effective at preventing severe disease process 28 days after a single dose of vaccine, with no significant safety Might have vaccine shortages, if concerns. Efficacy in preventing moderate to severe disease across effective, due to limited production geographic regions was 72% in the United States, 66% in Latin America, capacity and 57% in South Africa. A 2-dose protocol is also being studied in the phase 3 ENSEMBLE 2 trial, with primary completion expected in May 2022. JNJ-78436735 was granted Emergency Use Authorization (EUA) by FDA on February 27, 2021. The company plans to manufacture 100 million doses for the United States by the end of June 2021.

SECTION 6. VACCINES AND PROPHYLAXIS 90

Title Description Possible areas of impact Possible future impacts

Monoclonal Cellular entry of SARS-CoV-2 depends on an interaction between the viral Patient outcomes Might improve individual health antibodies targeting surface spike protein and the cell surface protein angiotensin-converting outcomes by reducing the risk or Population health SARS-CoV-2 spike enzyme 2 (ACE2). Monoclonal antibodies targeting the spike protein severity of SARS-CoV-2 infection protein receptor receptor-binding domain (RBD) might interfere with this interaction and Clinician and/or caregiver Might improve frontline health care binding domain for are being investigated for their ability to prevent SARS-CoV-2 infection in safety worker and/or patient safety in the preventing COVID-19 asymptomatic patients with known SARS-CoV-2 exposure. These virus- Health care delivery and health care setting neutralizing antibodies might provide short-term, passive immunity process against SARS-CoV-2, potentially preventing or limiting viral infection. Might limit the extent of SARS-CoV-2 These antibodies would likely be used in vulnerable populations such as Health care disparities outbreaks in workplace or residential individuals with known exposure to SARS-CoV-2-infected individuals. settings Health care costs Neutralizing antibodies in development include single monoclonal Might increase health disparities based antibodies and cocktails containing 2 or more monoclonal antibodies that on socioeconomic status due to likely bind nonoverlapping RBD epitopes. A phase 3 trial is assessing high cost Regeneron’s antibody cocktail REGN-COV2 compared with placebo in 2450 asymptomatic, healthy adults in household contact with a SARS-CoV- 2-positive individual. Positive interim data on REGN-COV2 reported that passive vaccination resulted in 100% prevention of symptomatic infection and roughly 50% lower overall rates of infection (symptomatic and asymptomatic). The phase 3 BLAZE-2 trial is assessing Lilly/Abcellera’s antibody LY-CoV555 compared with placebo in 5000 skilled nursing and assisted-living facility residents and staff. The phase 3 PROVENT and STORM CHASER trials are assessing AstraZeneca’s antibody cocktail AZD7442 for preexposure and postexposure prophylaxis, respectively.

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Title Description Possible areas of impact Possible future impacts

NVX-CoV2373 vaccine NVX-CoV2373 is a recombinant nanoparticle vaccine in development by Patient outcomes Might reduce coronavirus infection risk for preventing SARS- Novavax that purportedly generates a protective immune response against and improve patient health outcomes Population health CoV-2 infection SARS-CoV-2. The vaccine consists of a full-length SARS-CoV-2 spike Might reduce costs associated protein, which is essential for host receptor binding, viral fusion, and viral Clinician and/or caregiver with treating severe infections entry and, therefore, represents a rational immunogen with which to safety develop a protective immune response. NVX-CoV2373 may be Might relax social distancing protocols Health care delivery and coadministered with Novavax’s proprietary Matrix-M1 adjuvant to enhance process Might have undiscovered adverse immune responses. Primary efficacy data announced through a company events due to the accelerated approval press release of a phase 3 randomized trial involving 15 000 adults in the Health care disparities process United Kingdom found that the vaccine was 89.3% effective in preventing Health care costs mild to severe COVID-19 occurring at least 7 days after the second Might have vaccine shortages, if vaccination. More than 50% of cases in the analysis were attributed to the effective, due to limited production UK variant. Severe adverse events purportedly occurred at low levels and capacity were balanced between vaccine and placebo groups. In a South African phase 2b trial, the vaccine was 60% effective in preventing mild to severe COVID-19. A phase 3 randomized US trial is enrolling 30 000 participants, with primary completion expected in March 2021. The vaccine is part of Operation Warp Speed, and the manufacturer announced plans to produce up to 150 million doses per month globally by May or June 2021. Novavax has begun a rolling review process with FDA for authorization of NVX-CoV2373.

SECTION 6. VACCINES AND PROPHYLAXIS 92 Table 6.2. Currently Monitored Topics: 5 Topics

Title Description Possible areas of impact Possible future impacts

ARCT-021 vaccine for ARCT-021 (Arcturus Therapeutics) is a lipid nanoparticle–encapsulated Patient outcomes Might reduce coronavirus infection risk preventing messenger RNA (mRNA) vaccine that encodes the viral spike protein and improve patient health outcomes Population health SARS-CoV-2 infection responsible for receptor binding and cellular entry. The vaccine Might reduce strain on vaccine supply purportedly enters host antigen-presenting cells and induces expression of Clinician and/or caregiver chain the viral spike protein, which acts to elicit a host immune response against safety the virus to prevent future infection. The mRNA component of the vaccine Might reduce the cost of treating Health care delivery and is self-amplifying, which purportedly increases immunogenicity. Interim severe infections process study results from the phase 1/2 trial in 106 participants given either 1 or 2 Might relax social distancing protocols doses of ARCT-021 (1 to 10 μg per injection) or placebo showed that Health care disparities participants receiving doses in the range of 5 to 7.5 μg achieved serum Might improve understanding of Health care costs neutralizing antibody levels similar to those in patients who recovered mRNA vaccine technologies from COVID-19. The manufacturer has chosen the 7.5-μg dose to be advanced into later-stage clinical trials. ARCT-021 is in phase 2 development with primary completion expected in April 2022. The randomized, placebo-controlled trial will evaluate the safety and efficacy of ARCT-021 in 600 healthy adults. Due to the low dose of vaccine required to induce immune responses, the manufacturer plans to be able to produce hundreds of millions of doses in 2021, if approved by FDA.

SECTION 6. VACCINES AND PROPHYLAXIS 93

Title Description Possible areas of impact Possible future impacts

AZD1222 (ChAdOx1 AZD1222 (ChAdOx1 nCoV-19) is a recombinant, attenuated adenovirus Patient outcomes Might reduce coronavirus infection risk nCoV-19) vaccine for vector vaccine in development by AstraZeneca (licensed from the and improve patient health outcomes Population health preventing University of Oxford) that is purported to generate a strong immune Might reduce the cost of treating SARS-CoV-2 infection response from 2 doses without replicating (avoiding an active infection Clinician and/or caregiver severe infections from the vaccine). The modified vector contains the gene for the SARS- safety CoV-2 spike protein, which is expressed on the surface of the Might relax social distancing protocols Health care delivery and coronavirus and is responsible for viral fusion and entry. AZD1222 process Might not provide the level of purportedly enters the cytosol of antigen-presenting cells and induces the protection hoped for due to the expression of viral spike protein, which can induce host immune responses Health care disparities accelerated approval process to prevent future infection. The vaccine is part of the US government’s Health care costs Operation Warp Speed. AZD1222 is in a phase 3 trial in 40 000 adults, with Might have undiscovered adverse primary completion expected on March 23, 2021. Interim results from the events due to the accelerated approval phase 2/3 trials of AZD1222 in the United Kingdom and Brazil stated that process AZD1222 was 90% effective in preventing COVID-19 in participants given a Might have vaccine shortages, if half dose followed by a full dose at least 1 month later. Vaccine efficacy effective, due to limited production was 62.1% when 2 full doses were given at least 1 month apart. Vaccine capacity efficacy against the new B.1.1.7 variant seen in the United Kingdom was 74.9% after 2 doses. A separate trial found that efficacy was significantly lowered to 10.4% against the B.1.351 variant seen in South Africa.

SECTION 6. VACCINES AND PROPHYLAXIS 94

Title Description Possible areas of impact Possible future impacts

BNT162 mRNA Pfizer and BioNTech have partnered to develop and manufacture the Patient outcomes Might reduce coronavirus infection risk vaccines for Pfizer-BioNTech COVID-19 vaccine (BNT162b2), a lipid nanoparticle– and improve patient health outcomes Population health preventing encapsulated messenger RNA (mRNA) vaccine that encodes the viral spike Might reduce the cost of treating SARS-CoV-2 infection protein. This protein is expressed on the virus surface and is responsible Clinician and/or caregiver severe infections for receptor binding and cellular entry. mRNA vaccines purportedly enter safety the cytosol of antigen-presenting cells and induce the expression of viral Might relax social distancing protocols Health care delivery and proteins that can elicit host immune responses to prevent future infection. process Might not provide the level of The vaccine is part of the US government’s Operation Warp Speed, and the protection hoped for due to the manufacturers expect to produce 200 million doses by July 31, 2021. The Health care disparities accelerated approval process vaccine is being investigated at a 30-μg dose in a phase 2/3 trial in 43 998 Health care costs healthy adults, with estimated completion in August 2021. A safety and Might have undiscovered adverse efficacy analysis of the phase 2/3 trial data found that the vaccine was 95% events due to the accelerated approval effective in preventing COVID-19. The analysis also reported that the process vaccine was well tolerated across all populations, with the most common Might have vaccine shortages, if adverse events being fatigue and headache, experienced at a frequency of effective, due to limited production 3.8% and 2%, respectively. A retrospective cohort study from Israel of 596 capacity 618 vaccinated people found that estimated vaccine efficacy against documented infection at days 14 through 20 after the first dose or at 7 or more days after the second dose was 46% and 92%, respectively. The Pfizer-BioNTech vaccine was granted Emergency Use Authorization (EUA) by FDA on December 11, 2020. The US government has purchased 300 million doses of the vaccine.

SECTION 6. VACCINES AND PROPHYLAXIS 95

Title Description Possible areas of impact Possible future impacts

mRNA-1273 vaccine The Moderna COVID-19 vaccine (mRNA-1273, Moderna, Cambridge, Patient outcomes Might reduce coronavirus infection risk for preventing Massachusetts) is a lipid nanoparticle–encapsulated messenger RNA (mRNA) and improve patient health outcomes Population health SARS-CoV-2 infection vaccine against coronavirus. It encodes a prefusion stabilized form of the Might reduce the cost of treating spike protein expressed on the surface of the virus, which is responsible for Clinician and/or caregiver severe infections viral fusion and entry into cells. The mRNA vaccine purportedly enters the safety cytosol of antigen-presenting cells and induces the expression of viral Might relax social distancing protocols Health care delivery and proteins that can induce host immune responses to prevent future infection. process Might not provide the level of On May 12, 2020, FDA granted the vaccine Fast Track designation. The protection hoped for due to the Moderna vaccine is in phase 3 development in 30 000 adults, with primary Health care disparities accelerated approval process completion expected in October 2022. Primary efficacy data from the phase Health care costs 3 randomized trial, announced through a company press release, found that, Might have undiscovered adverse of the 196 confirmed cases of COVID-19 included in the analysis, 185 cases events due to the accelerated approval of COVID-19 were observed in the placebo group versus 11 cases observed process in the vaccine group, resulting in a point estimate of vaccine efficacy of Might have vaccine shortages, if 94.1%. There were 30 severe cases of COVID-19, all of which occurred in the effective, due to limited production placebo group, leading to a point estimate of vaccine efficacy of 100% capacity against severe COVID-19. Moderna COVID-19 Vaccine was granted Emergency Use Authorization (EUA) by FDA on December 18, 2020.

SECTION 6. VACCINES AND PROPHYLAXIS 96

Title Description Possible areas of impact Possible future impacts

Sanofi-GSK SARS- The Sanofi-GSK SARS-CoV-2 vaccine is an adjuvanted, recombinant Patient outcomes Might reduce coronavirus infection risk CoV-2 vaccine for protein–based vaccine that is intended to generate a protective immune and improve patient health outcomes Population health preventing response against SARS-CoV-2. The vaccine consists of a recombinant Might reduce the cost of treating SARS-CoV-2 infection SARS-CoV-2 spike protein, which is expressed on the surface of SARS- Clinician and/or caregiver severe infections CoV-2 and is responsible for viral fusion and entry. The vaccine is expected safety to engage the immune system in a manner similar to that of other Might relax social distancing protocols Health care delivery and recombinant protein vaccines (eg, hepatitis B vaccine, human process Might not provide the level of papillomavirus vaccine). The recombinant protein vaccine is formulated protection hoped for due to the with an adjuvant intended to boost the immune response to the vaccine, Health care disparities accelerated approval process thereby requiring less antigen to stimulate a response. The vaccine is part Health care costs of the US government’s Operation Warp Speed and is in a phase 1/2 Might have undiscovered adverse randomized trial in 440 adults with an estimated completion of events due to the accelerated approval November 2021. Due to inadequate results in older adults, caused by a process vaccine formulation error in the phase 1/2 trial, the company has pushed Might have vaccine shortages, if back its target date of a request for regulatory approval to the second half effective, due to limited production of 2021. Unlike vaccines further in development that are based on capacity messenger RNA (mRNA) platforms and need to be kept frozen before use, the Sanofi-GSK vaccine is intended to be stable in liquid form at Might reduce the burden on the cold refrigerator temperatures. storage chain required for vaccine distribution

SECTION 6. VACCINES AND PROPHYLAXIS 97

Appendix. Abbreviations and Acronyms

ACE2 angiotensin-converting enzyme 2 ACEI angiotensin-converting enzyme inhibitor ADHS Arizona Department of Health Services AI artificial intelligence ARB angiotensin II receptor blocker ARDS acute respiratory distress syndrome BARDA Biomedical Advanced Research and Development Authority CCL5 (RANTES)-CCR5 C-C chemokine ligand 5 (regulated upon activation, normal T-cell expressed, and secreted)-C-C chemokine receptor type 5 CDC Centers for Disease Control and Prevention CLIA Certified Laboratory Improvement Amendments of 1988 COVID-19 coronavirus disease 2019 CP convalescent plasma CRAC calcium release–activated calcium CRISPR clustered regularly interspaced short palindromic repeats CT computed tomography EAP expanded access protocol DVT deep vein thrombosis ELISA enzyme-linked immunosorbent assay EPA US Environmental Protection Agency EUA Emergency Use Authorization FDA US Food and Drug Administration FIA fluorescent immunoassay GM-CSF granulocyte-macrophage colony-stimulating factor HCHSS Health Care Horizon Scanning System HFNC high-flow nasal cannula HGF hepatocyte growth factor

Appendix. Abbreviations and Acronyms 98

H-IG hyperimmune immunoglobulin ICU intensive care unit IFN interferon IFNλ interferon lambda IL-1/IL-6 interleukin-1/interleukin-6 IL-1R1 interleukin-1 receptor type I IL-6 interleukin-6 IL-7 interleukin-7 LAMP loop-mediated isothermal amplification JAK janus kinase MERS-CoV Middle East respiratory syndrome caused by coronavirus Mpro SARS-CoV-2 main protease mRNA messenger RNA N95 not resistant to oil mists, filters at least 95% of 0.3 micrometer droplets NASEM National Academies of Sciences, Engineering, and Medicine NAT nucleic acid–based test NGS next-generation sequencing NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health NPA negative percentage agreement PCORI Patient-Centered Outcomes Research Institute PCR polymerase chain reaction PE pulmonary embolism POC point-of-care PPA positive percentage agreement PPE personal protective equipment RADx Rapid Acceleration of Diagnostics RADx-rad Rapid Acceleration of Diagnostics Radical RAS renin-angiotensin system

Appendix. Abbreviations and Acronyms 99

RBD receptor-binding domain RCT randomized controlled trial rhu-pGSN recombinant plasma gelsolin RMAT Regenerative Medicine Advanced Therapy RT-PCR reverse transcription polymerase chain reaction SARS severe acute respiratory syndrome SARS-CoV severe acute respiratory syndrome–associated coronavirus SARS-CoV-2 severe acute respiratory syndrome coronavirus 2; the virus that causes COVID-19 SNRI serotonin-norepinephrine reuptake inhibitor SoC standard of care SSRI selective serotonin reuptake inhibitor sTNF soluble tumor necrosis factor TF tissue factor TMPRSS2 transmembrane serine protease 2 tmTNF transmembrane tumor necrosis factor TNF tumor necrosis factor VIP vasoactive intestinal peptide VLP virus-like particle VAERS Vaccine Adverse Event Reporting System WHO World Health Organization

Appendix. Abbreviations and Acronyms 100