PCORI Health Care Horizon Scanning System: Horizon Scanning COVID-19 Supplement Status Report Volume 2, Issue 1

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 Prital Patel, MPH Donna Beales, MLIS Eloise DeHaan, BS Eileen Erinoff, MSLIS Madison Kimball, MS Maria Middleton, MPH Melinda Rossi, BA Diane Robertson, BA Kelley Tipton, MPH Rosemary Walker, MLIS Andrew Furman, MD, MMM, FACEP

January 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 1. Patient-Centered Outcomes Research Institute; January 2021. Prepared by ECRI under Contract No. MSA-HORIZSCAN-ECRI-ENG-2018.7.12.

HORIZON SCANNING SUPPLEMENT STATUS REPORT ● JANUARY 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 to have high impact on 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 ● JANUARY 2021 ii

Contents

Introduction ...... 1 Section 1. Devices: 10 Topics ...... 5 Table 1.1. Topics Added Since Last Status Report: 1 Topic ...... 5 Table 1.2. Currently Monitored Topics: 7 Topics ...... 6 Table 1.3. Recently Archived Topics: 2 Topics ...... 13 Section 2. Identifiable Risk Factors and Prognostic Indicators: 7 Topics ...... 14 Table 2.1. Topics Added Since Last Status Report: 1 Topic ...... 14 Table 2.2. Currently Monitored Topics: 2 Topics ...... 15 Table 2.3. Recently Archived Topics: 4 Topics ...... 17 Section 3. Screening and Diagnostics: 22 Topics ...... 21 Table 3.1. Topics Added Since Last Status Report: 4 Topics...... 21 Table 3.2. Currently Monitored Topics: 13 Topics ...... 25 Table 3.3. Recently Archived Topics: 5 Topics ...... 38 Section 4. Systems and Management: 15 Topics ...... 41 Table 4.1. Topics Added Since Last Status Report: 4 Topics...... 41 Table 4.2. Currently Monitored Topics: 8 Topics ...... 45 Table 4.3. Recently Archived Topics: 3 Topics ...... 51 Section 5. Treatments: 39 Topics ...... 53 Table 5.1. Topics Added Since Last Status Report: 4 Topics...... 53 Table 5.2. Currently Monitored Topics: 24 Topics ...... 57 Table 5.3. Recently Archived Topics: 11 Topics ...... 77 Section 6. Vaccines and Prophylaxis: 9 Topics ...... 84 Table 6.1. Topics Added Since Last Status Report: 1 Topic ...... 84 Table 6.2. Currently Monitored Topics: 7 Topics ...... 85 Table 6.3. Recently Archived Topics: 1 Topic ...... 92 Appendix. Abbreviations and Acronyms ...... 93

HORIZON SCANNING SUPPLEMENT STATUS REPORT ● JANUARY 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 potential to have high impact on 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, or archived), then no table will be included for that category in that section. Tables for newly added and currently monitored topics summarize information in each row, as shown in the following columns: Title, Description, Possible areas of impact, and Possible future impacts. Tables of archived topics summarize information in each row, as shown 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 represents prospective views of ECRI Horizon Scanning and has 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 claims, where it might have impact and what its possible future impacts may 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 in this report. 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 ● JANUARY 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; they then categorize the leads 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 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-person 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 review 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 have an 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-person 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 December 16, 2020, review of about 3800 information leads has led to the identification and selection of more than 160 COVID-19-related topics. After subjecting the potential topics to our inclusion criteria and nomination process, 102 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 102 topics, included in this Status Report, are distributed across the 6 content areas as follows (also see Figure 1): • Devices: 10 topics (10%) • Identifiable risk factors and prognostic indicators: 7 topics (7%) • Screening and diagnostics: 22 topics (22%) • Systems and management: 15 topics (15%) • Treatments: 39 topics (38%) • Vaccines and prophylaxis: 9 topics (9%) Note: Total does not equal 100% because of rounding.

Figure 1. Percentage of Topics by Content Area

HORIZON SCANNING SUPPLEMENT STATUS REPORT ● JANUARY 2021 4

Section 1. Devices: 10 Topics

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

Title Description Possible areas of impact Possible future impacts

External laser therapy for Pneumonia in patients with COVID-19 can severely damage lung Patient outcomes Might improve patient outcomes by treating COVID-19 tissue. 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 pneumonia safety may help resolve COVID-19 pneumonia. The treatment, dubbed Might reduce costs if patients can be photobiomodulation, delivers low-level laser energy to the lungs Health care delivery and discharged sooner through the back, with the patient lying face down. The process treatment purportedly starts a cascade of molecular reactions that Might expose more health care staff Health care costs improve cellular function and promote natural healing. The research to infection risk if bedside lasers team reported that one of the first patients treated in a pilot study require specially trained personnel to showed improved oxygenation, reduced inflammatory markers, and operate 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 5

Table 1.2. Currently Monitored Topics: 7 Topics

Title Description Possible areas of impact Possible future impacts

Decontamination systems Rapidly depleted supplies of N95 respirators for health care personnel Clinician and/or caregiver Might reduce shortages of N95 for reprocessing of single- have prompted several manufacturers to seek Emergency Use safety respirators for health care personnel use N95 respirators Authorization (EUA) from FDA for systems that purportedly Health care delivery and Might cost less than disposing of decontaminate N95 respirators designed for single use, allowing them process single-use respirators and purchasing to be reused safely. A systematic review found that relatively few new respirators at inflated costs recent studies have assessed the safety and effectiveness of N95 Health care costs during supply shortages respirator decontamination, and most available studies have examined the use of ultraviolet radiation for decontamination, among 21 Might raise safety concerns among different decontamination methods. As of December 9, 2020, FDA had health care personnel if subsequent granted 13 EUAs for the use of N95 respirator decontamination issues with respirator reprocessing systems during the COVID-19 outbreak. These systems typically arise employ vapor hydrogen peroxide or steam for decontamination of compatible N95 respirators that may be contaminated with SARS- CoV-2 (the virus that causes COVID-19) or other pathogenic 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.

SECTION 1. DEVICES 6

Title Description Possible areas of impact Possible future impacts

Extracorporeal blood Early available data suggest that a major contributor to poor outcomes Patient outcomes Might improve patient outcomes by filtration to treat COVID-19 in patients with COVID-19 infection is a cytokine storm, an overly avoiding or lessening severity of Health care delivery and aggressive immune response to the pathogen that can damage cytokine storm process healthy tissue. Removing inflammatory mediators from patients Might require additional staff through an external blood filtering circuit has been proposed to lessen experienced with extracorporeal or prevent the cytokine storm. As of December 9, 2020, FDA had blood filtration procedures granted Emergency Use Authorization (EUA) to 4 manufacturers of extracorporeal blood filtration devices for use during the COVID-19 Might increase treatment complexity pandemic. When used with appropriate systems (eg, apheresis and necessitate additional patient systems, continuous renal replacement therapy systems), these devices monitoring to quickly identify purportedly remove inflammatory cytokines and, depending on the hematologic complications specific filter, pathogens from patients’ blood. Extracorporeal blood 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 7

Title Description Possible areas of impact Possible future impacts

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

SECTION 1. DEVICES 8

Title Description Possible areas of impact Possible future impacts

Negative-pressure tents to Negative-pressure rooms can contain the spread of airborne Clinician and/or caregiver Might increase the availability of limit airborne transmission pathogens, but COVID-19 case volume can overload this resource. safety negative-pressure environments to of coronavirus Portable negative-pressure tents might reduce the need for negative- enhance protection for frontline Health care delivery and pressure rooms, decrease airborne transmission risk to health care health care providers process providers, and increase patient throughput. Compact tents are placed Might reduce treatment costs of over the patient’s head and shoulders. Larger designs enclose the Health care costs providing negative-pressure entire patient bed. Tents are constructed of either clear rigid plastic or environments compared with clear soft plastic over reusable frames. Providers reach patients standard negative-pressure rooms through hand-access ports or slits in the walls. A vacuum hose connected to the hospital air-evacuation system creates the negative- pressure environment. As of December 9, 2020, FDA had granted Emergency Use Authorization (EUA) for 5 negative-pressure tents—3 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 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 an EUA.

SECTION 1. DEVICES 9

Title Description Possible areas of impact Possible future impacts

Nickel foam air filter to According to the US Environmental Protection Agency (EPA), indoor air Patient outcomes Might increase safety of indoor reduce the risk of is about 2 to 100 times more polluted than outdoor air because of the spaces by reducing circulation of Population health coronavirus transmission continuous circulation of particulates and bioaerosols (airborne airborne coronavirus, potentially particles of microbial, animal, or plant origin) within indoor spaces. Clinician and/or caregiver reducing risk of transmission in With the reopening of schools and businesses during the COVID-19 safety businesses, schools, and other pandemic, new methods of improving indoor air quality are needed. enclosed environments Health care costs Researchers at the University of Houston and collaborators developed Might increase risk of COVID-19 an air filter intended to remove airborne biothreats, including transmission if people stop following coronavirus. The proposed use of the filter is in air handling systems public health guidance (eg, social for central air conditioning units; however, researchers envision other distancing) owing to installation of uses, such as mobile personal air-purification devices to yield clean these air filters 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. Manufacturer Integrated Viral Protection (Houston, Texas) reports its air filtration systems have already been installed in elementary schools in Texas and Florida and in some colleges, restaurants, and gyms in Texas.

SECTION 1. DEVICES 10

Title Description Possible areas of impact Possible future impacts

Reusable silicone respirators Shortages of N95 respirators can increase risk of COVID-19 infection Clinician and/or caregiver Might help alleviate shortages of to protect against COVID- for frontline personnel. Massachusetts Institute of Technology safety single-use N95 respirators for health 19 infection researchers have designed a reusable filtering facepiece respirator as care providers and emergency Health care costs an alternative to single-use N95 respirators. The new silicone-based services responders during surges in design purportedly can be mass produced at a relatively low cost with COVID-19 cases standard injection molding manufacturing. The reusable mask, a tight- Might allow simpler reprocessing of fitting, elastomeric respirator with a bidirectional filter, can be used respirators compared with that sterilized and reused multiple times while retaining its elasticity. The of conventional single-use N95 single-use filter inserts are replaced during decontamination respirators, which must meet certain reprocessing. Based on early user feedback, researchers redesigned eligibility requirements for safe the device, now called the transparent, elastomeric, adaptable, long- decontamination and reuse lasting (TEAL) respirator, to improve fit and increase visibility of the user’s mouth and facial expressions. In an evaluation of TEAL Might help reduce personal respirators among 47 physicians, nurses, and technicians, users rated protective equipment (PPE) supply the following parameters as good to excellent: fit, 90%; breathability, costs if reusable respirators can be 77.5%; and ease of filter exchange, 95%. Respirators retained elasticity mass produced with standard and fit after multiple decontamination methods, including 100 cycles manufacturing techniques of autoclaving, microwaving, ultraviolet 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 an Emergency Use Authorization (EUA) from FDA for the TEAL respirator, possibly by December 31, 2020.

SECTION 1. DEVICES 11

Title Description Possible areas of impact Possible future impacts

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

SECTION 1. DEVICES 12

Table 1.3. Recently Archived Topics: 2 Topics

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

Low-dose radiation to treat The global resurgence of severe COVID-19 has increased interest in new therapeutic Stakeholders reviewing this topic judged it to COVID-19 pneumonia approaches. Low-dose radiation therapy (LDRT) is one approach under study to have low disruptive potential. Early data reflect a treat COVID-19-related pneumonia. Researchers theorize LDRT might dampen immune very small patient group without a control system hyperactivation that can severely damage lung tissue in patients with COVID-19. As group. Localized radiation might control lung of mid-November 2020, multiple trials investigating LDRT to treat COVID-19-related inflammation but would be unlikely to reduce pneumonia were registered in the National Clinical Trials database. In September systemic inflammation, limiting its effectiveness. 2020, Emory University (Atlanta, Georgia) researchers reported on their first 5 oxygen- The long-term cancer risk from radiation in dependent patients treated with LDRT in the phase 1 through 2 RESCUE 1-19 trial. Median younger patients suggests this treatment will be patient age was 90 years, and 4 were nursing home residents with multiple coexisting used only as a last resort in a very limited patient conditions. Patients received a single 1.5-Gray dose to both lungs over about 10 to 15 population. minutes. Researchers weaned 3 of 5 patients from supplemental oxygen to room air within 24 hours, with a fourth weaned after 96 hours. Consciousness measured by median score on the Glasgow Coma Scale improved from 10 to 14. Mean time to clinical recovery was 35 hours. Researchers reported no acute toxic effects from LDRT. Emory researchers concluded their initial results support further trials of LDRT to treat COVID-19-related pneumonia. One concern with this approach is the potential risk of cancers arising from radiation exposure. In one analysis, the lifetime risk of cancer from LDRT for treating COVID-19 was estimated to range from 4.9% for females 20 years of age to 0.29% for males 80 years of age.

Robotic remote control of Mechanical ventilators supporting patients with COVID-19 may need multiple adjustments Stakeholders reviewing this topic cited low mechanical ventilators in as patients’ respiratory needs change. However, shortages of personal protective equipment overall potential for disruption. Several ventilator intensive care units (ICUs) (PPE) have complicated efforts to manage the settings of multiple mechanically ventilated models can already be remotely controlled patients in ICUs while protecting frontline providers moving between rooms. Johns Hopkins through wired connections. Further, remote University researchers have developed a simple robotic system to control ventilator settings control of ventilators is neither widely accepted remotely. The robotic component is attached to a ventilator’s touch screen and includes a nor used for other respiratory conditions, camera that displays the ventilator screen on a wireless tablet for a remote user outside the making wide use for COVID-19 unlikely. patient room. The robot consists of 2 motors mounted on metal rods that can move a stylus along the x and y axes. Users move the stylus to a location on the ventilator touch screen by touching the corresponding location on the image of the screen displayed on the remote tablet. Once the stylus is positioned, users can activate the stylus to press the ventilator touch screen, changing the ventilator settings. In early testing, investigators successfully used the system from an adjoining room to change the percentage and volume of oxygen delivered by a ventilator attached to a mannequin.

SECTION 1. DEVICES 13 Section 2. Identifiable Risk Factors and Prognostic Indicators: 7 Topics

Table 2.1. Topics Added Since Last Status Report: 1 Topic

Title Description Possible areas of impact Possible future impacts

Selective serotonin An observational study found that SSRI and serotonin-norepinephrine Patient outcomes Might reduce burden and costs reuptake inhibitor (SSRI) reuptake inhibitor (SNRI) use might be associated with a lower risk of associated with intubation Population health use as a risk modifying death or intubation in patients with COVID-19. A time-to-event analysis Might improve understanding of the factor for COVID-19 compared 460 patients with COVID-19 who received antidepressants Health care delivery and pathogenesis of COVID-19 during hospitalization with 6885 adult inpatients without process 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 (the virus that causes COVID-19) 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: a 152-patient trial of fluvoxamine to prevent clinical deterioration 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 14 Table 2.2. Currently Monitored Topics: 2 Topics

Title Description Possible areas of impact Possible future impacts

Artificial intelligence (AI)– Early identification of patients with COVID-19 who may develop critical Patient outcomes Might assist health care professionals based assessment of clinical illness is of great importance and may aid in delivering proper to make better treatment decisions Population health data to determine COVID- treatment and optimizing the use of hospital resources. AI algorithms Might help manage the surge of 19 prognosis based on assessment of patient clinical data are now being used to Clinician and/or caregiver patients requiring ventilators and assist with determining which patients may need intensive critical care. safety alleviate the burden on health care On May 26, 2020, FDA granted Emergency Use Authorization (EUA) for Health care delivery and professionals and facilities the CLEWICU system (CLEW Medical, San Francisco, California), which process assesses electronic health record data to assist with the early Might help inform future triage identification of patients who are likely to be diagnosed with Health care costs paradigms respiratory failure or hemodynamic instability, which are common Might lead to inappropriate care in complications associated with COVID-19. Additionally, existing AI- cases of misclassification by the based predictive analytics systems are being used to assess patients algorithm with COVID-19. AlgoMarkers software by Medial EarlySign (Aurora, California) uses 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 2. IDENTIFIABLE RISK FACTORS AND PROGNOSTIC INDICATORS 15

Title Description Possible areas of impact Possible future impacts

Interleukin-6 (IL-6) levels as Some COVID-19 patients have relatively mild symptoms, whereas Patient outcomes Might streamline the triage of a prognostic factor in others develop severe disease. Additionally, the clinical course of patients based on the potential need Population health COVID-19 patients patients hospitalized for COVID-19 is variable, and patients may for mechanical ventilation deteriorate rapidly to respiratory failure, requiring ventilation and Clinician and/or caregiver Might reduce overall costs by intensive care unit (ICU) admission. Research suggests IL-6 levels might safety improving utilization of hospital be a potential predictor of severe COVID-19. Elevated IL-6 levels have Health care delivery and resources been associated with cytokine-mediated lung damage that can result in process severe respiratory distress in COVID-19 patients. Results from a clinical Might improve understanding of the study conducted in hospitalized patients suggested that IL-6 levels Health care disparities pathogenesis of COVID-19 above 80 pg/mL are indicative of a high risk of respiratory failure. To Health care costs that end, FDA has granted the Roche Diagnostics (Basel, Switzerland) Elecsys IL-6 test 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 for 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 16

Table 2.3. Recently Archived Topics: 4 Topics

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

Coronary artery calcification CAC can lead to chest pain, vasospasm, and increased risk of heart attack. The Most patients admitted to the hospital for COVID-19 (CAC) as a prognostic factor for presence of CAC on chest CT scans might mark poorer COVID-19 prognosis, typically do not undergo chest CT that can find CAC; COVID-19 patients according to a French cross-sectional study of 209 hospitalized COVID-19 patients therefore, knowledge of CAC as a prognostic factor aged 40 to 80 years with no history of cardiovascular disease. Chest CT scans would have no impact on health care processes. performed at hospital admission showed that 32% of patients younger than 62 Clinicians look at multiple markers to monitor COVID- years of age (n = 104) and 69% of patients aged 62 years and older (n = 105) had 19 progression, so another prognostic factor like CAC CAC. Investigators found that, within 30 days of hospitalization, 55% of CAC- would have a very low disruptive impact. Most positive patients younger than 62 years of age experienced mechanical ventilation, patients who have CAC also have other risk factors for extracorporeal membrane oxygenation, or death (primary composite outcomes); COVID-19 complications, such as diabetes, high body only 20% of CAC-negative patients in this age group experienced one of these mass index, high blood pressure, lipid abnormalities, events. In patients older than 62 years of age, one of these events occurred in 48% and older age, and will be monitored closely for of those who were CAC positive compared with 13% of those who were CAC COVID-19 complications regardless of having CAC. negative. Multivariate analysis led the investigators to postulate that CAC was significantly associated with the primary outcome. Determining the presence of CAC in COVID-19 patients might aid in appropriately managing and monitoring the clinical course of disease.

SECTION 2. IDENTIFIABLE RISK FACTORS AND PROGNOSTIC INDICATORS 17 Title Description Archive reason(s) based on data review and/or stakeholder ratings and comments

Low maternal plasma choline Choline supplementation might protect fetal development and support infant The study that determined plasma choline levels as a levels as a risk factor for early behavioral development in offspring of mothers who contract COVID-19, risk factor for altered development was small and did altered development following according to a study published by investigators from the University of Colorado not include proper demographics and COVID-19 School of Medicine. The study reported that, among infants of mothers who had a acknowledgment of confounding factors. Proper viral respiratory infection during the first 16 weeks of pregnancy (n = 43), infants research is needed using women with COVID-19 and born to mothers with choline levels above 7.5 µM had significantly increased a larger population to determine if direct evidence scores for attention and self-regulatory behavior on the Infant Behavior points to the impact of maternal plasma choline levels Questionnaire-Revised (IBQ-R) at 3 months of age compared with infants born to on fetal brain development. Choline supplementation mothers who had lower gestational serum choline levels. Although this association is likely to have a low disruptive impact on the has not been directly studied in pregnant women with COVID-19 infection, the population. investigators note that C-reactive protein (CRP) levels (a marker of inflammation) in women who experienced a respiratory infection were similar to CRP levels observed in pregnant Chinese women infected with COVID-19. Maternal inflammatory responses caused by viruses are thought to put offspring at increased risk for attention deficit disorder, autism spectrum disorder, and schizophrenia. Maternal choline levels consistent with FDA’s dietary recommendations for pregnancy purportedly decrease inflammation during maternal immune activation, potentially mitigating the adverse effects of inflammation on infant behavior. The researchers suggest that pregnant women should maintain appropriate choline levels through dietary supplementation.

SECTION 2. IDENTIFIABLE RISK FACTORS AND PROGNOSTIC INDICATORS 18

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

Proton pump inhibitor use as a Investigators released preprint data from an online survey that revealed an Many patients take PPIs when they have exhausted risk factor for COVID-19 independent dose-response association between proton pump inhibitor (PPI) use other approaches, such as H2 receptor blockers, over- and COVID-19 positivity. Among 53 130 respondents, individuals taking PPIs once the-counter antacids, and lifestyle/diet changes, and or twice daily had a significantly increased (2.15-fold and 3.67-fold, respectively) they might not be willing to discontinue PPI use until risk of reporting a positive COVID-19 test result compared with participants not stronger data come out that conclusively link PPI use taking PPIs. The acidic environment of the stomach plays a key role in the body’s to COVID-19 susceptibility. response to microbial infections. PPIs, a commonly prescribed class of heartburn medications, raise the pH in the stomach by lowering acid production, which might increase susceptibility to infection with SARS-CoV-2 (the virus that causes COVID-19). In vitro research published in August 2004 demonstrated that a pH below 3 (acidic) impaired the infectivity of SARS-CoV, the virus responsible for the 2002 SARS (severe acute respiratory syndrome) outbreak, while a less acidic pH did not inactivate SARS-CoV. Additionally, people taking a less potent class of heartburn medication, histamine (H2) receptor inhibitors, were not found to be at elevated risk for a positive COVID-19 test result. The investigators of the study suggest that clinicians use PPIs at the lowest indicated effective dose.

SECTION 2. IDENTIFIABLE RISK FACTORS AND PROGNOSTIC INDICATORS 19

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

Vitamin D deficiency as a risk Investigators reported data from 20 European countries indicating that Vitamin D deficiency might not have a significant factor for COVID-19 populations with lower average vitamin D levels were more likely to be diagnosed enough impact on COVID-19 susceptibility to warrant with, as well as die from, COVID-19. Vitamin D is an important factor in the a public health campaign in the United States. More immune system. It has been found to protect against acute respiratory tract research is needed to determine the extent of risk infections, and its deficiency has been linked to increased susceptibility to viral prevention that vitamin D adds and how much of it is infections. Additionally, vitamin D may beneficially modulate host immune necessary to lower risk. responses to SARS-CoV-2 (the virus that causes COVID-19). SARS-CoV-2 infection leads to the release of inflammatory proteins, such as cytokines, that can lead to hyperinflammation known to contribute to severe COVID-19 and poor outcomes. Immune cells express vitamin D receptors that regulate hundreds of genes, including cytokines, and vitamin D deficiency purportedly increases cytokine production, potentially contributing to COVID-19-induced hyperinflammation. These mechanisms have led researchers to hypothesize that patients with vitamin D deficiency might be at a higher risk of developing COVID-19 or experiencing worse outcomes. A Canadian phase 3 randomized trial is comparing high-dose vitamin D supplementation with placebo in 2414 health care workers with a high risk of COVID-19 infection to determine if supplementation reduces the risk or severity of COVID-19 infection. The trial’s estimated primary completion date is May 2021.

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Section 3. Screening and Diagnostics: 22 Topics

Table 3.1. Topics Added Since Last Status Report: 4 Topics

Title Description Possible areas of impact Possible future impacts

Assure COVID-19 IgG/IgM The Assure COVID-19 IgG/IgM Rapid Test Device (Azure Biotech, Inc) Patient outcomes Might enable more timely and Rapid Test Device point-of- is a rapid lateral flow chromatographic immunoassay for use as a convenient results for individuals who Population health care test to detect point-of-care (POC) fingerstick test for COVID-19. The test qualitatively want to know if they have been antibodies against SARS- detects and differentiates IgM and IgG antibodies against SARS-CoV-2 Health care delivery and previously infected with SARS-CoV-2 CoV-2 (the virus that causes COVID-19) nucleocapsid protein and spike process Might aid in identifying plasma protein in human venous whole blood, serum, plasma, or fingerstick Health care disparities donors by allowing the detection of whole blood. Although the test first received Emergency Use antibodies against SARS-CoV-2 Authorization (EUA) in July 2020 for use in Clinical Laboratory Health care costs Improvement Amendments of 1988 (CLIA)–certified laboratories, the Might misinform public health EUA has been reissued to authorize the test for POC use in patient decisions based on false test results care settings such as doctor’s offices, hospitals, urgent care centers, and emergency departments. The test consists of individually packed test devices, disposable pipettes, 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 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 is the first FDA- authorized COVID-19 POC serology test and is available by prescription only. The Assure test has a specificity of 99.04%; the sensitivity of the test early after infection has not been determined.

SECTION 3. SCREENING AND DIAGNOSTICS 21

Title Description Possible areas of impact Possible future impacts

cPass SARS-CoV-2 test to The cPass SARS-CoV-2 neutralization antibody detection kit developed Patient outcomes Might help researchers and detect neutralizing by GenScript detects antibodies capable of blocking infection (ie, policymakers assess herd immunity Population health antibodies against SARS- neutralizing antibodies) with SARS-CoV-2 (the virus that causes and duration of protective immune CoV-2 COVID-19) in human serum or plasma using an enzyme-linked Clinician and/or caregiver responses immunosorbent assay (ELISA)–based test. The test assay purportedly safety Might aid with identifying and mimics the binding interaction between the virus and host cell Health care delivery and prioritizing plasma donors and receptor, which allows neutralizing antibody activity to be detected in process samples for the national convalescent patient samples. If neutralizing antibodies are present in the sample, plasma study they will block the interaction between the 2 key components of the Health care disparities test kit, a recombinant subunit of the coronavirus spike surface protein Might be used to assess the efficacy Health care costs and a recombinant form of the human angiotensin-converting enzyme of vaccine candidates by measuring 2 (ACE2) receptor protein. Detecting the presence of neutralizing generated neutralizing antibodies antibodies might help identify individuals with an adaptive immune Might be used to ease social response to COVID-19 that indicates prior infection. By specifically distancing directives for the detecting neutralizing antibodies, the test might provide a more population biologically relevant assessment of an individual’s antibody levels compared with typical serology tests that detect antibodies against Might misinform public health actions SARS-CoV-2 without regard for neutralizing activity. However, the level based on erroneous test results or of neutralizing antibodies needed to prevent COVID-19 is still policies 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 22

Title Description Possible areas of impact Possible future impacts

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

SECTION 3. SCREENING AND DIAGNOSTICS 23

Title Description Possible areas of impact Possible future impacts

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

SECTION 3. SCREENING AND DIAGNOSTICS 24 Table 3.2. Currently Monitored Topics: 13 Topics

Title Description Possible areas of impact Possible future impacts

3-Dimensional (3D)-printed As COVID-19 infections increased in the early months of 2020, the Population health Might improve testing availability by nasopharyngeal swabs for rapid, unprecedented demand for COVID-19 testing overwhelmed the alleviating shortages of some testing Health care costs COVID-19 testing supply chains of many health care facilities. One early impediment to accessories widespread availability of testing was a lack of testing accessories, Might reduce costs for testing including nasopharyngeal swabs to collect patient samples. To help supplies if more manufacturers are alleviate shortages, a consortium of researchers, health care providers, supplying nasopharyngeal swabs academic medical centers, and manufacturers collaborated to develop nasopharyngeal swabs comparable to commercially available swabs that could be produced in high volumes using 3D printing techniques. The consortium developed 4 prototypes and tested them for noninferiority against commercially available control swabs. At the study conclusion, 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 laboratories strongly consider their use during pandemic-related supply shortages.

SECTION 3. SCREENING AND DIAGNOSTICS 25

Title Description Possible areas of impact Possible future impacts

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

SECTION 3. SCREENING AND DIAGNOSTICS 26

Title Description Possible areas of impact Possible future impacts

BinaxNOW COVID-19 Ag BinaxNOW COVID-19 Ag Card (BinaxNOW) is a lateral flow antigen Patient outcomes Might allow health centers to Card point-of-care (POC) immunoassay developed by Abbott Diagnostics Scarborough as a POC diagnose COVID-19 soon after a Population health antigen test to diagnose test. BinaxNOW consists of a single-use card containing color-labeled patient arrives COVID-19 antibodies that detect the coronavirus’s nucleocapsid protein, which is Health care delivery and Might help triage infected and detectable during the first 7 days of symptom onset. A patient’s nasal process uninfected patients on the same day swab is inserted into a small test card along with an extraction reagent Health care disparities they are tested that exposes the viral nucleocapsid. Test results are read on the card like a pregnancy test, with 1 line indicating a negative result and 2 Health care costs Might be more affordable than are lines indicating a positive result. Results can be sent to a mobile device tests performed in central app (NAVICA), which can be used as a temporary digital health pass laboratories that is renewed each time an individual is tested. The manufacturer Might increase the rate of false- claims that each $5 BinaxNOW card yields results in about 15 minutes. negative test results if the assay does In August 2020, FDA granted BinaxNOW Emergency Use Authorization not detect very low levels of viral (EUA) based on a study that compared BinaxNOW with an EUA reverse nucleocapsid proteins transcriptase 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 27

Title Description Possible areas of impact Possible future impacts

College and university College and university COVID-19 testing programs are services offered Patient outcomes Might help faculty, staff, and students SARS-CoV-2 testing by clinical laboratories (eg, Quest Diagnostics [Secaucus, New Jersey]; feel safe about returning to colleges Population health programs to prevent Laboratory Corporation of America Holdings [LabCorp, Burlington, or universities COVID-19 spread among North Carolina] ; Bio-Reference Laboratories, Inc [Elmwood Park, New Health care disparities Might catch COVID-19 cases in the returning students Jersey] ; Color Genomics, Inc [Burlingame, California] ) and are Health care costs campus early and help to quickly intended to limit SARS-CoV-2 (the virus that causes COVID-19) spread suppress spread of the virus and boost student confidence about returning to campus. Schools implementing a testing program may give all returning students, Might create supply shortages via faculty, and staff a SARS-CoV-2 molecular test along with an antibody frequent testing in large campus test at the beginning of the school year, with several levels of populations surveillance throughout the year. This will help schools assess a Might create disparities in colleges baseline for their community, understand the prevalence of the virus and universities where these testing on campus, and make decisions about quarantines and other distance programs are not available measures for the population returning to campus. Schools may provide self-collection kits to avoid overwhelming health centers and Might cause the virus to initially clinical laboratories. Upon receiving samples, central laboratories will spread undetected if test results yield have test results available through an online platform in about 3 to 5 a high number of false negatives days. College and university testing programs have the potential to Might increase the rate of false- detect COVID-19 cases early and prevent coronavirus from spreading negative test results if students using among students. a self-collection kit do not acquire a proper specimen with detectable virus

Might be difficult to triage students if it takes days for test results to become available

SECTION 3. SCREENING AND DIAGNOSTICS 28

Title Description Possible areas of impact Possible future impacts

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

SECTION 3. SCREENING AND DIAGNOSTICS 29

Title Description Possible areas of impact Possible future impacts

Clustered regularly CRISPR-based assays, such as Sherlock (Sherlock Biosciences, Inc) and Patient outcomes Might deliver comparable test results interspaced short DETECTR (Mammoth Biosciences, Inc), are intended to diagnose quicker than do RT-PCR–based assays Population health palindromic repeats COVID-19 by detecting SARS-CoV-2 (the virus that causes COVID-19) Might decrease costs by allowing (CRISPR)–based SARS-CoV- nucleic acids. These assays employ a loop-mediated isothermal Health care delivery and laboratories to process hundreds of 2 assays to diagnose amplification (LAMP) reaction to intensify nucleic acids in the sample. process patient samples per day COVID-19 The products of this amplification reaction are exposed to an RNA- Health care disparities guided nuclease (eg, Cas12a, Cas13a) that becomes activated only in Might increase the rate of false- the presence of SARS-CoV-2 nucleic acids. If activated, the nuclease negative test results if the assays do cleaves a fluorophore-labeled reporter nucleic acid. Depending on the not detect very low levels of viral reporter technology used, reporter cleavage is measured by nucleic acids fluorimeter or lateral flow assay. CRISPR-based assays can purportedly Might create disparities for patients detect SARS-CoV-2 nucleic acids within an hour in a highly specific who do not have access to health way. FDA has granted Emergency Use Authorization (EUA) to the centers and laboratories that offer Sherlock SARS-CoV-2 kit and the SARS-CoV-2 RNA DETECTR Assay for CRISPR-based testing use in Clinical Laboratory Improvement Amendments of 1988 (CLIA)– certified laboratories. Sherlock Biosciences and Mammoth Biosciences have also developed CRISPR-based diagnostic tests for use in the point-of-care (POC) and/or consumer use settings. Two studies comparing the assays’ performance with that of reverse transcriptase polymerase chain reaction (RT-PCR) reported a 94.9% concordance with DETECTR and a 100% concordance with Sherlock. These studies also demonstrated that DETECTR and Sherlock POC assays performed as well as their EUA versions.

SECTION 3. SCREENING AND DIAGNOSTICS 30

Title Description Possible areas of impact Possible future impacts

Employee SARS-CoV-2 Employee COVID-19 testing programs offered by clinical laboratories Patient outcomes Might help employees feel safe about testing programs to reopen (eg, Quest Diagnostics; Laboratory Corporation of America Holdings returning to their workplace Population health businesses [LabCorp]; Bio-Reference Laboratories, Inc; Color Genomics, Inc) are Might catch COVID-19 cases in the intended to limit novel coronavirus spread in the workplace and boost Health care disparities workplace early and thus help quickly confidence that employees can return to a safe work environment. Health care costs suppress spread of the virus Testing programs emphasize operating under simple and streamlined conditions that allow COVID-19 cases to be caught early and prevent Might create disparities in regions disease spread. COVID-19 testing programs might incorporate where employee testing programs are unreliable screening methods, including health questionnaires and not available temperature screening, or more reliable screening methods, such as Might cause the virus to initially nucleic acid testing, either at the employer site or offsite using an at- spread undetected if test results yield home self-collection kit. Pilot programs (eg, Quest Diagnostics, high numbers of false negatives LabCorp) have used tests performed at central laboratories that provide results within 2 to 5 days after receiving the sample. The Might create supply shortages via employer and employee have access to test results through an online frequent testing in large corporate platform. While point-of-care (POC) tests offer same-day test results, populations they are currently not being used because of recent concerns about Might be difficult to triage employees their higher false-positive and false-negative rates compared with if it takes days for test results to central laboratory tests. become available

SECTION 3. SCREENING AND DIAGNOSTICS 31

Title Description Possible areas of impact Possible future impacts

Next-generation Several next-generation sequencing (NGS) assays have been Patient outcomes Might allow laboratories to process sequencing assays to developed to diagnose COVID-19, including ClearDx SARS-CoV-2 thousands of patient samples per day Population health diagnose COVID-19 (Clear Labs, Inc), COVIDseq (Illumina, Inc), COVID-19 NGS (Fulgent Might allow screening for COVID-19 Genetics, Inc), Guardant-19 (Guardant Health, Inc), and Helix COVID-19 Health care delivery and in the general population, as well as NGS (Helix OpCo, LLC). These assays may be performed only at Clinical process diagnosing the disease in Laboratory Improvement Amendments of 1988 (CLIA)–certified Health care disparities symptomatic individuals laboratories, including central laboratories and some laboratories at hospitals, research institutions, and academic institutions. These assays Health care costs Might be more expensive than are employ deep sequencing (ie, a genetic sequencing technique that standard nucleic acid and antigen requires only a very small nucleic acid sample) and computational tests performed in central methods to detect nucleic acids of the coronavirus. Tests can amplify laboratories and in point-of-care and detect sequences from the whole viral genome (ie, a string of (POC) settings about 30 000 nucleic acids) or several genomic regions. NGS assays Might create disparities for patients purportedly offer high throughput, enabling 2000 to 3000 samples to who do not live near health centers be processed in about 12 hours, with comparable accuracy to standard with capabilities and certifications to reverse transcriptase polymerase chain reaction (RT-PCR) tests. These offer NGS testing assays might also be used in epidemiology studies to track the spread of coronavirus or to screen individuals who are planning to return to work or school. FDA has granted Emergency Use Authorization (EUA) to ClearDx SARS-CoV-2, COVIDseq, Guardant-19, and Helix COVID-19 NGS.

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Title Description Possible areas of impact Possible future impacts

Population-wide antibody The COVID-19 pandemic has caused substantial public health and Patient outcomes Might inform actual infection rates testing to quantify economic crises, which makes testing for the prevalence of and more accurately track the spread Population health coronavirus infection rates coronavirus infection, as well as for potential immunity, critical to of coronavirus measuring the spread of the disease. Medicare beneficiaries who may Clinician and/or caregiver Might misinform public health be at greater risk of serious COVID-19 can get an antibody test at no safety guidance if the employed serology cost. Testing for coronavirus-specific antibodies in the blood of Health care delivery and tests generate high numbers of false individuals has the potential to identify those who have been exposed process positives or false negatives to the virus regardless of whether they developed symptoms, and widespread serosurveys have the potential to provide data on the Health care disparities Might misrepresent true infection extent of COVID-19 spread. The US Centers for Disease Control and rates by depending on blood donors, Health care costs Prevention (CDC) is conducting a countrywide COVID-19 study that who are disproportionately healthy will test blood samples of up to 325 000 donors in 25 selected cities and may not be the ideal population over the course of 18 months. A nonprofit blood service in which to evaluate the spread of provider, Vitalant, will be partnering with CDC and National Institutes coronavirus infection of Health (NIH) to collect samples for this serologic study. 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) to collect samples from 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, Nevada) is a Patient outcomes Might enable health centers to SARS-CoV-2 Panel test to polymerase chain reaction (PCR) assay intended to diagnose COVID- diagnose COVID-19 soon after a Population health diagnose COVID-19 19 and differentiate it from 20 other causes of respiratory infection. patient arrives and determine whether The panel consists of a single-use cartridge that includes all reagents Health care delivery and symptoms are caused by SARS-CoV-2 needed for nucleic acid extraction, nucleic acid amplification, and process or a different infectious agent detection of 3 bacteria and 18 viruses (or their subtypes), including Health care disparities Might help triage infected and SARS-CoV-2 (the virus that causes COVID-19), that cause respiratory uninfected patients on the same day symptoms. A nasopharyngeal swab sample is added into the cassette, Health care costs they are tested which is then placed in the QIAstat-Dx Analyzer 1.0. At the end of the reaction, results indicating whether pathogen nucleic acids have been Might be more affordable than are detected in the sample are displayed on the analyzer’s screen. The tests performed in central panel purportedly requires a small sample volume and minimal hands- laboratories on time, and the results are available in about 1 hour. In March Might increase the rate of false- 2020, FDA granted the QIAstat-Dx Respiratory SARS-CoV-2 Panel negative test results if the assay does Emergency Use Authorization (EUA) for use in Clinical Laboratory not detect very low levels of viral Improvement Amendments of 1988 (CLIA)–certified laboratories. A nucleic acids published study evaluated the performance of the panel for detecting SARS-CoV-2 in 69 samples previously tested by a reverse transcriptase Might create disparities for patients PCR test recommended by the World Health Organization. QIAstat-Dx who do not live near health centers had a sensitivity of 100%, a specificity of 93%, and an overall with capabilities and certifications to agreement of 97%. offer the test

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Title Description Possible areas of impact Possible future impacts

Rapid point-of-care (POC) Ben-Gurion University (Beer-Sheva, Israel) researchers are developing Patient outcomes Might enable more rapid POC testing breath test to detect a POC test that purportedly detects COVID-19 in breath samples from in public areas, such as airports or Population health COVID-19 both symptomatic and asymptomatic carriers in less than 1 businesses, to facilitate economic minute. The test measures electroacoustic properties specific to Health care costs reopening coronavirus viral particles using terahertz spectroscopy. To test for Might help slow the spread of COVID- COVID-19, a subject breathes into a tube containing thousands of 19 if more asymptomatic carriers are electro-optical sensors. The tube is then placed in a spectrometer identified sooner connected to a laptop computer that transmits data for cloud-based analysis. Results are automatically recorded into a database that public Might improve consumer confidence health authorities can use to track viral spread. In preliminary tests, the in public health efforts through breath test matched polymerase chain reaction (PCR)–based swab test simple, rapid, and effective POC results in more than 90% of tests performed. Researchers estimate that testing test kits will cost about $50 each. Technion-Israel Institute of Technology (Haifa, Israel) researchers developed an automated, self- contained, handheld device that purportedly detects coronavirus- specific biomarkers in breath samples within 30 seconds with 92% accuracy. Nanose Medical, Ltd (Haifa, Israel), is commercializing the device and estimates per-test costs between $2 and $3, with the first regulatory approvals by early 2021. Other research groups are developing COVID-19 breath tests using alternative detection methods, including COVID-19-specific metabolic profiles and direct detection of viral nucleic acid or protein.

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Title Description Possible areas of impact Possible future impacts

Saliva-based nucleic acid Saliva-based nucleic acid assays use a process known as polymerase Patient outcomes Might reduce the risk of patients assays to diagnose chain reaction (PCR) to diagnose COVID-19 by detecting coronavirus transmitting SARS-CoV-2 (the virus Population health COVID-19 nucleic acids from a patient’s saliva sample. Compared with that causes COVID-19) to medical nasopharyngeal swab sampling, which is considered the standard of Clinician and/or caregiver staff and patients if sample collection care (SoC), saliva sampling is less invasive and less costly and can be safety is performed at home, and might help performed at home or at a health center without the supervision of a triage infected and uninfected Health care delivery and health care worker. Some saliva-based assays have been validated to patients process use minimally processed saliva samples, obviating the need for a Might decrease costs associated with nucleic acid extraction step, which might save time and testing Health care disparities sample collection and ease the supplies. Results from 2 systematic reviews suggest that saliva-based Health care costs burden at testing sites with limited tests yield similar outcomes to those of nasopharyngeal swab–based personal protective equipment (PPE) tests for detecting coronavirus nucleic acids. Two published studies and testing supplies comparing COVID-19 positivity on paired saliva samples and nasopharyngeal swabs tested by PCR reported that saliva samples had Might increase the rate of false- an overall agreement between 94% and 99% for detecting coronavirus negative test results if assays testing nucleic acids when compared with simultaneously collected saliva do not detect viral nucleic acids nasopharyngeal swabs. FDA has granted Emergency Use Authorization at all stages of infection (EUA) to 8 saliva-based assays (Advanta Dx SARS-CoV-2, Clarifi Might create disparities for patients COVID-19, CRL Rapid Response, DxTerity SARS-CoV-2, Phosphorus who do not live near health centers COVID-19, SalivaDirect, TaqPath SARS-CoV-2, and Wren COVID-19) for with capabilities and certifications to use in Clinical Laboratory Improvement Amendments of 1988 (CLIA)– offer saliva-based testing certified laboratories to diagnose COVID-19.

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Title Description Possible areas of impact Possible future impacts

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

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Table 3.3. Recently Archived Topics: 5 Topics

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

Artificial intelligence (AI)–assisted People with asymptomatic COVID-19 can unintentionally spread the infection. To Stakeholders reviewing this topic noted low overall cough analysis to detect help identify asymptomatic cases, Massachusetts Institute of disruptive potential. More research is needed to asymptomatic COVID-19 Technology researchers developed an artificial intelligence model that purportedly analyze if the population samples used to train the AI detects asymptomatic COVID-19 cases by analyzing cough recordings submitted algorithm were truly representative of the intended through web browsers on smartphones or laptop computers. They trained their user population (eg, age, coexisting diseases). Further, convolutional neural network using forced-cough samples collected from the variability in recording quality from multiple web- thousands of healthy volunteers and individuals who reported no symptoms based devices outside a laboratory setting is unlikely but had positive COVID-19 laboratory tests. Researchers then used the AI model to to consistently and accurately detect nuances in evaluate new cough recordings, achieving a 98.5% sensitivity (ie, true-positive rate) recorded cough samples, limiting the accuracy of this and a 94.2% specificity (ie, true-negative rate) among all COVID-19-positive approach. subjects, regardless of symptoms. Among asymptomatic COVID-19-positive subjects, sensitivity was 100% and specificity was 83.2%. Researchers cautioned their model is not intended to be used to differentiate between symptomatic coughs from COVID-19, influenza, asthma, or other respiratory conditions. Researchers are now working on a free, downloadable application to identify asymptomatic cases. Ideally, users could check their coughs daily for instant feedback about whether they should follow up with a conventional laboratory test. Researchers are also partnering with several hospitals globally to collect more cough recordings to enhance system training and improve accuracy.

CoviTact point-of-care protease CoviTact is a coronavirus protease detection assay developed by ViroTact BV, a In May 2020, ViroTact secured funding to develop the assay to diagnose COVID-19 subsidiary of Detact Diagnostics BV, as a point-of-care (POC) COVID-19 test. It is CoviTact assay. However, the company has not intended to be used in temporary screening facilities, physician office laboratories, released any update on the test’s status. Even if urgent care, and long-term nursing facilities. CoviTact consists of a short peptide CoviTact became available in the United States within that is bound to a near-infrared light (NIRL)–emitting molecule and a quencher a year, it is unlikely to have significant impact on molecule that absorbs NIRL. The peptide has been designed to contain a specific diagnosing COVID-19 because FDA has granted amino acid sequence that can be recognized and cleaved only by the SARS-CoV-2 Emergency Use Authorization (EUA) to several POC (the virus that causes COVID-19) main protease (Mpro). Once Mpro cleaves the assays that are currently in use. peptide, the NIRL-emitting molecule is no longer in close proximity to the quencher molecule and NIRL can be detected using a fluorimeter. CoviTact can purportedly detect SARS-CoV-2 in saliva samples, nasal swabs, or other possibly infectious bodily fluids. If Mpro is present in a patient sample, CoviTact purportedly confirms COVID-19 cases within minutes in a highly specific way.

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

Isothermal amplification assays The BioFrontiers Institute and University of Oxford are developing isothermal These assays use an approach that delivers results to test for COVID-19 in amplification assays that provide a low-complexity, portable way to amplify viral within 30 minutes and might help screen for COVID- community or field settings nucleic acids in community and field settings, including temporary screening 19 in settings such as airports, schools, and facilities, hospitals, long-term nursing facilities, schools, universities, offices, and workplaces. However, these tests have a high rate of airports. These assays require only sample collecting kits, pipettes, a heating false-negative results, which might cause individuals source (eg, water bath, heat blocks), and tubes containing amplification reagents. to decrease their social distancing practices and thus Isothermal amplification assays purportedly require a small sample volume and promote the spread of minimal hands-on time to yield laboratory-quality results in approximately 45 COVID-19. minutes, and their low complexity might allow them to be performed by non– health care professionals. Individuals who test positive would be recommended to undergo confirmatory testing and self-quarantine. In addition to these investigational assays, FDA has granted 5 isothermal amplification-based assays Emergency Use Authorization (EUA) in central laboratories or point-of-care (POC) settings, and these tests could eventually become authorized for screening in community and field settings.

Mount Sinai Coronavirus The Mount Sinai Hospital Clinical Laboratory COVID-19 ELISA Antibody Test is Lack of knowledge about the levels of antibody Antibody Test for the made up of serial direct enzyme-linked immunosorbent assays (ELISAs). The test is required to maintain immunity and confer protection quantification of COVID-19 intended for the detection of human SARS-CoV-2 (the virus that causes COVID-19) lowers the disruptive potential of this test. As more antibodies IgG antibodies in the serum and plasma of individuals suspected of prior infection quantitative tests are being approved by FDA, the by SARS-CoV-2. The assay first tests for antibodies against the SARS-CoV-2 impact of each is decreasing, especially for this test, receptor binding domain (RBD), followed by confirmatory testing of positive which is approved for use only in New York. The specimens against full-length SARS-CoV-2 spike protein. The antibody efficacy and use of convalescent plasma have also test recently received emergency use authorization from the New York State been called into question, lowering the utility of Department of Health for quantitative use. With the ability to quantify antibody antibody tests. levels, the test might be able to determine whether an individual who has been exposed to COVID-19 is eligible for convalescent plasma donation as well as measure their immune response related to COVID-19 over time. Use of the test is limited to the Mount Sinai Laboratory, which is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) to perform high-complexity tests. The assay was previously granted Emergency Use Authorization (EUA) by FDA in April 2020 for qualitative use.

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

Sepsis diagnostic tests to assess Sepsis is characterized by an overactive immune response to infection that can Tests that can help predict sepsis before a patient risk of severe COVID-19 cause life-threatening organ damage. Severe COVID-19 can involve virus-induced becomes critically ill have the potential to save lives. sepsis. Multiple companies (eg, Beckman Coulter, Inc; Cytovale, Inc; Immunexpress, However, these tests have a low impact potential Inc) are developing sepsis diagnostic tests intended to detect early signs of virus- because of limited efficacy data and the availability of induced sepsis. Immunexpress’s assay measures the nucleic acid levels of genes other interventions to assess the risk of severe associated with pathogen-specific immune responses. The tests from Beckman disease. Coulter and Cytovale measure changes in the morphology of white blood cells as part of a routine complete blood count. Currently, acute respiratory distress is the earliest and the most common sign of severe COVID-19 in critical patients. However, early markers of sepsis may precede these symptoms. Sepsis diagnostic test results, combined with other laboratory findings and clinical information, might help clinicians identify patients with a higher likelihood of severe disease. This could allow earlier management to moderate immune responses and prevent sepsis-related symptoms and complications. Cytovale has initiated SQuISH-COVID, a clinical trial enrolling 300 participants arriving at an emergency department with symptoms suggestive of COVID-19 or another respiratory infection. FDA granted 510(k) clearance to Beckman Coulter’s Early Sepsis Indicator to diagnose sepsis, but its utility in COVID-19 management remains unclear.

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Section 4. Systems and Management: 15 Topics

Table 4.1. Topics Added Since Last Status Report: 4 Topics

Title Description Possible areas of impact Possible future impacts

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

SECTION 4. SYSTEMS AND MANAGEMENT 41

Title Description Possible areas of impact Possible future impacts

Post-COVID-19 recovery Many hospitals across America are setting up post-COVID-19 recovery Patient outcomes Might improve management of long- programs programs to accommodate the growing need for continued care in term COVID-19 symptoms Population health long haulers, patients experiencing long-term side effects from COVID- Might help increase knowledge of 19. Some long haulers who have recovered from COVID-19 have an Health care delivery and long-term COVID-19 effects increased risk of long-term health problems because of permanent process damage to their lungs, heart, kidneys, and brain. Even with no Might increase health care costs if detectable damage to these organs, some patients still report lingering clinic visits are not covered by and debilitating symptoms months after clearing the infection. insurance Ongoing post-COVID-19 medical, psychological, and rehabilitation Might suffer from long wait times programs may help ensure a full recovery from COVID-19. Patients and limited clinic access due to lack who have cleared the viral infection but are still experiencing of programs in many areas and symptoms can go to these postinfection programs with or without a increased demand for services referral, where they will be screened to identify their clinical needs and establish a therapeutic 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 risk of viral spread, such as negative-pressure rooms for patients in need of inpatient rehabilitation and isolation, as well as therapy through telemedicine.

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Title Description Possible areas of impact Possible future impacts

Public-private partnerships As of September 2020, FDA had issued Emergency Use Authorization Patient outcomes Might enhance efficiency to fast-track COVID-19 (EUA) for only one treatment for COVID-19, and there were no FDA- in the clinical trial process Population health treatment and vaccine approved vaccines to prevent infection with SARS-CoV-2 (the virus that Might improve understanding of development causes COVID-19). The National Institutes of Health (NIH) is leading a Clinician and/or caregiver COVID-19 prevention public-private partnership called Accelerating COVID-19 Therapeutic safety Interventions and Vaccines (ACTIV) that aims to identify, improve, and Health care delivery and accelerate the development of promising treatments and vaccines for process COVID-19. Government agencies, nonprofit organizations, and biopharmaceutical companies will work together to contribute to the 4 Health care disparities identified fast-track areas: developing a collaborative, streamlined forum to identify preclinical treatments; accelerating clinical testing of promising vaccines and treatments; improving clinical trial capacity and effectiveness; and accelerating the evaluation of vaccine candidates to enable rapid authorization or approval. The NIH and National Institute of Allergy and Infectious Diseases (NIAID) created the COVID-19 Prevention 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 aims to deliver substantial quantities of a safe, effective vaccine by January 2021.

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Title Description Possible areas of impact Possible future impacts

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

SECTION 4. SYSTEMS AND MANAGEMENT 44 Table 4.2. Currently Monitored Topics: 8 Topics

Title Description Possible areas of impact Possible future impacts

3-dimensional (3D)-printed The rapid influx of patients with COVID-19 infection substantially Clinician and/or caregiver Might alleviate face shield shortages face shields to protect depleted many health care facilities’ supplies of personal protective safety for frontline health care personnel against COVID-19 infection equipment (PPE) for staff. Competition among hospitals for limited Might reduce supply costs if face vendor supplies of PPE has resulted in dramatically rising prices, shields can be 3D printed locally prompting some academic 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 (AI)– Identification and monitoring of patients with COVID-19 who are at Patient outcomes Might assist health care professionals assisted radiographic image risk of developing severe disease is of great importance and may help to make better treatment decisions Population health assessment for determining health care facilities prioritize care and efficiently allocate resources. AI Might help manage the surge of COVID-19 prognosis algorithms are being investigated for use in assisting with radiographic Clinician and/or caregiver patients requiring ventilators and image (eg, chest x-ray, computed tomography) analysis to predict the safety alleviate the burden on health care clinical course of COVID-19. Examples of AI-assisted image assessment Health care delivery and professionals and facilities in development include an AI-driven computational tool to decide process which patients need the most extensive treatment (eg, mechanical Might help inform future triage ventilation), a machine learning–based model for predicting length of Health care costs paradigms hospital stay, and an AI-driven model for predicting malignant Might lead to inappropriate care in progression of COVID-19 pneumonia. cases of misclassification by the algorithm

SECTION 4. SYSTEMS AND MANAGEMENT 45

Title Description Possible areas of impact Possible future impacts

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

SECTION 4. SYSTEMS AND MANAGEMENT 46

Title Description Possible areas of impact Possible future impacts

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

SECTION 4. SYSTEMS AND MANAGEMENT 47

Title Description Possible areas of impact Possible future impacts

Machine learning to predict COVID-19 has had significant social, political, economic, and public Patient outcomes Might help predict changes in the spread of COVID-19 health impacts globally. The Centers for Disease Control and national and state-level spread of Population health Prevention (CDC) has partnered with several universities to develop coronavirus machine-learning models to forecast national and state-level changes Clinician and/or caregiver Might inform public health agencies in infection rates and deaths due to COVID-19. The UCLA-SuEIR model, safety to establish appropriate reopening developed at the University of California, Los Angeles, purportedly Health care delivery and procedures infers the spread of infection while accounting for underlying epidemic process dynamics, making it a more comprehensive prediction model. Might reduce overall health care California Institute of Technology researchers developed a deep Health care disparities costs by predicting possible learning model to predict COVID-19 deaths at the county level with a resurgence in cases earlier compared Health care costs 2-week forecast window. The DeepCOVID model is trained on Google with other models, thereby helping and Unacast human mobility data to yield accurate forecasts of with emergency preparedness COVID-19 spread to purportedly quantify the effects of government interventions such as lockdowns 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 let local health authorities compare them in regional, state, and nationwide 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 chain through clinical trials and, in parallel, readying manufacturing to supply chain management and help Health care delivery and during COVID-19 prepare for deployment if their candidate proves to be safe and prepare for future public health process effective. A recent news brief highlighted a shortage of the medical- emergencies grade glass vials needed to distribute vaccines. A shortage of these Health care disparities Might change standards for quality glass vials or syringes could create access issues for millions of people. and manufacturing throughput of Currently, the industry has decided to use 10-mL vials that are capable pharmaceutical packaging of holding 8 to 15 doses of coronavirus vaccine to conserve glass supply. Corning, Inc, will receive funding from the Biomedical Might increase access to COVID-19 Advanced Research and Development Authority (BARDA) to accelerate vaccine, potentially accelerating herd the manufacturing of glass vials for COVID-19 vaccines and treatments. immunity to control the spread of COVID-19 Might increase risks of iatrogenic illness due to cross-contamination

SECTION 4. SYSTEMS AND MANAGEMENT 48

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 not only for those affected Population health mental health effects of the efforts for mental health conditions in the wake of COVID-19. directly by COVID-19 but also for COVID-19 pandemic Pandemic response strategies specifically designed to address mental Health care delivery and those affected indirectly health issues might lessen the many negative mental health effects process Might improve interdisciplinary associated with the current COVID-19 pandemic. These structured Health care disparities collaboration and institutional frameworks are intended to mobilize and optimize health care delivery cohesion to meet public health needs during a pandemic. To address mental Health care costs health demands during the COVID-19 pandemic, a recently published Might revolutionize the mental behavioral health pandemic response strategy proposed actionable health care delivery system if steps related to 6 pandemic phases. Examples of action steps include implemented processes are adapted identifying and training crisis leadership teams, designing sustainably psychologically informed prevention and education campaigns and Might decrease the stigma of mental programs, training future behavioral health specialists for public health health disorders crisis response, developing flexible and scalable behavioral health services, advancing behavioral health research, and ameliorating health Might increase health disparities for disparities and discrimination through outreach and raising awareness. individuals living in rural areas, who Caring Communities is one such initiative to implement a behavioral cannot readily access mental health health response strategy during the COVID-19 pandemic, using a team resources, or decrease health of more than 100 psychologists, psychiatrists, transdisciplinary disparities through efforts aimed physicians, social workers, interdisciplinary trainees, and staff with specifically to do so 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.

SECTION 4. SYSTEMS AND MANAGEMENT 49

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 management during the statewide patient load balancing system (ie, surge line) to help with of patients during COVID-19 or Population health COVID-19 pandemic transferring patients between facilities during the COVID-19 public similar emergency situations health emergency. ADHS hopes that the system will help Clinician and/or caregiver Might assist health care staff with accommodate potential surges in the number of COVID-19 cases, safety effective time management by which have led some hospitals to cancel or postpone elective Health care delivery and reducing their call time to find the procedures. The Arizona Surge Line is a 24/7 toll-free call line for process right level of care for their patients health care providers. For each call, a surge line transfer agent reviews critical care availability for each hospital in the state and transfers the Health care disparities Might improve patient survival call to the appropriate destination, thereby assisting with interfacility outcomes by Health care costs transfer of patients with presumed or confirmed COVID-19 or transfer providing appropriate care in a of patients to post–acute care facilities. It can assist with effectively timely manner distributing new staffing placements from out of state. The surge line Might enhance government policies may also provide clinical consultation if a transfer is declined or and public health emergency delayed. The Oregon Health Authority has also developed a statewide guidance hospital capacity system using a real-time data-tracking tool to efficiently manage the surge in COVID-19 patients. 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.

SECTION 4. SYSTEMS AND MANAGEMENT 50

Table 4.3. Recently Archived Topics: 3 Topics

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

Neutralizing masks to limit the The transmission of coronavirus might be limited by face masks thought to Masks that effectively kill the COVID-19 virus might spread of COVID-19 block respiratory droplets released during coughing, sneezing, or talking. Multiple have a positive impact, but the intervention has many companies are investigating novel materials with virus-neutralizing properties with limitations, such as reduced efficacy due to improper which to construct face masks. Vomaris Innovations, Inc, has developed a material mask sizing and/or sealing, as well as cost of with moisture-activated microcell batteries that is currently in use as a broad- development and distribution. More research is spectrum antimicrobial dressing. A recent study of this material demonstrated that needed to prove that these masks are far more the low-level electric field–generating fabric could reduce the infectivity effective than standard masks. of coronavirus when the virus was in contact with the fabric for 1 to 5 minutes. Another material, Acteev Biodefend, uses active zinc ions embedded in polyamide- based nonwoven and nanofiber materials and has been shown to be 99% effective against various microbes and viruses (including coronavirus). On July 30, 2020, Ascend Performance Materials submitted its first FDA 510(k) to market surgical masks made using Acteev technology.

Portable Remote Operational The COVID-19 public health emergency creates localized surges in the number of Remote electronic ICU technology has been around Wireless Enabled Surge Specialist patients requiring critical care, potentially leading to shortages of critical care long before the COVID-19 crisis, making this ICU (PROWESS-ICU) for remotely equipment and personnel in areas experiencing large surges or lacking substantial intervention not particularly disruptive. The time it monitoring critical COVID-19 critical care resources. One approach to addressing intensive care unit (ICU) takes to bring remote monitoring to remote locations, patients capacity shortages is the PROWESS-ICU being developed by the Medical as well as cost and logistics of delivery, also lowers University of South Carolina (MUSC) and multiple collaborating institutions. This the impact potential of the intervention. virtual network would provide technical, operational, clinical, and telehealth expertise to address ICU resource shortcomings. To operationalize the network, wireless monitoring technology will collect clinically relevant data to be analyzed by an artificial intelligence (AI) algorithm and transferred to an electronic health record system. Remote specialists at MUSC or other facilities would be able to access this information and guide appropriate medical care to patients who need critical care. For areas that lack sufficient critical care equipment to address ICU surges, PROWESS-ICU also involves rapid delivery and deployment of makeshift ICUs.

SECTION 4. SYSTEMS AND MANAGEMENT 51

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

Rapid expansion of telemedicine Response to the COVID-19 pandemic (eg, stay-at-home orders, strict social In August 2020, electronic medical records firm Epic driven by widespread COVID-19 distancing guidelines) has prompted health care providers across all clinical Systems Corporation reported that telemedicine use response specialties to rapidly adopt methods of care for non-COVID-19 patients. Whether peaked in April 2020 (about 70% of US health care for patients with acute or chronic conditions, the new methods are meant to visits versus 30% office visits) and declined to about maintain the safety of patients and clinical staff. Telemedicine technologies offer 21% of US health care visits versus 79% office visits by providers and patients multiple ways to connect with virtual visits that attempt to July 2020. This trend occurred across all US compensate for the lack of in-person physician-patient contact and to help geographic regions, suggesting a preference for in- maintain care plans. The pandemic has prompted regulators and insurers to person visits where available as the wider economy loosen regulations and reimbursement restrictions that traditionally limited gradually reopened. telemedicine to rural areas with limited access to providers. Thus, adoption has increased broadly. Some experienced centers have offered guidance for quickly implementing a telemedicine system in clinical practice. Other experts have noted that the broad expansion of health care information technology (IT) use prompted by COVID-19 provides an opportunity to improve public health surveillance during infectious disease outbreaks that would be optimized by an as-yet unrealized robust national health IT infrastructure. The long-term impact of these changes remains unclear. In August 2020, electronic medical records firm Epic Systems Corporation reported that telemedicine use peaked in April 2020 (about 70% of US health care visits versus 30% office visits) and declined to about 21% of US health care visits versus 79% office visits by July 2020.

SECTION 4. SYSTEMS AND MANAGEMENT 52

Section 5. Treatments: 39 Topics

Table 5.1. Topics Added Since Last Status Report: 4 Topics

Title Description Possible areas of impact Possible future impacts

CD24Fc (SACCOVID) for CD24Fc (SACCOVID) is an investigational recombinant fusion protein Patient outcomes Might prevent COVID-19 disease treating severe COVID-19 under development by OncoImmune to treat severe COVID- progression and/or mortality Health care costs 19. CD24Fc purportedly modulates immune responses through Might decrease the need and/or multiple mechanisms. First, it purportedly acts as an agonist of Siglec duration of mechanical ventilation 10, a receptor that dampens host immune responses. Second, CD24Fc purportedly binds and blocks the activity of danger-associated Might cause adverse events related molecular patterns, molecules that can initiate and perpetuate to immunomodulation inflammatory responses. A phase 3 randomized, placebo-controlled trial is studying the safety and efficacy of CD24Fc in 241 hospitalized patients with severe or critical COVID-19. In this trial, which had an estimated completion date of December 30, 2020, 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 53 Title Description Possible areas of impact Possible future impacts

Combination baricitinib and Baricitinib received Emergency Use Authorization (EUA) from FDA on Patient outcomes Might improve patient health remdesivir to treat November 19, 2020, for use in combination with remdesivir to treat outcomes and increase survival Population health COVID-19 COVID-19 in hospitalized adults and pediatric patients who require Might improve population health respiratory support. Baricitinib plus remdesivir is the first combination Health care costs outcomes by reducing burden on the therapy to receive an EUA from FDA for COVID-19. Baricitinib is an health care system oral janus kinase (JAK) inhibitor intended to reduce inflammation in COVID-19 by blocking a proinflammatory signaling pathway. It is FDA Might decrease health care costs approved to treat moderate to severe active rheumatoid arthritis. It is associated with hospitalizations and the first drug acting on an inflammatory pathway to receive an EUA for intensive care resources COVID-19. Remdesivir is an intravenous antiviral that was FDA Might improve understanding of approved on October 22, 2020, to treat patients hospitalized with combination therapies for COVID-19. The EUA for the combination of baricitinib with remdesivir COVID-19 was issued based on data from the Adaptive COVID-19 Treatment Trial (ACTT-2), which demonstrated that patients taking the drug combination, compared with remdesivir alone, experienced improved recovery time (7 versus 8 days, respectively), better clinical status at day 15, lower progression to ventilation (23% versus 28%), and decreased death (4.7% versus 7.1%). 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, making the cost of a single course of the combined regimen up to $8300.

SECTION 5. TREATMENTS 54

Title Description Possible areas of impact Possible future impacts

MultiStem for treating Patients with severe COVID-19 can develop ARDS, a complication that Patient outcomes Might increase the number of COVID-19-induced acute is associated with a high likelihood of death. MultiStem is an ventilator-free days in patients with Health care costs respiratory distress investigational cell-based therapy under development by Athersys for COVID-19-induced ARDS syndrome (ARDS) the treatment of ARDS. The stem cell product is developed from Might reduce death related to multipotent adult progenitor cells obtained from the bone marrow of COVID-19-induced ARDS 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 administered without tissue-matching procedures or to cell therapy immunosuppressive 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 55

Title Description Possible areas of impact Possible future impacts

Quellor (XPro1595) for Quellor (XPro1595) is a next-generation tumor necrosis factor Patient outcomes Might improve overall health and treating immune-mediated (TNF) inhibitor thought to selectively neutralize only soluble TNF quality of life by reducing health Health care costs complications of COVID-19 (sTNF). sTNF activates immune cells that contribute to acute respiratory complications from overactive distress syndrome (ARDS), a condition that often leads to the need for immune responses mechanical ventilation. Currently approved TNF inhibitors are Might reduce health care costs nonselective, blocking both sTNF and transmembrane TNF (tmTNF). related to length of hospitalization tmTNF purportedly does not contribute to COVID-19, but and use of intensive care resources does contribute to normal immune function. Quellor purportedly decreases inflammation and inflammatory immune Might increase cost of treatment 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 the ability of Quellor 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 has an estimated completion date of February 2021.

SECTION 5. TREATMENTS 56 Table 5.2. Currently Monitored Topics: 24 Topics

Title Description Possible areas of impact Possible future impacts

Anakinra (Kineret) for Anakinra (Kineret) is an interleukin-1 receptor antagonist approved by Patient outcomes Might improve health outcomes by treating COVID-19 with FDA for treating rheumatoid arthritis and cryopyrin-associated periodic reducing mechanical ventilation time Population health acute respiratory distress syndromes. It is also under study for treating COVID-19. Some patients and increasing survival in patients syndrome and with COVID-19 develop a maladaptive inflammatory response that can Health care costs with ARDS hyperinflammation lead to acute lung injury and respiratory insufficiency. Anakinra acts as Might improve overall health and a competitive antagonist of the cytokine receptor IL-1R1, which acts as quality of life by reducing related a driver of proinflammatory signaling. A small, retrospective study of health complications and risk for patients with moderate to severe COVID-19-related acute respiratory long-term sequelae distress syndrome (ARDS) reported 21-day survival of 90% for patients (n = 29) receiving high-dose anakinra (5 mg/kg, twice daily) plus Might improve population health standard of care (SoC) compared with 56% survival in a cohort of outcomes if mechanical ventilator patients (n = 16) receiving SoC alone. A second study of patients with shortages are minimized severe COVID-19-related bilateral pneumonia reported that 25% of Might reduce health care costs patients (n = 52) who received anakinra (200 mg/day on days 1 to 3, related to length of hospitalization 100 mg/day on days 4 to 10) required mechanical ventilation or died and intensive care resources needed compared with 73% of patients (n = 44) in a historical control group. Additionally, multiple studies involving anakinra treatment for patients with COVID-19 are registered at the National Library of Medicine trial registry. However, enrollment in a large French trial (ANACONDA) was recently suspended after excess mortality was observed in patients receiving anakinra.

SECTION 5. TREATMENTS 57

Title Description Possible areas of impact Possible future impacts

ANG-3777 to treat patients Some patients with COVID-19 experience severe respiratory distress Patient outcomes Might improve health outcomes and hospitalized with COVID- and multiple organ failure due to the direct effects of viral infection quality of life by preventing or 19 pneumonia and indirect effects associated with the body’s response to the virus. reducing the risk of acute lung and ANG-3777 is an investigational hepatocyte growth factor (HGF) kidney injury due to COVID-19 mimetic that might mitigate or prevent acute lung or kidney injury pneumonia caused by COVID-19. HGF is purportedly essential for activating the c- Might reduce burden on the health Met cascade in response to acute organ injury, which promotes tissue care system by reducing demand for and organ repair. ANG-3777 was developed to have a longer half-life mechanical ventilators and dialysis (3 hours) than does HGF (less than 5 minutes) and is being devices as well as hospitalization administered as a daily intravenous infusion for 4 days in clinical trials. length of stay A phase 2 randomized trial is comparing ANG-3777 with placebo in patients (n = 100) hospitalized in Brazil with severe COVID-19 pneumonia and receiving standard of care (SoC). 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 58

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

SECTION 5. TREATMENTS 59

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 shortening recovery Population health pneumonia calcium (CRAC) channel that is in clinical development to treat severe time and minimizing need for COVID-19-related pneumonia. Auxora might protect the cells lining Health care disparities invasive mechanical ventilation the lungs against damage, increase oxygen saturation, and prevent the Might improve population health release of cytokines (proinflammatory proteins) thought to contribute outcomes by decreasing the burden to hyperinflammation and respiratory disease severity in COVID-19. on the health care system Data published August 14, 2020, from an open-label, randomized portion of an ongoing developer-sponsored phase 2 trial showed that Might improve understanding of patients with severe or critical COVID-19 given Auxora in addition to mitigating hyperinflammation to standard-of-care (SoC) treatment (20 patients) had a median time to treat COVID-19 recovery of 5 days and a mechanical ventilation rate of 18% compared Might increase health disparities if with patients receiving SoC treatment alone (10 patients), who had a Auxora is available in only limited median time to recovery of 12 days and a mechanical ventilation rate quantities after authorization or of 50%. The developer began a second phase 2 trial in December 2020 approval for clinical use investigating the use of Auxora in 400 patients with critical COVID-19. Its expected primary completion date is in April 2021.

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

SECTION 5. TREATMENTS 60

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 with therapeutic form of interleukin-7 (IL-7), a key cytokine involved in quality of life by reducing health Health care costs COVID-19-related human T-cell survival and expansion. The factor purportedly can complications from lymphopenia induce the proliferation of naïve T cells to help replenish immune cells immunosuppression lost during the course of COVID-19-related cytokine storms and sepsis. Might reduce health care costs T-cell counts are dramatically reduced during COVID-19 infection, related to length of hospitalization which studies have shown has a negative correlation with patient and use of intensive care resources survival. Results from a 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 is studying the ability of CYT107 to improve clinical outcomes in lymphopenic patients with COVID-19, with a primary completion date of December 30, 2020. Participants (n = 48) with COVID-19 and absolute lymphocyte counts less 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.

SECTION 5. TREATMENTS 61

Title Description Possible areas of impact Possible future impacts

Dexamethasone to treat Dexamethasone is a corticosteroid being investigated as an Patient outcomes Might improve patient health severe COVID-19 intravenous or oral treatment for severe COVID-19. It is an outcomes and increase survival Population health immunosuppressant that might mitigate hyperinflammation observed Might reduce the burden on the in patients with severe COVID-19, which is thought to contribute to Health care costs health care system and the risk of acute respiratory distress syndrome (ARDS), multiorgan failure, and mechanical ventilator shortages death. Preliminary clinical trial data suggest dexamethasone significantly lowers 28-day mortality among hospitalized patients Might decrease health care costs receiving either invasive mechanical ventilation or oxygen alone associated with hospitalization and compared with participants receiving standard-of-care (SoC) intensive care resources, especially treatment. No benefit was seen in patients not receiving respiratory because dexamethasone is a widely support. A meta-analysis performed by the World Health Organization available, inexpensive drug showed that systemic corticosteroids in those critically ill with COVID- Might improve understanding of 19 was associated with lower 28-day all-cause mortality. There have hyperinflammation in COVID-19 and been concerns about potential risks of immunosuppression and the role of anti-inflammatory drugs increased replication of SARS-CoV-2 (the virus that causes COVID-19), in treatment although a clinical study found no association between early intervention with glucocorticoids and mortality or need for mechanical intervention. Ongoing clinical trials of dexamethasone to treat COVID- 19 include phase 2/3 (United Kingdom), phase 3 (United States and international), and phase 2 (United States) trials. 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.

SECTION 5. TREATMENTS 62

Title Description Possible areas of impact Possible future impacts

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

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 analogue developed to treat respiratory viruses. EIDD- Health care delivery and outcomes if burden on the health 2801 has demonstrated broad-spectrum antiviral activity in animal process care system is reduced models, including activity against SARS-CoV-2 (the virus that causes Health care costs COVID-19), SARS-CoV (severe acute respiratory syndrome–associated Might decrease health care costs coronavirus), and MERS-CoV (Middle East respiratory syndrome associated with hospitalization and coronavirus). Like remdesivir, another antiviral in development to treat intensive care resources COVID-19, EIDD-2801 targets viral RNA polymerase to block successful Might provide more convenient viral RNA replication. Preclinical studies suggest that EIDD-2801 might dosing compared with intravenous have activity against viral RNA polymerase with remdesivir resistance antivirals, which might help shift the mutations. EIDD-2801 is taken by mouth, which might be more treatment of COVID-19 to the home convenient than the intravenous route of remdesivir. Ongoing clinical setting sooner trials of EIDD-2801 to treat COVID-19 include developer-sponsored phase 2 studies in the outpatient setting and the inpatient setting, with primary completion dates in January and February 2021, respectively.

SECTION 5. TREATMENTS 63

Title Description Possible areas of impact Possible future impacts

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

SECTION 5. TREATMENTS 64

Title Description Possible areas of impact Possible future impacts

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

SECTION 5. TREATMENTS 65

Title Description Possible areas of impact Possible future impacts

Leronlimab for treating Some patients with COVID-19 experience an inflammatory condition Patient outcomes Might improve health outcomes by COVID-19 leading to pulmonary dysfunction and cardiovascular events thought reducing mechanical ventilation time Population health to contribute to COVID-19-related death. The CCL5 (RANTES)-CCR5 and increasing survival in patients signaling axis might contribute to this hyperinflammatory response by Health care costs with acute respiratory distress promoting the chemotaxis (homing and accumulation) of immune Might improve overall health and cells, thereby amplifying inflammatory responses. Leronlimab is an quality of life by reducing related investigational monoclonal antibody that purportedly acts as a C-C health complications and risk for chemokine receptor type 5 (CCR5) antagonist, inhibiting CCR5- long-term sequelae mediated trafficking of proinflammatory immune cells. A study of 10 patients treated with compassionate-care leronlimab found reductions Might improve population health in proinflammatory cytokines (eg, interleukin-6 [IL-6]) and coronavirus outcomes if mechanical ventilator in the blood. Additionally, the developer (CytoDyn, Inc) has announced shortages are minimized preliminary data from a randomized phase 2 trial of lemonime in 84 Might reduce health care costs if patients with mild to moderate COVID-19. An additional randomized length of hospitalization is reduced phase 2/3 trial in 390 patients with severe or critical COVID-19 is and fewer intensive care resources ongoing, with primary completion in December 2020. Although are needed lemonime is not commercially available, it is being developed as a potential 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 66

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 increase survival Population health and disease progression in patients who have COVID-19 with or Might improve population health without underlying high blood pressure. ARBs are inhibitors of the Health care disparities outcomes if burden on the health renin-angiotensin system (RAS), a complex hormone system that Health care costs care system is reduced regulates blood pressure and fluid and electrolyte balance. SARS-CoV- 2 (the virus that causes COVID-19) is thought to disrupt the RAS Might reduce health care costs if (specifically through binding to angiotensin-converting enzyme 2 hospitalization can be avoided, [ACE2] receptors for cellular entry) and increase inflammation, hospitalization length is shortened, contributing to the various renal, cardiovascular, and immune or fewer intensive care resources are symptoms seen in COVID-19. Losartan blocks activation of a receptor needed in the RAS (ie, angiotensin II type 1) involved in stimulating fibrosis and Might improve understanding of the inflammatory processes. It has been shown preclinically to reduce lung role of the RAS in COVID-19 inflammation in SARS-CoV (severe acute respiratory syndrome– pathology and ACEIs or ARBs as associated coronavirus) infection and improve survival in avian potential treatments influenza H5N1 infection. Investigators had concerns that RAS inhibitors might enhance the infectivity of SARS-CoV-2 by increasing Might complicate care delivery and the number of cellular surface ACE2 receptors. Results of recent adherence for patients with research, published in May 2020 and June 2020, have not observed hypertension that effect. Instead, a lower risk of all-cause death in patients with hypertension and COVID-19 who take an ARB or 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 67

Title Description Possible areas of impact Possible future impacts

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

SECTION 5. TREATMENTS 68

Title Description Possible areas of impact Possible future impacts

Machine learning to identify The widening coronavirus pandemic has prompted researchers to Population health Might expedite search for approved drug candidates to treat evaluate whether artificial intelligence (AI) can identify therapeutic drugs that could benefit patients Health care costs COVID-19 agents that might offer potential benefit in treating COVID-19. Gates with COVID-19 if used off-label and Hamed (Norwich University, Northfield, Vermont) developed the Might expedite search for drug CovidX Network Algorithm to identify drugs approved for other candidates that could benefit indications that might help treat COVID-19 (ie, repurposing drugs for patients with COVID-19 off-label use). Kowalewski and Ray (University of California, Riverside) used machine-learning techniques to predict drugs’ effectiveness Might provide a useful model for against COVID-19 from an analysis of 100 000 FDA-approved drugs rapid discovery of potential drugs to and registered chemicals and about 14 million other commercially target emerging pathogens in future available chemicals. They propose that findings could identify FDA- pandemics approved drugs suitable for repurposing or short-term approval and other agents that require longer-term study. Piplani et al 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 69 Title Description Possible areas of impact Possible future impacts

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

SECTION 5. TREATMENTS 70

Title Description Possible areas of impact Possible future impacts

Nitazoxanide (NT-300) to Nitazoxanide, an oral drug with broad-spectrum antiviral properties, is Patient outcomes Might reduce recovery time and risk treat mild to moderate being developed as the extended-release formulation NT-300 (Romark of progression to severe COVID-19 Population health COVID-19 Laboratories LC) to treat mild to moderate COVID-19. In cell cultures in Might decrease burden on the health the laboratory, nitazoxanide has been found to inhibit the replication Health care costs care system of multiple coronaviruses, including SARS-CoV-2 (the virus that causes COVID-19), SARS-CoV (severe acute respiratory syndrome–associated Might improve understanding of coronavirus), and MERS-CoV (Middle East respiratory syndrome mitigating hyperinflammation to coronavirus), as well as other viruses, such as those that cause the flu treat COVID-19 and the common cold. In addition to inhibiting replication of viruses, Might result in cost savings if the nitazoxanide purportedly suppresses the production of various drug cost is outweighed by potential proinflammatory proteins called cytokines. This action might treat mild health care costs saved with better to moderate COVID-19 by moderating an overexaggerated outcomes, or result in higher costs if inflammatory response to SARS-CoV-2 (ie, hyperinflammation), which the drug is more expensive than is thought to contribute to severe disease and poor outcomes. NT-300 potential health care costs saved was investigated in a developer-sponsored phase 3 trial (n = 800) that had a completion date in December 2020. Participants took NT-300 by mouth twice daily for 5 days.

SECTION 5. TREATMENTS 71

Title Description Possible areas of impact Possible future impacts

Proteomics to identify Researchers at the University of California, San Francisco, have Patient outcomes Might speed development of human protein targets for developed a protein interaction map for SARS-CoV-2, the virus that new COVID-19 therapeutics from Health care costs treating COVID-19 causes COVID-19. The map might facilitate repurposing of drugs approved drugs approved or in development for other indications to treat COVID-19. Might uncover potential The team identified 66 human proteins or host factor targets and 69 treatment targets for new compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 therapeutic agents preclinical compounds) as potential treatment candidates. Researchers 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 result in new therapeutic approaches to treat COVID-19. Other researchers at the Chinese Academy of Sciences have created a publicly available web server to explore potential COVID-19 treatments. The web server has 2 intended 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.

Recombinant plasma rhu-pGSN is an investigational anti-inflammatory treatment under Patient outcomes Might reduce the incidence or gelsolin (rhu-pGSN) for study for treating severe COVID-19 pneumonia. Gelsolin is a naturally severity of COVID-19 organ damage, Population health treating COVID-19 occurring protein that acts through multiple mechanisms to modulate potentially reducing the need for pneumonia host inflammatory reactions and enhance immune clearance of Health care costs mechanical ventilation or dialysis microbes and toxins. The protein is abundant in healthy individuals but Might reduce the burden on the is depleted by severe injury and infection. Depletion may contribute to health care system by reducing the excessive inflammatory responses, organ damage, and death. Gelsolin length of stay in the intensive care depletion has been associated with poor outcomes in COVID-19, and unit (ICU) and hospitalization supplementing depleted levels of gelsolin with rhu-pGSN might help mitigate the debilitating effects of cytokine storm and severe Might reduce long-term effects from inflammation seen in COVID-19 patients. A phase 2 randomized severe COVID-19 organ damage controlled trial evaluating rhu-pGSN compared with placebo in adults with COVID-19 pneumonia (n = 60) had an estimated study completion date in October 2020. Patients were given 3 doses of rhu-pGSN, along with standard of care (SoC), to evaluate the efficacy of rhu-pGSN (survival without organ failure on day 14), safety, and tolerability.

SECTION 5. TREATMENTS 72

Title Description Possible areas of impact Possible future impacts

Remdesivir (Veklury) to treat Remdesivir (Veklury, Gilead, Foster City, California) is an intravenously Patient outcomes Might reduce COVID-19 course COVID-19 administered antiviral adenosine analogue prodrug that purportedly length and severity Population health inhibits the replication of SARS-CoV-2 (the virus that causes COVID- Might improve population health if 19). Remdesivir became the first FDA-approved treatment for COVID- Health care delivery and the burden on the health care system 19 on October 22, 2020. It is indicated for use in hospitalized patients process is reduced aged 12 years or older weighing at least 40 kg. FDA also revised its Health care costs previous Emergency Use Authorization (EUA) for remdesivir to include Might reduce health care costs children younger than the age of 12 weighing enough to receive the related to hospitalization and drug intravenously (ie, 3.5 kg). The approval was based on data from 3 intensive care resources randomized clinical trials that suggested remdesivir significantly Might improve understanding of reduced time to recovery and increased odds of clinical improvement. antiviral treatments for COVID-19 The developer previously reported that the drug reduced mortality, although a later study from the World Health Organization (WHO) did not observe any effect on mortality. Although remdesivir is approved, there have been reports of its underuse due to efficacy skepticism, and the WHO weakly recommends against its use in any severity of COVID- 19, citing “no important difference” in several clinical outcomes with its use. Gilead announced the cost of a 5-day course of remdesivir would be $2340 to the US government and the list price for this course would be $3120.

SECTION 5. TREATMENTS 73

Title Description Possible areas of impact Possible future impacts

RLF-100 (Aviptadil) for RLF-100 (Relief Therapeutics and Neuro Rx, Inc) is a synthetic human Patient outcomes Might reduce risk of progression to treating COVID-19-induced vasoactive intestinal polypeptide (VIP) being investigated as an acute respiratory distress syndrome Population health nonacute lung injury and intravenous treatment for COVID-19. It is intended as a rescue therapy (ARDS) in patients who have acute respiratory distress for patients with critical COVID-19 (ie, respiratory failure) and to Health care costs nonacute lung injury, shorten syndrome prevent respiratory failure in those with moderate to severe COVID-19. mechanical ventilation time, and RLF-100 purportedly inhibits novel coronavirus replication, prevents increase survival in patients who have formation of inflammatory proteins (ie, cytokines), reduces cell death, ARDS and increases production of a protein important for lung function (ie, Might reduce health complications surfactant). RLF-100 became available through an expanded access and risk for long-term sequelae protocol (EAP) in July 2020 to patients aged 12 years or older who have critical COVID-19 with respiratory failure. In October 2020, the Might improve population health developers reported topline efficacy data from an open-label outcomes if mechanical ventilator prospective study of patients enrolled in the EAP; 21 patients treated shortages are minimized and burden with RLF-100 had an 80% survival rate at 60 days compared with only on the health care system is 17% in 30 patients receiving the control treatment. A phase 2/3 clinical decreased trial in patients aged 12 to 85 who have moderate or severe COVID-19 Might reduce health care costs if without respiratory failure is ongoing and has a primary completion length of hospitalization is shortened date in June 2021. In September 2020, NeuroRx submitted a request or fewer intensive care resources are for Emergency Use Authorization (EUA) to FDA for the use of RLF-100 needed in patients with critical COVID-19 and respiratory failure who have exhausted all approved treatments. RLF-100 previously received FDA Fast Track designation for the treatment of COVID-19.

SECTION 5. TREATMENTS 74

Title Description Possible areas of impact Possible future impacts

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

TD-0903 for treating acute TD-0903 (Theravance Biopharma, Dublin, Ireland) is an investigational Patient outcomes Might improve patient health lung injury in COVID-19 inhaled janus kinase (JAK) inhibitor intended to prevent the outcomes and increase survival Population health progression of acute lung injury to life-threatening acute respiratory Might improve population health distress syndrome (ARDS) in patients with COVID-19. ARDS in COVID- Health care costs outcomes if it reduces burden on the 19 is thought to be caused, in part, by a rapid influx of inflammatory health care system and decreases the proteins called cytokines into the lungs (ie, cytokine storm). This causes risk of mechanical ventilator severe inflammation and impaired oxygen exchange that can result in shortages the need for mechanical ventilation. Intervening early to block cytokine storm in COVID-19 pneumonia might be critical for survival. TD-0903 Might decrease health costs purportedly broadly inhibits the activity of JAKs that play a central role associated with hospitalization and in cytokine signaling. It is taken in a nebulized form to directly target intensive care resources hyperinflammation in the lungs and limit systemic suppression of the Might improve understanding of JAK immune system. A phase 2 study enrolling 222 hospitalized COVID-19 inhibitors and/or inhibiting cytokine patients is ongoing. Primary completion was expected in December storm in acute respiratory illnesses 2020. such as COVID-19

SECTION 5. TREATMENTS 75 Title Description Possible areas of impact Possible future impacts

Tranexamic acid for treating Tranexamic acid is a commercially available antifibrinolytic protease Patient outcomes Might improve patient health 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 process Might improve population health the conversion of plasminogen to the protease plasmin as well as the outcomes by reducing burden on the activity 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, which might contribute to COVID-19 organ damage caused by Might decrease health care costs if misregulation of coagulation. Additionally, plasmin could cleave the hospitalizations are reduced, viral spike protein (a step required for viral entry) and, therefore, hospitalization lengths are elevated plasmin might increase the infectivity and virulence of SARS- shortened, and/or fewer intensive CoV-2, the virus that causes COVID-19. Tranexamic acid might increase care resources are needed per the risk of local blood clot formation (thrombosis) when administered patient alone. Concomitant anticoagulation administration might mitigate this Might improve understanding of risk. Tranexamic acid is in two phase 2 trials for treating adults with antifibrinolytics used to treat COVID-19 in the outpatient setting and the non–intensive care COVID-19 inpatient setting. Additionally, a novel formulation of tranexamic acid, LB1148, is in phase 2 development for hospitalized patients who have COVID-19 with acute respiratory distress syndrome (ARDS) and lung dysfunction. Generic tranexamic acid costs as little as $26 for a 30-day supply (650-mg tablets) and is covered by Medicare.

SECTION 5. TREATMENTS 76

Table 5.3. Recently Archived Topics: 11 Topics

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

Canakinumab (Ilaris) for treating Some patients with COVID-19 experience an inflammatory condition leading to On November 6, 2020, Novartis announced that the COVID-19 pulmonary dysfunction and cardiovascular events thought to contribute to COVID- phase 3 randomized controlled trial (RCT) 19-related death. An interleukin signaling pathway involving interleukin-1 (IL-1) investigating canakinumab plus standard of care and interleukin-6 (IL-6) is thought to be a key driver of this inflammation, and (SoC) failed to meet its primary end point of a greater patients with COVID-19 have exhibited elevated levels of various proinflammatory chance of patient survival without the need for cytokines, including interleukin-1 beta (IL-1ß). Therefore, investigators are studying mechanical ventilation. whether the anti-IL-1ß monoclonal antibody canakinumab (Ilaris), intended to block IL-1 signaling, can treat COVID-19. Canakinumab is commercially available, having been FDA approved to treat periodic fever syndromes and systemic juvenile idiopathic arthritis. Multiple canakinumab trials are registered at the National Library of Medicine trial registry, including a Novartis-sponsored randomized, placebo-controlled trial of a single intravenous infusion of canakinumab in 450 patients hospitalized for COVID-19 pneumonia who are not currently on mechanical ventilation. On November 6, 2020, Novartis announced that an interim analysis of this trial indicated that canakinumab compared with placebo failed to meet its primary end point of a greater chance of patient survival without the need for intensive mechanical ventilation or its key secondary end point of reduced COVID-19 mortality.

Colchicine to treat COVID-19 Colchicine is an oral drug approved by FDA to treat gout and familial Efficacy data are not yet sufficient to determine Mediterranean fever. It is being investigated as a repurposed treatment for COVID- whether colchicine will significantly improve patient 19 because of its immunomodulatory, anti- health outcomes. Some study outcomes have not inflammatory, and antiviral properties. It might counter cytokine storm to decrease demonstrated statistically significant improvements. inflammation as well as prevent cardiovascular complications, although more While colchicine’s side effect profile is already research is needed. Preliminary data from patients with COVID-19 treated with established and considered to be generally safe, colchicine suggest longer time to clinical deterioration, earlier discharge from the certain side effects, such as nausea, vomiting, and hospital, and lower rates of mortality and intubation compared with standard-of- diarrhea, may be dangerous for patients with COVID- care (SoC) treatment only. Colchicine is being investigated in 4 ongoing clinical 19, who are especially susceptible to dehydration. trials in the United States (phase 3 trial, phase 3 trial, phase 2 trial, phase 2 trial) that plan to enroll about 7000 patients combined, in both inpatient and outpatient settings, and anticipate primary study completion within the next year. Based on trial dosing information and colchicine pricing information, one treatment course costs approximately $80 to $150.

SECTION 5. TREATMENTS 77

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

Dapagliflozin to reduce risk of Dapagliflozin (Farxiga) is a sodium glucose cotransporter 2 (SGLT2) inhibitor that Efficacy data are not yet available to suggest complications from mild to lowers blood glucose by promoting the excretion of glucose into the urine. It is an dapagliflozin significantly improves patient health moderate COVID-19 oral drug approved by FDA to treat type 2 diabetes mellitus and heart failure and outcomes and thus might disrupt health care during has been shown to improve outcomes in patients with type 2 diabetes, heart the COVID-19 pandemic. Insulin might be more likely failure with reduced ejection fraction, and chronic kidney disease. Worse outcomes to be used in the acute setting to control from COVID-19 have been seen in patients who have preexisting heart, kidney, hyperglycemia compared with dapagliflozin, and and metabolic diseases, as well as in patients with elevated blood glucose levels dapagliflozin might not be widely available on without a previous diagnosis of diabetes. Dapagliflozin is being investigated as a hospital formularies or might be cost prohibitive for potential treatment to reduce the risk of serious complications and organ failure in some patients. patients with mild to moderate COVID-19 who have cardiovascular, metabolic, or kidney disease risk factors. A retrospective study of diabetic patients with COVID- 19 found that well-controlled blood glucose correlated with improved outcomes. AstraZeneca sponsored a phase 3 trial in the United States that had a primary completion date in October 2020. The trial enrolled 900 hospitalized participants with mild to moderate COVID-19 who had at least one of the following: hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, or stage 3 or 4 chronic kidney disease. No data have been released yet.

EDP1815 for treating EDP1815 is an investigational, orally administered probiotic consisting of the Incomplete efficacy data on the intervention, as well hospitalized patients with bacterium Prevotella histicola that is under development by Evelo Biosciences for as the time the trial is taking to complete, significantly COVID-19 symptoms and treating COVID-19 symptoms and complications. EDP1815 purportedly engages lower the disruptive potential of this treatment. While complications the immune system in the small intestine to modulate systemic immune data on EDP1815 regarding psoriasis are promising, responses, an interface the developer refers to as the small intestinal axis (SINTAX). the treatment needs more research on how effective Immune cells from around the body circulate through lymphoid tissues of the it will be treating patients with COVID-19 and the small intestine and become conditioned by exposure to antigens, impact it will have. immunomodulatory agents, and microbes in the gut. EDP1815 is a strain of a naturally evolved human gut commensal microbe that reprograms immune cells in the small intestine, which go on to modulate effector cells in lymph nodes. The effector cells purportedly circulate through the lymphatic system to exert systemic therapeutic effects. Early data from a phase 1b trial in psoriasis suggest that EDP1815 might modulate multiple immune pathways associated with cytokine storms in COVID-19 patients without the risks associated with immunosuppression. A phase 2 double-blind trial is investigating daily dosing of EDP1815 versus placebo for 14 days in patients (n = 60) hospitalized with COVID- 19. Study completion was expected in December 2020.

SECTION 5. TREATMENTS 78

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

Favipiravir to treat COVID-19 Favipiravir is an antiviral drug first approved in Japan to treat influenza (Avigan, Favipiravir is one of numerous potential antiviral Fujifilm, Tokyo, Japan) that has recently been approved in Russia, China, and India treatment options for COVID-19, rendering it to treat COVID-19 and is now being investigated in the United States as a incremental and unlikely to cause large disruption in treatment for COVID-19. Favipiravir inhibits viral RNA-dependent RNA the current COVID-19 treatment landscape. polymerases, preventing RNA virus replication, and has been shown preclinically to inhibit replication of SARS-CoV-2 (the virus that causes COVID-19). Fujifilm announced in September 2020 that a phase 3 clinical trial of 156 patients in Japan with nonsevere pneumonia showed that patients who took favipiravir experienced a significantly shorter time to negative SARS-CoV-2 test results and symptom resolution (11.9 days) compared with the placebo group (14.7 days). Another developer of favipiravir (FabiFlu, Glenmark Pharmaceuticals, Mumbai, India) similarly observed reduced time to improvement (28.6% faster viral clearance) in patients with mild to moderate COVID-19 who took favipiravir compared with the control arm in a phase 3 clinical trial of 150 patients in India. A developer-sponsored phase 2 trial in hospitalized patients recently completed in November 2020. Data have not yet been released. A Stanford University- sponsored phase 2 trial and a phase 3 trial sponsored by Appili Therapeutics, both in outpatients, are ongoing.

Garadacimab (CSL312) for Garadacimab (CSL312) is an investigational monoclonal antibody that functions as Many other monoclonal antibodies are in treating respiratory distress a factor XIIa (FXIIa) antagonist and might reduce the incidence of tracheal development for treating respiratory distress caused caused by COVID-19 intubation or death in patients with COVID-19-related respiratory distress. Patients by COVID-19, significantly lowering the impact of this with severe COVID-19 have severe inflammatory cascades that can trigger intervention. More research is needed to determine intravascular coagulation and thrombus formation, leading to multiple organ the treatment’s success at stopping the coagulation failure. Garadacimab blocks the action of FXIIa, a serum protein involved in the cascade that eventually leads to respiratory and organ blood clotting cascade. Garadacimab is being evaluated in a phase 2 randomized failure. controlled trial compared with placebo for treating adults (n = 124) with COVID- 19-related pneumonia. Study completion was expected in December 2020.

SECTION 5. TREATMENTS 79 Title Description Archive reason(s) based on data review and/or stakeholder ratings and comments

Intermediate- or therapeutic- Coagulopathy is a common complication of COVID-19 and might lead to While the rationale behind increasing heparin dosing dose heparin anticoagulation increased rates of venous thromboembolic events, such as deep vein thrombosis is sound and increasing anticoagulant dosing has the for patients hospitalized for and pulmonary embolism, in affected patients. Additionally, extensive potential to improve patient health outcomes, the COVID-19 microvascular thrombosis in the lungs has been observed in autopsies of COVID- shift from prophylactic to intermediate- or 19 patients, suggesting coagulopathy might play a role in disease pathogenesis. therapeutic-dose heparin was seen by stakeholders as Guidelines from both the American Society of Hematology and the American being incremental in terms of patient outcomes and College of Chest Physicians recommend that all patients hospitalized with COVID- disruption to health care processes. 19 receive anticoagulant thromboprophylaxis with low-molecular-weight heparin (LMWH) at the standard prophylactic dose. However, retrospective studies have observed the persistence of thromboembolic events in patients despite receiving the standard prophylactic heparin dosing, prompting researchers to investigate if patients hospitalized with COVID-19 should receive higher doses of heparin. A 20- patient randomized controlled trial (RCT) found that therapeutic-dose enoxaparin improved gas exchange and decreased the need for mechanical ventilation in patients with severe COVID-19 compared with standard anticoagulant thromboprophylaxis. Additional RCTs are ongoing, including a large international trial (n = 3000) with primary completion in January 2021 and a large Italian trial (n = 2712) with study completion expected in November 2020. Multiple smaller, US-based trials of heparin dosing are also registered in the National Library of Medicine’s clinical trials registry.

SECTION 5. TREATMENTS 80

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

Intravenous immune globulin Excessive release of proinflammatory proteins in response to infection with SARS- IVIG treatment requires healthy blood donors and (human) to treat severe CoV-2 (the virus that causes COVID-19) is thought to contribute to COVID-19 donations, making it hard to create large clinical trials, COVID-19 severity and poor clinical outcomes. Intravenous immunoglobulin (IVIG) is a which are necessary to prove the efficacy of the human plasma product consisting of normal human immune globulins treatment. Since there is insufficient supply of IVIG or (antibodies) derived from a pool of several thousand healthy donors. It is FDA evidence for the impact and effectiveness of the approved for, and used off-label to treat, a variety of immune deficiency and treatment, overall disruption potential is limited. autoimmune disorders. IVIG might reduce hyperinflammation and risk of cytokine storm in patients hospitalized with severe COVID-19 by increasing levels of autoreactive antibodies that bind cytokines and by blocking innate immune effector cell activation. A prospective study evaluating IVIG found that IVIG significantly improved hypoxia and reduced hospital length of stay as well as the rate of progression of respiratory failure requiring mechanical ventilation in COVID-19 patients. US clinical trials investigating the use of IVIG to treat COVID-19 include phase 4 (n = 40), phase 3 (n = 208), and phase 2 (n = 100) trials, all with primary completion dates in 2020. Based on a treatment regimen consisting of a total dose of 2 g per kg body weight and an average patient weight of 88.8 kg, 2 representative IVIG options, Gamunex-C and Octagam, cost between about $22 000 and $32 000.

SECTION 5. TREATMENTS 81

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

Opaganib to treat pneumonia Opaganib (Yeliva, RedHill Biopharma, Tel-Aviv, Israel) is a selective inhibitor of the Although opaganib has an already established safety associated with COVID-19 enzyme sphingosine kinase-2 (SK2). It is in development to treat various cancers. profile and might have both antiviral and anti- Opaganib has demonstrated antiviral activity against SARS-CoV-2 (the virus that inflammatory effects, efficacy data are insufficient to causes COVID-19) and anti-inflammatory properties in preclinical models and suggest large disruption potential at this time. might improve outcomes in patients with pneumonia associated with COVID-19. Numerous treatments are being developed for Specifically, its inhibition of sphingolipid metabolism might attenuate COVID-19 pneumonia, and it is likely that several will proinflammatory processes that are thought to contribute to severe disease course soon become clinically available, lessening the and worse prognosis in COVID-19. Additionally, SK2 purportedly plays a role in the disruption potential for opaganib in the overall replication of single-stranded RNA viruses such as SARS-CoV-2, and, therefore, COVID-19 treatment landscape. opaganib may have antiviral activity. In clinical trials, opaganib is taken by mouth in addition to standard-of-care (SOC) therapy by hospitalized patients with COVID-19-associated pneumonia requiring supplemental oxygen. A phase 2 proof-of-concept study (n = 40) had expected primary completion in November 2020. A phase 2/3 study (n = 270) has a primary completion date in January 2021. Data published June 23, 2020, on compassionate use of opaganib in 7 patients with severe COVID-19 suggested opaganib was well tolerated and improved clinical and laboratory parameters. In August 2020, the developer announced plans to potentially submit applications for several Emergency Use Authorizations (EUAs) as early as the end of 2020.

Pamrevlumab for treating Pamrevlumab is an investigational monoclonal antibody that inhibits the activity of Other monoclonal antibodies are currently in hospitalized patients with acute connective tissue growth factor (CTGF). CTGF is associated with fibrotic and development, and some have already been approved COVID-19 proliferative diseases that cause persistent and excessive scarring, which can lead for treatment of COVID-19; therefore, pamrevlumab to organ dysfunction and failure. The factor might promote vascular leakage and would not likely have a significant impact. A lack of lead to pulmonary edema related to acute COVID-19 pulmonary disease. These data on efficacy and how the intervention works also processes may cause a reduction in oxygenation that can lead to severe lowers the impact potential. respiratory failure. Pamrevlumab might mitigate or reverse the edema caused by CTGF by inhibiting the growth factor, protecting the lungs from COVID-19- induced pneumonia and improving oxygenation. A phase 2 randomized trial is ongoing, comparing weekly intravenous infusions of pamrevlumab with placebo in patients (n = 130) aged 40 to 85 years hospitalized with acute COVID-19. Primary completion was expected in December 2020.

SECTION 5. TREATMENTS 82

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

Sargramostim (Leukine) for Sargramostim (Leukine) is a recombinant form of human granulocyte-macrophage Sargramostim data are based on 6 patients, and while treating patients with COVID-19- colony-stimulating factor (GM-CSF) approved by FDA for various applications sargramostim could be a useful intervention, many associated respiratory illness requiring the proliferation or reconstitution of myeloid cells. Some patients with other treatments for COVID-19-related ARDS are in COVID-19 develop severe immune reactions that can cause edema, coagulopathy, development and have reached later-stage clinical and lung damage, resulting in acute hypoxic respiratory failure. GM-CSF is a trials with more patients. GM-CSF is associated with cytokine involved in antiviral immunity, innate immune responses, and promoting severe respiratory complications; therefore, this lung repair. A 2014 compassionate use study found that GM-CSF had beneficial treatment may have adverse effects when used in a effects in patients (n = 6) with pneumonia-associated acute respiratory distress larger population. syndrome (ARDS) due to various pathogens, including significant improvement in oxygenation and about a 40% mean increase in lung compliance 10 days post GM-CSF inhalation. Sargramostim is being evaluated in a phase 2 trial with 60 COVID-19-positive patients and estimated completion in November 2020, as well as a phase 4 trial with estimated completion on October 31, 2020. The phase 4 trial is randomly assigning patients (n = 80) with COVID-19-related acute hypoxic respiratory failure to treatment with sargramostim for 5 days through inhalation via mesh nebulizer (125 μg twice daily) plus standard of care (SoC) or to SoC alone. Patients in either group exhibiting clinical deterioration may receive intravenous sargramostim. Sargramostim costs about $1447 for a 5-day supply.

SECTION 5. TREATMENTS 83

Section 6. Vaccines and Prophylaxis: 9 Topics

Table 6.1. Topics Added Since Last Status Report: 1 Topic

Title Description Possible areas of impact Possible future impacts

Sanofi-GSK SARS-CoV-2 The Sanofi-GSK SARS-CoV-2 vaccine is an adjuvanted, Patient outcomes Might reduce coronavirus infection vaccine for preventing recombinant protein–based vaccine that is intended to generate a risk and improve patient health Population health SARS-CoV-2 infection protective immune response against SARS-CoV-2 (the virus that causes outcomes COVID-19). The vaccine consists of a recombinant SARS-CoV-2 spike Clinician and/or caregiver Might reduce the cost of treating protein, which is expressed on the surface of SARS-CoV-2 and is safety severe infections responsible for viral fusion and entry. The vaccine is expected Health care delivery and to engage the immune system in a manner similar to that of other Might relax social distancing process recombinant protein vaccines (eg, hepatitis B vaccine, human protocols papillomavirus vaccine). The recombinant protein vaccine is formulated Health care disparities Might not provide the level of with an adjuvant intended to boost the immune response to the Health care costs protection hoped for due to the vaccine, thereby requiring less antigen to stimulate a response. The accelerated approval process vaccine is part of the US government’s Operation Warp Speed and is in a phase 1/2 randomized trial in 440 adults with an estimated Might have undiscovered adverse completion of October 2021. Due to inadequate results in older adults events due to the accelerated caused by a vaccine formulation error in the phase 1/2 trial, the approval process company has pushed back its target date of a request Might have vaccine shortages, if for regulatory approval to the second half of 2021. Unlike vaccines effective, due to limited production further in development that are based on messenger RNA platforms capacity and need to be kept frozen before use, the Sanofi–GSK vaccine is intended to be stable in liquid form at refrigerator temperatures. Might reduce the burden on the cold storage chain required for vaccine distribution

SECTION 6. VACCINES AND PROPHYLAXIS 84 Table 6.2. Currently Monitored Topics: 7 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 preventing SARS-CoV-2 mRNA vaccine that encodes the viral spike protein responsible for risk and improve patient health Population health infection receptor binding and cellular entry. The vaccine purportedly enters outcomes host antigen-presenting cells and induces expression of the viral spike Clinician and/or caregiver Might reduce the cost of treating protein, which acts to elicit a host immune response against the virus safety severe infections to prevent future infection. The mRNA component of the vaccine is Health care delivery and self-amplifying, which purportedly increases immunogenicity. ARCT- Might relax social distancing process 021 is in phase 1/2 development, and primary completion was protocols expected in December 2020; the randomized, placebo-controlled study Health care disparities Might improve understanding of enrolled healthy volunteers (n = 92) to evaluate the safety of, and Health care costs mRNA vaccine technologies immune response to, ARCT-021. Interim study results from the phase 1/2 trial in 106 participants given either 1 or 2 doses of ARCT-021 (1 to 10 μg per injection) or placebo showed that participants receiving doses in the range of 5 to 7.5 μg achieved serum neutralizing antibody levels similar to those in patients who recovered from COVID- 19. The manufacturer has chosen the 7.5-μg dose to be advanced into later-stage clinical trials. Due to the low dose of vaccine required to induce immune responses, the manufacturer plans be able to produce hundreds of millions of doses in 2021, if approved by FDA.

SECTION 6. VACCINES AND PROPHYLAXIS 85

Title Description Possible areas of impact Possible future impacts

AZD1222 (ChAdOx1 nCoV- AZD1222 (ChAdOx1 nCoV-19) is a recombinant, attenuated adenovirus Patient outcomes Might reduce coronavirus infection 19) vaccine for preventing vector vaccine in development by AstraZeneca (licensed from the risk and improve patient health Population health SARS-CoV-2 infection University of Oxford) that is purported to generate a strong immune outcomes response from 2 doses without replicating (avoiding an active infection Clinician and/or caregiver Might reduce the cost of treating from the vaccine). The modified vector contains the gene for the SARS- safety severe infections CoV-2 spike protein, which is expressed on the surface of SARS-CoV-2 Health care delivery and (the virus that causes COVID-19) and is responsible for viral fusion and Might relax social distancing process entry. AZD1222 purportedly enters the cytosol of antigen-presenting protocols cells and induces the expression of viral spike protein, which can Health care disparities Might not provide the level of induce host immune responses to prevent future infection. The vaccine Health care costs protection hoped for due to the is part of the US government’s Operation Warp Speed. AZD1222 is in a accelerated approval process phase 3 trial in 40 000 adults with primary completion on March 23, 2021. The trial was put on a temporary pause on September 9, 2020, Might have undiscovered adverse due to a single event of a neurological illness. FDA authorized the events due to the accelerated resumption of trials on October 23, 2020. Interim results announced in approval process a company press release from the phase 2/3 trials of AZD1222 in the Might have vaccine shortages, if United Kingdom and Brazil stated that AZD1222 was 90% effective in effective, due to limited production preventing COVID-19 in participants given a half dose followed by a capacity full dose at least 1 month later. Vaccine efficacy was 62.1% when 2 full doses were given at least 1 month apart.

SECTION 6. VACCINES AND PROPHYLAXIS 86

Title Description Possible areas of impact Possible future impacts

JNJ-78436735 (Ad26.COV2- JNJ-78436735 (Ad26.COV2-S; Johnson & Johnson) is a recombinant, Patient outcomes Might reduce coronavirus infection S) vaccine for preventing attenuated adenovirus vector vaccine that is purported to generate a risk and improve patient health Population health coronavirus infection strong immune response from a single dose without replicating outcomes (avoiding an active infection from the vaccine). The vector was Clinician and/or caregiver Might reduce the cost of treating modified to contain the gene for the SARS-CoV-2 spike protein, which safety severe infections is expressed on the surface of SARS-CoV-2 (the virus that causes Health care delivery and COVID-19) and is responsible for viral fusion and entry. JNJ-78436735 Might relax social distancing process purportedly enters the cytosol of antigen-presenting cells and induces protocols the expression of viral spike protein, which can induce host immune Health care disparities Might not provide the level of responses to prevent future infection. The company reported positive Health care costs protection hoped for due to the interim phase 1/2a results, finding that most participants had vaccine- accelerated approval process induced binding and neutralizing antibody levels that were in the same range as COVID-19 human convalescent sera. The vaccine is part of Might have undiscovered adverse the US government’s Operation Warp Speed and is in a phase 3 events due to the accelerated trial with 40 000 adults with primary completion in March 2023. On approval process October 12, 2020, Johnson & Johnson announced a temporary pause Might have vaccine shortages, if of all JNJ-78436735 trials due to a single unexplained illness that effective, due to limited production occurred in a participant. The trials were resumed on October 23, 2020, capacity after a recommendation from the Data Safety Monitoring Board.

SECTION 6. VACCINES AND PROPHYLAXIS 87

Title Description Possible areas of impact Possible future impacts

Monoclonal antibodies Cellular entry of SARS-CoV-2 (the virus that causes COVID-19) depends Patient outcomes Might improve individual health targeting SARS-CoV-2 spike on an interaction between the viral surface spike protein and the cell outcomes by reducing the risk or Population health protein receptor binding surface protein angiotensin-converting enzyme 2 (ACE2). Monoclonal severity of SARS-CoV-2 infection domain for preventing antibodies targeting the spike protein receptor binding domain (RBD) Clinician and/or caregiver Might improve frontline health care COVID-19 might interfere with this interaction and are being investigated for safety worker and/or patient safety in the their ability to prevent SARS-CoV-2 infection in asymptomatic patients Health care delivery and health care setting with known SARS-CoV-2 exposure. These virus-neutralizing antibodies process might provide short-term, passive immunity against SARS-CoV-2, Might limit the extent of SARS-CoV-2 potentially preventing or limiting viral infection. These antibodies Health care disparities outbreaks in workplace or residential would likely be used in vulnerable populations such as individuals with settings Health care costs known exposure to SARS-CoV-2-infected individuals. Neutralizing Might increase health disparities antibodies in development include single monoclonal antibodies and based on socioeconomic status due cocktails containing 2 or more monoclonal antibodies that bind to likely high cost nonoverlapping RBD epitopes. A phase 3 trial is assessing Regeneron’s antibody cocktail REGN-COV2 compared with placebo in 2000 asymptomatic, healthy adults in household contact with a SARS-CoV- 2-positive individual. The phase 3 BLAZE-2 trial is assessing Lilly/Abcellera’s antibody LY-CoV555 compared with placebo in 2400 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.

SECTION 6. VACCINES AND PROPHYLAXIS 88

Title Description Possible areas of impact Possible future impacts

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

SECTION 6. VACCINES AND PROPHYLAXIS 89

Title Description Possible areas of impact Possible future impacts

NVX-CoV2373 vaccine for NVX-CoV2373 is a recombinant nanoparticle vaccine in development Patient outcomes Might reduce coronavirus infection preventing SARS-CoV-2 by Novavax that purportedly generates a protective immune response risk and improve patient health Population health infection against SARS-CoV-2 (the virus that causes COVID-19). The vaccine outcomes consists of a full-length SARS-CoV-2 spike protein, which is essential Clinician and/or caregiver Might reduce costs associated for host receptor binding, viral fusion, and viral entry and, therefore, safety with treating severe infections represents a rational immunogen with which to develop a protective Health care delivery and immune response. NVX-CoV2373 may be coadministered with Might relax social distancing process Novavax’s proprietary Matrix-M1 adjuvant to enhance immune protocols responses. Interim results from a randomized, placebo-controlled, Health care disparities Might have undiscovered adverse phase 1/2 study (n = 131) found that adjuvanted NVX-CoV2373 was Health care costs events due to the accelerated well tolerated and able to trigger similar antibody responses in the 5- approval process µg and 25-µg dosage groups. Patients given adjuvanted NVX-CoV2373 at days 0 and 21 developed anti-spike IgG and neutralizing antibody Might have vaccine shortages, if responses that were 4-fold higher than those found in convalescent effective, due to limited production sera from patients who recovered from COVID-19. NVX-CoV2373 is in capacity a phase 3 randomized trial in 30 000 participants, with primary results expected in March 2021. The vaccine is part of the US government’s Operation Warp Speed.

SECTION 6. VACCINES AND PROPHYLAXIS 90

Title Description Possible areas of impact Possible future impacts

Pfizer-BioNTech COVID-19 Pfizer and BioNTech have partnered to develop and manufacture Patient outcomes Might reduce coronavirus infection Vaccine for preventing Pfizer-BioNTech COVID-19 Vaccine (BNT162b2), a lipid nanoparticle– risk and improve patient health Population health SARS-CoV-2 infection encapsulated mRNA vaccine that encodes the viral spike protein. This outcomes protein is expressed on the virus surface and is responsible for Clinician and/or caregiver Might reduce the cost of treating receptor binding and cellular entry. mRNA vaccines purportedly enter safety severe infections the cytosol of antigen-presenting cells and induce the expression of Health care delivery and viral proteins that can elicit host immune responses to prevent future Might relax social distancing process infection. The vaccine is part of the US government’s Operation Warp protocols Speed, and the manufacturers expect to produce 200 million doses by Health care disparities Might not provide the level of July 31, 2021. The vaccine is being investigated at a 30-μg dose in Health care costs protection hoped for due to the a phase 2/3 trial in 43 998 healthy adults, with estimated completion in accelerated approval process August 2021. A safety and efficacy analysis of the phase 2/3 trial data stated that, of the 170 confirmed cases of COVID-19 included in Might have undiscovered adverse the interim analysis, 162 cases of COVID-19 were observed in the events due to the accelerated placebo group versus 8 cases observed in the vaccine group (95% approval process effective in preventing COVID-19). The analysis also reported that the Might have vaccine shortages, if vaccine was well tolerated across all populations, with the most effective, due to limited production common adverse events being fatigue and headache, experienced at a capacity frequency of 3.8% and 2%, respectively. The Pfizer-BioNTech vaccine was granted Emergency Use Authorization (EUA) by FDA on December 11, 2020.

SECTION 6. VACCINES AND PROPHYLAXIS 91

Table 6.3. Recently Archived Topics: 1 Topic

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

Prophylactic heparin Coagulopathy is a common complication of COVID-19 and may lead to increased Difficulties associated with implementing and anticoagulation for rates of venous thromboembolic events, such as deep vein thrombosis and monitoring use of prophylactic heparin in nonhospitalized patients with pulmonary embolism, in affected patients. Additionally, extensive microvascular nonhospitalized patients were seen by stakeholders as COVID-19 thrombosis in the lungs has been observed in autopsies of COVID-19 patients, reducing the likelihood that such a program would be suggesting a potential role of coagulopathy in the pathogenesis of the disease. widely adopted. While guidelines from both the American Society of Hematology and the American College of Chest Physicians recommend that all patients hospitalized with COVID-19 receive anticoagulant thromboprophylaxis, anticoagulation is not routinely prescribed to nonhospitalized patients with COVID-19. The Thrombosis Research Institute, in collaboration with Sanofi, is conducting a randomized study to determine the safety and efficacy of prophylactic dosing with low-molecular- weight heparin (LMWH) for treating newly diagnosed, nonhospitalized, high-risk patients with COVID-19. The trial will randomly assign 1370 patients to treatment with LMWH (enoxaparin) or standard of care (SoC) and assess rates of hospitalization and mortality. Primary data completion is expected in January 2021.

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Appendix. Abbreviations and Acronyms

3D 3-dimensional ACE2 angiotensin-converting enzyme 2 ACEI angiotensin-converting enzyme inhibitor ACTIV Accelerating COVID-19 Therapeutic Interventions and Vaccines 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 CAC coronary artery calcification CCL5 (RANTES)-CCR5 C-C chemokine ligand 5 (regulated upon activation, normal T-cell expressed, and secreted)-C-C chemokine receptor type 5 CCR5 C-C chemokine receptor type 5 CDC Centers for Disease Control and Prevention CLIA Clinical Laboratory Improvement Amendments of 1988 COVID-19 coronavirus disease 2019 COVPN COVID-19 Prevention Network CP convalescent plasma CRAC calcium release–activated calcium CRISPR clustered regularly interspaced short palindromic repeats CRP C-reactive protein CT computed tomography CTGF connective tissue growth factor EAP expanded access protocol ELISA enzyme-linked immunosorbent assay EPA US Environmental Protection Agency EUA Emergency Use Authorization

Appendix. Abbreviations and Acronyms 93

FDA US Food and Drug Administration FXIIa factor XIIa GM-CSF granulocyte-macrophage colony-stimulating factor H2 histamine HCHSS Health Care Horizon Scanning System HGF hepatocyte growth factor H-IG hyperimmune immunoglobulin IBQ-R Infant Behavior Questionnaire-Revised ICU intensive care unit IgG immunoglobulin G IgM immunoglobulin M IL-1 interleukin-1 IL-1β interleukin-1 beta IL-1R1 interleukin-1 receptor type I IL-6 interleukin-6 IL-7 interleukin-7 IT information technology IVIG intravenous immunoglobulin JAK janus kinase LAMP loop-mediated isothermal amplification LDRT low-dose radiation therapy LMWH low-molecular-weight heparin MERS-CoV Middle East respiratory syndrome coronavirus Mpro SARS-CoV-2 main protease mRNA messenger RNA MUSC Medical University of South Carolina N95 not resistant to oil mists, filters at least 95% of 0.3 micrometer droplets NASEM National Academies of Sciences, Engineering, and Medicine NGS next-generation sequencing

Appendix. Abbreviations and Acronyms 94

NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health NIRL near-infrared light NPA negative percentage agreement PCORI Patient-Centered Outcomes Research Institute PCR polymerase chain reaction POC point-of-care PPA positive percentage agreement PPE personal protective equipment PPI proton pump inhibitor RAS renin-angiotensin system RBD receptor binding domain RCT randomized controlled trial rhu-pGSN recombinant plasma gelsolin RMAT Regenerative Medicine Advanced Therapy RT-PCR reverse transcriptase 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 SGLT2 sodium glucose cotransporter 2 SINTAX small intestinal axis SK2 sphingosine kinase-2 SNRI serotonin-norepinephrine reuptake inhibitor SoC standard of care SSRI selective serotonin reuptake inhibitor sTNF soluble tumor necrosis factor TMPRSS2 transmembrane serine protease 2 tmTNF transmembrane tumor necrosis factor TNF tumor necrosis factor

Appendix. Abbreviations and Acronyms 95

VAERS Vaccine Adverse Event Reporting System VIP vasoactive intestinal polypeptide WHO World Health Organization

Appendix. Abbreviations and Acronyms 96