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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Suggested Citation:"5 Therapeutics." National Academies of Sciences, Engineering, and Medicine and National Academy of Medicine. 2021. Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19. Washington, DC: The National Academies Press. doi: 10.17226/26283.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

5 Therapeutics Until a vaccine is developed, public health countermeasures provide the major defense against a novel respiratory virus, and effective pharmaceuti- cal and biologic agents can substantially reduce the burden that pandemics impose on individuals and health care systems. The availability of treat- ments—thereby reducing the need for hospitalization, shortening illness, averting death, and even preventing viral transmission—would not only reduce morbidity and mortality but also avoid harm to health care provid- ers and patients with other diseases seen when surges in coronavirus disease 2019 (COVID-19) cases overwhelmed clinics and hospitals in country after country. However, the evidence for current pharmacological therapies for most respiratory virus infections is low to mixed. While early treatment of influenza viruses can both prevent the spread of infection to close contacts and shorten symptom duration, pharmacotherapy for respiratory viruses has otherwise largely been unsuccessful (Villamagna et al., 2020). Even potent antivirals, such as the neuraminidase inhibitors and the most recent endonuclease inhibitors, provide only a partial benefit by reducing the days of prostration and fever if begun by the first day of symptoms (Hata et al., 2014; Hayden et al., 2018). Recent outbreaks of several novel viruses with pandemic potential— severe acute respiratory syndrome coronavirus 2 (SARS-CoV) in 2003, an H1N1 influenza virus in 2009, and Middle Eastern respiratory syndrome (MERS) in 2013—stimulated scientists to pursue effective antivirals. Yet, with the end of each outbreak, the attention of most public and private laboratories shifted to other conditions and research on antivirals faded, without having produced a collection of promising agents with established 125 PREPUBLICATION COPY—Uncorrected Proofs

126 NON-VACCINE INFLUENZA INTERVENTIONS safety data. Thus, when SARS-CoV-2 emerged in 2019, few potential an- tiviral compounds were available and ready to be tried (Nature Editorials, 2021). This chapter examines the role that therapeutics can play in mitigat- ing the impact of future respiratory virus outbreaks, particularly influenza, drawing on lessons learned during the COVID-19 pandemic in the research, scale up, and use of therapeutic resources. IMPACT OF PANDEMICS ON HEALTH SYSTEM CAPACITY The COVID-19 pandemic has starkly exposed the extent to which a viral respiratory pathogen outbreak can overwhelm the capacity of health care systems, leaving people in need of acute and/or chronic care without access to potentially life-saving services and therapeutics. In Brazil, for example, a surge of cases in spring 2021 filled its public and private hos- pitals to capacity and drove shortages of sedative drugs needed to intubate COVID-19 patients in intensive care units (ICUs) (Alves, 2021). Some hospitals reported having access to just a single substitute sedative that is not typically used for intubation and may not work as effectively for that purpose, potentially causing adverse health consequences for the patients. Beyond the impact on COVID-19 patients in need of critical acute care, outbreak-induced health system capacity issues can have life-threatening consequences for people with noncommunicable diseases or living with chronic conditions. An analysis of the impact of the pandemic on health services in multiple countries found that the Chinese National Health Com- mission reported reductions in outpatient visits and admissions of 21.6 percent and 16.6 percent, respectively, between January and June 2020 compared to the same period in 2019 (Tangcharoensathien et al., 2021). In Wuhan, reduced use of health services was attributed to travel restrictions and lengthy wait times for prescriptions to be filled for noncommunicable diseases. Thailand’s health system was less overwhelmed during the same period, although the number of outpatient visits nonetheless declined across the country. An evaluation of the impact of the COVID-19 pandemic on cancer care worldwide surveyed cancer care centers across 54 countries and 6 continents (Jazieh et al., 2020). The majority (88 percent) had encountered care delivery challenges, with more than half reducing their volume of ser- vices to help preemptively mitigate those challenges. Many centers reported challenges related to overwhelmed health systems (20 percent) and limited resources of personal protective equipment (PPE) (19 percent), staff (18 percent), and medications (10 percent). Almost half the centers reported that at least 10 percent of patients had missed one or more cycles of treat- ment. More than one-third reported that their patients had been exposed to harm due to interruptions in both cancer- and non-cancer-related care; PREPUBLICATION COPY—Uncorrected Proofs

THERAPEUTICS 127 some centers reported that the majority (up to 80 percent) of their patients had been exposed to harm. People living with human immunodeficiency virus (HIV) have experi- enced similar types of treatment interruptions and consequent impacts on health outcomes during the pandemic. A survey of more than 1,000 HIV care providers in Guangxi, China, found that many patients were unable to attend follow-up visits on schedule or obtain timely refills of their an- tiretrovirals, undermining their ability to adhere to treatment (Qiao et al., 2020). Providers identified a lack of patient guidance for accessing HIV services, overwhelmed clinics, and conflicts between the delivery of HIV and COVID-19 care as significant sequelae of the pandemic response. FINDINGS, OPPORTUNITIES, AND CHALLENGES IN THE USE OF THERAPEUTIC RESOURCES DURING OUTBREAKS This section explores the landscape of evidence, opportunities, and challenges related to the use of therapeutics during the COVID-19 pan- demic and considers their potential applications to seasonal and pandemic influenza outbreaks. For the purposes of this study, the committee has defined therapeutics as the actual medications (both those directed against the virus itself and those needed to address associated symptoms and com- plications) and any supplies needed for their delivery, including PPE, infu- sion chairs, hospital beds, and ventilators. Oxygen is a particularly critical therapeutic resource for patients with severe viral respiratory diseases and can be prone to shortages, as demonstrated by the COVID-19 pandemic (Malta et al., 2021). Strengthening Capacities to Manufacture, Mobilize, and Scale Up Therapeutic Resources The COVID-19 pandemic has underscored the need for collaborative global efforts to prepare for future influenza events by evaluating and strengthening countries’ capacities to manufacture, allocate, stockpile, mo- bilize, and scale up therapeutic resources. Vulnerability of Global Supply Chains for Therapeutics Medical product shortages can be caused by supply chain disruptions on both the demand side, such as changes in prescribing practices, stock- piling, and hoarding, and the supply side, such as manufacturing issues (Burry et al., 2020). Shortages of critical medical products that occurred at the global, national, and local levels during the COVID-19 pandemic have revealed systemic vulnerabilities and gaps within the medical product PREPUBLICATION COPY—Uncorrected Proofs

128 NON-VACCINE INFLUENZA INTERVENTIONS supply chain (Miller et al., 2021). Due to the globalization of that sup- ply chain in recent decades, manufacturing certain components that are essential to produce finished medical products has become increasingly concentrated in certain geographic regions and a relatively small number of manufacturers. Supply chain vulnerabilities are intensified when links in the chain are overreliant on specific regions or manufacturers because a single incident—be it a natural or human-made disaster, geopolitical crisis, or pharmaceutical company’s business decision—can lead to supply dis- ruptions and shortages of therapeutics on a national or global scale. For instance, approximately 80 percent of the world’s supply of active pharmaceutical ingredients (APIs) is manufactured in India and China (Burry et al., 2020). India produces large proportions of pharmaceutical finished dosage forms for the United States and many other countries, yet its pharmaceutical sector is also heavily dependent on China for up to 70 percent of its APIs (NASEM, 2021b). In Iran, more than 95 per- cent of the finished dosage forms consumed are produced domestically. However, around half of the APIs used to manufacture those products is imported from China, India, and countries in Europe (Ayati et al., 2020). Even less visibility exists into the geographic concentration or reliance on sources for essential pre-API raw materials (e.g., chemical compounds, fermentation processes for antibiotics) than for APIs or finished dosage forms. Disruptions will likely continue to occur with greater frequency if production capacity is not sufficiently diversified across geographies and manufacturers. Many lower-resource countries lack sufficient capacity to manufacture therapeutics to meet their domestic needs. For instance, only 3 percent of global drug manufacturing occurs in countries in Africa, while 70–90 per- cent of drugs consumed in countries in sub-Saharan Africa are imported (Bright et al., 2021). At the outset of the COVID-19 pandemic in Rwanda— where the pharmaceutical sector depends heavily on imports—interruptions to the drug supply chain resulted in widespread retail stockouts of supplies (Uwizeyimana et al., 2021). Lack of manufacturing capacity in a country can undermine its population’s access to critical supplies during times of normal demand, and particularly during demand surges, but the global pharmaceutical industry often privileges the more profitable markets in higher-income countries in Europe and North America over markets in lower-income countries. During the COVID-19 pandemic, equity issues have been exacerbated as some higher-income countries—which already had greater access to pharmaceutical products—have hoarded medical sup- plies and halted the export of critical medical products to conserve them for domestic use (Burry et al., 2020). PREPUBLICATION COPY—Uncorrected Proofs

THERAPEUTICS 129 Allocation and Triage of Scarce Therapeutic Resources Due to the surge in hospitalizations and ICU admissions during the COVID-19 pandemic, hospitals and health care systems around the world faced shortages of hospital beds, oxygen, ventilators, and critical therapeutic drugs—including sedatives, analgesics, and paralytics that are often used to care for patients receiving invasive mechanical ventilation (Ammar et al., 2021; BBC News, 2021; Burry et al., 2020). In January 2021, the deaths of as many as 40 patients hospitalized with COVID-19 in Brazil were at- tributed to oxygen shortages; the same month, Brazilian police reported that oxygen cylinders were being illegally hoarded and sold to affluent families for their personal use (Malta et al., 2021). The United States also experi- enced shortages of hospital beds, ventilators, and other necessary supplies, exposing substantial gaps in the nation’s health care infrastructure (The New York Times, 2020). In addition to shortages, situations in which therapeutics were unexpectedly underused have occurred. For example, although supply shortages of new monoclonal antibodies (mAbs) used to treat COVID-19 did occur in some areas of the United States (NGA, 2021), supplies have largely been underused in other areas of the country (Bendix, 2020). Con- tributing factors globally include the prohibitive cost of the treatments, the lack of specialized capacities needed to administer the therapy by infusion, and the need for patients to receive the treatment within a narrow time win- dow after symptom onset to achieve the optimal therapeutic effect. While this was arguably the first time this challenge of allocation during a health emergency was so widespread, it was by no means the first time communities have been faced with a patient demand that outpaced the supply. For example, following Hurricane Katrina in the Gulf region of the United States in 2005, isolated hospitals were faced with critical decisions on how to care for patients without enough resources for everyone. This austere environment and incredible burden on health care workers led to more than a decade of work on crisis standards of care. Institute of Medi- cine reports from 2012 and 2013 outline a systems framework for crisis standards of care and indicators and triggers to guide health care systems at all levels for use during disasters when needed, grounded in ethical and legal principles (IOM, 2012, 2013). Stakeholders well versed in crisis standards of care argue that the goal of any health care system should be to never need them. The transition from conventional to contingency to crisis care comes with a concomitant increase in morbidity and mortality, so it is important to recognize when the system is becoming overwhelmed so other mitigation measures can be put into place and avoid this transition wherever possible. It is also critical that these decisions occur before a health emergency has begun. Many public health and health care leaders have been working to engage their communities and institutional leadership to develop indicators PREPUBLICATION COPY—Uncorrected Proofs

130 NON-VACCINE INFLUENZA INTERVENTIONS and triggers for shifting their standards of care across a continuum during an emergency, but it is essential that this work is more widely implemented to be best prepared for future emergencies. Framework for Equitable Distribution of Scarce Resources During the COVID-19 pandemic, shortages of critical therapeutics and other medical supplies repeatedly highlighted the need for conserva- tion, allocation, triage, and distribution strategies for scarce resources, as well as evidence-based alternative and substitute therapeutic approaches. These strategies warrant difficult decisions about when and why to use scarce therapeutic resources for particular patients. However, alternative approaches may not be as safe, tolerable, or effective. For example, even if a substitute achieves an adequate level of sedation for patients receiving venti- lation, it may not be commonly used in an ICU setting or may be associated with greater risks of adverse effects (Ammar et al., 2021). During shortages, strategies for distributing scarce resources warrant careful consideration to avoid exacerbating existing inequities among vulnerable populations. When oxygen was in shortage during the COVID-19 pandemic in India, inadequate capacity to distribute and deliver limited supplies of costly oxy- gen cylinders to health facilities in remote, rural, and low-income areas left many patients without access to the live-saving therapy (Bhowmick, 2021; McKeever, 2021). The COVID-19 Vaccines Global Access Facility experi- ences with equitable vaccine distribution have also highlighted challenges that could be applicable to future distribution of effective therapeutics in a pandemic should they be new or in short supply (Khoshnood et al., 2021). Developing strategies for allocating scarce resources in a transparent, rational, and equitable way gives rise to a host of ethical implications, which have been carefully considered in frameworks developed for vac- cines and therapeutics during the COVID-19 pandemic (Dejong et al., 2020; Emanuel et al., 2020; Laventhal et al., 2020; Lim et al., 2020). A National Academies consensus report released in October 2020 outlined a Framework for Equitable Allocation of COVID-19 Vaccine that used four risk-based criteria to set priorities among different population groups (NASEM, 2020): 1. Risk of acquiring infection, 2. Risk of severe morbidity and mortality, 3. Risk of negative societal impact, and 4. Risk of transmitting the infection to others. The authors developed four phases of priority allocation within the framework, focusing on underlying causes of health inequities linked to PREPUBLICATION COPY—Uncorrected Proofs

THERAPEUTICS 131 systemic racism and the social determinants of health to mitigate the dis- proportionate burden COVID-19 has had on certain population groups. To strengthen preparedness for future influenza outbreaks, similar frameworks could be developed and refined in advance to guide the prioritization of scarce therapeutics using an ethical and evidence-based protocol that can be clearly communicated to public health decision makers, health care facili- ties, and the general public. Ideally, such a framework would be founded upon universal principles but flexible enough to be adapted based on pathogen type, mode of transmission, and evidence that emerges or evolves over the course of an influenza epidemic or pandemic. Frameworks for the equitable distribution of COVID-19 therapeutics would benefit from lever- aging existing platforms for international collaboration to ensure flexible, trusted governance and engage trusted international institutions to develop, coordinate, and implement the framework (Bollyky et al., 2020). Decisions about allocation and distribution should also be shaped by accurate health surveillance data, evidence about affected populations, and information about national distribution capacities. Stockpiling, Mobilizing, and Scaling Up Therapeutics The global supply of therapeutics—including medications, oxygen, and various supplies needed to deliver therapeutics—must be rapidly mobilized and scaled up in a pandemic context to meet global demand. Some countries have taken steps to lift preexisting export restrictions. For instance, influ- enza was not as prevalent in 2020 compared to prior years, decreasing the demand for the neuraminidase inhibitor oseltamivir, an antiviral commonly used for treatment. In March 2020, India lifted restrictions to allow oselta- mivir to be freely exported and repurposed for the experimental treatment of COVID-19 (Thepharmaletter, 2020). Stockpiling critical medical supplies allowed countries to meet demand on health systems to an extent during the pandemic, from national to facility levels, but most countries still appeared to be inadequately prepared to quickly scale up therapeutic resources dur- ing demand surges. Most reported inadequacies related to PPE and ventila- tors, with less visibility into whether countries had adequate stockpiles of other therapeutic supplies. Where other COVID-19-related shortages were reported, these extended beyond antivirals to a number of other drugs and supplies used in intensive care and hospital management (Socal et al., 2021). In countries that had stockpiles of medical supplies, some reported challenges with adequately distributing them (Cohen and Rodgers, 2020) or even misallocating medications within a national supply chain (Kuo et al., 2021). Moreover, stockpiling can have the unintended consequences of un- deruse and waste of scarce resources. For instance, N95 filtering facepiece respirators were not designed to be stored for long periods, highlighting the PREPUBLICATION COPY—Uncorrected Proofs

132 NON-VACCINE INFLUENZA INTERVENTIONS need for stockpile quality assurance sampling plans to complement shelf-life extension programs (Yorio et al., 2019). In Canada, the media reported that millions of expensive PPE supplies in the National Emergency Stockpile Sys- tem had expired and gone to waste (Laing and Westervelt, 2020). The lack of a national centralized ordering system likely contributed to inaccurate supply and demand predictions that informed those stockpiling strategies. Likewise, countries that depend highly on imported medical supplies, such as the United States, had difficulties maintaining and scaling up stockpiles when global supply chains and overseas manufacturing were disrupted during COVID-19 (Cohen and Rodgers, 2020; Kuo et al., 2021). Lessons learned that could bolster preparedness for future events include the need for coordinated regional stockpiles to mitigate underuse. The use of blockchain technology to forge links across supply chains and stakeholders could also help to manage stockpiles more efficiently and effectively (Bhaskar et al., 2020). Need for International Mechanisms to Predict, Prevent, and Mitigate Shortages No robust, agile international mechanisms or platforms exist for coun- tries to collaborate in predicting, preventing, and mitigating shortages of therapeutics at the global and national levels. The International Health Regulations do not establish compliance, evaluation, and accountability mechanisms for essential public–private partnership functions. Existing mechanisms include the World Health Organization (WHO) voluntary Joint External Evaluations (JEE), but it occurs only every 5 years and does not provide a specific mechanism for countries to assist each other amidst resource shortages in a pandemic context (WHO, 2021). The JEE time line may provide certain checkpoints and nudges that encourage countries to invest more substantially in pandemic preparedness and response. However, the absence of an assistance mechanism for therapeutic shortages leaves countries unprepared to proactively anticipate and evaluate the efforts required to respond to pandemics rapidly and nimbly. THERAPEUTICS PREVIOUSLY USED FOR INFLUENZA AND THOSE TRIALED IN COVID-19 WITH POTENTIAL APPLICATIONS TO PANDEMIC INFLUENZA The COVID-19 pandemic has highlighted the dearth of knowledge and limited evidence base about treatments for severe viral respiratory infec- tions in general. Moreover, little is known about the applicability of specific treatments across diseases caused by different respiratory pathogens, such as SARS-CoV-2 and influenza. At the end of this section, Table 5-1 pro- vides an overview of evidence and research needs related to treatments for COVID-19 with potential applications to influenza. PREPUBLICATION COPY—Uncorrected Proofs

THERAPEUTICS 133 TABLE 5-1 Overview of Therapeutics with Potential Application to Influenza Treatment Available Evidence and Research Category Examples Needs Antiviral Studied for COVID-19 • Mixed evidence for COVID-19 agents remdesivir (recommended in the United States under National Institutes of Health (NIH) treatment guidelines for hospitalized patients on oxygen; World Health Organization guidance provides a conditional recommendation against use) • No data on influenza Studied for influenza • Oseltamivir, zanamivir, oseltamivir (neuraminidase inhibitor) peramivir, and baloxavir zanamivir (neuraminidase inhibitor) marboxil approved for seasonal peramivir (neuraminidase inhibitor) influenza baloxavir marboxil (endonuclease • Need to evaluate clinical inhibitor) outcomes of mono- versus favipiravir (viral RNA-dependent RNA combination therapies on polymerase selective inhibitor) different strains of influenza • Need to further investigate additional broad-spectrum inhibitors of the RNA polymerase enzyme common to both COVID-19 and influenza • Need to explore the impact of host factors on replication of coronaviruses and influenza viruses Monoclonal Used for COVID-19 • Limited evidence of clinical antibody bamlanivimab benefit in COVID-19 patients if (mAb) bamlanivimab-etesevimab mAbs are administered early therapies casirivimab-imdevimab • Limited evidence of clinical sotrovimab benefit of mAbs in treating patients with uncomplicated Used for Influenza A influenza A VIS410 • Need to expand the evidence base about effectiveness in treating COVID-19 and influenza, given their potential for rapid development and manufacturing continued PREPUBLICATION COPY—Uncorrected Proofs

134 NON-VACCINE INFLUENZA INTERVENTIONS TABLE 5-1 Continued Treatment Available Evidence and Research Category Examples Needs Systemic dexamethasone (systemic) • Evidence of improved outcomes corticosteroids budesonide (inhaled) in patients with moderate to severe COVID-19 treated with corticosteroids, but limited data on influenza • Need further data to substantiate the potential to reduce host inflammatory response in patients with severe COVID-19 and influenza both with and without cytokine inhibitors Cytokine Tocilizumab • Both agents currently inhibitors Baricitinib recommended by NIH in hospitalized, hypoxic COVID patients with rapid worsening of oxygenation and/or inflammation • Effectiveness data limited for severe COVID cases, particularly patients requiring mechanical ventilation • Case report evidence of effectiveness of tocilizumab in influenza among a small number of patients taking it for other conditions, but otherwise insufficient or no data on use of either medication in influenza Combination Antibiotic agents added to antivirals • Limited to no evidence of treatments for clinical benefit for empirically coinfection treating COVID-19 patients and secondary with antibiotics to prevent infections secondary infections • Studies of the prevalence of risk factors for bacterial coinfections and secondary infections in COVID-19 patients ongoing and would need to be performed for any novel pathogen PREPUBLICATION COPY—Uncorrected Proofs

THERAPEUTICS 135 Antiviral Treatments Several antivirals are already approved for seasonal influenza, includ- ing multiple neuraminidase inhibitors—oseltamivir, zanamivir, and per- amivir—and an endonuclease inhibitor, baloxavir marboxil. Both types of agents have mechanisms of action against influenza A and B viruses: neuraminidase inhibitors block the viral neuraminidase enzyme, while the endonuclease inhibitor interferes with RNA transcription and blocks virus replication. Evidence exists that influenza antivirals can reduce mortality in severely ill patients (Muthuri et al., 2014). However, it has not yet been established whether these inhibitors are more effective alone or in combi- nation, highlighting the need to evaluate combination treatments for dif- ferent strains of influenza to prepare for future outbreaks and epidemics. Future research should target influenza and broader respiratory illnesses and be encouraged to help identify treatments for both mild and severe cases. Research should continue during the interpandemic period, with the assumption that identified treatments have a good chance of being useful against a pandemic strain. Studies during the COVID-19 pandemic explored antiviral agents with activity against SARS-CoV-2 and the impact of combination therapies on clinical outcomes and opportunities for dose sparing; these research efforts could inform therapeutic regimens for influenza. Remdesivir was found to decrease the time to recovery in hospitalized patients with COVID-19 (Beigel et al., 2020), though no benefit was seen for mortality, need for inva- sive mechanical ventilation, or length of hospital stay in the WHO Solidar- ity trial (Pan et al., 2021; WHO Solidarity Trial Consortium, 2021). It may be more effective in combination: a randomized controlled trial (RCT) of baricitinib plus remdesivir versus baricitinib alone in hospitalized patients found that the former was more effective in reducing recovery time and im- proving clinical status (Kalil et al., 2021). To further elucidate the potential application of therapeutics between different viruses, it will be important to evaluate additional broad-spectrum inhibitors of RNA polymerase—an enzyme common to both SARS-CoV-2 and influenza—expanding the thera- peutic options for treating coronavirus (Neogi et al., 2020; Vicenti et al., 2021) and influenza (Hayden and Shindo, 2019; Wu et al., 2017). Monoclonal Antibody Therapies These therapies rely on mAbs, which are laboratory-created proteins that function like natural antibodies and mimic the immune system’s abil- ity to defend against pathogens. In the past 30 years, mAb therapies have transformed the landscape of safe and effective treatment for a range of diseases. They hold promise for the influenza and other novel viruses, par- PREPUBLICATION COPY—Uncorrected Proofs

136 NON-VACCINE INFLUENZA INTERVENTIONS ticularly because they can be developed and manufactured more rapidly than other types of therapeutics. During the COVID-19 pandemic, two mAb monotherapies and two combination therapies were developed and received Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA): bamlanivimab, bamlanivimab-etesevimab (Chen et al., 2021; Gottlieb et al., 2021), casirivimab-imdevimab (Chen et al., 2021), and sotrovimab (FDA, 2021). Evidence about the clinical benefit of mAb therapies for COVID-19 remains relatively limited, but they have been associated with reduced hos- pitalizations if administered early to patients with mild or moderate symp- toms at high risk of disease progression. While results have been promising for the initial strain of SARS-CoV-2, emerging research for newer variants of concern present new challenges for the efficacy (Wang, P. et al., 2021). Numerous mAb therapies are currently undergoing clinical trials to measure effectiveness, but it is not clear whether one is more effective than others or a combination might be beneficial. A Rapid Expert Consultation convened by the National Academies in early 2021 noted this as well, commenting that insufficient evidence is available to define optimal dosing or identify differential benefits and risks across various types of patients (NASEM, 2021a). The authors of that rapid report argue that current mAb therapies should not be considered standard of care for COVID-19 and called for more evidence to prioritize patients based on their likely clinical benefit and understand risk factors. Tocilizumab is another mAb therapy that has been used in treating COVID-19, but it is directed against IL-6 rather than the virus, so it is discussed below. The use of mAb therapies for influenza has also been investigated, although the evidence remains limited. An RCT examined the broadly neutralizing mAb VIS410 in treating patients with uncomplicated influenza A infection, finding that the therapy was safe and well tolerated and had beneficial impacts on symptom resolution and virus replication (Hershberger et al., 2019). Targeting Immune Response Another important avenue of research is host factors related to corona- viruses (de Wilde et al., 2018; Fung and Liu, 2019) and influenza (Gounder and Boon, 2019; Jones et al., 2020) that may contribute to viral replication or exacerbate a patient’s response and drive disease. Corticosteroid Treatments Systemic corticosteroids have been used to treat patients with severe COVID-19 who develop a systemic inflammatory response; they can also be used for influenza. A prospective meta-analysis of clinical trials investi- PREPUBLICATION COPY—Uncorrected Proofs

THERAPEUTICS 137 gating patients with severe COVID-19 found that systemic corticosteroids were associated with lower 28-day all-cause mortality compared to usual care or a placebo (WHO REACT Working Group, 2020). Inhaled cortico- steroids may also have potential for COVID-19 and influenza: a multicenter RCT reported that budesonide was associated with a median 3-day reduc- tion in time to recovery among patients at higher risk of adverse outcomes from COVID-19 (Yu et al., 2021). Additional Immune Regulators A systematic review of the efficacy of another COVID-19 treatment mAb therapy, tocilizumab, which targets cytokine IL-6, found that adding it to the standard of care could reduce mortality and the risk of mechanical ventilation in patients with severe disease (Aziz et al., 2021). A different systematic review found that tocilizumab has evidence of moderate cer- tainty that it may reduce the likelihood that hospitalized patients will need mechanical ventilation, although it was not associated with a lower risk of short-term mortality (Tleyjeh et al., 2021). However, a meta-analysis of more than 10,000 patients found that IL-6 antagonist treatment resulted in a lower all-cause mortality at 28 days compared with a placebo (WHO REACT Working Group, 2021). Baracitinib is a Janus kinase inhibitor that received EUA from FDA in combination with remdesivir, a broad-spectrum antiviral, to treat hospital- ized COVID-19 patients who need supplemental oxygen, invasive mechani- cal ventilation, or extracorporeal membrane oxygenation. It decreased time to recovery more than remdesivir alone when given in combination, partic- ularly in patients with significant oxygen requirements (Kalil et al., 2021). Combination Treatment for Patients with Coinfection Antibiotics have been used to treat patients with COVID-19 who present with coinfections of other respiratory pathogens—particularly sec- ondary bacterial pneumonia, which may also co-occur with influenza and can exacerbate disease (Contou et al., 2020; Wang et al., 2020; Zhu et al., 2020). Coinfections were commonly reported in patients during prior out- breaks of SARS-CoV and MERS-CoV, but the rate of bacterial coinfections in patients with COVID-19 is not yet well characterized, and evidence for empiric antibiotics in this clinical context remains mixed. One early study of a small number of patients found that the prevalence of any type of coinfection (both viral and bacterial) was estimated as high as 50 percent among people who died of COVID-19 (Lai et al., 2020). However, a sys- tematic review found that only small proportions of hospitalized patients had bacterial (about 7 percent) or viral (3 percent) coinfection, suggesting PREPUBLICATION COPY—Uncorrected Proofs

138 NON-VACCINE INFLUENZA INTERVENTIONS that antibiotics should not be routinely used to manage patients with con- firmed COVID-19 (Lansbury et al., 2020; Oldenburg et al., 2021). The pre- emptive use of antibiotics in COVID-19 patients has also raised concerns about exacerbating antimicrobial resistance (Afshinnekoo et al., 2021; Jacobs, 2020; Pelfrene et al., 2021; Richtel, 2021). Preparation for future outbreaks of influenza or other novel viruses would benefit from ongoing identification and evaluation of patients most at risk of secondary bacte- rial infections so that empiric antibiotic use can be appropriately targeted. Potential for Therapeutics to Mitigate Transmission In addition to mitigating the impact of a disease, therapeutics may reduce the risk of transmitting it to close contacts—particularly if the re- spiratory pathogen is thought to have a high secondary attack rate, such as SARS-CoV-2. If antiviral drugs are administered early enough after the onset of symptoms, they may reduce viral shedding in the respiratory secretions and thus the risk that contacts may become infected (Mitjà and Clotet, 2020). Targeted prophylactic treatment of contacts with antivirals could confer an additional reduction in risk. Limited evidence also suggests that mAb therapies may mitigate the transmission of SARS-CoV-2 in ways that could be applicable to influenza, but more research is needed (Cohen, 2021; Wiersinga et al., 2020). However, although it has been suggested that therapies may mitigate transmission to contacts, quarantine is the only intervention that has been demonstrated to be effective in decreasing the SARS-CoV-2 contagion rate (Pascarella et al., 2020). Self-Medication and Therapeutics Without Evidence In an outbreak or epidemic context, the lack or scarcity of evidence- based therapeutics—coupled with misinformation and fear among the public—can drive people to self-medicate with therapeutics that are not evidence based or not indicated for the disease, with potentially deleterious effects. In the United States and some low- and middle-income countries (LMICs), such as India, some people have used nonprescribed hydroxychlo- roquine and chloroquine in an attempt to prevent COVID-19 (Malik et al., 2020). In other settings worldwide, particularly LMICs that lack a strong regulatory environment in health care, this has been a serious problem, resulting in private-sector businesses exploiting the public’s fear, threats to health care quality, and wastage of scarce financial resources. Continued efforts to strengthen the quality of countries’ health care delivery, as well as oversight mechanisms and regulatory approvals, can help to address this. In South America, people have commonly self-medicated with iver- mectin—an antiparasitic agent with antiviral effects that is often available PREPUBLICATION COPY—Uncorrected Proofs

THERAPEUTICS 139 over the counter (Molento, 2020). Many herbal drugs have been used to treat COVID-19 in China, Pakistan, and other countries (Malik et al., 2020) without an evidence-based approach (Krouse, 2020). Self-medication has caused serious adverse effects, including mortality (CBS News, 2021). While self-medication has not been as widely documented or known for influenza, such trends could be seen with an influenza pathogen that is similarly novel and highly virulent, highlighting a need for research and availability of drugs for novel pathogens along with public education. RESEARCH AND DEVELOPMENT OF NEW DRUGS AND REPURPOSED DRUGS Despite multiple coronavirus outbreaks and epidemics with pandemic potential in recent decades, no effective antiviral treatments have been developed, and little progress has been made in the realm of novel thera- peutics during the COVID-19 pandemic (Pagliano et al., 2021). However, a few places recognized the need for greater preparation. In 2014, the National Institutes of Health (NIH) began in vitro testing of existing drugs for potential effectiveness against several types of viruses. Its Antiviral Drug Discovery and Development Center supported studies of remdesivir, which Gilead Sciences developed for hepatitis C and respiratory syncytial virus. The drug’s safety in humans was demonstrated in clinical trials during the Ebola outbreak in central Africa in 2016–2019. When SARS-CoV-2 struck, remdesivir was one of the few potential therapeutic candidates ready to be tested for clinical efficacy (Nature Editorials, 2021). In the absence of specific antivirals with an established effect on SARS- CoV-2, many clinicians have resorted to antivirals that were developed for other types of viruses (e.g., remdesivir, lopinavir/ritonavir) and medications that are not approved as antivirals (e.g., hydroxychloroquine) (Pagliano et al., 2021). Limited evidence from clinical trials suggests that some of these repurposed therapeutics may have benefit against COVID-19, but their safety and efficacy is not yet well established; phase III clinical trials are ongoing for certain agents, including remdesivir and favipiravir (Pagliano et al., 2021). COVID-19 has clearly established the value of maintaining govern- ment and private-sector research efforts on antiviral therapies to identify a range of drugs with established safety profiles and potential efficacy against a variety of viruses in humans. Overall, very few scientifically rigor- ous, large-scale evaluations exist of therapeutic approaches for COVID-19 (Saesen and Huys, 2020). However, more robust evidence is beginning to emerge about the benefits—or lack thereof—of some therapeutics for through larger-scale international collaborative research efforts, such as the Randomized Evaluation of COVID-19 Therapy (RECOVERY) platform PREPUBLICATION COPY—Uncorrected Proofs

140 NON-VACCINE INFLUENZA INTERVENTIONS trial, which enrolled more than 37,000 patients, and the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community- Acquired Pneumonia (REMAP-CAP), with more than 5,600 patients largely recruited from the United Kingdom (Angus et al., 2020; Tikkinen et al., 2020), along with WHO’s global Solidarity trial. The therapeutics being tested through that project include convalescent plasma therapy, soluble human angiotensin-converting enzyme 2, lopinavir-ritonavir, fa- vipiravir, chloroquine and hydroxychloroquine, remdesivir, tocilizumab, and kinases. These large-scale studies have generated evidence suggesting the benefits of corticosteroids, IL-6 receptor antagonists, and anticoagu- lants, as well as the lack of benefits associated with treatments such as convalescent plasma, hydroxychloroquine, and lopinavir-ritonavir. These research efforts benefit from support and coordination by in- ternational bodies in developing research platforms for rapidly testing and screening potential antiviral drugs for safety. These platforms will need to be available for rapid testing of therapeutics against novel influenza viruses. This was illustrated by the Solidarity trial, in which WHO’s support facili- tated broader inclusion of an international sample of patients and a flexible study architecture, which benefited from prior pragmatic trials (Gadebusch Bondio and Marloth, 2020). These features allowed for quicker and wider recruitment and expedited results and evaluations. Limitations of Randomized Controlled Trials and Advantages of Adaptive Trial Design The COVID-19 pandemic has exposed fundamental flaws in current clini- cal trial research systems and incentive structures. Due to the design of RCTs, they can be poorly suited to evaluating complex treatment and subgroup interactions. RCTs initiated in the midst of an outbreak or epidemic scenario are also often unable to generate useful evidence as quickly as needed. Many ongoing interventional studies of candidate agents are being conducted on a small scale (i.e., single-country or single-center trials) or are methodologically unsound, which limits their validity and undermines the extrapolation of their observed outcomes to other settings. Moreover, the potential application of these therapeutics to influenza remains largely unknown (Gul et al., 2020). In addition to underscoring the importance of appropriately designed RCTs aligned with a master protocol, research efforts during the pandemic have highlighted barriers to scaling up the size of these trials in a coordinated way and ensuring that lower-resource settings are better represented in study popu- lations (Park et al., 2021). Furthermore, strategic incentives and infrastructure are needed to enable rapid sharing of anonymized data. These and other limitations of the clinical trial research paradigm have led to calls for a shift away from the prevailing overreliance on RCTs for PREPUBLICATION COPY—Uncorrected Proofs

THERAPEUTICS 141 demonstrating significant clinical benefit of new therapeutics in a pandemic context—a practice that has ethical and practical implications related to restricting the use of yet-unapproved therapies outside of an RCT (Keane, 2020). Developing more efficient systems for generating clinical knowledge to supplement RCT evidence could enable faster and more equitable dissemi- nation of rational treatment innovations and approaches that are informed by evolving understanding of a pathogen. For instance, the COVID-19 pan- demic has demonstrated the feasibility and value of adaptive platform trials with master protocols used worldwide. An adaptive design approach can contribute to greater efficiency in a clinical trial—thus accelerating the development process for a therapeu- tic—by adjusting an ongoing trial’s design and objectives based on interim results (see Box 5-1). This encourages more monitoring and evaluation in “real time” instead of waiting until trial completion. Certain treatments may be ready based on evidence in animal models or seasonal influenza, but it will be necessary to demonstrate that these work during a true influenza pandemic. For example, corticosteroids for the first SARS-CoV in 2003 BOX 5-1 Adaptive Trial Design: Opportunities and Limitations Adaptive trial design has emerged as a leading strategy for curbing stagna- tion in the development of novel compounds. This approach allows for modi- fying the design or statistical procedures of an ongoing trial based on data collected during it. Unlike a traditional trial, an adaptive trial allows for review and adaptation processes to be nested within its implementation—before final analysis. Allowing researchers to iteratively modify trial designs can make trials more efficient, informative, and ethical, thus promoting innovation in novel drug development. These adaptations can be broadly classified into three catego- ries: prospective, concurrent (ad hoc), and retrospective. Modifications within adaptive trial designs must be preplanned and based on data generated by the study. Adaptive trial design can afford heightened trial flexibility and efficiency by reducing sample sizes, improving the efficiency of treatment development, and increasing the chances of correctly answering clinical questions of interest. However, wider implementation will require greater clarity about when and how this type of design can be used, the implications of its use, and the interpreta- tion and reporting its results. Logistical and regulatory barriers may limit it, for example, if funding often does not offer the flexibility required to implement it. Furthermore adaptive trial designs may not be well understood throughout the field, posing a potential barrier to peer-review processes. SOURCES: Kairalla et al., 2012; Pallman et al., 2018. PREPUBLICATION COPY—Uncorrected Proofs

142 NON-VACCINE INFLUENZA INTERVENTIONS remained controversial and perhaps did not work well but certainly have some levels of efficacy for severe COVID-19 patients. Thus, even when treatments have levels of evidence behind them, rapid monitoring, evalu- ation, and potential pivoting are necessary when studying applications of novel therapeutic approaches against new pathogens. A master protocol is an adaptive design element that is applicable across trials for evaluating different permutations of treatments and patient populations. Adaptive approaches can be used to make iterative adjust- ments to sharpen a study’s focus on specific patient populations, clinical outcomes, and regimens that appear most promising based on the accu- mulating evidence of a drug’s effectiveness. This approach is particularly advantageous in studies that enroll patients from multiple countries under the auspices of national health authorities. It also offers flexibility and agil- ity in studies designed to compare interventions—such as the REMAP-CAP, RECOVERY, and Solidarity platforms—that can be adjusted or excluded based on the evolving evidence. Adaptive trial approaches could also have economic benefits; research has estimated that a design that could increase the clinical trial success rate by 4 percent could lower the overall develop- ment cost associated with a new drug by 0.4 billion USD (Mahlich et al., 2021). However, uncertainty remains about the potential drawbacks of these approaches compared to traditional RCT design (Natanegara et al., 2020). A caveat is that the innovative trial designs require evaluation upon studies’ completion to ensure the accuracy of the conclusions by validating the data and disease-severity metrics. An evaluation of multiple larger-scale RCTs that investigated COVID-19 therapeutics, including RECOVERY, Adap- tive COVID-19 Treatment Trial 1 (ACTT-1), and Solidarity, found that the randomization methodologies were suboptimal for comparing matched groups according to disease severity among hospitalized patients, suggest- ing that improving these across trials would yield higher-quality and more robust data (Emani et al., 2021). Additionally, the lack of coordination in developing innovative research protocols has led to inefficiencies and inad- equacies in many of the COVID-19 clinical trials conducted. For example, current models lack consistency in both clinical efficacy endpoints and in measurement methodologies. Building a more robust corpus of evidence about therapeutics will largely depend on sharing information more broadly through a common dataset (Natanegara et al., 2020). Partnerships and Therapeutic Research During the COVID-19 pandemic, incentives for the pharmaceutical industry have largely been directed toward accelerating vaccine develop- ment, but similar incentives have not been put in place for non-vaccine PREPUBLICATION COPY—Uncorrected Proofs

THERAPEUTICS 143 therapeutics. Developing and manufacturing treatments have also been hindered by impacts of the pandemic on the global pharmaceutical industry. Among the short-term effects on the health market that have impacted the pharmaceutical sector are increases in demand for therapeutics and medical supplies—which can lead to shortages caused by panic buying and stock- piling—and changes in regulatory requirements, research and development (R&D) processes, and care delivery (e.g., the shift toward telemedicine). Longer-term impacts will likely include slowed industry growth, delays in regulatory approval, changes in consumption patterns for medical prod- ucts, and the sector’s shift toward a self-sufficient supply chain (Ayati et al., 2020). The COVID-19 pandemic has demonstrated the value of public–private partnerships in therapeutic research by streamlining research efforts, de- velopment processes, and marketing authorization and broadening access. Such partnerships can facilitate international cooperation, boost regulatory agility, and serve as platforms for sharing information on product devel- opment, clinical trials, and supply chain issues (Bolislis et al., 2021). For example, the Access to COVID-19 Tools Accelerator is a cross-sectoral partnership formed by governments, private-sector businesses, civil society, and other stakeholders to advance the development and equitable distri- bution of medical resources during the pandemic. It was launched by the Bill & Melinda Gates Foundation, Wellcome, and Mastercard to facilitate the evaluation of new and repurposed therapeutics and vaccines, with a particular focus on expanding affordable access to those therapeutics in lower-resource settings. The International Coalition of Medicines Regula- tory Authorities was convened as a forum for international collaboration by regulatory authorities; it also aims to expedite R&D for treatments and vac- cines by streamlining regulatory processes (Bolislis et al., 2021). The United Kingdom developed the International COVID-19 Data Alliance, which serves as a global collaborative data platform (Health Data Research UK, 2020). However, each country presents unique challenges that should be considered in creating data-sharing platforms, and optimal representation of all interested partners is needed in the committees designed to prioritize these treatments. This goes beyond pharmaceutical stakeholders to include academic researchers and clinicians. Moreover, the COVID pandemic has spurred the private sector to form consortia to allow cooperation and exploit synergies in research on thera- peutics as well as vaccines. For example, the 23 life science companies in the COVID R&D Alliance are screening hundreds of new drugs (Nature Editorials, 2021). Nonprofit organizations, such as the Moonshot Initiative, have also been formed to convene meetings of experts and share access to high-technology equipment on a volunteer basis to pursue therapies for COVID-19 (Scudellari, 2020). PREPUBLICATION COPY—Uncorrected Proofs

144 NON-VACCINE INFLUENZA INTERVENTIONS CONCLUSIONS AND RECOMMENDATIONS Global Pandemic Preparation Conclusion: COVID-19 illustrated critical gaps in preparation to dis- tribute the therapeutic resources needed to care for infected patients in a respiratory viral pandemic, including antiviral medications, oxygen, and equipment necessary for the delivery of supportive care (e.g., ven- tilators, personal protective equipment [PPE]). Most documentation on stockpile inadequacies focused on the lack of ventilators and PPE, and there was less transparency around the adequacy of country stockpiles with regard to other therapeutic supplies. Conclusion: COVID-19 emphasized a need to take a global view of the preparation for pandemic influenza, including the capacities of countries around the world to manufacture, stockpile, mobilize, and scale up therapeutic resources, as well as to conduct research on the effectiveness of therapeutics. Recommendation 5-1: National governments should mandate that the appropriate authorities (ministries of health or comparable government agencies): • Regularly evaluate existing stockpiles of therapeutics (includ- ing antivirals, other antimicrobials for treatment of secondary infection, and supportive care treatments, such as oxygen) and other articles needed for care delivery (e.g., personal protective equipment); • Secure sources that can reliably supply all items needed during an influenza pandemic; and • Assess, and establish where possible, local production capabili- ties for all such items. Pandemic Response Conclusion: COVID-19 demonstrated the need for a framework to guide distribution of scarce and/or novel therapeutic resources in the most rational and equitable way. That framework needs to allow for ad- justment based on disease prevalence, pathogen type, mode of transmis- sion, mortality rates, and impacted populations, but universal principles will help with both insulating frontline providers from difficult resource allocation decisions and preventing health care systems from collapse. PREPUBLICATION COPY—Uncorrected Proofs

THERAPEUTICS 145 Recommendation 5-2: The government agencies responsible for public health guidance in each country (e.g., United Kingdom Health Secu- rity Agency, U.S. Centers for Disease Control and Prevention) should develop a framework to guide the use and prioritization of treatments that can be flexible with changing evidence during a respiratory viral pandemic. That framework should be able to be adjusted depending on the pathogen, taking into account its transmission route, the at-risk populations, and associated morbidity and mortality rates. The frame- work should identify: • Who will evaluate guidance from global and national health organizations and from professional societies in order to define evidence-based treatment guidelines; • How guidelines for treatment selection and delivery will be communicated to health agencies in the country’s states/prov- inces/regions and to frontline health care facilities, with a focus on avoiding the use of non-evidence-based therapeutics outside of clinical trials; • How suitable places to administer care will be selected, with consideration of options that provide alternatives for care deliv- ery outside of already overwhelmed health facilities and primary care clinics; • Which populations should be the focus for therapeutic delivery with scarce resource availability (e.g., prevention in those not yet infected, versus treatment of those who are mildly or criti- cally ill), who will make those determinations, and how com- munity interests will be incorporated; and • How to distribute a treatment modality equitably throughout the country and among patients including when health systems have moved to crisis standards of care because the available resources have become inadequate to meet the needs of all patients. Recommendation 5-3: Global (World Health Organization) and re- gional (e.g., African Centres for Disease Control and Prevention, Euro- pean Centre for Disease Prevention and Control, Pan American Health Organization) health organizations should collaborate to determine how therapeutics and the resources needed for their delivery can be shared among countries to ensure equitable distribution and reduce or slow the spread of the pandemic. PREPUBLICATION COPY—Uncorrected Proofs

146 NON-VACCINE INFLUENZA INTERVENTIONS Therapeutic Research: Current Focus and Continuation During a Pandemic Conclusion: Research during the COVID-19 pandemic has emphasized the potential benefits of “repurposed” therapeutics initially developed for another disease. Going forward, maintaining libraries of drugs that show antiviral effects and that have completed safety testing in humans could serve as a starting point for therapeutic research during a pandemic. It will also be important to test drugs—separately and in combination—that act on targets that respiratory viruses have in com- mon (e.g., possible broad-spectrum inhibitors of RNA polymerase, an enzyme common to both COVID-19 and influenza). COVID-19 has also demonstrated the benefits of therapeutics that target exacerbated host response rather than the virus itself (e.g., steroids, tocilizumab). Continuing to evaluate host factors that might impact the severity of respiratory viral infections, either because they are required for vi- ral replication or because they are involved in exacerbated response, could be beneficial in developing therapeutic approaches with broad applicability. Conclusion: Open repositories, which include negative research results, need to be maintained to house these efforts, in order to identify public health measures of prevention and assessment and to ensure resources are effectively used rather than used for repeated assessment studies. Conclusion: COVID-19 has shown the necessity of ongoing research focused on treatment of both existing and novel respiratory viruses, including those that cause seasonal and pandemic influenza, and has highlighted the success of collaborative efforts and innovative part- nerships. Work done during the COVID-19 pandemic, including the Solidarity program, has demonstrated the feasibility of research efforts that integrate government programs, private companies, and public– private collaborations, and that involve research institutions cooperat- ing internationally. Conclusion: COVID-19 has shown the feasibility of performing rapid research on therapeutic efficacy during a pandemic through the use of adaptive platform trials with common global protocols, adding and deleting interventions in light of accumulating evidence. The Ran- domized, Embedded, Multifactorial Adaptive Platform Trial for Com- munity-Acquired Pneumonia, Randomized Evaluation of COVID-19 Therapy, and Solidarity platforms all demonstrated that this type of trial platform has many advantages, including the ability to adjust PREPUBLICATION COPY—Uncorrected Proofs

THERAPEUTICS 147 study enrollment, include patients from many countries to achieve sufficient power to make evidence-based treatment recommendations more quickly, react to changing evidence prior to study conclusion, and compare interventions to one another, singly and in combination. Being able to build on this work could also expedite the development of evidence-based treatment guidelines when a novel pathogen is identi- fied. In the COVID-19 pandemic, use of unproven therapeutics in an early evidence vacuum led to patient harm, which can be avoided if professional organizations and health authorities encourage clinicians to emphasize study participation from the beginning of an outbreak when previously validated therapeutic options are lacking. Conclusion: The ability to perform adaptive trials during future pan- demics could be improved by putting infrastructure in place that would allow for accelerated regulatory approvals and access to trials of thera- pies. This is especially important for therapeutic trials that must be con- ducted in multiple sites in different countries, since rounds of scientific and ethics review can otherwise take years. Establishing networks of high-quality clinical trial sites and developing and obtaining preap- proval for generic study protocols from scientific and research ethics committees across all sites could allow for more rapid study enrollment and results. Recommendation 5-4: Intergovernmental organizations, government agencies, foundations, pharmaceutical and biotechnology companies, universities, and research institutes should focus their efforts on re- search strategies and platforms that were shown to be particularly effective during the COVID-19 pandemic: screening potential antiviral drugs for safety and efficacy; evaluating therapeutic approaches that target host responses in addition to the viruses themselves; developing and maintaining national and international research collaboratives; and building the capacity for rapid adaptive therapeutic evaluation during a pandemic to inform evidence-based treatment guidelines. REFERENCES Afshinnekoo, E., C. Bhattacharya, A. Burguete-García, E. Castro-Nallar, Y. Deng, C. Desnues, E. Dias-Neto, E. Elhaik, G. Iraola, and S. Jang. 2021. COVID-19 drug practices risk antimicrobial resistance evolution. Lancet Microbe 2(4):e135–e136. Alves, L. 2021. Brazilian ICUs short of drugs and beds amid COVID-19 surge. The Lancet 397(10283):1431–1432. Ammar, M. A., G. L. Sacha, S. C. Welch, S. N. Bass, S. L. Kane-Gill, A. Duggal, and A. A. Ammar. 2021. Sedation, analgesia, and paralysis in COVID-19 patients in the setting of drug shortages. Journal of Intensive Care Medicine 36(2):157–174. PREPUBLICATION COPY—Uncorrected Proofs

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Public Health Lessons for Non-Vaccine Influenza Interventions: Looking Past COVID-19 Get This Book
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The COVID-19 pandemic has challenged the world's preparedness for a respiratory virus event. While the world has been combating COVID-19, seasonal and pandemic influenza remain imminent global health threats. Non-vaccine public health control measures can combat emerging and ongoing influenza outbreaks by mitigating viral spread.

Public Health Lessons for Non-Vaccine Influenza Interventions examines provides conclusions and recommendations from an expert committee on how to leverage the knowledge gained from the COVID-19 pandemic to optimize the use of public health interventions other than vaccines to decrease the toll of future seasonal and potentially pandemic influenza. It considers the effectiveness of public health efforts such as use of masks and indoor spacing, use of treatments such as monoclonal antibodies, and public health communication campaigns.

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