5

Therapeutics

Until a vaccine is developed, public health countermeasures provide the major defense against a novel respiratory virus, and effective pharmaceutical and biologic agents can substantially reduce the burden that pandemics impose on individuals and health care systems. The availability of treatments—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 providers 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

safety data. Thus, when SARS-CoV-2 emerged in 2019, few potential antiviral compounds were available and ready to be tried (Nature Editorials, 2021). This chapter examines the role that therapeutics can play in mitigating 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 hospitals 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 Commission 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 services 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 treatment. More than one-third reported that their patients had been exposed to harm due to interruptions in both cancer- and non-cancer-related care;

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 experienced 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 antiretrovirals, 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 pandemic 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 complications) and any supplies needed for their delivery, including PPE, infusion 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, mobilize, 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, stockpiling, 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

supply chain (Miller et al., 2021). Due to the globalization of that supply 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 disruptions 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, greater than 95 percent 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 percent 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 supplies and halted the export of critical medical products to conserve them for domestic use (Burry et al., 2020).

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 attributed 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 experienced 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). Contributing 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 window 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 Medicine 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

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 conservation, 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 ventilation, 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 oxygen 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 experiences 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 vaccines 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 authoring committee developed four phases of priority allocation within the framework, focusing on underlying causes of health inequities

linked to systemic racism and the social determinants of health to mitigate the disproportionate 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 facilities, 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 leveraging 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, influenza 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 oseltamivir 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 during demand surges. Most reported inadequacies related to PPE and ventilators, 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 underuse and waste of scarce resources. For instance, N95 filtering facepiece respirators were not designed to be stored for long periods, highlighting the

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 System 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 countries 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 infections 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 provides an overview of evidence and research needs related to treatments for COVID-19 with potential applications to influenza.

TABLE 5-1 Overview of Therapeutics with Potential Application to Influenza

Antiviral Treatments

Several antivirals are already approved for seasonal influenza, including multiple neuraminidase inhibitors—oseltamivir, zanamivir, and peramivir—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 combination, highlighting the need to evaluate combination treatments for different 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 invasive mechanical ventilation, or length of hospital stay in the WHO Solidarity 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 improving 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 therapeutic options for treating coronavirus (Neogi et al., 2020; Vicenti et al., 2021) and influenza (Hayden and Shindo, 2019).

Monoclonal Antibody Therapies

These therapies rely on mAbs, which are laboratory-created proteins that function like natural antibodies and mimic the immune system’s ability 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-

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 hospitalizations if administered early to patients with mild or moderate symptoms 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 coronaviruses (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-

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 corticosteroids may also have potential for COVID-19 and influenza: a multicenter RCT reported that budesonide was associated with a median 3-day reduction 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 certainty 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 hospitalized COVID-19 patients who need supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. It decreased time to recovery more than remdesivir alone when given in combination, particularly 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 secondary 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 outbreaks 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 systematic review found that only small proportions of hospitalized patients had bacterial (about 7 percent) or viral (3 percent) coinfection, suggesting

that antibiotics should not be routinely used to manage patients with confirmed COVID-19 (Lansbury et al., 2020; Oldenburg et al., 2021). The preemptive 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 bacterial 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 respiratory 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 hydroxychloroquine 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 ivermectin—an antiparasitic agent with antiviral effects that is often available

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 therapeutics 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 government 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 rigorous, 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 through larger-scale international collaborative research efforts, such as the Randomized Evaluation of COVID-19 Therapy (RECOVERY) platform

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, favipiravir, chloroquine and hydroxychloroquine, remdesivir, tocilizumab, and kinases. These large-scale studies have generated evidence suggesting the benefits of corticosteroids, IL-6 receptor antagonists, and anticoagulants, 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 international 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 facilitated 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 clinical 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 populations (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

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 dissemination of rational treatment innovations and approaches that are informed by evolving understanding of a pathogen. For instance, the COVID-19 pandemic 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 therapeutic—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

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, evaluation, 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 adjustments to sharpen a study’s focus on specific patient populations, clinical outcomes, and regimens that appear most promising based on the accumulating 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 agility 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 development cost associated with a new drug by USD 0.4 billion (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, Adaptive 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, suggesting 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 inadequacies 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 development, but similar incentives have not been put in place for non-vaccine

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 stockpiling—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 products, 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, development 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 development, 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 distribution 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 Regulatory Authorities was convened as a forum for international collaboration by regulatory authorities; it also aims to expedite R&D for treatments and vaccines 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 therapeutics 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).

CONCLUSIONS AND RECOMMENDATIONS

Global Pandemic Preparation

Pandemic Response

Therapeutic Research: Current Focus and Continuation During a Pandemic

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