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.

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.

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, particularly 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 investigating 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.

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.

BOX 5-1

Adaptive Trial Design: Opportunities and Limitations.

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).

Global Pandemic Preparation

Conclusion: COVID-19 illustrated critical gaps in preparation to distribute 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., ventilators, 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 (including 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 capabilities 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 adjustment based on disease prevalence, pathogen type, mode of transmission, 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.

Recommendation 5-2: The government agencies responsible for public health guidance in each country (e.g., United Kingdom Health Security 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 framework 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/provinces/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 delivery 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 critically ill), who will make those determinations, and how community 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 regional (e.g., African Centres for Disease Control and Prevention, European 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.

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 common (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 viral 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 partnerships. 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 cooperating 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 Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-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 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 identified. 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 pandemics could be improved by putting infrastructure in place that would allow for accelerated regulatory approvals and access to trials of therapies. This is especially important for therapeutic trials that must be conducted 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 preapproval 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 research 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.