Background
Since it quickly became evident that SARS-CoV2 spread rapidly and could not be eradicated, it was critically important to promptly find treatments to minimize mortality and reduce hospitalizations. Because developing new pharmaceutical drugs from scratch is a lengthy and expensive process, it was important to quickly evaluate existing drugs to see if they could be repurposed as COVID-19 treatments. In addition, the clinical medicine community urgently needed data and guidance concerning costs and benefits of proposed and widely used treatments.
The NIH rapidly initiated preclinical and clinical trials to evaluate hundreds of new and repurposed drugs for potential antiviral effects. The difficulty of this task may explain why there are few drugs to treat COVID-19. Even to treat influenza, which is not a novel virus, there are few effective approved antiviral drugs.
Below we discuss the most notable drugs and interventions, and those that were most widely used. We also address issues surrounding data collection timeliness, information dissemination, drug accessibility, and politicization of certain therapeutics.
Exploring Potential COVID-19 Treatments
By April 2020, NIH had launched the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership between US and European health agencies and pharmaceutical companies in order to evaluate hundreds of existing drugs as potential COVID-19 treatments. These drugs spanned a variety of classes, including immune modulators, monoclonal and polyclonal antibodies, and blood thinners. These studies were also used to inform vaccine development. Later, other drug classes such as antidepressants and antiparasitic drugs were included for study as potential therapies.
Hundreds or even thousands of drugs must be evaluated to find a few that may work. By nature, most drugs evaluated will fail, but studies of failed drugs still provide important data. How many drugs were evaluated in pre-clinical in-vitro and in-vivo animal studies?
How many preclinical studies were sufficiently promising to be promoted to evaluation in humans? How many progressed to a randomized clinical trial?
How was this information disseminated to the larger scientific community?
Was the US-Europe-industry collaboration smooth and effective? Did other countries, in Asia, Africa or Latin America, also engage in this type of work?
Data mining of electronic health records can be used to explore potential treatments, by comparing outcomes among COVID-19 patients who happen to be on existing drugs for other reasons. To what extent were such data and methods utilized?
Clinical Guidelines
With limited knowledge and weak or no evidence about efficacy of existing drugs against COVID-19, physicians had to make treatment decisions in the absence of complete knowledge. This information void led to many controversies and disagreements among doctors, between patients and their doctors, and between the public and health authorities as to best practices for treating COVID-19. Even as post-vaccination infections mounted in the summer of 2021, trials to evaluate existing medications with unresolved potential for efficacy were not accelerated and some, even today, remain incomplete.
In early 2020, what clinical guidance, if any, did we glean from Asia and Europe, where the virus was spreading before reaching North America?
Many randomized trials were quickly funded and conducted by NIH and others. Were these study results disseminated to practicing clinicians and if so by what means?
At times, individual doctors and hospitals were left without solid guidance as to how to treat COVID-19 patients at various stages of illness. Who was responsible for assembling and updating best practice clinical guidelines? The CDC, NIH, FDA, the American Medical Association, the American College of Physicians, or leading academic hospitals? Who, if anybody, stepped up to the plate to support floundering front line doctors?
Mechanical Ventilators
Mechanical ventilation with intubation can be a life-saving intervention. However, during prolonged use, as occurred for many COVID-19 patients, it is associated with serious and potentially life-threatening complications. By February 2020, physicians in countries such as Hong Kong and China argued for the benefits of early intubation to reduce virus aerosolization. However, by March 2020, clinicians actively treating COVID-19, across multiple countries, concurred that the rush to mechanical ventilation needed to be rethought. By June 2020, many were urging providers not to routinely intubate COVID-19 patients, citing emerging data that non-invasive methods were no more aerosolizing than mechanical ventilation.
Was there sufficient evidence for providers to implement an invasive medical intervention to treat COVID-19 patients? Should there have been a randomized trial to evaluate the benefits versus risks of ventilating patients?
Did the CDC, NIH, or a medical society convene an expert panel to discuss the matter? Were there policy makers on the COVID-19 task force or at the CDC with clinical experience treating COVID-19 patients that could advise on this matter?
In March 2020, the federal government invoked the Defense Productions Act to force General Motors to produce more ventilators. At the same time, the New York State and City governments demanded more ventilators, even though current supply was not exhausted, claiming that ‘without a ventilator, doctors cannot save lives'. Did government officials ask for clinical evidence to support this intervention? If not, why not? Physicians in New York stated that they intubated patients early to “control the spread”. How many patients were intubated in New York City in March/April 2020 and what were their outcomes stratified by age and comorbidities? Could rapid gathering of such data have ended the practice earlier?
Anticoagulation Therapy
Anticoagulants such as heparin and apixaban are used as blood thinners to treat and prevent blood clots. Heparin is on the WHO list of essential medicines. Early on in the pandemic, there was an increase in use of anticoagulants in COVID-19 patients after observing that some patients developed blood clots in their lungs (pulmonary emboli) and/or deep peripheral veins (deep venous thrombi). However, while anticoagulation therapy can save lives in patients with blood clots, they can also have dangerous effects when used on patients that do not need them.
In 2020, some care-providers were starting potentially dangerous anticoagulant treatments on patients without blood clots. Were doctors considering the dangers of these drugs when they prescribed them for COVID-19? How were significant and complex clinical controversies around COVID-19 treatment, which required coordination of prescriptions, blood draws, and laboratory tests, addressed and resolved? Should the CDC, NIH, medical associations and/or the FDA have provided clinical guidance about using these medications for COVID-19 patients? If not, whose job was it to disseminate best-practices data and address clinical gray areas around treatment?
Monoclonal Antibodies
For more than 20 years, monoclonal antibodies (mAbs) have been used to mitigate the severity of viral infections such as Respiratory Syncytial Virus (RSV). Various monoclonal preparations have been effective against COVID-19, mitigating the severity of disease in both primary and vaccine-breakthrough infections. The FDA approved the first mAb treatments for COVID-19 in November 2020.
As one of the few proven early treatments for COVID-19, should the federal government have invested more resources to increase the supply of monoclonal antibodies? Should state governments have invested more resources to increase the distribution, awareness, and availability of this treatment? Did lack of funding or resources primarily harm poor and working-class Americans with inferior access to medical care?
During the Delta wave that spread through the Sun Belt in the summer of 2021, the federal government curtailed shipments of mAbs to southern states, preventing many Americans from receiving this life saving medical treatment. By the time the northern states had their 2021/22 seasonal winter surge, Omicron had largely displaced Delta, for which the same mAbs were of little use. How many Americans died because they were unable to obtain mAbs? How many mAb treatments went unused because they were not needed in the locations to which they had been allocated?
Currently, mAbs are only authorized for use in patients with mild-to-moderate COVID-19, but not in hospitalized patients. Are there data supporting this guideline?
Convalescent Plasma
In contrast to monoclonal antibodies, convalescent plasma contains “polyclonal antibodies” obtained from individuals who have recovered from a COVID-19 infection. The FDA issued an emergency use authorization in August 2020, which is ongoing with several subsequent modifications.
The largest RCT, from India in October 2020, did not demonstrate any benefit from inpatient convalescent plasma treatment. A February 2021 meta-analysis of ten RCTs also did not show any benefit. Subsequent RCTs evaluating higher levels of antibodies were also disappointing. Why is there an ongoing EUA for convalescent plasma from the FDA when multiple RCTs have demonstrated no benefit?
Remdesivir
Remdesivir is a patented anti-viral medication made by pharmaceutical company Gilead. On May 1, 2020, FDA approved its use for treating COVID-19 under an emergency use authorization. It received regular approval on October 22, 2020.
The efficacy of Remdesivir for hospitalized COVID-19 patients was evaluated in randomized controlled trials on 158 patients in a Chinese study (April 29, 2020); on 541 patients in an NIAID funded study (May 22, 2020); and on 2743 patients in the WHO Signature Trial (October 15, 2020). The Chinese and WHO trials showed no reduction in mortality, while the NIAID trials showed a modest non-statistically-significant reduction in mortality and a modest statistically significant reduction in time to recovery. Considering that the larger Signature Trial did not show a mortality benefit, should the FDA have given regular approval of Remdesivir for treating COVID-19? Why did the FDA approve Remdesivir without the customary consulting of their Antimicrobial Drugs Advisory Committee?
On October 8, 2022, Gilead signed a billion dollar contract to supply Remdesivir to the European Union, before the WHO Signature Trial results were publicly released on October 15, but after Gilead knew the results. Why was this contract approved before results were released? Was this process different from usual processes for such contracts?
Remdesivir requires continuous daily infusion at roughly $500/day. How does this high cost affect the cost-benefit ratio of this treatment?
Fluvoxamine (Luvox)
Fluvoxamine was approved by the FDA in 1994. It is a low toxicity, generic, and low cost medication with decades of use in non-infectious settings, primarily as an antidepressant. It is on the WHO list of essential medicines.
In November 2020, a small randomized trial showed a statistically significant decrease in progression to severe disease after Fluvoxamine administration compared to placebo (0% versus 8.3%, respectively). In October 2021, a Brazilian randomized controlled trial showed a statistically significant reduction using the primary endpoint of time in hospital, with varying results for secondary endpoints. However, a trial evaluating early out-patient use did not find a statistically significant reduction in hypoxemia, emergency department visit, hospitalization, or death.
After a December 2021 submission, in May 2022 the FDA rejected a EUA for Fluvoxamine for early treatment of COVID-19. Considering the positive clinical trial data, why was Fluvoxamine rejected? Was the decision based upon the lack of a known plausible mechanism of action for the anti-inflammatory effects? In contrast, Remdesivir was approved based on a plausible mechanism despite unimpressive clinical trial data. Who decides when to prioritize plausible biological mechanisms instead of clinical endpoints, and on what basis?
The NIH is currently funding an RCT to evaluate Fluvoxamine, to be completed in March 2023. Three years into the pandemic and with most of the population having some form of immunity, should there have been a larger effort to conduct this trial earlier?
Paxlovid (Nirmatrelvir)
Paxlovid is a patented antiviral made by Pfizer that was evaluated in a randomized controlled trial of high-risk unvaccinated patients during the Delta variant period (EPIC-HR). When started within 3 days of symptom onset, it reduced hospitalization or death with an absolute risk reduction of 6.3% and a relative risk reduction of 89%, There was no reduction in household transmission. It was authorized in December 2021 for treatment of mild-to-moderate disease in patients 12 years of age and older (who weigh at least 40 kg) and who are at high risk for progression to severe COVID-19.
A subsequent RCT in vaccinated and other low-risk patients (EPIC-SR) was terminated early by Pfizer as there was no statistically significant evidence of benefit. However, several subsequent retrospective cohort studies (not RCTs) showed a benefit in vaccinated patients and/or those with natural immunity, specifically older cohorts.
Despite the negative trial result for the EPIC-SR RCT, Pfizer contended that there was a trend towards disease reduction in these populations. Considering this trend, why did Pfizer not continue the trial to resolve this important question? Will there be an RCT to evaluate Paxlovid in low-risk populations?
Should Paxlovid have been authorized to treat lower risk and/or vaccinated patients before randomized trial data were available showing efficacy? Considering that by mid-2022, 95% of Americans had a prior COVID-19 infection, should this cohort have been evaluated in earlier trials? Should Paxlovid be available for 12-17 year olds since this age group has not been included in any study?
The CDC’s definition of an underlying health condition that exacerbates risk for severe disease is extremely broad, including mental health conditions, pregnancy, and being a former or current smoker. Will there be further evaluation to determine which specific groups benefit from taking Paxlovid, particularly for young people?
How many Paxlovid doses have been prescribed for low-risk patients despite lack of evidence of effectiveness?
In October 2022, why did White House COVID-19 coordinator Ashish Jha use a low-quality unadjusted observational study to promote Paxlovid for use in vaccinated patients and patients with infection-acquired immunity?
“Viral rebound” occurs in about 2-5% of patients, with some studies showing less or more. Is viral rebound taken into account when creating guidelines for Paxlovid use? In a May 2022 report, the CDC did not advise further Paxlovid courses after rebound. What contributed to this decision?
In April 2022, at a cost of $530 per treatment course, the Federal Government purchased 20 million courses of Paxlovid from Pfizer, at a total cost of around $10 billion. How did the US government assess the need for this drug, given that most older high-risk Americans had already been vaccinated or recovered from the disease by then? Was this investment cost effective?
Dexamethasone (Decadron)
Dexamethasone is a generic drug on the WHO list of essential medicines. In 2020, UK researchers conducted the large randomized RECOVERY Trial, showing that dexamethasone improved survival of hospitalized patients. It is widely used in the US to treat very severe COVID illness.
A US randomized trial, however, did not find a difference in hospitalized patients receiving dexamethasone plus remdesivir versus baricitinib plus remdesivir. An observational study of hospital patients not receiving supplemental oxygen found increased mortality after receiving dexamethasone, which could be an accurate finding or an artifact due to more serious COVID-19 patients being more likely to receive dexamethasone.
Considering the wide use of dexamethasone in treating hospitalized COVID patients, should there have been a large randomized-trial of dexamethasone to determine for whom the drug was effective and safe?
Is dexamethasone helpful in outpatients and/or patients with less severe COVID-19 patients? Should there have been randomized trials of effectiveness of dexamethasone in a wider range of patients, such as in outpatients with moderate illness?
Budesonide (Pulmicort) and Other Inhaled Steroids
Early reports from Italy noted that patients with chronic respiratory illness were under-represented among hospitalized COVID-19 patients. Some investigators hypothesized that use of chronic inhaled steroids such as budesonide, common in this population, may be protective against COVID. Budesonide was developed in the 1970s and is on the WHO list of essential medicines.
Several countries, including Spain, Argentina, and the UK, ran trials in 2020 to evaluate budesonide treatment in hospitalized patients as well as in the outpatient setting. These early trials showed a decrease in disease progression for both populations. However, an outpatient RCT (part of ACTIV-6) conducted in the US during the Delta and Omicron waves and after vaccination was available, found that the generic inhaled steroid, Fluticasone, did not significantly reduce time to recovery in interim results.
In the early days of the pandemic, did clinicians understand the potential benefits of starting inhaled steroids early in disease? How were the budesonide results disseminated to American clinicians?
Trials conducted in populations with high immunity, through vaccination or prior infection, such as the Fluticasone ACTIV-6 trial, are going to yield very different results than trials conducted in immune naive populations. Should there have been studies of budesonide and/or other inhaled steroids earlier in the pandemic?
Hydroxychloroquine
Hydroxychloroquine is an anti-malarial drug that can also be used to treat arthritis and lupus. It is on the WHO list of essential medicines, and its safety profile is well known. In March 2020, the FDA granted emergency use authorization of the drug to treat hospitalized COVID-19 patients. However, that approval was revoked in June 2020.
In June 2020, an NIH RCT of hydroxychloroquine was halted early after concluding that the drug was safe but ineffective for hospitalized COVID-19 patients. In October 2020, the larger WHO Solidarity Trial also showed that hydroxychloroquine does not benefit hospitalized COVID-19 patients if given during their hospitalization. In February 2021, an evidence-based Cochrane Review of these and other RCTs concluded that hydroxychloroquine had ‘little or no effect on the risk of death’ for hospitalized COVID-19 patients. A meta analysis of randomized trials found hydroxychloroquine to cause increased mortality in hospitalized patients with COVID-19. Globally, many other trials were conducted which produced negative results in patients both in the hospital and outpatient settings. An important medical question was studied in a timely manner and hydroxychloroquine is no longer used to treat hospitalized COVID-19 patients.
What was the rationale for the March 2020 FDA approval? What were the key factors leading to the rapid gathering of RCT evidence? How was this information disseminated to the public and medical community?
In 2020, some physicians promoted early outpatient hydroxychloroquine treatment for mild to medium severe COVID-19 to prevent hospitalization and subsequent mortality. This was based on retrospective studies, prospective observational studies and larger case series. Observational studies generally suffer from confounding differences between the treatment and control group making definitive conclusions more difficult than with randomized studies. For case series, one cannot know whether the high survival rate is due to the treatment or to a low infection mortality rate. Was it appropriate to promote the outpatient use of hydroxychloroquine without high quality RCT evidence?
Ivermectin
Approved by the FDA in 1996, ivermectin is an anti-parasitic drug that is on the WHO list of essential medicines. In 2020, it was proposed as a potential drug for COVID.
A systematic review published in June 2020 showed ivermectin to be effective against several viruses in in vitro experiments using cultured cells, including SARS-CoV2. A few smaller human trials published in 2021-2022 showed faster SARS-CoV2 viral clearance in patients taking ivermectin compared to a placebo, but clinical endpoints were unaffected or not measured.
In July 2021, an evidence-based Cochrane Review used available RCTs to conclude that ‘based on the current very low‐ to low‐certainty evidence,” they were “uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies were “small and few are considered high quality.”
The largest RCT on ivermectin as an early outpatient treatment against COVID-19 is the Brazilian Together Trial. It was published in March 2022 and found ivermectin to be safe but with a statistically insignificant mortality reduction.
Another systematic review and meta-analysis of 19 RCTs published in June 2022 reached similar conclusions: that “ivermectin did not have any significant effect on outcomes of COVID-19 patients.” The authors failed to identify a benefit against severe disease, recovery time, or viral load or clearance but found, based on low certainty, that it may reduce mortality. Published in August 2022, another RCT conducted in the US found that the early treatment with ivermectin was safe but did not provide a statistically significant reduction in hypoxia, emergency visits, hospitalization, or death. Similar results were found in an NIH funded ACTIV-6 RCT published in late 2022 which evaluated both low and high dosing.
Considering the in vitro plausibility, early positive clinical data, and the politicization and controversy surrounding ivermectin, should there have been a large randomized controlled trial in early 2020 to evaluate whether ivermectin reduces COVID-19 mortality for hospital and/or outpatient use?
The NIH concluded their high dose ACTIV-6 ivermectin trial nearly 3 years into the pandemic when there was already a high (>95%) level of immunity from either prior infection or vaccination. Were these trials completed in a timely manner?
Because of the controversy and repeated warnings from the CDC, NIH and FDA on the dangers of taking ivermectin, physicians were hesitant to prescribe it and pharmacies were hesitant to dispense it. However, ivermectin is a useful and safe drug to treat diseases and conditions such as ascariasis, head lice, lymphatic filariasis, river blindness, scabies, strongyloidiasis, and trichuriasis. Were Americans denied appropriate use of ivermectin for these conditions because of controversies surrounding ivermectin for COVID-19? Were side effects of ivermectin of COVID-19 exaggerated by some media outlets and some health providers?