Grim pandemic tolls, clinical trials of therapeutics, and more

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Dean Jonathan Samet on the roof of the Fitzsimons building at CU Anschutz.

Last week, total deaths in the United States resulting directly from COVID-19 reached one million, a count that was unimaginable at the pandemic’s start. This total does not include the excess deaths indirectly attributable to the COVID-19 pandemic, resulting from its sweeping consequences for personal health and healthcare systems. The first death reported from COVID-19 was on February 29, 2020, although revised death certificates identified earlier COVID-19 deaths. The count mounted quickly at the pandemic’s start, and by April 2020 the total was 5,000. An early 2020 forecast from the White House projected 100,000 to 240,000 deaths from the pandemic. Now, we are at one million with the pandemic still in progress, albeit with a less virulent clinical picture because of vaccination and naturally acquired immunity, plus improved care and therapeutics.

Scientific American probes the demographics of these deaths and their consequences. We know that older people were the majority of the deceased. Of those 65 and older at the pandemic’s start, one in 74 died from COVID-19. Too many of these deaths were among residents of long-term care facilities, but healthy elders with years of quality life expectancy remaining were also pandemic victims. About one-quarter of the deaths were in the age range 18-64 years and over 240,000 children lost their caregivers as a result. The demographic and human impact of the one million deaths will be long-lasting. 

Last week, the World Health Organization (WHO) released its (delayed) report on the global total of deaths from the pandemic. The WHO considered excess all-cause mortality to be the most useful measure, particularly with widespread variation in the validity of specific attribution of deaths to COVID-19. Excess mortality is defined as “the mortality above what would be expected based on the non-crisis mortality rate in the population of interest.” In other words, the WHO calculates the excess as the difference between the deaths that occurred in comparison to a counterfactual of what would have been expected to occur in the absence of the pandemic. Given widespread data gaps and variation in data quality, the estimation of excess deaths required extensive modeling

Overall, the WHO attributes 15 million excess deaths to the COVID-19 pandemic worldwide, far above the total of about 5.5 million deaths directly assigned to COVID-19. The gap varies across regions and by level of the national economy. These estimates of excess deaths have broad implications, in part because the estimated gaps indict national governments for their responses. Release of the report was delayed for months because of India’s objections to the estimates for that country.  

I am not a “trialist,” but to my understanding, a clinical trial is justified when there is a reasonably hypothesized and supported benefit of a therapeutic agent, the risks are acceptable, and the evidence for its use hangs in the balance, i.e., at the point of equipoise. Last week’s New England Journal of Medicine reports findings of a clinical trial of ivermectin, a touted cure-all and preventive therapy for COVID-19. The trial, carried out in Brazil, showed no benefit of ivermectin for two clinical outcome measures in people with an early diagnosis of COVID-19: hospital admission due to progression of COVID-19, and prolonged emergency department observation. Hydroxychloroquine, an anti-malarial also used for treating rheumatoid arthritis, was touted early on in the pandemic as beneficial for preventing and treating COVID-19. Former president Trump praised the drug and took it for a time. In November 2020, the National Institutes of Health released findings of a clinical trial showing no benefit of hydroxychloroquine for people hospitalized with COVID-19. Results from a trial by the WHO were confirmatory.

For both agents, there was little prior basis for anticipating therapeutic efficacy against SARS-CoV-2 for an anti-malarial (hydroxychloroquine) and an anti-parasitic (ivermectin). Rather, the need for the trials was driven by misinformation and politically empowered proponents. Notably, 206 clinical trials of hydroxychloroquine were launched by November 2020, a number that seems far too large. The problem of “pandemic research exceptionalism” received attention early in the pandemic as multiple trials of hydroxychloroquine were initiated. It seems reckless and ethically questionable to have launched large numbers of uncoordinated trials on testing for purported but a priori unsupported benefits. In the case of ivermectin, was there sufficient indication of potential benefit to launch a trial? or was the underlying intent to achieve a hoped for null finding? There will be more therapies advanced based on speculation and whim, and clinical trials will be needed to generate evidence that they are, or are not, efficacious. 

Decisions of the Supreme Court may have powerful implications for public health. The leaked decision concerning Roe v. Wade is alarming; let’s stay tuned for the final opinion.     

Jon Samet's Signature

Jonathan Samet, MD, MS
Dean, Colorado School of Public Health





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ColoradoSPH COVID-19 Dean’s Notes
ColoradoSPH Dean’s Notes




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