On May 25, the FDA approved nirmatrelvir-ritonavir (Paxlovid) for treating adult outpatients with mild to moderate COVID-19 who are at risk for severe disease. Until then, nirmatrelvir-ritonavir had only received emergency use authorization. Upon approval, the Center for Drug Evaluation and Research director Patrizia Cavazzoni, MD, , "Today's approval demonstrates that Paxlovid has met the agency's rigorous standards for safety and effectiveness."
But, just how rigorous were the standards? This question matters in terms of the risk-benefit analysis for prescribing nirmatrelvir-ritonavir to patients, as well as for the standard it sets for approval of other drugs.
The approval was based on two studies. Published in February 2022, the EPIC-HR (HR is for High Risk) randomized trial reported that nirmatrelvir-ritonavir reduces the risk of hospitalization and death at 28 days by 86% compared to placebo. The 86% relative risk was calculated from hospitalizations and deaths among those taking nirmatrelvir-ritonavir in relation to the rate for those randomly assigned to placebo. Eight of 1,039 (0.77%) patients who started nirmatrelvir-ritonavir within the first 5 days of COVID symptom onset were hospitalized within 28 days. None died. In contrast, 66 out of 1,046 (6.3%) people who took the placebo were hospitalized and 7 died.
Notably, this study was completed during the dangerous -- and it was against this backdrop that the 6.3% hospitalization rate in the control group resulted. Times have now changed, with cases at a significantly lower level than pandemic peaks. During the EPIC-HR study in fall 2021, hospitalizations peaked at 25.4/100,000. For the week ending June 3, 2023, 2.17/100,000 hospitalizations -- a rate approximately 12 times lower than during the EPIC-HR study. Furthermore, EPIC-HR turned away people who had been vaccinated or previously infected. According to CDC estimates, now meet these exclusion criteria. In 2023, it is difficult to find people like the participants in the EPIC-HR study.
A second Pfizer study addressed the concern that participants in the EPIC-HR study were atypical. EPIC-SR included "standard risk" patients who could have been vaccinated or previously infected. For both people with more than one risk factor and those with no risk factors, the benefit of nirmatrelvir-ritonavir for preventing deaths and hospitalizations was non-significant. About 1.9% of those taking placebo were hospitalized or died in comparison to about 0.9% of those taking nirmatrelvir-ritonavir -- a difference of about 1%. Among those with no risk factors, the difference was about 1/2 of 1 percentage point. A newer high-quality from the VA also reported that absolute differences in hospitalization or death were only about 1% to 1.5% lower among those who took nirmatrelvir-ritonavir in comparison to those who did not.
The EPIC-SR Trial study, which was cited in the FDA hearing as supporting the efficacy of nirmatrelvir-ritonavir, was terminated due to futility in July 2022 and the final results have never been publicly reported. The for study termination was "Enrollment ceased due to a very low rate of hospitalization or death observed in the standard-risk patient population."
Clinicaltrials.gov reveals that EPIC-HR and EPIC-SR are not the only studies to evaluate nirmatrelvir-ritonavir. At the time evidence was by the Antimicrobial Drugs Advisory Committee, 19 studies had been registered and 12 had been completed. Seven of the completed studies were randomized trials. Yet, Pfizer chose not to post data from all but the EPIC-HR trial (unfortunately not posting results within 1 year of study completion is a fairly common practice in clinical research; FDA can but rarely does). After the FDA hearing, Pfizer posted results from a comparing a 5- versus a 10-day course of nirmatrelvir-ritonavir to placebo for preventing COVID infections among adults exposed to an infected family member. The study failed to show either course of nirmatrelvir-ritonavir worked better than placebo.
In summary, FDA approved nirmatrelvir-ritonavir based on two studies: one highly relevant to current practice, and one that may be less informative. EPIC-HR, completed during the more lethal Delta wave, concentrated on the high-risk, unvaccinated, and never infected -- a group now estimated to be less than 4% of the population. EPIC-SR, conducted during the Omicron wave with a more representative sample, was terminated because the probability of achieving a significant benefit was judged as futile. Yet, the FDA disregarded a null result from the more representative EPIC-SR study and concentrated on the EPIC-HR trial, which has little relevance to current practice.
To be clear, I would never oppose a drug that may significantly reduce the risk of hospitalization and death. The good news is that the rate of hospitalization and death without treatment is now hovering around 1%. But that also means the number needed to treat to avoid one hospitalization or death is about 100. The probability of benefiting from the medicine is about one in 100.
It's also important to consider the risk-benefit analysis among carefully screened patients.
Some minor concerns need continued surveillance. For example, "Paxlovid rebound" gained public attention after it was observed in President Joe Biden, NIAID Director Anthony Fauci, MD, CDC Director Rochelle Walensky, MD, MPH. The official Pfizer for patients does not mention rebound, and CDC quickly released an assuring the public that rebound was rare and mild. But, anecdotal reports of rebound persist. Despite the experience of millions of nirmatrelvir-ritonavir takers, are hard to find. The few systematic evaluations show , although these are not estimated in RCTs. We simply need more data.
The public should have a vested interest in the approval of nirmatrelvir-ritonavir, given that the entire $530 cost for the 5-day course is covered by taxpayers. The U.S. government purchased courses for about $12.6 billion. For context, the money spent on this one drug is about twice the of the National Institute of Allergy and Infectious Diseases. That agency provides grants for research and training to thousands of institutions to address not only COVID, but also many other diseases including HIV, influenza, shingles, and tuberculosis, just to name a few. Meanwhile, Pfizer is raking in huge profits, as its marketing campaign "If it's COVID, Paxlovid" dominates the airways. Nirmatrelvir-ritonavir was authorized for emergency use in , and then quickly gained for distribution in Europe, China, Asia, and Central and South America. This contributed to Pfizer's revenues of in 2022.
As consumers and taxpayers, we should be able to review the evidence from all relevant studies, whether or not the results support the value of nirmatrelvir-ritonavir. And federal agencies -- including CMS -- should examine all evidence before committing to continued public funding.
is a faculty member at Stanford University's Clinical Excellence Research Center, a former associate director of the National Institutes of Health, and a former chief science officer for the U.S. Agency for Health Care Research and Quality.