Why is remdesivir so controversial?

Published December 1, 2020, 5:17 PM

by Dr. Edsel Salvana

Is this drug really effective and worth its price?

Dr. Edsel Maurice T. Salvana

Other than hydroxychloroquine, no other anti-Covid-19 drug has generated as much controversy as remdesivir. Originally developed as a drug against the Ebola virus, remdesivir was repurposed for use against the SARS-CoV-2. Like hydroxychloroquine, early data on the efficacy of remdesivir as an antiviral against Covid-19 was mixed. 

Unlike hydroxychloroquine which showed no effect and potentially severe side effects, remdesivir has been shown to shorten recovery time and is relatively safe. As more studies are completed, remdesivir is clearly not a “magic bullet.” It does help Covid-19 patients recover, but it is not going to save the sickest patients.

The US Federal Drug Administration (US FDA) recently approved remdesivir for use in hospitalized Covid-19 patients. Several other countries have approved the use of remdesivir.

SOLIDARITY TRIAL. The World Health Organization do not allow the use of Gilead remdesivir in hospitalized COVID-19 patients regardless of disease severity.

Many people were puzzled because the World Health Organization (WHO) recently reported that remdesivir had not decreased the risk of dying from Covid-19 in an interim clinical trial report. Much discussion has centered on whether the steep price of the treatment is worth the relatively modest benefit. To understand the circumstances of the US FDA approval and its consequences for local use, some insight into how clinical trials are conducted is helpful.

When drugs are developed, there are hierarchies to the studies that prove or disprove efficacy. In descending order of certainty, these studies are randomized controlled trials (RCTs), prospective cohorts, retrospective cohorts, case controls, and case reports. 

MALARIATREATMENT. Hydroxychloroquine showed no effect and potentially severe side-effectsfor patients. (Photo by Geroge Frey)

Among RCTs, there are placebo-controlled, double-blinded, single-blinded, open label, adaptive, clustered, nested, and more. All these designs have strengths and weaknesses. It is important to treat scientific findings within the limits of the trial design, and within the context of the entire body of scientific knowledge.

Clinical trial results are determined through outcome measures. There are primary outcome measures and secondary outcome measures. There are “hard” outcomes that are unequivocal like death or hospital discharge. There are “soft” outcomes like whether a patient seems to be improving or feels better. The number of people who are enrolled in a clinical trial and the length of time they are observed depend on the outcomes of interest. For instance, to determine if a drug helps someone with a disease that lasts five days, at least five days should be allowed to pass before measuring the outcome. If it takes someone at least one year to die of a disease, measuring whether a drug decreases the death rate before one year will not be meaningful.

There are several RCTs that have been done on remdesivir. One of the most important of these is ACTT-1 (Adaptive Covid-19 Treatment Trial), which was done by the United States National Institutes of Health. ACTT-1 showed that “remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection.” Layman translation: Remdesivir helps hospitalized patients with Covid-19 pneumonia recover faster.

A newer RCT sponsored by the WHO known as the SOLIDARITY trial recently released interim results. SOLIDARITY looked at 28-day mortality in the hospital—how many patients who got remdesivir and other treatments died compared to standard care. SOLIDARITY did not meet its primary outcome in any of the tested drugs: hydroxychloroquine, lopinavir/ritonavir, interferon, or remdesivir. The hydroxychloroquine and lopinavir/ritonavir arms were stopped early due to futility—it did not look like continuing the study for these two drugs would detect any difference. The interferon arm was stopped in October. Remdesivir showed a potential effect toward improving survival, and so the trial is moving forward and will continue to enroll patients. Out of all the four drugs that were studied, only remdesivir was carried forward to further testing. 

ACTT-1 did not show a mortality benefit (it did not decrease deaths) just like SOLIDARITY and this is a consistent finding. There are major differences, however, in the primary outcome measures of the two studies. ACTT-1 had time for recovery as a primary outcome. Remdesivir met this efficacy measure since it decreased time of recovery in hospitalized patients from 15 days to 10 days. SOLIDARITY did not meet its primary outcome for any of the study drugs because all four drugs failed to significantly decrease Covid-19 deaths after 28 days. 

The US FDA approval for remdesivir hinged on the findings of ACTT-1. It did not include SOLIDARITY findings because available results are from an interim report, which had not yet been peer reviewed or published in a scientific journal at the time of the review. Even with the finding of no effect on mortality, SOLIDARITY did not show harm for remdesivir and it suggested a potentially beneficial effect in reducing deaths. It is unlikely there would have been an adverse impact from SOLIDARITY results, even if it had been included in the assessment of the US FDA.

Despite no clear impact of remdesivir on Covid-19 deaths, ACTT-1 did shorten time to recovery. Since this result is from an RCT, it is strong evidence of benefit and this was enough to convince the US FDA to give approval. Remdesivir may yet show a small effect on reduction of deaths with SOLIDARITY and that is why they are continuing to enroll patients in the remdesivir arm. There is strong evidence remdesivir has a good effect on recovery and evidence that earlier use is more effective.

The two major remdesivir RCTs ACTT-1 and SOLIDARITY do not contradict each other. ACTT-1 and SOLIDARITY did not show a significant effect on deaths and this is consistent with what is currently known about Covid-19 and the way remdesivir is used. ACTT-1 did show benefit for shortening recovery time, and nothing in SOLIDARITY contradicts this. That is why the US FDA approved remdesivir.

In the absence of a better drug, remdesivir is the only known effective antiviral that is available and should continue to be used on our patients in accordance with local guidelines. PSMID currently recommends it for compassionate use in patients with severe to critical Covid-19 disease. As more data comes in and more drugs are studied, the role of remdesivir in the fight against Covid-19 will continue to be refined and redefined. In the meantime, it remains a useful tool in our growing armamentarium against the pandemic.

 

 
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