Congratulations on developing the antiviral remdesivir, which is now being tested for the treatment of patients with coronavirus infection. While you have had great success with antiviral drugs for HIV and hepatitis C virus infections, remdesivir could have an even greater societal benefit.
Your company has also demonstrated goodwill in the timely reporting of compassionate use of remdesivir in 61 patients with COVID-19. This series found improvement in the clinical status of 69% of patients treated with remdesivir.
The global community welcomes the fact that you will be funding randomized clinical trials of remdesivir. Obviously, the randomized trial is the best way to know whether a drug works.
This letter is to commend you for recent protocol changes to the major trial in patients with severe COVID infection but also to ask you to consider some other changes to help reduce bias and allow a clear assessment of remdesivir benefit: blinding and a placebo control.
Most clinicians welcome the decisions to increase the sample size (from 400 to 2400) and to change to a 7-point ordinal endpoint, which includes the outcomes of death, use of mechanical ventilation or extracorporeal membrane oxygenation, use of high-flow oxygen or noninvasive ventilation, low-flow oxygen, hospitalization without oxygen but other medical care, hospitalization only for protocol remdesivir, and no hospitalization, assessed on day 14.
[For those unfamiliar with the ordinal outcome endpoint, it’s often used in clinical trials of antiviral agents in hospitalized patients with influenza to increase statistical power relative to time-to-event endpoints because the follow-up in flu trials is short.]
This endpoint provides for the maximum use of clinical information. Indeed, a reduction in patients requiring aggressive measures is an important metric. The problem is that with the exception of death, the other outcomes in this endpoint depend on clinician choice. In an open-label trial, as currently planned, this could lead to bias.
It is early in the course, and the change I propose is to add blinding. You don’t want to spend millions of dollars and end up with a biased result.
Since remdesivir is an intravenous (IV) drug, you could simply add an IV placebo infusion to the standard care. While oral placebos can be quite expensive, an IV placebo infusion would be inexpensive and easy to add to standard care.
I recognize that some would bring up the ethics of a placebo infusion. That would be easy to refute because each of the four arms of the trial feature standard care plus remdesivir vs standard care alone.
With blinding and placebo control, the findings would be more reliable because they would be free from the potential biases of clinicians—who, out of the desire to have an available treatment, may consciously or unconsciously make or delay decisions to reduce oxygen and avoid mechanical ventilation in patients in the remdesivir arm.
I reached out to Andrew Althouse, PhD, a biostatistician at the University of Pittsburgh, who agreed that without a placebo control there will be problems in outcome ascertainment and uneven patient dropout. And on the matter of analyzing a changed trial, he wrote that if the treatment effect appeared consistent during the open-label and placebo period, the results could be analyzed together, but if there was a pronounced change in magnitude of treatment effect between periods, separate analyses may be required.
As I write this letter, the number of coronavirus cases is set to exceed 2 million.
Given that hundreds of thousands of humans may die from either the viral infection or the societal interventions to stop the virus, having a clear answer on whether remdesivir works is vital.
Thank you for your consideration.
John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.
Follow John Mandrola on Twitter
New data on the investigational antiviral drug remdesivir (Gilead) suggest clinical improvement in 36 of 53 patients (68%) hospitalized for severe COVID-19, according to a new study published online April 10 in the New England Journal of Medicine.
But experts are warning that these data come from compassionate use in a wide variety of patients, with no randomization and no control group.
"It is impossible to know the outcome for this relatively small group of patients had they not received remdesivir," commented Stephen Griffin, PhD, associate professor at the University of Leeds School of Medicine, United Kingdom, who was not involved with the study.
"As the authors point out, a randomized clinical trial is necessary to determine the true effectiveness of this drug," Griffin added in comments he provided to the Science Media Centre in London. Such trials are underway.
The data from this paper are almost uninterpretable. Prof Stephen Evans, London School of Hygiene & Tropical Medicine
"The data from this paper are almost uninterpretable," said Stephen Evans, MSc, FRCP, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, who provided comments to the Science Media Centre.
Evans notes that the authors describe multiple caveats that limit interpretation of the results, including the small sample size, the relatively short follow-up, missing data, no follow-up on eight patients, and lack of a randomized control group.
Meanwhile, Josh Farkas, MD, who writes the PulmCrit blog, details his criticisms in a piece entitled, "Eleven reasons the NEJM paper on remdesivir reveals nothing." Beyond the issues the authors list, he points out several more, including cherry picking of patients. "Remdesivir was aggressively sought-after by thousands of patients with COVID-19," he writes. "Of these patients, 61 ended up receiving the drug. Why did these patients receive medication, out of scores of patients applying to receive it?"
Also, there are no follow-up data for 8 of the 61 patients who received an initial dose of the drug, leaving 53 for the published analysis, continues Farkas, who is an assistant professor of pulmonary and critical care medicine at the University of Vermont in Burlington.
"What happened to these patients? Did they die from anaphylaxis? Did they get well, sign out against medical advice, and go party? This is unknown — but I'm worried that these patients actually didn't fare so well," Farkas writes.
Farkas, like Evans and Griffin, concludes that the data are largely unusable. "Until [a randomized controlled trial] is performed, further compassionate use of remdesivir probably isn't justified," he writes.
Data from Compassionate Use Program
The data in the NEJM article come from a compassionate use program set up by Gilead. The company says it has provided emergency access to remdesivir for several hundred patients in the United States, Europe, and Japan.
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The authors, led by Jonathan Grein, MD, from Cedars–Sinai Medical Center, Los Angeles, California, report on 61 patients who received remdesivir as part of this program.
The authors, several of whom are employees of Gilead, note that data on 8 patients could not be analyzed (including 7 patients with no posttreatment data and 1 with a dosing error).
Of the 53 patients whose data were included, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan.
These were patients hospitalized with COVID-19 who had confirmed SARS-CoV-2 infection and had an oxygen saturation of 94% or less while they were breathing ambient air, or who were receiving oxygen support.
Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment.
At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation.
During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 (57%) of 30 patients receiving mechanical ventilation who were extubated.
A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation
While the authors acknowledge limitations of the data they collected, they nevertheless comment that "comparisons with contemporaneous cohorts from the literature, in whom general care is expected to be consistent with that of our cohort, suggest that remdesivir may have clinical benefit in patients with severe COVID-19."
"Currently there is no proven treatment for COVID-19. We cannot draw definitive conclusions from these data, but the observations from this group of hospitalized patients who received remdesivir are hopeful," said Grein in a Cedars–Sinai press release. "We look forward to the results of controlled clinical trials to potentially validate these findings."
Experts are not convinced, however.
"The drug was being used in patients who were severely ill, but reporting on 61 out of several hundred makes it clear that generalizations about the efficacy and safety must be treated with great caution," said Evans. "There is some evidence suggesting efficacy, but we simply do not know what would have happened to these patients had they not been given the drug."
"I would say it's impossible to discern whether there is a treatment effect or not," said Duncan Richards, MA, DM, FRCP, clinical pharmacologist and professor of clinical therapeutics, University of Oxford, UK. "This is in part due to the mixed patient population, ranging from those needing low dose oxygen, who are more likely to survive anyway, to much more severe cases…[who] show a much more mixed picture."
"There are ongoing large international randomized controlled trials with remdesivir — we really need to see those data, " he said in comments to Science Media Centre. "Safe and effective treatments for COVID-19 are critically needed and should be expedited wherever possible, but it's important not to compromise on the quality of the research."
Multiple coauthors are employees of Gilead, the company developing remdesivir. Griffin, Evans, and Farkas have disclosed no relevant financial relationships. Richards consults for GlaxoSmithKline in the field of drug safety. GSK does not manufacture any of the products mentioned.
There is currently insufficient evidence to recommend any particular medication for treatment of COVID-19, an expert panel of the Infectious Diseases Society of America (IDSA) has concluded.
Many pharmacologic therapies are being used or considered for the treatment of patients with COVID-19. Given the rapidly emerging literature on treatment, the IDSA convened the panel to develop interim evidence-based guidelines to support clinicians in making decisions about treatment and management of patients with COVID-19.
This is a "living document" that represents the best understanding to date on the treatment of patients with COVID-19, and it will be updated frequently as new information becomes available, IDSA member Rajesh Gandhi, MD, from Harvard Medical School and the Massachusetts General Hospital, Boston, said today during a media briefing.
Adarsh Bhimraj, MD, associate staff physician, Department of Infectious Diseases, Cleveland Clinic, Ohio, chaired the IDSA COVID-19 rapid guidelines expert panel. He urged caution in using unproven agents.
"Over the last few weeks, in caring for these patients, we have used therapeutic agents which were not proven, and some of these patients had adverse reactions, and as a team, we wondered, are we actually helping these patients, or could we be potentially harming these patients by using these medications?," he told the briefing.
On the subject of hydroxychloroquine, Bhimraj acknowledged that it's "frustrating not to do anything when people are suffering, but [the panel] objectively looked at all the data, and we all individually were able to conclude that at this point in time, the benefits do not outweigh the harms, so we cannot recommend the routine use of this medication."
Recommendations and Narrative Summaries
Following a rigorous review and data synthesis, the panel agreed on seven treatment recommendations. They note that in their recommendations, the word "recommend" indicates strong recommendations, and the word "suggest" indicates conditional recommendations. In their recommendations about drugs, the guideline panel used the word "only" when there was "higher uncertainty and/or more potential for harm."
They also used the phrase "knowledge gap" to accentuate their statements on the seven recommendations.
- Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine in the context of a clinical trial. (Knowledge gap)
- Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends hydroxychloroquine/chloroquine plus azithromycin only in the context of a clinical trial. (Knowledge gap)
- Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends the combination of lopinavir/ritonavironly in the context of a clinical trial. (Knowledge gap)
- Among patients who have been admitted to the hospital with COVID-19 pneumonia, the IDSA guideline panel suggests not using corticosteroids. (Knowledge gap)
- Among patients who have been admitted to the hospital with acute respiratory distress syndrome associated with COVID-19, the IDSA guideline panel recommends the use of corticosteroids in the context of a clinical trial. (Knowledge gap)
- Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends tocilizumab only in the context of a clinical trial. (Knowledge gap)
- Among patients who have been admitted to the hospital with COVID-19, the IDSA guideline panel recommends COVID-19 convalescent plasma in the context of a clinical trial. (Knowledge gap)
The document also includes "narrative summaries" of other treatments currently undergoing evaluation and for which more data are needed to formulate recommendations.
These treatments are the following: HIV antivirals, lopinavir-ritonavir combined with interferon beta or other antivirals; COVID-19 convalescent plasma for prophylaxis; ribavirin; oseltamivir; intravenous immunoglobulin; remdesivir; stopping nonsteroidal anti-inflammatory drugs or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy for COVID-19 patients.
Guided by Science, 100+ Clinical Trials Underway
The guidelines further state that "when an explicit trade-off between the highly uncertain benefits and the known putative harms of these therapeutic agents were considered, a net positive benefit was not reached and could possibly be negative (risk of excess harm)."
"The only way to find a treatment for COVID-19 is to do the clinical trials. We really need to be guided by the science," Gandhi told the briefing. He said that more than 100 clinical trials are currently underway in the United States, and around the world, many more trials are investigating treatment options. "Some of these trials we think will have results in the next few weeks," he said.
The IDSA plans to issue COVID-19 guidelines on diagnostic testing and infection prevention in healthcare settings.
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