The US Food and Drug Administration has provided Emergency Use Authorisation for the drug remdesivir to be used on hospitalised patients with COVID-19 in the US.
Dr Stephen Griffin, Associate Professor at Leeds Institute of Medical Research (LIMR), University of Leeds, said:
“The emergency FDA approval for remdesivir is an important landmark in the way that COVID19 might be dealt with. Specifically, it is the first approved direct intervention, rather than supportive hospital care or preventative measures within the community.
“Whilst some conflicting reports have emerged from different patient studies, it appears that the early reports from the NIAID trial are sufficiently robust to meet FDA requirements. Whilst a reduction in time to recovery may not, to some, seem impressive, it is important to remember that the scenario in which these patients are being treated is complex, and one in which the virus infection is usually already widespread with extensive inflammation in the lungs and elsewhere. COVID19 is a relatively fast-paced disease and patients can deteriorate quickly and suddenly. Thus, it might be expected that speedier recovery may lessen the extent of longer term damage to the lungs and a reduction to time spent on ventilators might also be significant. Moreover, being able to free up critical care berths sooner could significantly reduce the burden upon the healthcare system.
“Nevertheless, there are limitations to how remdesivir might be deployed as the requirement for intravenous administration restricts this to a hospital setting. It is therefore likely that more severely unwell patients will receive it, as is right, yet we know from preclinical work that the drug is most effective when given early. However, this paradox is commonplace with the introduction of a new therapy under such circumstances. I have every confidence that remdesivir will make a substantial difference to the clinical management of severe COVID19, in a similar fashion to how neuraminidase inhibitors are used to treat severe influenza. However, whilst the quest for a vaccine continues we must not rest on our laurels. The longer term management of SARS-COV2 will require additional second, third and fourth line therapies that might not only be more amenable to widespread use, but could also form future combination therapies to mitigate the potential emergence of virus resistance.”
Dr Penny Ward, Visiting Professor in pharmaceutical medicine at Kings College London and the Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, said:
– What is emergency approval?
“Emergency approval is a mechanism by which the FDA approves medicines, devices or diagnostics which may have shown some usefulness in assisting the management of a national emergency. It does not mean that the product is approved for general use but restricts use to a defined circumstance. In this instance, the EUA for remdesivir restricts use of the product for patients with proven SARS CoV2 and very low oxygen saturation.
– Why had the FDA done this?
“Doctors in the USA are not allowed to prescribe medications which are not approved for use by the FDA. There are no approved medications for the treatment of SARS CoV2 infection and illness and mortality is high in patients with severe symptoms requiring oxygen support in hospital. In order for doctors across the USA to be able to use a product which might be effective for the condition, it must be approved otherwise the product can only be used in a clinical trial (where patients may be randomized to a control arm) or on a named patient compassionate use basis which may delay access to potentially lifesaving treatment in severely ill persons.
– Is it warranted by the evidence?
“The FDA approved this product on the basis proven in vitro antiviral effect against SARS CoV2, animal data documenting in vivo efficacy against COVID-19 infection and a clinical trial conducted by the National Institutes of Health in which receipt of remdesivir decreased the time taken to recover from COVID-19 and reduced mortality by ~30% (from 11% to 8% p=0.059). The FDA also had data from trials in Ebola infection which demonstrated that remdesivir is generally well tolerated. The NIH trial is the second of two randomized trials of remdesivir in COVID-19 patients. The first trial was conducted in China but was terminated early as the outbreak was over before the trial was fully recruited. This study was recently reported in the Lancet, and the authors concluded that there were no differences between the patients receiving remdesivir and those receiving only standard of care. However, in patients starting treatment before day 11 of illness, some benefits were observed including more patients recovering quicker. There remains uncertainty about the best time of use and patients likely to benefit most from this treatment, but given that severely ill patients are the most likely to die and that there are no other treatments available, the FDAs decision to permit use for these patients is reasonable.”
Dr Gillies O’Bryan-Tear, Chair, Policy and Communications, Faculty of Pharmaceutical Medicine, said:
“The emergency authorisation of remdesivir by the FDA – not the same thing as full approval – is not unexpected given the promising results announced from the NIAID randomised study last week. In that study, a significant shortening of hospital stay (from 15 to 11 days) and time to recovery was observed in patients receiving the medicine, compared to those on placebo. The NIAID and Gilead are to be commended for their rapid enrolment of over 1000 patients to this study, and equally rapid announcement of the main results. Several UK centres were involved in this study, including hospitals in Oxford, Leeds, St Thomas’ hospital in London where the Prime Minister was treated, and others.
“While not a cure – overall mortality just failed to reach a significant reduction – it is the first medicine associated with a significant treatment effect in this hard to treat condition. Although a study of remdesivir from China, published in the Lancet last week, failed to show improvement, that study was much smaller, did not enrol the planned number of patients, and was considered inconclusive. It’s well known that antiviral treatments work best when used early: the patients in this study were already in hospital and thus had severe disease, so there is potential for greater effectiveness if and when remdesivir can be used earlier in the disease.
“The FDA has taken a pragmatic decision that on the balance of evidence, remdesivir is active against this lethal virus, and in the absence of other effective antiviral treatments, and given the widespread healthcare and economic turmoil around the world caused by Covid-19, the right thing to do was to approve its immediate use.
“It’s hard to disagree with this decision, and the hope is that the European Medicines Agency, UK MHRA and other regulatory authorities worldwide will quickly follow suit. Otherwise, non-US patients may be at a disadvantage.
“In political terms it will be interesting to see how the US administration reacts to requests to Gilead, a US company, for supplies of the drug for non-US patients, which may grow rapidly. We hope that distribution will be based on need, which is what Gilead has announced. Gilead has also announced they are able to make over a million doses available free of charge, and have formed a partnership with another manufacturer to ramp up production within the current year.
“One dilemma which this approval will pose for clinical researchers conducting studies on remdesivir, is whether all patients should now receive the drug. This will complicate, but not necessarily halt, the ongoing large randomised trials in which remdesivir is one of the treatments being studied, for example the UK ACCORD study. This is a decision for the researchers overseeing those studies, and may be determined by availability of remdesivir also.”
Prof Derek Hill of UCL, an expert in medicine and medical device regulation, said:
“The FDA regulates medicines to ensure they are safe and effective for use on patients. Because a high level of scientific evidence is required, alongside detailed documentation of everything that was done in the clinical trials, drug approval is a long and slow process. Getting approval for a new medicine to be used on patients normally takes many years and on average costs well over $1bn. However, within its regulatory framework, the FDA has special arrangements in time of chemical, biological, radiological, nuclear (CBRN) and emerging infectious disease threats. In such times of public health emergency, the FDA can therefore dramatically speed up the time taken to make a medicine available.
“This highly streamlined process is not the same as approval. It is an “Emergency Use Authorization” (EUA). Remdesivir has now received this emergency use authorization so can be used on severely ill, hospitalised COVID-19 patients.
“This is done as a result of the preliminary data from the US government run trial that published preliminary results earlier this week. There is nothing like sufficient data to justify a drug approval, but the FDA has decided that under these extraordinary circumstances, remdesivir may be used on COVID patients entirely legally. That authorization means that Gilead can invest in ramping up production to make sufficient medicine available for use on patients.
“Remdesivir is not a cure for COVID-19. There is evidence from the preliminary analysis that it speeds up patient recovery. There is a hint in the data that it may also reduce mortality, but that result was not statistically significant, so is quite likely to be a chance finding. When more data is available, this may tell us whether or not remdesivir can save lives as well as speed up recovery. More data may also help determine whether or not remdesivir can improve recovery for more mild COVID-19 patients who are not hospitalised. At the moment, the EUA is just for severely ill, hospitalized patients.
“The FDA has no jurisdiction in the UK or the rest of Europe, so this EUA does not enable remdesivir to be used here.”
Prof Stephen Evans, Professor of Pharmacoepidemiology in the Dept of Medical Statistics, London School of Hygiene & Tropical Medicine, said:
“The US Food and Drug Administration (FDA) has issued an Emergency Use Authorization for the anti-viral drug remdesivir for use in hospitalized patients with Covid-19.
“included allowing the FDA to bypass the usual procedures for assessment of efficacy and safety of medicines and to allow use of otherwise unapproved medicines to be used to treat Covid-19.
– What does approval for emergency use mean?
“The key element is that “There is no adequate, approved, and available alternative to the emergency use of remdesivir for the treatment of COVID-19.”. It sets out the conditions under which remdesivir may be distributed and used. It does not allow Gilead to market the drug. In this case it allows doctors to obtain and use the drug in hospitalized patients with known or suspected severe Covid-19 and who require at least supplemental oxygen. The doses are set out and it must be injected in a hospital.
– How is this different to normal drug approval?
“This means that the usual processes of assessment of efficacy, safety and quality are bypassed. There is a very basic check that there is some evidence of efficacy and that there are no known serious harms that outweigh the potential benefits. In this case the large (probably 800-100 patients) multi-national trial sponsored by the US National Institute of Allergy and Infectious Diseases (NIAID) has preliminary results showing convincing benefit in time to recovery of about 4 days. However very few details are available about the results though there is a suggestion, though not convincing, that mortality is also improved.
“This is almost unprecedented, since Gilead, the manufacturer, has not carried out the trial and has only conducted trials that involved remdesivir alone. It is relying on others to conduct trials with a comparison group that does not have remdesivir, which is the only way to provide convincing evidence of the drug’s efficacy and lack of harm.
“It is possible that further data from randomised trials will be submitted to the FDA and other regulators around the world at a later date to try and obtain approval for marketing the drug, but it is speculated that may never happen if its use is sufficient in the absence of the normal marketing approval process. The usual process would require another separate trial also showing convincing evidence of efficacy and safety before approval would be given.
– Why had the FDA done this?
“Gilead had approached the FDA requesting this, supplying their own data from trials they had conducted without a remdesivir group, and presumably they had been provided the NIAID trial data which have not been made public. It is obvious that there is an emergency with large numbers of patients dying in spite of the best efforts of doctors, and there are no drugs which have even reasonable evidence that they work. The NIAID trial does provide good evidence, based on fairly large numbers, that the time to recovery is improved and mortality may be improved, certainly not made noticeably worse.
– Is it warranted by the evidence?
“We do not really know. The main evidence has only been made public in a brief press release that does not even state how many patients were studied. The estimate of the numbers included were calculated by me on making various assumptions about the minimal data that were provided. Some concerns have been expressed about changes in the primary outcome studied, which may not be well-founded concerns, but the absence of information does not allay them.
The well-conducted trial from China and fully published in The Lancet [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext] was too small to draw conclusions, and while compatible with the results shown in the NIAID trial, taken together they show the evidence of efficacy may not be quite as great as shown in the NIAID trial on its own. In addition, there is another Chinese trial, also stopped because the numbers of new patients with Covid-19 had fallen in China so they were unable to recruit, which has not yet published its data. There are other trials where remdesivir is compared with non-remdesivir treatments currently been done and results from some of these should appear soon. A wider view will give a better understanding of the benefits and harms with remdesivir, but in this emergency, it is not totally unreasonable of the FDA to allow for its use, but it would undoubtedly have been better to provide more of the evidence in public.”
Dr Michael Head, Senior Research Fellow in Global Health, University of Southampton, said:
“The ‘approval for emergency use’ refers to rapid approvals of drugs by the US FDA during public health emergencies. This is done here because COVID-19 is caused by a high-threat pathogen with very limited treatment options. Remdesivir has shown some effectiveness in clinical trials, and so may be useful as a treatment option, in addition to usual packages of care. It’s use at the moment is limited to hospitalised patients (so not available ‘over the counter’).
“This is an important step in options available to clinicians to treat those hospitalised with COVID-19. The data shows that many hospitalised patients will die, so although the effectiveness of remdesivir is limited, it may be a useful addition as an option for treatment. The drug was designed for addressing Ebola, but there was little effectiveness in clinical trials. However, that research has given us knowledge around drug safety and toxicity that can be applied to research and treatments here with COVID-19. It shows the importance of exploring the use of existing therapeutics when new pathogens emerge.”
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