April 11, 2020

expert reaction to a study about compassionate use of remdesivir for patients with severe COVID-19

A study, published in The New England Journal of Medicine, has investigated the use of the drug remdesivir for patients with severe cases of COVID-19.

Prof Duncan Richards, clinical pharmacologist and CLIMAX Professor of Clinical Therapeutics, University of Oxford, said:

“‘Compassionate use’ is better described as using an unlicensed therapy to treat a patient because there are no other treatments available. Research based on this kind of use should be treated with extreme caution because there is no control group or randomisation, which are some of the hallmarks of good practice in clinical trials.

“In the case of the new research on remdesivir as a potential treatment of COVID-19 recently published in the New England Journal of Medicine, I would say it’s impossible to discern whether there is a treatment effect or not. 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. The latter group of patients show a much more mixed picture.

“There is also a wider question of which are the right patient populations to look at. There is an increasing view that the most serious consequences of the disease result from the immune response as opposed to viral replication per se. The performance of anti-viral treatments in general has been disappointing, perhaps for this reason. However, a bigger effect with these drugs might therefore be expected earlier in the disease rather than later phases.

“There are ongoing large international randomized controlled trials with remdesivir – we really need to see those data. 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.”

Dr Stephen Griffin, Associate Professor, School of Medicine, University of Leeds, said:

 “It is critical not to over-interpret this study. Most importantly, it is impossible to know the outcome for this relatively small group of patients had they not received remdesivir. As the authors point out, a randomised clinical trial is necessary to determine the true effectiveness of this drug. It will also be important to test the drug on this scale to ensure safety in COVID19 patients.

“The patients in this study are from different places with diverse healthcare practices, and are at various stages of severe disease. Remdesivir was given on a ‘compassionate use’ basis, which doctors apply for when no other option is considered useful for treatment and patients are particularly unwell. This, much like other rapid access drug programmes, sets a high bar for the drug in terms of being able to achieve an effect – the virus is already well ahead in the race and patient health is usually poor as a result, and/or often confounded by underlying issues. An important aspect of the RCTs being set up by Gilead, the company behind the drug, is that they include multiple stages of COVID19 disease.

“Remdesivir, based upon preclinical data, is one of the more promising candidate drugs in terms of efficacy against SARS-CoV2. It is a nucleotide analogue drug, which means that it mimics the essential building blocks that the viral replication machinery needs to build new copies of its genome. Unlike similar, bespoke drugs developed to treat viruses such as HIV and hepatitis C virus (HCV), remdesivir is a broad spectrum antiviral, meaning that it can interfere with the replication machinery of a number of different viruses. A one size fits all drug is a somewhat of an antiviral utopia, yet the flip side is of course that a Jack of all trades is master of none. That’s not to say that remdesivir won’t work, just that we should remember that it wasn’t designed specifically to treat SARS-CoV2.

“Whilst several therapies have been proposed for treating COVID19, it is the case that only a handful of candidates currently in trials specifically attack the virus itself, so-called direct acting antivirals. The fact is that our repertoire of antiviral drugs has become increasingly limited compared to e.g. antibiotics, apart from the cases of HIV, HCV, and to a lesser extent influenza. This is due to a progressive disinvestment in antiviral research by large pharma over the past decade, particularly for emerging diseases, which hitherto affected small numbers of people in mainly developing countries; this simply isn’t a viable market for companies to recoup the massive costs incurred during drug development. Pharmaceutical companies need to remain viable at the end of the day. However, now that the unthinkable has happened and we face this pandemic with nothing more than preventative measures, the associated cost to the global economy makes the cost of developing even multiple drugs a drop in a very large ocean. Thus, surely world governments might be persuaded to invest more in both antiviral and vaccine development in the future, thereby mitigating the cost of this, and future pandemics.”

Prof Simon Maxwell, Professor of Clinical Pharmacology and Prescribing, University of Edinburgh, said:

 “The research is interesting but doesn’t prove anything at this point: the data are from a small and uncontrolled study. Remdesivir is currently being assessed in large scale clinical studies, which will be critical in determining whether it is a safe and effective treatment for COVID-19. This is not least because there were some adverse events (60%) reported in the current study, some of them serious (23%), including multiple organ failure, septic shock, acute kidney injury, and hypotension.”

Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

“The data from this paper are almost uninterpretable. It is very surprising, perhaps even unethical, that the New England Journal of Medicine has published it. It would be more appropriate to publish the data on the website of the pharmaceutical company that has sponsored and written up the study. At least Gilead have been clear that this has not been done in the way that a high quality scientific paper would be written.

“The authors make it clear that ‘Interpretation of the results of this study is limited by the small size of the cohort, the relatively short duration of follow-up, potential missing data owing to the nature of the program, the lack of information on 8 of the patients initially treated, and the lack of a randomized control group.’

“Individual clinicians have an understandable desire to do their best for the patient for whom they are caring, but under conditions of uncertainty it is ethical to enter patients into a randomised trial, and it could be regarded as unethical to fail to enter them into such a trial if it is available and the patient meets the entry criteria, instead requesting compassionate use. Compassionate use is intended for when no other treatment is available in a life-threatening situation and is generally used when no trials are available for a patient. It was reasonable to have remdesivir made available prior to the trials being started. 

“There was obviously unprecedented demand for this drug in spite of lack of good evidence for its efficacy and safety and Gilead suspended new requests to its compassionate use program (https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-access-to-remdesivir-outside-of-clinical-trials). At the time of this statement (I think it is March 23 2020, but it is undated on their website) they said ‘To date, we have provided emergency access to remdesivir for several hundred patients in the United States, Europe and Japan.’

“Gilead themselves say ‘Wherever possible, use of an investigational medicinal product by a patient as part of a clinical trial is preferable because clinical trials generate data regarding the efficacy and safety of the investigational medicinal product. Those data help inform whether the benefits of the investigational medicinal products outweigh the risks, whether it should be approved by the regulatory authorities leading to wider availability and, if approved, when and how it should be used.’ (https://www.gilead.com/science-and-medicine/research/compassionate-use).

“The drug was being used in patients who were severely ill, but reporting on 61 out of several hundred makes it clear that generalisations about the efficacy and safety must be treated with great caution.  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.

“The data from properly conducted randomised trials for remdesivir and possibly other treatments will be available very soon. Clearly some patients still, sadly, died. 

“There do not seem to be any unexpected major adverse effects seen in this small collection of patients, but as the authors say ‘the safety and side-effect profile of remdesivir in patients with Covid-19 require proper assessment in placebo-controlled trials.’ We need randomised studies to know if these expected adverse effects occur at a greater or lesser rate.

 “It is good that Gilead have collected data on at least some of the patients to whom they gave this drug, and it would be entirely reasonable to publish this on their website.

“Some of the currently recruiting trials have more than one active treatment as well as a placebo group, and they will have even more valuable results. It is a first step to show that a drug is better than nothing (the intention of using a placebo as a comparator), but it is as important to know which of perhaps several drugs that work, which is better or best.”

Prof Adam Finn, Professor of Paediatrics, University of Bristol, said:

 “It’s very hard to draw useful conclusions from uncontrolled studies like this particularly with a new disease where we really don’t know what to expect and with wide variations in outcomes between places and over time. One really has to question the ethics of failing to do randomisation – this study really represents more than anything else, a missed opportunity.” 

‘Compassionate Use of Remdesivir for Patients with Severe Covid-19’ by Grein et al was published in The New England Journal of Medicine on Friday 10^th April.

www.nejm.org/doi/full/10.1056/NEJMoa2007016

All our previous output on this subject can be seen at this weblink: www.sciencemediacentre.org/tag/covid-19

Declared interests

Prof Stephen Evans: No conflicts of interest.

Prof Adam Finn: No conflicts