The remdesivir story may actually be good news for the rest of the world, argues James M Brophy

On 30 June, The Guardian ran an article with the headline “US secures world stock of key Covid-19 drug remdesivir” that laments the monopolization for “the next three months of one of the two drugs proven to work against covid-19, leaving none for the UK, Europe, or most of the rest of the world.” [1] This “me first” attitude should surprise nobody as we recall the current US administration’s attitude toward anything involving international collaboration (cf. its stance on climate change, WHO, trade, immigration).

Paradoxically the remdesivir story may actually be good news for the rest of the world. Say what?! Let’s elaborate. The scientific evidence for remdesivir’s purported clinical benefit is provided by a randomized controlled trial of 1063 patients published in the New England Journal of Medicine showing a shortened median time to recovery in the remdesivir group (11 days 95% confidence interval [CI], 9 to 12), versus 15 days (95% CI, 13 to 19) in the placebo group (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). [2] There was no effect on mortality. Moreover, there are numerous reasons why the shortened reported time to symptomatic recovery may be an over-estimate of its true value.

First, let’s recall some basic principles of controlled trials. It has been established that company sponsored trials, prematurely stopped trials, poorly executed trials with unsuccessful blinding, and large lost to follow-up, all contribute to exaggerated, embellished and unreliable effect measures. [3-7] Well, this NEJM remdesivir study was company sponsored, prematurely stopped, had incomplete blinding, and only about 15% of patients had their outcome determined at the specified primary endpoint of 28 days. An additional concern for some is the modification of the primary trial endpoint shortly before publication, although apparently before unblinding of any results. In contrast, a non-company sponsored trial looking at the same remdesivir doses found no benefit for either symptom duration or mortality. Hmmm, are we still convinced about the magnitude of any potential benefit? [8]

Obviously in a pandemic there is a strong push to quickly find efficacious treatments, but this becomes increasingly difficult when results are now first presented not in peer reviewed journals, but in press conferences and pre-prints. Moreover, we must be aware of associated extra-scientific cognitive biases which can influence the clarity of our decision making. For example, when the leading US coronavirus expert describes the above-mentioned study in a prepublication White House press conference as showing “a clear-cut, significant, positive effect in diminishing the time to recovery” the stage is set for optimism, confirmation, and group think biases that can impede an objective, critical, and comprehensive assessment of the totality of the evidence. [9] These biases are exemplified in a quote in the Guardian article from Andrew Hill, senior visiting research fellow at Liverpool University, stating “Remdesivir would get people out of hospital more quickly, reducing the burden on the NHS, and might improve survival” and “Once again we’re at the back of the queue.”

I would argue that in this case, it is good to be at the back of the queue. It is worth repeating that no remdesivir study has demonstrated any reduction in hospital stay or mortality. Even ignoring the uncertainty about the magnitude of any reduction in symptomatic recovery time, it is far from obvious that reductions in length of hospital stay would follow. Most patients hospitalised from covid are older with multiple comorbidities and often are frail with limited social support systems that may lead to a prolongation of hospital stay beyond the duration of their infectious symptoms. For this marginal and uncertain benefit, the manufacturer now proposes charging in the vicinity of $3000 USD per treatment. Remdesivir’s past history may also provoke additional reservations since its investigation as a treatment for other viral diseases including hepatitis C and Ebola has not demonstrated any clinical successes. [10] Also, the last time countries stockpiled billions of dollars of antivirals, at least $10 billion for oseltamivir (Tamiflu), could hardly be considered a success as that medication was eventually removed from the WHO list of essential medications. [11] The aphorism “Those who don’t know history are doomed to repeat it” does seem appropriate.

In conclusion, yes, the US action may be viewed as unfriendly and is truly the apotheosis of a self-centered nation, but its course of action is potentially beneficial for other countries. Better to have the plutocratic American healthcare system dominate this market with an expenditure of $1.5 billion for such uncertain benefits. The money other countries save can surely be better spent on further research for this and other drugs as well as for public health measures, including testing, contact tracing, and maintaining universal healthcare, all notable lacunae in the American system.

James M Brophy, Professor of Medicine & Epidemiology (McGill University) McGill University Health Center,

Competing interests: There are no relationships with industry. JMB is a research scholar supported by Les Fonds de Recherche Québec Santé

References:

1. Guardian T. US buys up world stock of key Covid-19 drug remdesivir. p. https://www.theguardian.com/us-news/2020/jun/30/us-buys-up-world-stock-of-key-covid-19- drug?CMP=share_btn_tw.
2. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the Treatment of Covid-19 – Preliminary Report. N Engl J Med. 2020.
3. Gaudino M, Hameed I, Rahouma M, Khan FM, Tam DY, Biondi-Zoccai G, et al. Characteristics of Contemporary Randomized Clinical Trials and Their Association With the Trial Funding Source in Invasive Cardiovascular Interventions. JAMA Intern Med. 2020.
4. Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev. 2012;12:MR000033.
5. Bassler D, Briel M, Montori VM, Lane M, Glasziou P, Zhou Q, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA. 2010;303(12):1180-7.
6. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995;273(5):408-12.
7. Akl EA, Briel M, You JJ, Sun X, Johnston BC, Busse JW, et al. Potential impact on estimated treatment effects of information lost to follow-up in randomised controlled trials (LOST-IT): systematic review. BMJ. 2012;344:e2809.
8. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-78.
9. NBC news2020. p. https://www.nbcnews.com/health/health-news/coronavirus-drug- remdesivir-shows-promise-large-trial-n1195171.
10. Mulangu S, Dodd LE, Davey RT, Jr., Tshiani Mbaya O, Proschan M, Mukadi D, et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019;381(24):2293-303.
11. Ebell MH. WHO downgrades status of oseltamivir. BMJ. 2017;358:j3266.