This post is not up to the standards of the New England Journal of Medicine
Compassionate Use of Remdesivir for Patients with Severe Covid-19
is an important article written and published with amazing speed. The (many) authors (including professional writers) assess the experience of 53 “patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day.”
I think I’m just going to fair use most of the abstract
… Patients were those
with confirmed SARS-CoV-2 infection who 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. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day.
Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. 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 of 30 patients (57%) 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.
I find the results *very* encouraging. As I have written from time to time, I don’t agree with current interpretation of the pure Food and Drug Act. I think Remdesivir should be approved with possible revocation of the approval if the results of the controlled trials are disappointing (that is, as always, I reject the current FDA approach). I know that won’t happen. I am going to try to add something interesting (while noting why the NEJM would not and should not publish it).
An impressive aspect of the medical literature is that they take mathematical statistics seriously. This is partly due to the FDA rules and very strictly applied to drug trials. It is required to describe the hypothesis test *before* collecting the data. This is the only way to rule out cherry picking.
The authors note that they report point estimates and standard errors and warn us to refrain from dividing, calling the quotient a t-statistic and claiming the null was rejected if there is a t-statistic greater than 2. Yes exactly. If one runs multiple tests and rejects if any reject, then the size must be adjusted (a safe way to do this is to bonforronize and assume that the overall size is the sum of the sizes of the individual tests — this is the worst case so it is safe).
They also do not test the statistical signficance of differences between the treated group and comparison groups from the published literature. Hypothesis testing is allowed only for genuine experiments with a control group and randomization. Economists often do such things and often obtain empirical results which are not valid at all.
I applaud this discipline. Also I can’t force myself to be so disciplined. I will do exactly what they refuse to do. They give the raw numbers; just typing some numbers, no insinuation of a hypothtest here, except it is humanly impossible to resist the temptation to guess what would happen if they (incorrectly) treated the two groups as two wings of a randomized trial.
My guess is that, if the comparison group were an actual control group, then the null that Remdesivir doesn’t help would be overwhelmingly rejected. For mechanically ventilated patients the death rate was 18%. The number one sees in the literature for the (non control) group is 67%. That’s a huge difference.
So the numbers I will analyse are death rates of patients who are ventilated or not and with and without Remdesivir. Those without are from published articles cited in the NEJM article.
Before going on, I have to explain one of the reasons this post is a sin against statistics and science. At the end of the sample period, 8 patients were still on ventilators and 2 on the even more extreme extracorporeal membrane oxygenation [ECMO]. Tragically their chances are not great. The 7 deaths so far are not all deaths due to Covid 19 of patients discussed in the manuscript. I am just going to assume that there is similar follow up of patients in the studies which I used as if they were control groups. There are many reasons that this isn’t up to NEJM standards, but I think the most important is that I am just assuming that the time from treatment until the end of counting deaths is the same in different studies.
From the abstract we have 6 of 34 ventilated patients who received Remdesivir died, 1 of 19 of non ventilated patients who received Remdesivir died.
Later for non ventilated non remdesivir
In a recent randomized, controlled trial of lopinavir–ritonavir in patients hospitalized for Covid-19, the 28-day mortalitywas 22%. It is important to note that only 1 of
199 patients in that trial were receiving invasive ventilation at baseline.
So that gives 43 deaths out of 198 patients who were not ventilated and did not receive Remdesivir.
among 201 patients hospitalized in Wuhan, China, mortality was 22% overall and 66% (44 of 67) among patients receiving invasive mechanical ventilation
so 1 of 19 vs 43 of 198 among non ventilated patients
6 of 34 vs 44 of 67 among ventilated patients
One way to test is to estimate the probability of dying with the frequency, calculated variances and note that, for independent samples the variance of the difference is the sum of the variances. This is a Wald type test.
for ventilated with Remdesivir
mean 1/19 = 0.05263
variance = (1/19)(18/19)/19 = 0,002624
mean 43/198 = 0.21717
variance = 0,0008586
the z score is
estimated reduction of the probability of dying is 16.45%
The z – score is -2,788
If this were a legitimate hypothesis test, the null that Remdesivir does not help patients who aren’t ventilated would be rejected at standard confidence levels
for Ventilated patients the estimated reduction in the probability of death is 48.03% with a z-score of -5,495
This rejected the null at all confidence levels that anyone ever uses.
A big problem is that I am acting as if the patients treated with Remdisivir who are still ventilated will survive as long as patients in the comparison groups survived. The Ritonavir study looked at death within 28 days. Not all surviving patients in the NEJM paper have lived that long. The Wuhan paper (as quoted) did not explain how long the patients were followed.
I think a conservative estimate of the effect of Remdesivir can be obtained by assuming that the patients who were still on ventilators when the study ended and the patients on ECMO will die of Covid 19.
This makes the estimate of deaths for the non ventilated patients 2 of 19 and the estimate for the ventilated patients 15 of 34.
The estimated benefit of Remdesivir is, of course, reduced.
For the non ventilated patients the reduction in probability of death is just 11.29 % with a z-score of -1.467 so the null is not rejected at standard confidence levels.
For the ventilated patients the estimated reduction is 21.55 % with a z-score of -2.092. This means that, even with the theextemely pessimistic guess about the fate of patients still on ventilators, the null of no benefit is rejected at the 5% level.
Personally, I think it is time to allow all MDs to prescribe Remdesivir which permission can be repealed if the genuine controlled trials are disappointing. I think my radical approach would save many lives.
“I think it is time to allow all MDs to prescribe Remdesivir”.
I tend to agree with these caveats. Does one’s doctor know who to prescribe this to, when to administer, in what dosage, and for how long? This is more than a yes or no question, which is one reason for doing all this testing.
Back on the 11th I posted this comment to PGL. In brevity, I posted a comment without the benefit of detailed numeric(s), and requiring the reader to actually review both the article and its referencing of the NEJM article.
Also added information
To your other point on letting doctors prescribe Remdesivir. They should be allowed to prescribe; however, a Remdesivir supply is not readily available and presently there is no plan to manufacture millions of doses. Rationing a drug ? To whom, the wealthy? the most politically connected? the most important? It is a nice thought and not achievable today and maybe not in the next year.
Most recently, Hydroxychloroquine in combination with zinc was used on my neighbor’s father (1 year younger than I at 70) who contracted COVID 19. You already know what Hydroxychloroquine does so I will not discuss it. The zinc ions attach to the virus resulting in limiting/decreasing the intensity of the COVID 19. Relativity inexpensive and available in 30-60 tab lozenges (suck on them). Three days later he was released from Univ. of Michigan Hospital and told to quarantine for 14 days as he still had the cough.
Since we are on well water, we were all ready adequately supplied with Lysol wipes, 409 spray, toilet paper, water for toilets and drinking, two quarts of alcohol, and a freezer of food which we stock when prices are low. We were mostly prepared.
There is a lot of hope that this treatment will prove effective. I’d argue that your statistical crimes are less than you make them out (ego te absolvo).
In general, you can use statistical significance to compare any two populations and the p-value will be valid. Where people get tripped up is in the interpretation of the significant finding. You are rejecting the null that the populations are the same. If they are different, this can be do to either differences in the populations or differences in how the populations were treated. You correctly point out these potential differences.
Outside of a randomized controlled trial, it would have been great and potentially feasible, to do a controlled observational study. In this design each treated individual is matched to a “control” who had demographic and clinical characteristics as close as possible to the treated individual at time of initial treatment. If the outcome differences held, it would provide orders of magnitude more evidence for effectiveness compared to what we have currently.
Yes Remdesivir production should be ramped up now. I think the Federal Government should order 1,000,000,000 doses at some negotiated price and treat that as a price support. That is, if someone else wants to buy the Remdesivir (especially for a higher price) they can. if not the US FedGov delivers $ 9,000,000.000 to Gliead and picks up the stuff.
Pocket change compared to $ 2.200,000,000,000 and you know it would have an impact (Gilead gets quadruple A rated with an order like that). Oh just in case they don’t also loan to them up to the full $ 9 B at the Treasury rate.
This won’t make the drug appear instantly, but it will make it appear very quickly.
Oh nooo not Zinc too. That would mean blind squirril Trump found two acorns. Anyway, so long as it works. As far as I know Zinc is pretty safe (but don’t trust me — I haven’t checked so as far as I know is not one full angstrom).
On side effects, was that the Remdesivir or the Ebola ? Some healthy volunteers took Remdesivir. What happened to them ? The NEJM article says no new safety concerns, but the therapy was stopped for some patients so that sure doesn’t mean no safety concerns.
Robert (I assume you are talking to me):
$9 billion is cost to manufacture. Then there is the issue of recouping R&D costs of not just Remdesivir; but, any other way this drug has been trialed, and then the plant cost. I am assuming pilot production for the supply of the drugs they are manufacturing now. They could run the hell out of the pilot line till the manufacturing facility is up which I have done. From what I know, the manufacturer typically follows what the ICER suggests as a list price. Gilead will also want to make “some” profit. This short document from Journal of Virus Eradication 2020, Minimum costs to manufacture new treatments for COVID-19 The charts are interesting. I would put one up but I can not copy them.
The $9 is for manufacture in other countries such as India. They would allow other countries to produce as much as they would like to do so. Royalty back to Gilead would be a discussion point.
Forget Trump, he is just parroting what someone told him. I am sure if you pulled the string on his back he would repeat the same construct again without understanding what he has said. Some of us do read and investigate, you know? I wish he would shut up on this topic. He will not do so as he is struggling to come out of this looking good.
“On side effects, was that the Remdesivir or the Ebola ?” I looked at this comment and you got me wondering for a moment. The side effects were the result of taking the Remdesivir as mentioned in the Bloomberg article without a link for ebola.
It doesn’t work. Stop with these posts.
Dosage is described in the trials. I would say that if it were available it should be prescribed for all Covid 19 positive people, but I would settle for all people hospitalized with Covid 19.
This certainly depends on my belief that side effects are known to be rare and manageable. I might be totally wrong about that, but the side effects are fairly well understood.
Always I support phase III trials. The question is what is to be done while the trials are ongoing. I basically support the current policy of expanded access, which is basically making compassionate use routine.