What do we want ? Hydroxychloroquine (update without Azithromycin) and Remdesivir. When do we want it ? Now
I will never forgive Donald Trump for saying something exceedingly controversial with which I agree. I hate to say this but I agree with Trump and disagree with Fauci on hydroxychloroquine and Remdesivir.
Update: But don’t mix the Hydroxychloroquine with Azithromycin
“Azithromycin: (Major) Avoid coadministration of hydroxychloroquine and azithromycin.”
I will discuss hydroxychloroquine here because there is no legal issue. It can be prescribed for Covid 19 under current law and regulation. As noted here, the FDA has no say in the matter — they regulate food, drugs, and advertising and do not regulate the practice of medicine.
Consider the different treatment of Remdesivir, Hydoxychloroquine, and sever control measures. Because it is not proven that hydroxychloroqine works, it is considered a Trump average level outrage to say it should be tried. The side effects have been known for decades (and are acceptable given the circumstances). It inhibits SARS Cov2 replication in vitro https://www.nature.com/articles/s41421-020-0156-0 . There is anecdotal evidence that it has saved lives.
This does not amount to proof. Therefore, it is argued (by many people I respect) that it is irresponsible to type the following: all Covid 19 patients should be given hydroxychloroqine now. There is no morally acceptable alternative to doing this now. Now.
In contrast, there is extremely limited evidence on extreme control measures. There is no control group. The sample size is maybe one or two. And yet, it is perfectly responsible to advocate extreme control measures. Indeed it is perfectly responsible to impose them by decree (I am in Rome and have been ordered by prime minister Conte not to leave this apartment without a good reason).
Note the contrast here
The NYTimes.com presents a model graphically on page 1. It shows estiamtes. It is, in fact, theory, forecast not fact. The effectiveness of “severe control measures” is assumed. The data on which the estimate is based isn’t presented (on page 1)
Consider this published the same day (no longer on page 1)
“Trump’s Embrace of Unproven Drugs to Treat Coronavirus Defies Science”
Notice there is no headline about how Cuomo’s, Newsome’s and Conte’s embrace of unproven public health measures defies science (and I absolutely don’t assert that — I think they are making reasonable policy choices given necessarily incomplete knowledge)
It is absolutely clear that there is no general rule for acting without proof or solid knowledge. Sometimes, the rule is to not do something new until there is proof that it works. Usually, the rule is entirely different.
I do not think that anyone can justify the current dichotomy. I don’t think anyone tries. It is just assumed that the FDA rules are laws of nature and must be accepted.
I am trying to understand why this is. There are many possible good explanations which I will try to consider over after the jump
OK so here I am defending Trump from criticism in the New York Times (as written by the terminally ballanced headline writers) . Definitely preferable to having Covid 19 anyway, but no fun.
First, advising people do do something does not defy science. Science gives predictions of outcomes. It doesn’t tell us what to do. Trump defies the current policy of the FDA and the Medical Profession. He violates medical professional ethics (he can he’s not a doctor) and gives advice on health care (he has a first amendment right to do that as do I).
But second, there is the assumption that, when one considers pharmaceuticals, there is a dichotomy between proven and unproven (a false dichotomy is the most common error of thought and more common than any valid method of thought). So hydroxychloroquine for Covid 19 which is supported by preclinical evidence and anecdotal evidence is like Goop (link is not endorsement).
Again, I don’t think anyone can come up with a rational for treating pharmaceuticals in a way which is fundamentally different from everything else. In that case, decisions are not made based on cost benefit analysis given necessarily imperfect information. In that case, the fact that one *might* regret an action with the benefit of hindsight is considered decisive. Of course this is always always true — “might” makes right, anything might happen.
OK so why.
1. History. The difference is based on law. Laws are passed based on specific circumstances, then are imposed and interpreted. The question of what the law should be is considered by few, the question of what it is by many. Lawyers treat their laws as physicists treat theirs. Normal people respect the law. Obedience becomes ingrained.
I think this is expecially true for people like Tony Fauci one of whose core competencies is an ability to get along with the FDA (here for a change I am not speaking from ignorance).
A problem with explanation 1 is that the rules are similar world wide. It isn’t all Upton Sinclair and Teddy Roosevelt. The US used to lead by example. The FDA was explicitly praised and admired. But, in the end, the policy can’t be the result of “The Jungle”, it is too universal.
2. Regulations are needed to stand up to powerful concentrated interests. Alphabet soup FDA, FCC, SEC. The pharmaceutical companies have a very strong interest in selling pharmaceuticals. Tight rigid rules are needed to stand up to them.
The is not relevant to off label use of an off patent pharmaceutical.
3. Malpractice liability. It is very important to MDs to have a standard of care and to have no obligation to provide care which works better than the standard care. This is very explicitly a limit on malpractice liability. Better safe than sorry is true for the doctor and the hospital. They can be safe even if the patient dies, so long as they followed standards of care. This is a very strong incentive for small c Conservatism.
Again, my hypothesis has a problem that, if this were the issue, it should be US specific. I think it should be US specific. It isn’t. I honestly don’t know why Italian doctors act as if Italian civil justice actually works, but they do.
I can’t think of anything else. The explanations are completely insufficient. I do not understand.
Also give everyone with Covid 19 hydroxychloroquine NOW.
I actually think shelter-in-place policies for COVID-19 and not using hydroxychloroquine prophylactically *are* consistent. Both choose the (small c) conservative approach of preferring the avoidance of known risks with severe consequences
The risk of exponential growth without social distancing measures is fairly known based on other country’s experiences and other pandemics. While there is no evidence that shelter-in-place as enacted will actually slow transmission, whatever adverse effects they cause is deemed more acceptable than mass casualties and the total collapse of the health care system
The risk of severe consequences from taking hydroxychloroquine—even if extremely rare—are known: permanent blindness, damage to the heart, death
Knowing a large majority of COVID-19 cases recover fully without any intervention, I doubt the minuscule risk of retinopathy, cardiomyopathy, or death would be acceptable
That risk is even less acceptable if you plan on giving it to healthy individuals not yet affected by COVID-19
Victor:
Because the US and Italy waited so long to test, enact quarantine or social distancing, we are past the point where quarantine of people who are not presenting COVID 19 will be effective unless you are saying the people with COVID 19 should just die? I also believe you are confusing hydroxychloroquine with chloroquine. The former is a milder version of the latter and does not present the degree of risk you attribute to it which is prevalent to a greater degree in chloroquine.
Robert:
I am in agreement. If you look at New Deal Democrat’s presentation of Mark Handley’s Graphs, one can see we are in deep shit and must do something besides quarantine people so you die in private.
I do not understand the logic being applied to doing nothing until you get the ok while we are in the midst of a pandemic. F**k, it makes no sense and no one is hurrying along with a solution. We have a French small clinical trial and we have practical evidence from China (thank you for providing it) which I created a link for in your post. Keep screaming foul Robert as little will be done till we see deaths rise in the US. If you look at Handley’s graphs New York State’s trend has surpassed Italy’s and is 4 days behind Italy
My understanding is that hydoxychloroquine or chloroquine are already being given to patients at Montefiore Medical center, and perhaps many others.
mgk:
To back you up; a link: Chloroquine May Fight Covid-19—and Silicon Valley’s Into It
As little as I want to see Trump survive this disaster, that is outweighed by my intense desire to see this disaster mitigated. I suspect that Fauci’s push back is not to suggest that medical providers do not start prescribing unproven treatments now but to push back on the loyal supporters of Trump ceasing even their limited efforts at social distancing because a “cure” is available. How did he try to do that? By citing the science and regulations. As to the regulations as a recovering lawyer I do like think they are important and I have known people whose moms took Thalidomide. Plainly that should not be an issue with the anti malaria drug because Trump is right that it has been around and in use for years. It may well be ineffective and could even hasten death but if only given to the critically ill folks with their consent would seem to have no down side. Indeed, if we get to the point ( and we will be there next week in some parts of the country) where we are triaging who gets treatment and who dies maybe they should send them away with an overdose of morphine. That is only a half facetious statement. Desperate times call for desperate measures.
Terry:
Robert presented a document of effectiveness as well as the small trial documented in France I have presented. The stuff works. Did you click on his link or are you another who believes the Chinese just lie? If you look at Handley’s charts, the Chinese and Koreans have flattened the curve and the US is going up the same at what Italy is doing.
I am not confusing chloroquine with hydroxychloroquine
Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. https://www.ncbi.nlm.nih.gov/pubmed/29858838
Hydroxychloroquine retinopathy — implications of research advances for rheumatology care https://www.nature.com/articles/s41584-018-0111-8
I acknowledge that the risks of morbidity and mortality from hydroxychloroquine are fairly small, dependent on dosing and duration of treatment. But so is the individual risk of dying from COVID-19. So issues arise only when you take those small risks and multiply it by large numbers of individuals.
As Robert points out, it is completely already feasible for anyone with prescription-writing privileges to treat whomever with hydroxychloroquine for whatever reason. No need for approval. I know doctors are already doing it.
But clearly only treating people who are confirmed positive for COVID-19 will not blunt transmission. People who present with symptoms have likely already transmitted the virus to their close contacts.
The only way it would make any sense is to prophylactically treat *everyone* regardless of confirmed COVID-19 status or even regardless of symptoms. So is the small known risk of significant mortality and morbidity from hydroxychloroquine really worth it since the majority of people who contract COVID-19 will recover fully without any interventions?
Run,
I think it would be prudent to take info from China with a large dose of doubt. They have lied about and covered up this topic since the beginning.
“Chinese scientists destroyed proof of virus in December
Philip Sherwell, Bangkok
Sunday March 01 2020, 12.01am GMT, The Sunday Times
Chinese laboratories identified a mystery virus as a highly infectious new pathogen by late December last year, but they were ordered to stop tests, destroy samples and suppress the news, a Chinese media outlet has revealed.
A regional health official in Wuhan, centre of the outbreak, demanded the destruction of the lab samples that established the cause of unexplained viral pneumonia on January 1. China did not acknowledge there was human-to-human transmission until more than three weeks later.
The detailed revelations by Caixin Global, a respected independent publication, provide the clearest evidence yet of the scale of the cover-up in the crucial early weeks when the opportunity was lost to control the outbreak.”
https://www.thetimes.co.uk/article/chinese-scientists-destroyed-proof-of-virus-in-december-rz055qjnj
How China’s Incompetence Endangered the World
As the deadly coronavirus began to spread, Beijing wasted the most critical resource to fight it: trust.
The novel coronavirus epidemic has reached a critical juncture. Steps taken over the next few days, particularly by Beijing’s leadership, will decide the fate of the virus and whether it spreads internationally to become a genuine pandemic. Time is short for the Chinese government to prevent a catastrophe.
Are China’s official reports, including claims that its control efforts are succeeding and the epidemic will soon peak, credible? Omens look bad. Once praised by the World Health Organization (WHO) and scientists worldwide for its quick, transparent response to the newly named COVID-19, China now faces international vilification and potential domestic unrest as it blunders through continued cover-ups, lies, and repression that have already failed to stop the virus and may well be fanning the flames of its spread.”
The reason that there is no headline about “Cuomo’s, Newsome’s, and Conte’s embrace of unproven public health measures” is that they aren’t embracing unproven public health measures. They are embracing measures that have been proven to moderate the impact of epidemics for centuries. This is probably a good time to reread Defoe’s Journal of the Plague Year. (It’s interesting to compare the civic response and effects in the 14th and 17th century through the lens of the evolving modern state.)
For an analysis of why we shouldn’t be embracing random widespread, as opposed to systematic focussed, drug testing, consider checking out In the Pipeline. Pharma folks have a lot of scar tissue. I’ll suggest a Bayesian statistics based argument. There are a lot of people out there who are not infected and will not get infected and if they do get infected will only have mild cases. Dumping dangerous chemicals into them is not necessarily a great idea, especially if we have only limited evidence that those dangerous chemicals will do some good.
https://blogs.sciencemag.org/pipeline/
Run—Please understand I am all for cutting through the regulations under the current circumstances and I would certainly encourage health care providers to rely on Chinese experience for dosing protocols unless it is contra indicated by the patient’s underlying condition and the known toxicity and side effects. I am almost to the point of seeking divine intervention and I make Ron Reagan look like a true believer. My real point was to tamp down expectations while trying the therapy everywhere in the country NOW.
Terry:
I understand you are being overly nice to me in your comment. Thank you.
@victor a 1% death rate is not a small chance of death. Chloroquine is used to treat less deadly syndromes. The risks are well known and manageable. The drug is regularly used.
The case for using it for Covid 19 is that there is evidence that it works. This is not enough to make the FDA approve a new drug or new advertizing for an old drug. But it is enough that any sane calculation of expected welfare implies prescribing it to Covid patients. Do the math. How many people have been killed by Chloroquine (not zero) how many driven blind (not zero). We are talking about a drug which was used as a prophylactic for decades and a disease with a death rate on the order of 1%,
hydroxychloroqine is somewhat safer than Chloroquine but they aren’t fundamentally different. Both are still used. Chloroquine is not obsolete (note the Nature paper shows it is slightly more effective against Sars Cov2 in vitro) Relative costs and benefits are not known yet — it might be that in the end Chloroquine not Hydroxychloroquine or Remdesivir is standard of care. Note “might” practially anything might happen.
Kaleburg. What is the control group ? What is the p level of the test you consider ? What was the principal outcome measure of the trials you report ? The evidence for quarentine would not satisfy the FDA if quarnetine were a pharmaceutical. Tell me sample size, p level, prove that the principal outcome measure was chosen before the trial was conducted.
I agree with Cuomo et al. I don’t think that evidence other than randomized controlled trials should all be ignored (hell I’m an economist). But I do not accept that, when discussing what pills to put in patients mouths, then evidence other than randomized clinical trials should be ignored.
@Terry I agree that regulations are important. That is why I have been denouncing the FDA for about a decade now. Current regulations kill people. Yes Thalidomide was terrible, but so are the barriers to medical research and to rational choice of treatment based on available evidence.
I’m tired of looking up and posting the links. please google [robert waldmann ethics clinical trials].
Robert:
Tired of talking about it. I have pushed on this. If this is the best we have today and appears to work, then lets go with it, save as many as we can, until something better comes along.
I am attaching a link to news article about remdesivir study in alberta. there is a mention of one published article about how it might work against covid-19. could be research worth keeping an eye on.
https://www.ctvnews.ca/health/coronavirus/canadian-researchers-look-to-previous-outbreaks-in-search-of-covid-19-treatment-1.4863911
dave:
Welcome to Angry Bear. First time commenters always go to moderation to weed out spam, spammers, and advertising.
dave:
I do not believe anyone would disagree with you. Time is of the essence though and we need something that works now.
Null hypothesis of no benefit of hydroxychloroquine not rejected in a small (15 case 15 controls) trial in Shanghai
http://subject.med.wanfangdata.com.cn/UpLoad/Files/202003/43f8625d4dc74e42bbcf24795de1c77c.pdf
remember failure to reject the null is not necessarily strong evidence against the alternative. I think this trial had zero power
The probability that the prncipal outcome measure was significantly better for the treated group was zero no matter how effective the treatment (instant cure in 100% of cases would not have been statistically significantly better than the control group outcome)
2 Other measures show point estimate of a bit worse than control one a bit better. Nothing statistically significant. I am confident that doctors will continue to prescribe hydroxychloroquine as they have been doing,
Robert:
This; “The prognosis of common COVID-19 patients is good. Larger sample size study are needed to investigate the effects of HCQ in the treatment of COVID-19. Subsequent research should determine better endpoint and fully consider the feasibility of experiments such as sample size.” was not adequate?