Deeply flawed

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Gob
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Deeply flawed

Post by Gob »

A deeply flawed study

In early March, as the coronavirus pandemic accelerated its spread around the globe, a group of scientists in Marseilles, France, launched an experiment to see whether hydroxychloroquine, a well-known old malaria drug, could be what everyone was searching for: a cure.

Most small scientific studies live and die within the rarified domain of academic journals, but the French trial had a much more auspicious debut. Before the study was even published, in the International Journal of Antimicrobial Agents (IJAA), a lawyer falsely claiming an affiliation with Stanford University appeared on Fox News’s Tucker Carlson Tonight to declare the results: a “100% cure rate against coronavirus”. From Fox News, it was only a matter of time (hours, in fact) before the drug was being hailed as a “game changer” by the president of the United States.

Trump made his first endorsement of hydroxychloroquine on 19 March. Export controls, shortages, overdoses, and scientific recriminations rapidly ensued, but the controversy could not extinguish the power of presidentially endorsed hope. Across the globe and throughout diverse communities on the internet, hydroxychloroquine had been anointed the miracle cure for Covid-19.

The only problem? The study that all this fervid hope is based on doesn’t show what its authors claim it does.

The gold standard for a clinical trial is a double-blinded, randomized controlled trial (RCT). What this means in plain English is that the study has been designed to reduce biases that would render its results meaningless. Neither the physician nor the patients knows whether they received the drug (“double-blinded”), a safeguard that reduces the possibility that the doctor will treat the two groups differently. The researchers also do not get to choose which patients go into which group (“randomized”) and the makeup of the two groups is roughly equivalent (“controlled”).

The French hydroxychloroquine study did not follow any of these rules.

The treatment group and the control group were drawn from separate populations: the treatment group were all patients at the institution where the researchers worked, the Méditerranée Infection University Hospital Institute in Marseille, while the control patients came from other hospitals in the south of France. The treatment group (mean age 51.2) was significantly older than the control group (mean age 37.3), introducing another variable that could undermine the meaning of the results. The study was “open label”, meaning the physicians and patients knew which treatment they were receiving. The French researchers also treated some but not all of the treatment group patients with azithromycin, a common antibiotic, another complicating factor that was not randomized.

But even more important than these shortcomings in the design of the study is how the researchers chose to measure and report their results. Forty-two patients were initially included in the study. Three were transferred to the intensive care unit; one died, one left the hospital, and one stopped taking the treatment due to nausea. The other 36 eventually recovered, and those who received the drug cleared the virus from the system faster than those who did not.

If you had only heard about this study from the Fox News assertion of a “100% cure rate”, you might assume that the four patients with poor clinical outcomes (the three ICU visits and one death) had been unlucky enough to be in the group that did not receive the “cure”.

And yet, those four patients, as well as the patient with nausea and the one who left the hospital early, were all part of the treatment group. They were excluded from the topline results of the study because of the way that the researchers chose to measure and report the results: strictly based on the measurable presence of viruses in nasal swabs taken each day of the study. Since the patients were in the ICU or dead, their samples could not be taken and they were left out of the final analysis. Based on the nasal swabs of just the 36 patients who completed the study, those who received the drug cleared the virus from their systems faster than those who did not.

This is how an experiment in which 15% of the treatment group and 0% of the control had poor clinical outcomes could end up being reported as showing a “100% cure rate”.

On 3 April, two weeks after the study was first published online, the International Society of Antimicrobial Chemotherapy, which publishes the IJAA, said in a statement that the group’s board “believes the article does not meet the Society’s expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety”.

Didier Raoult, the corresponding author for the French study, did not respond to questions from the Guardian.

Andrew Noymer, a professor of public health at the University of California, Irvine, described the results of the French study as “meaningless”. “They should have done an RCT,” he said.

“This idea that we’re all manning the lifeboats and there’s no time for that is just absurd,” Noymer added. “They could have already done it. They could have had the answer by now … Doctors have always gone with their guts and saved many lives, but I don’t know. If they had done RCTs on Thalidomide” – a drug that caused birth defects – “they would have figured out its dangers a lot sooner.”

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Burning Petard
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Re: Deeply flawed

Post by Burning Petard »

I wish sometime somebody would insist on a'triple blind test.' That is, one test group gets the new drug, one gets the placebo, and one gets the drug that has been used for this ailment as the standard treatment. The conventional double blind test only established whether or not the new one is better than nothing. I suspect that the success of this drug touted by POTUS has actual success rates very similar to what happens when they just treat the symptoms--or do nothing because the symptoms are not that evident to give them bed space in a hospital.

It is known to have some very nasty side effects.

snailgate

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Crackpot
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Re: Deeply flawed

Post by Crackpot »

Err double blind means the one giving the treatment doesn’t know wether the patient is getting the placebo or not. I have no idea what you’re talking about
Okay... There's all kinds of things wrong with what you just said.

ex-khobar Andy
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Re: Deeply flawed

Post by ex-khobar Andy »

And in fact, under double blind protocol, the person administering the dose and assessing the patients' responses, does not know who got what. Doses and patients are coded by a third party. This eliminates the subconscious tendency to 'see' an improvement in a patient because you know that s/he received the drug rather than the placebo.

Not sure what you mean by 'triple blind' SG. A double blind trial (i.e., both the patient and the assessor do not know who got what) can test multiple dosage levels and multiple drugs. Administratively and statistically it's easiest to vary one thing at a time.

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Scooter
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Re: Deeply flawed

Post by Scooter »

Burning Petard wrote:
Wed Apr 08, 2020 8:23 pm
I wish sometime somebody would insist on a'triple blind test.' That is, one test group gets the new drug, one gets the placebo, and one gets the drug that has been used for this ailment as the standard treatment. The conventional double blind test only established whether or not the new one is better than nothing.
That's actually not true. International conventions on research ethics say that it is unethical in most cases to allow a research participant to go without treatment by giving them a placebo in a trial, when there is an established effective treatment. From the Declaration of Helsinki:
The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention, except in the following circumstances:
  • The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or
  • Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.
For COVID-19, there is of course no known effective treatment, so placebo controls would probably be acceptable. And your proposed three-arm trial would be impossible.
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Burning Petard
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Re: Deeply flawed

Post by Burning Petard »

treating the symptoms is the current treatment. Is it known to be effective? I dunno.

snailgate

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Scooter
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Re: Deeply flawed

Post by Scooter »

So what are you going to do, withhold oxygen from someone to test an unproven treatment?
"If you don't have a seat at the table, you're on the menu."

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