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Drug Trials
There is a lot of noise now about azithromycin and hydroxychloroquine as therapy for Wuhan flu. People are demanding drug trials, people are claiming 100% cure rates, people are calling for free access to the drugs.
There’s a problem here. You can’t do a proper drug trial during an epidemic. The results of treating a critical illness will vary with an astonishing number of co-factors, many of which cannot be foreseen as you begin. For example, treating menopause with estrogens will increase strokes and heart attacks if the drug is given orally, but not when it is given transdermally. That took about 40 years to figure out.
So you have to do a proper drug trial.
A proper drug trial takes an early observation (here, HC and Azo may be effective for Wuhan flu), creates a null hypothesis (here, “treatment with HC and Azo is no better than saline”), creates a set of endpoint characteristics which are studied (days on a respirator, death rate) and controlled (sex, age, co-morbidities).
A proper drug trial then calculates the difference in the endpoint and number of cases needing to be studied to make the results statistically significant, meaning there is less than a 5% chance that said results arose by chance. Here, the difference might be that a 50% difference in death rates between the two groups, after treating 100 patients in each group, would disprove the null hypothesis.
A proper drug trial then goes through the institutional research review board to get approval for experimentation on human subjects. This, in my small experience, is often the longest part of the process.
A proper drug trial then recruits patients, either directly or at the behest of their treating Docs.
A proper drug trial then blinds the investigators as to what they are using, by providing identical-looking supplies, here perhaps bags of IV solution, half providing the drug and half providing the placebo.
A proper drug trial then consults each patient and explains that this is a randomized, controlled trial, that you must give your informed consent to participate, that there is a 50% chance you will receive placebo.
A proper drug trial then enrolls consenting patients and distributes supplies to the participating institution’s pharmacies. The pharmacies use some random method, chosen by the trial designers, to allocate therapy versus placebo.
A proper drug trial then lets events run their course until some pre-determined time when they do an interim analysis. If the study results by then conclusively disprove the null hypothesis, the study ends (that is to say, if there IS a difference between treatment with HC/Azo and saline, the study ends). If the study results do not disprove the null hypothesis, the study continues. If the results show undue harm from the study drug, say the initiation of lethal cardiac arrhythmias, the study is stopped. This is what happened to my favorite bugaboo drug trial, the Women’s Health Initiative, in 2001.
A proper drug trial thus is neither easy to design and conduct, nor quick to happen.
In an epidemic, a crisis situation, you can’t do a proper drug trial. You might follow your gut instincts and treat people with a drug if you believe it will be helpful, then see how they do. Maybe you will get good results, maybe you won’t. You’ll never know if your intervention was responsible because of the failure to randomize and control for variables.
So my hat is off to the brave ICU, general med, ER and pulmonary Docs who are treating this epidemic by the seats of their pants. They can’t wait for results from a proper drug trial. Given that fact, the politicos who know more about medicine than we do and the commentators who demand perfection have to be ignored.
Perfection is the enemy of good. We can’t do a proper drug trial here. We have to make do.
Published in Healthcare
I have addressed the methodological flaws in this statement elsewhere on Ricochet. What he says may be true, but he hasn’t proven anything.
But note the qualifier. We’re still open to the other kind. (But try to get video.)
The “cocktail” with or without one or two of the ingredients, but all having, at least, Hydroxychloroquine as its base ingredient is being used in hospitals all over the world. It is being used by physicians personally all over the world. We have heard of positive, even miraculous, recoveries because of using the cocktail. The ingredients are old school, having been used in other treatments for years…decades. I am asking all here who are participating in this discussion. Has anyone heard of even one anecdotal incident with a negative reaction? Here’s the thing. We are about to willfully destroy our economy. Are we such cowards, considering the risk/reward confronting our nation, that we are unwilling to utilize this option.?
I don’t understand where this notion of doctors being unwilling to prescribe this medication is coming from. As your own comment says, doctors are administering it around the world. That doesn’t sound like unwillingness to me.
Or take this article from the NYT yesterday. It’s from doctors at an ICU in Brooklyn and it’s intended to depict how critical the situation is there. If ever there were an anti-Trump setting, it’s an article about New Yorkers published in the New York Times. From the article:
Even they are prescribing it aggressively. Further down, the doctor basically says they don’t know whether it’s working, a very small number of patients had adverse side effects, but they’re going to keep on giving it to patients.
This notion that doctors are unwilling to administer chloroquine/azithromycin is a myth.
UK government tells doctors NOT to prescribe it outside controlled trials.
Since the NHS is government health care, these kinds of injunctions may actually be dictating what doctors are doing.
Fair enough. There is quite a bit about the British response I’ve been shaking my head at, looks like there’s one more thing to add to the list.
At least in the US, and many countries in Europe (including Italy and Germany), doctors are free to administer the combo as they feel appropriate.
Also, be sure to stay more than six feet apart. Gotta stay safe in whatever you do.
Did you hear the order from the governor of Michigan? Administrative action (loss of license?) will be taken against any doctors who prescribe or pharmacists who dispense these drugs for Covid. That was about ten days ago, and I don’t know if it was rescinded, but since then you’ve heard Michigan discussed as the next hot spot.
And of course, Fauci said he would only prescribe it for a sick family member if they could be part of a clinical trial. Hopefully, that’s a lie, because if it’s true he’s a monster.
My point from #63 is that Fauci of the NIH and Hahn of the FDA are bureaucrat scientists who, understandably, because of their professions, need evidence that will take months to develop. That’s fine. Let them do their thing. But in the meantime, our country is burning. We need the firemen, not the bureaucrats. Things are moving very fast. It is possible that Trump is already buying up as much Hydroxy as he can and ordering more. But it appears to be very effective as a prophylactic against this scourge. If people took it in mass, wouldn’t that enable the country to get back to work while giving the studies time to find an ultimate cure? Old people and the unhealthy could still stay semi-quarantined while the 60 and younger take the Hydroxy and go back to work.
Followed four days later by a request to the Feds to ship the stuff to Michigan. Gretchen’s government is spinning like a top.
Fauci also said
Perhaps this circle can be squared by saying that Fauci himself wouldn’t write a prescription for off-label use for a relative because he runs NIAID. I’m not sure he’s actively seeing patients, either. [Addendum: I know and respect non-practicing physicians who for that reason alone wouldn’t write a scrip for a relative unless there was absolutely no other physician to do so; I doubt that that would be the case for any relative of the director of NIAID.]
I don’t like the man and I think his priorities are skewed, but I think that calling him a monster over this isn’t fair.
Doctor,
In your experience which pharmaceutical companies conduct good clincial trials?
I know Merck had a setback in 2002 or 2003 because of Vioxx.
What if pharma companies post results of their clinical trials and let the doctors and their patients decide on safety and efficacy?
You allude to a p-value <= 5% but what if p-value is 6%?
6% won’t get you published but is there a clinical difference between 5 and 6 percent?
If you wanted to employ 6 sigma, p-value would be <= 0.3%, in other words 99.7% confidence interval.
Sir Ronald Fisher said if you can replicate the same result 19 out of 20 times, it is unlikely due to random luck.
19/20 = 95%