Ricochet is the best place on the internet to discuss the issues of the day, either through commenting on posts or writing your own for our active and dynamic community in a fully moderated environment. In addition, the Ricochet Audio Network offers over 50 original podcasts with new episodes released every day.
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
Agreed.
Here’s the problem. Once we actually do have this beat, people will assess risk much differently. If this turns out to be much less effective than promised, that incorrect risk assessment will have some pretty negative consequences
Absolutely, we should be trying this treatment. Hopefully the results will be undeniable as that happens. All I’ve ever said – and frankly, all I’ve ever heard anyone else here say – is that we should reserve the victory lap for a time when we are actually assured of victory. To do otherwise seems very, very foolish.
You are a hypocrite
You said the exact opposite thing in another thread or two
wrong
check the instant replay
‘pretty much exactly’ is gibberish and a sign of equivocation and backtracking and prevaricating
Okay, okay. How about we just move on? It’s all on record here, for anyone who cares. Truce, alright?
There’s statistically best, and then there’s statistically valid, and then there’s statistically unconfirmed but still promising and safe.
Chloroquine started in that last category, which was very good for an emergency. I think it’s
moved intomoving into the middle category already. That’s great.We can figure out statistically best next year.
[Yes, edited. See below, with compliments to The Hammer!]
Statisticians care about ‘significance’ but significance is not the same as substance.
What’s more important is substance.
Is the treatment significant and substantial?
that is the 2 trillion dollar question
A comment regarding your statement that informed consent is part of a proper drug trial: I would never suggest that informed consent is inappropriate, but informed consent does not add to, and may detract from, the logical validity of a study. It is routine in some countries to randomly assign patients to a control group without ever disclosing to them that they are receiving a placebo as part of a study, rather than a treatment. This is unconscionable in American eyes, but it does not negatively affect the validity of the study. So, a proper drug trial can be performed in the absence of informed consent
Has it moved into the 2nd category?
It may well be that zinc helps;
But as the same author noted and as I posted in a comment to another post, if zinc transport is unlikely to be why chloroquine works.
What to do? My 2¢:
Large health care organizations with good data mining operations are well situated to clarify this.
• Establish a retrospective cohort of high risk patients in their 70s and 80s who had lab confirmed COVID-19 and CT scans
• Test similar patients with the new rapid tests and with the same COVID-19 test as in your comparison cohort
• If the consenting incoming patients who fit the retrospective cohort test positive on the rapid test, initiate treatment with chloroquine, zinc, and azithromycin, run CT scans and treat as early in the disease course as possible who have the characteristic peripheral lung appearance or who had diarrhea and/or loss of taste or smell in the prodrome with
• With clinical improvement, repeat CT scans
• Rinse, repeat with different doses
Ok, honestly, I don’t know.
Maybe it hasn’t. I suppose that whatever precisely “statistically valid” means in context of what iWe’s sister knows, we probably do not have that for chloroquine yet.
I think we have something better than mere promising and safe. Evidence establishing efficacy with a probability well over 50%. Enough rationally to believe chloroquine helps, way more than enough rationally to act on chloroquine.
But probably not the second category as delineated above. I probably overstated that!
“Yeah, though we could do a comparison of treatments with statistically matched groups. There are three treatments that I hear are being tossed around – HCQ / Z-pack, the HIV combination drug Kaletra, and another anti-viral from Japan. Randomize people to one of the different likely treatment groups, and compare them statistically. I think people on Ricochet have mentioned this approach before.”
“Doc Robert actually oversimplifies. There are ways to do statistically valid tests that do NOT use a Control Group who are given a placebo. At least this is what my sister, who has worked as a statistician for numerous drug companies, tells me………….In other words, we don’t have to deny access to a potentially life-saving drug to get results that even mathematicians could accept.”
Okay great , move forward with whatever studies that will give us greater information on various treatments as soon as possible.
But remember people in America are dying right now because they are being denied treatment that has been proven – yes proven but perhaps not ” proven” in the eyes of our elite bureaucrats by their own regulations and protocols that they surely wrote , so can we please get as much of these life saving drugs to as many of our infected citizens as possible, with whatever caveats and legal liability disclaimers you all think advisable as soon as possible?
I don’t really care who said what when or how here at Ricochet, but what I do care about is that those seemingly throwing mud at these treatments need to realize that our famed bureaucrats like Dr. Fauci and others have been using those comments to bolster their case to delay treatment often not because of an interest in protecting the American public but in their seemingly never ending destructive turf war these bureaucrats seem to be waging perpetually against appropriate oversight and the reduction of their Constitutionally abhorrent overly protected powers to regulate. These delays are killing people and ruining lives and these bureaucratic clowns seem not to care.
The political background underpinning these treatment arguments is the underlying argument whether we should be ruled by “experts” as desired by the Marxist Progressives or should we be ruled by the people as directed by our Constitution.
Note the vocabulary words. This guy probably knows what he’s talking about!
Nah. Armchair scientist/armchair critic. I’m not in the trenches with research or conventional medicine. I don’t do clinical trials, I just read some of them and have smart nerdy friends.
I hope so. But as I have said before, if it truly works wonders, the results in New York will be undeniable, and we should know that in the next few days.
Well, that beats me. Believe it or not, the word “coronavirus” doesn’t turn up even once in the Tanakh, the New Testament, Augustine, Plato, the Analects, Kant, William James, or Alvin Plantinga’s epistemology.
Not once!
My hot nerdy wife has watched three Star Trek series with me. My other nerdy friends do things like study Chinese Buddhism, translate Melancthon, and read John Calvin.
So yeah–I don’t know anything.
Hah! You just have to know how to look:
My nerdy friends have lifetime subscriptions to Dr. Najeeb lectures and listen to Chris Masterjohn on long drives.
Moderator Warning: @mbchoe – cool it with the insults. There are lots of Ricochet members I cannot stand. I still have to be polite to them.
Rules for survival if you’re trying to keep up with multiple fields:
Find writers/presenters/aggregators you trust, but regularly verify trustworthiness by reading some of the papers they cite and making sure that they are reading the actual paper and not just the abstract, and that the conclusions drawn are supported by the data.
My top two are Jeffrey Bland, who has a real gift for finding significant stuff in the literature very early, and Kerry Bone, who is the same type. The late Clara Felix was another in a smaller way; she was writing about omega three oils in the mid 1980s and vitamin D in the early ’90s.
I am an armchair doctor/scientist/coach/manager/GM/quarterback/economist
I didn’t start the insults. There are 3 ricochet members who insulted me first. I’m not allowed to reciprocate?
Well, I try not to. (I’ve been called a troll and a liar around here, and a few other things.) But you can always flag insulting comments, and a moderator will probably look into it.
The email alert isn’t working when someone mentions my username.
I checked my settings.
Is this a question for @max or @blueyeti ?
Can I challenge them to a duel like Burr vs Hamilton?
I do work in clinical trials. A lot.
Dr. Robert’s post is spot on that you can’t design an ideal clinical trial under these circumstances. Too urgent a situation, not enough known about the disease, most patients recover without medication anyway, too many combinations of right dose/right patient/right time, etc. etc. etc.
Conversely, going off anecdotes and reports by individual doctors or trials with no control groups also provides very little useful information, for all of the exact same reasons listed above. And here’s the danger: if word gets around that hydroxychloroquine is quite effective but it actually isn’t, that will also cost lives – since it will decrease the urgency to keep trying out other possible medications.
So throwing all scientific caution to the wind is also dangerous. @iwe is correct: there are ways of designing trials that balance the competing forces of urgency vs. scientific principle. One obvious way is to test a large number of different drugs against each other simultaneously, working off the assumption that at least one of the drugs will be completely ineffective. That drug is then used as a control group in the analysis.
And here’s the kicker: for all the yelling on this thread, these controlled studies have already started. One was commissioned by the NIH, the other by the WHO, both are fairly large-scale and dynamically structured to incorporate new candidates as they emerge.
So 90% of the bickering over hydroxychloroquine and clinical trials and control groups is completely moot: trials are already being conducted at the highest level of scientific rigor conceivable under the current circumstances.
That’s the spirit!
A Rap Battle?
Mendel: “And here’s the kicker: for all the yelling on this thread, these controlled studies have already started. One was commissioned by the NIH, the other by the WHO, both are fairly large-scale and dynamically structured to incorporate new candidates as they emerge.
So 90% of the bickering over hydroxychloroquine and clinical trials and control groups is completely moot: trials are already being conducted at the highest level of scientific rigor conceivable under the current circumstances.”
Okay Great! How long are these trials going to take? How long do we have to wait for their verdict while people are dying, people are getting sick and lives are being ruined? What do we do in the meantime?
Another comment for an expert, from the Daily Caller in “Infectious Disease Expert says Anti-Malaria Drug Marks “Beginning of the End ” of the Pandemic”:
“Infectious disease expert Stephen Smith predicted Wednesday night that an anti-malaria drug is ushering in the “beginning of the end” of the coronavirus pandemic.
Researchers have found that hydroxychloroquine (HCQ), a drug normally used to treat malaria, is also effective in treating the virus. A recent trial conducted at Renmin Hospital at Wuhan University from Feb. 4 until Feb. 28. treated 31 patients with a five-day regimen of 400 milligrams of HCQ.”
“President Donald Trump recently waived FDA regulations to allow the drug and others to be used to treat coronavirus patients. “
“Smith told Fox News’ Laura Ingraham that none of the people who have been treated with the drug have had to be intubated, or put on a ventilator.”
““The chance of that occurring by chance according to my sons who did some stats for me are .000 something,” Smith said. “We worry about selection bias in the situation, but I cannot think of a reason why, if all else is equal, why people that have received five days or more — even four days or more of this hydroxychloroquine regimen wouldn’t get intubated.””
“Smith called the drug a “game-changer,” and said it could put an end to this current crisis.”
Moderator’s Note: No, you are not allowed to reciprocate. If you believe you have been insulted in a comment then flag the comment and explain the reason for your complaint. The moderators will then see your flagged comment and address the issue. We do not allow rhetorical gunfights on this site.