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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