Premature Hydroxychloroquine After Action Report

The action sure isn’t over. The armies are still on the field, but I fear the outcome is no longer in doubt and hydroxychloroquine will lose this battle. There are two good studies which show almost exactly no benefit of hydroxychloroquine. They are reveiewed here. Basically the only benefit detected is as a nonspecific anti-inflamatory. There is essentially no evidence that hydroxychloroquine blocks replication of Sars Cov2 in people as it does in vitro.

I was an enthusiast for hydroxychloroquine so I have a lot of explaining to do. I will do it after the jump.

First the pattern of exciting pre-clinical results followed by a disappointing large clinical trial is very common. Usually large (phase III) trials come after promising small (phase II) trials. Also roughtly two thirds of the time, the results are disappointing and the pharmaceutical is not approved. Already going from observing cells cultured in a petri dish to phase III is extreme acceleration due to the crisis. Hoping for a change greater than 1 in 3 of success would have been stupid.

Second, the question of whether hydroxychloroquine should be prescribed off label based on the in vitro results is not the same as the question of should we be confident that it will work based on the in vitro results. In general we make choices under uncertainty try things that might work. In general we try to balance costs and benefits also when both are not known. I still think this was such a case. I note that a whole lot of actual doctors agreed with me. I think it was good practice to prescribe hydroxychloroquine for patients with normal EKGs while also keeping track of the EKG. All of this was about doing what could be done while waiting for results of clinical trials of hydroxychloroquine, chloroquine, Remdesivir, and Favipiravir. Also while asking for compassionate use (later expanded use) of Remdesivir.

I note also that the practical debate is not over. Even in the recent two important articles literature there is a disagreement Tange et al speek favorably of using hydroxychloroquine to relieve inflamation. Mahevaas et al comclude that their results do not support the use of hydroxychloroquine. I was lead to those papers by an article in the LA Times which quotes different experts with notably different opinions (all of whom stress that they don’t know as much as they would like to know and will soon know). I think I am going to bench myself for a bit and let doctors decide how to practice medicine without bothering them with my advice.

A third and still interesting aspect of the debate is what about Donald Trump and Fox News ? Somehow a scientific question which was being addressed and would be convincingly answered soon became part of the culture war. Clearly this starts with Trump who insists he is the top expert on everything, believes what he wants to believe, and will not just shut up for once. It is also true that Fox News lives off the culture war. They clearly decided to make hydroxychloroquine an us against them issue.

I also (still) think that this caused a not totally ideal and rational reaction from critics of Trump and Fox. From the statement that the President shouldn’t try to guess the answer to scientific questions, some people (no links I am thinking of tweets) concluded that the Presidents guess was wrong. That does not follow (although they seem to have guessed right). Also someone decided that advocating off label use was like advocating abolishing the FDA and legalizing heroin (I promise I am paraphrasing a tweet which I remember but can’t find). It is simply a fact that off label prescription is common. I think some people fell for a provocation. They (Trump and Fox) wanted a battle in the culture war. Many resisted the provocation and gave balanced replies to unbalanced arguments. Some allowed themselves to be provoked.

I think some people treat the Pure Food and Drug Act as if it were a law of nature and not just a law of Congress. The rules for approval of new pharmaceuticals are ordinary interpretations of an ordinary law. They are not the scientific method itself nor are they the result of scientific inquiry. I might add they are also more flexible than they may seem (for example to me). I did not predict the establishement of the expanded access to Remdesivir program. I advocated it (back on March 2) but also predicted that it wouldn’t happen. I was wrong about that. I guess I can still insist that it should have been larger and easier to get the Remdesivir, but the FDA did better than I guessed it would.