The FDA
I am back complaining about the FDA as I have in The Ethics of Clinical Trials and 10 years earlier Clinical Trial Ethics (an aside — I had forgotten the old post and Google reminded me that I have been banging this drum for a decade).
Now I have a lot of company, because of the pandemic. Many people (including the ex FDA director Gottlieb retweeted by a Senator Brian Schatz) argue that the extreme circumstances imply that delays that are normally acceptable aren’t acceptable in this case. I really should read these 5 pages written by the former Director of the FDA and the Former Director of the Center for Medicare and Medicaid Services . I’m going to give an (erasable) hostage to fortune, guessing that my comment will be “I told you so during January 2019” . Actually I just advocated expanded access, which is just one of their proposals.
I agree that policy which works in normal times is not appropriate during a pandemic. Small c conservatism implies accepting the status quo until one is sure a reform is an improvement. It is irrelevant when the status quo is not an option, because a virus is spreading. Crazy small c conservatism implies sticking to business as usual as if it implies staying in a steady state, as if the virus (and global warming) are willing to wait for us to make up our minds. This is important. However, I have also asserted that current policy was bad policy during normal times. I stand by that view.
Before going on, I should note that the FDA is doing amazing things within the limits of current law. A vaccine trial started (with vaccine in someone’s deltoid) less than two months after the Sars Cov2 sequence was published. This included the FDA approving the trial with record speed. Similarly, the time from the emergence of Covid 19 to phase III trials of many drugs (including Remdesivir and hydroxychloroquine) must have broken records. The staff and director of the FDA are dedicated, committed and moving bureaucratic mountains.
Still, I think that current law and policy are wrong. I think that it is time to make this case, because the FDA delayed testing for Covid 19 in the USA. The technical problem with one reagent in the CDC test kit should not have caused 3 weeks of delay. Two of them were due to the FDA not the CDC.
I think that the FDA should have the power to give temporary authorization of sale and prescription of a medicine during clinical trials. That is based on the experience of patients who have had compassionate access to Remdesivir, I think the FDA should say it is approved unless and until the clinical trials yield negative results.
A problem with this is that it might become difficult to recruit a control group for trials. I think that it is better to unfairly single out some people and tell them they have to risk getting the Placebo than to impose that cost (in expected value) on everyone. I think the current policy is Pareto inferior to the policy I proposed in “The Ethics of Clinical Trials”.
Also I am certain that I will not be able to convince anyone of the morality of my proposal. I guess I should not even bring it up during a crisis. I think that, right now, the FDA can authorise use of Remdesivir which Gilead must provide free of charge. I’m guessing that approach would work and save hundreds of thousands or millions of lives. My guess might be wrong, but the cost of being wrong is now known to be small, because it is clear that Remdesivir is fairly safe.
Note that hydroxychloroquine and azithromycin are already approved drugs, and they can be prescribed off label. The real issue is whether to approve them for broad use in practice. Being able to print “approved for use against COVID-19” on the label is a formality that can wait. However, there is no point encouraging the use of a dangerous drug if it doesn’t help, and the only way to find out if a drug helps and whether its side effects swamp whatever benefit it might provide is to perform a study with a control group. Given how much strain the lung damage from COVID-19 places on the heart, taking a drug noted for causing heart attacks requires caution.
I discussed Remdesivir which is not approved for anything and mentioned neither hydroxychloroquine nor Azithromycin. As you note, the FDA is not involved in the decision whether to prescribe those approved drugs off label. Your comment is, therefore, off topic.
I do think that hydroxychloroquine (without azithromycin) should be presecribed for patients with Covid 19. I have discussed that elsewhere, but I did not discuss it in the post above. Again your comment is off topic.
Doctors have to decide what to do now. They have patients who can’t wait for completion of clinical trials. You assert that they don’t know what they are doing and should listen to you, because you are an expert.
Many doctors are prescribing hydroxychloroquine for Covid 19. This is mostly based on in vitro evidence that it blocks coronavirus replication. You assume that you know more about how to treat infectious diseases than the chief of infectious disease therapy at the Albret Einstein College of Medicine and Montefiore Hospital NY.
I too do not bow down before credentials. However, I think that while waiting for proof, one should attempt to maximize expected patient welfare given limited knowledge. There is no safe option. There is no way to avoid the risk of killing a patient who could live.
I have personally advised a doctor to prescribe hydroxychloroquine (I admitted that I am not humble). She said that she already has. I note she has an MD (and her 3 patients are doing well).
in other fields we do things without a controlled trial proving that they work. In general indirect evidence is considered while collecting direct evidence. That is what I recommend.
The mention of Azithromycin is especially off topic. There is very little evidence that it helps. The PDR specifically warns against combining it with hydroxychloroquine as both cause Q-T bradycardia. I did not recommend prescribing it along with hydroxychloroquine.
“Azithromycin: (Major) Avoid coadministration of hydroxychloroquine and azithromycin. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes (TdP) have been reported with the use of hydroxychloroquine. There have been case reports of QT prolongation and TdP with the use of azithromycin in postmarketing reports.”
https://www.pdr.net/drug-summary/Plaquenil-hydroxychloroquine-sulfate-1911.7193
Again, the post discusses the FDA and a not yet approved Remdesivir not off label prescription which is very common and does not involve the FDA.