Hydroxychloroquine vs. REGN-COV2

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If you have COVID-19, your doctor can prescribe for you hydroxychloroquine. Its only FDA-authorized use is for malaria, and the FDA has cautioned against the use of hydroxychloroquine for COVID-19. But it's up to you and your doctor, whose only legal worry should be the prospect of malpractice liability.

As of this writing, your doctor cannot prescribe for you REGN-COV2 (though Trump has promised to issue an Emergency Use Authorization). That's the antibody treatment that President Trump received. Preliminary data suggests that this drug is promising. Another antibody treatment has produced even more promising though still preliminary results, but you can't yet get that one either.

What accounts for the asymmetric treatment of hydroxychloroquine and REGN-COV2? Hydroxychloroquine is approved to treat malaria, and in the United States, once a drug is approved, doctors may prescribe it off-label for other uses. Doctors are advised to weigh the risks and benefits of off-label uses, but the matter is ultimately left in their discretion. Some commentators have observed that much off-label use is not based on scientific evidence and others have called for government regulation to quantify risks and benefits of off-label use. Yet another says that off-label use "is the death of the idea of regulation."

But the idea of regulation is alive and well. We still prevent pharmaceutical companies from selling drugs like REGN-COV2, which have not been established to be safe and effective for any use (but which a rational doctor might well prescribe in some cases). One argument in defense of this regime is that once a drug is approved, it has been established that it is safe, so there is no harm from off-label use. But that can't be quite right. The FDA compares the costs and benefits of a drug. That cost-benefit analysis will  focus especially on the condition for which the drug is approved. Just because the drug is safe enough to be used for that condition does not mean that the cost-benefit analysis would come out the same way as to other indications.

The discrepant treatment of off-label drugs on the one hand and promising-but-not-yet-proven drugs on the other requires some justification. The status quo could reflect a compromise between those who would prefer less FDA regulation and those who prefer more, but this seems unlikely, because the discrepancy is rarely noted. Another theory is enforceability. Once we allow a drug on the market, it's too difficult to enforce off-label use prohibitions, so we don't even try. But if that were the reason, we would expect at least a nominal little-enforced prohibition. Many doctors would follow the law, even if violations were difficult to detect.

Maybe the discrepancy arises from the need to encourage clinical trials. I recently argued here that many shy from this justification for FDA regulation more generally, because it means that we are denying people treatments that we (or at least their doctors) think are more likely beneficial than not on the ground that we need test subjects. But at least a utilitarian should not be embarrassed by this argument. Eugene Volokh recognizes the possibility as a possible constraint on a right to medical self defense (p. 27), and others are even more unafraid to make it. It might seem that the need to encourage clinical trials should lead both to prohibition of off-label use and insistence on keeping promising drugs off the market until we can be sure of their efficacy. But drug companies may have reduced incentives to conduct controlled trials of off-label use anyway, and thus, there is less reason to prevent such uses.

REGN-COV2 may present an exceptionally strong case for keeping the drug off the market so that more clinical trials can be conducted. Supplies of the drug are scarce, and it appears that it will take a while to ramp up production. With scarcity, not everyone can obtain the drug anyway, and so we might as well use whatever drug supply exists for clinical trials. If we don't use it all up, but the drug proves effective, we should still find uses for what has been produced so far. Indeed, scarcity is a standard justification for randomization in a variety of contexts, such as charter schools with only so many seats for students. Though interest in hydroxychloroquine caused some shortages, in general, supply is likely to be less constrained for off-label uses of a drug already on the market, especially in comparison to an exotic drug like an antibody that is expensive to manufacture.

Where does this leave someone suffering from COVID-19 who wants the Presidential treatment? You may be able to receive REGN-COV2 under the Right to Try Act, which would more accurately be named the Right to Ask Act, because it authorizes a patient "who has exhausted approved treatment options" to request the drug. Presumably, that is how President Trump received the drug. It's not clear exactly how Trump exhausted approved treatment options, but the Right to Try Act essentially removes FDA oversight from the process. Still, the drug companies may refuse and moreover have strong incentives to do so.

Can a drug company use the Right to Try Act to do an end run around the requirement of FDA approval (or emergency use authorization)? No. The drug must be currently "under investigation in a clinical trial," and the patient must be "unable to participate in a clinical trial involving the eligible investigational drug." These requirements solidify the theory that the goal of our drug regulatory system is to coerce people into clinical trials. If the goal were just doing the best thing for each patient, it shouldn't matter that some other patients are currently participating in a clinical trial for which one is eligible. But if we accept the goal of coercing patients into participating in clinical trials, then the provisions advance that goal, both by requiring the pharmaceutical company to be running a clinical trial before it authorizes a "Right to Try" request and by limiting the emergency use to someone who cannot participate in the trial.

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  1. The big regulation is that pharm reps can’t promote off-label uses…so doctors AND patients are free to figure out if a drug works off-label.

    1. Hydrocloroquine has been rejected as a cure for COVID-19 because Trump endorsed it.
      REGN-COV2 is doomed before hand because Trump used it.
      Damn medical practice and clinical trials. Listen to the omniscient authorities at CNN.

      1. “Hydrocloroquine has been rejected as a cure for COVID-19 because Trump endorsed it.”

        Well, because of that and because hydrocloroquine doesn’t currently exist.

  2. Oh boy… OK, let’s get a few things straight.

    1. There is no law that says you can’t BUY bleach, REGN-COV2, or any other unapproved drug, chemical, or substance you want for COVID (Except for DEA prohibited substances, which is a different category). And you can take any of these substances you want, and inject them into your veins if you want. Yes, if you’re so inclined, you can buy bleach for COVID-19, and inject it into your veins. I highly discourage it however. And in fact companies do sell a wide range of drugs that are not FDA approved. They are almost always marketed as “not for patient use”. But what you choose to do with them is your own business.

    2. The law you’re arguing against is being able to MARKET the drugs, compounds, etc. for specific indications and patients. That is what the FDA is doing. It is regulating the MARKETING of these drugs and compounds. And it’s doing it to ensure that they are 1. Safe; and 2. Effective at what it claims to be/do. The FDA does this across a range of items, including foods. It ensures that Milk is actually Milk, and is actually safe. It ensures that beef is actually beef and safe. And it ensures that if a company sells drug A for curing COVID, it actually cures COVID and is safe.

    3. What you asking is that the FDA remove the requirement that demonstrates the drug is effective. Remember, you can buy the drug now (if the company will sell to you), but you want the company to be able to MARKET the drug to you, even if its not proven effective.

    4. The good companies have a STRONG incentive not to change this regulation. Good companies, with effective drugs, like the lack of competition from ineffective drugs. They also like the trust that comes from the public, in knowing the drugs are effective.

    5. Crappy companies that would like to sell ineffective drugs would like to change this regulation. They’d like to be able to sell you pond water, crap in a bottle, or whatever else, and market it as being able to cure COVID. It’s much cheaper to sell pond water than develop something effective. And it’s not like the patient will know, until they’ve already bought the product.

    1. I think 1 is a little misleading. Often times the versions of pharmaceutical substances available outside the world of drug sales and marketing are not simply labeled “not for patient use”; they are not in a form where patients can use them. For instance, most obviously, they may not be sterile. They may not be injectable, or bioavailable if taken orallly. They may contain poisonous additives.

      And there are significant legal restrictions that would come into play if someone tried to reformulate such a substance so that it could be taken as a pharmaceutical by a human being. They would be liable for the foreseeable misuse of the product, and not shielded by any of the liability rules that protect drug manufacturers in clinical trials.

      As a result, you really can’t get many of these substances outside the drug system, even if they aren’t scheduled as controlled substances.

      With respect to the other points, I generally agree, but the real issue is that it’s actually pretty obvious that the effectiveness requirement, while perfectly useful in most cases, probably fails a cost-benefit analysis with respect to the most extreme, experimental situations. I.e., the “Dallas Buyers Club”, for instance. You get AIDS in the 1980’s, it’s a death sentence, basically why not let people try anything, or at least anything where a modicum of safety is established. They’re dying anyway.

      Coronavirus is somewhere in the middle. It isn’t an automatic death sentence. But it does kill a percentage of those who get it, and the treatments are still very experimental. And people want to take the risk and try new treatments.

      My point is, there’s nothing wrong with a special rule for cases where the effectiveness requirement may reasonably be relaxed, while not changing the basic legal framework for most drugs.

      1. Re 1: The individual can still use them. They simply assume all the risk. They can assume the risk of the non-sterile product (or they could sterilize the product themselves). Everything is injectable, if formulated properly. Again, the individual needs to do so. And, in terms of oral bioavailibility, if the compound made it to phase 2 or 3 oral trials, we can safety assume it’s at least partially orally bioavailable.

        But yes, there are significant legal restrictions if someone ELSE tried to reformulate such a substance to be taken as a pharmaceutical. Because now that someone ELSE is marketing the compound as for human use. If you “reformulated” bleach as “For injection and treatment of COVID”…well, there would be severe liability doing so, especially outside of the current regulations.

        So, you CAN buy many of these substances. The issue at hand is you want them marketed for an indication which they aren’t shown to be effective for.

        1. I am not talking about marketing. Even if the third party does no marketing they can still be sued for foreseeable misuse.

      2. “Coronavirus is somewhere in the middle. It isn’t an automatic death sentence. But it does kill a percentage of those who get it, and the treatments are still very experimental.”

        The problem is people who don’t have coronavirus disease, and want to keep it that way, and who aren’t clear on the difference between treating a disease and preventing a disease.

    2. “in fact companies do sell a wide range of drugs that are not FDA approved. ”

      A good number of them are marketed to veterinarians.

  3. Let’s go a little further…

    1. ” It’s not clear exactly how Trump exhausted approved treatment options,”

    That’s simple. There are no FDA approved treatment options for COVID. There are so Emergency Use Authorizations for other treatments, but there are no actual approved treatment options for COVID.

    2. The “Right to Try Act”.

    This gets into a bit of a grey area.

    With some drugs under development, it’s not known if they are effective. The entire purpose behind phase 2 and 3 trials is to demonstrate if a drug is, indeed effective. In order for a drug to be marketed as curing a disease, it needs to actually….cure the disease. (I know, crazy, right). And the way to demonstrate if a drug actually cures the disease is to run controlled, clinical trials.

    However, not everyone can get into a clinical trial. And for certain, life-threatening diseases, where every option has been exhausted, a “It might work” is better than nothing. And typically, if a drug company is spending hundreds of millions on a clinical trial, they think it might work. They still need to show it though (and a lot of the time, the company is wrong, and the drug doesn’t work) That’s where the “Right to try” act comes in. It allows that “maybe” to be done sooner, rather than later.

    But why have a clinical trial requirement? Because, if the company isn’t running a clinical trial, they aren’t trying to demonstrate the drug’s effectiveness. They’re trying to MARKET a drug as effective for something, without even trying to demonstrate its effectiveness (That’s not great). And we’re back to pond water. Here’s some pond water. It cures COVID. “Trust me”. What? You weren’t cured? Well, we waived that silly FDA requirement that required our drug actually be effective. We can say it will cure whatever we want to. And why spend money on a clinical trial (that will probably be negative), if we can make billions now….

  4. RISK-benefit.

    Not COST.

    Important difference. Drugs aren’t priced prior to approval.

    1. ” Drugs aren’t priced prior to approval.”

      This would be a very poor business practice if it were true. One of the challenges we see with modern Western medicine is so called “orphan drugs”… drugs which have been identified and synthesized, where the cost to produce them outweighs the profit possibility created by the rarity of the condition it treats combined with the relative poverty of the sufferers of that condition. Thus, the profit potential of Minoxidil or Viagra vastly exceed the profit potential of several other drugs that effectively treat life-threatening illnesses.

  5. “The discrepant treatment of off-label drugs on the one hand and promising-but-not-yet-proven drugs on the other requires some justification.”

    Thalidomide.

  6. An interesting therapy studied in a a single pilot trial in Spain, published end-August, treated 76 patients with calcifediol (a metabolite of Vitamin D3) or no calcifediol. Of 50 in the calcifediol arm of the study, one entered the ICU and all were discharged; of the 26 non-calcifediol patients, 13 entered the ICU and two died.
    https://www.sciencedirect.com/science/article/pii/S0960076020302764
    While calcifediol is prescription drug, vitamin D3 is not. It seems that one would need 3x the amount of D3 as calcifediol.
    A trial of 1008 patients is underway

    1. Also note the following from that study:

      All hospitalized patients received as best available therapy the same standard care, (per hospital protocol), of a combination of hydroxychloroquine (400 mg every 12 h on the first day, and 200 mg every 12 h for the following 5 days), azithromycin (500 mg orally for 5 days.

      “Best available therapy”, but not approved in the U.S. because Trump recommended it.

  7. “Where does this leave someone suffering from COVID-19 who wants the Presidential treatment?”

    Where they should be – waiting for the medical and scientific community to decide whether the treatment is good. It’s absolutely insane how drugs for very specific conditions are advertised as if they were soda and potato chips. Even doctors themselves have gotten into the act – I get diagnosed with something and my doctors ask me what drug I want. I just look at them with astonishment and ask them why they are asking me, given that they went to medical school and I didn’t.

    Patients shouldn’t be picking their treatments unless their doctors are offering them a choice. I wonder how many pandemics it’s going to take until people, especially libertarians, get it into their heads that the universe doesn’t care about their feelings, or their freedoms, or their rights, or their choices. Medicine either works or it doesn’t, and the way we determine that is by proper studies. Yes, that takes a long time, and yes, people are dying right now. Too bad. If you want to shovel crap into your veins, you shouldn’t expect the medical profession to help.

  8. Replace the FDA with Yelp reviews.

  9. I think I’d give a bit more credence to the idea that the discrepancy is due to enforceability. I don’t think I’d necessarily expect or want an unenforced prohibition on off-label prescribing. Imagine what happens if there were such a prohibition. A doctor who wants to prescribe a drug for an off-label use isn’t going to write in the patient’s medical record “I prescribed drug X to treat this condition that the patient has but for which drug X is not approved.” The doctor is going falsify the diagnosis. They are going to write in the medical record that the patient has whatever drug X is approved for, even though the doctor knows damn well that the patient doesn’t have it. And what happens when a different doctor reads those records and takes them at face value? The second doctor falsely believes that the patient has the condition that drug X was approve for, and the second doctor makes poor decisions that harm the patient as a result. Given that a prohibition on off-label prescribing would be difficult to enforce, and even a nominal prohibition would result in falsifying medical records and thereby harming patients, it seems plausible to me that we would have this disparate treatment because of the enforceability problem, without even a nominal prohibition on off-label prescribing.

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