Why We Really Keep Seemingly Beneficial Drugs Off the Market

|The Volokh Conspiracy |

President Trump has received a non-FDA approved drug under a "compassionate use" exemption. Can a legal regime that allows the President access to a medicine but generally prohibits the public from purchasing it be justified?

The most obvious justification is that the President should receive special treatment. Sure, it is worthwhile for the country to spend a great deal of resources protecting the people's electoral choice by giving the best medical care possible. But that does not explain why the government forbids voluntary transactions between others and the drug maker. If the bulk of the evidence right now is that the drug is helpful, then why not approve the drug at least provisionally? Tyler Cowen advances this line of argument, suggesting that there should be more individual freedom to buy drugs.

One potential counterargument is that drugs might be misused. Doctors might have conflicts of interest, and anyway they might make bad decisions. We'll allow the President to use the drug because we can be fairly confident in his medical team. But if we allowed just any doctor to prescribe the drug, then on net we would do more harm than good. But it doesn't sound like President Trump's doctors have performed an especially complicated calculation here. It's worth it for the President to take the drug given his age and weight. Why then can't the drug be approved for everyone meeting certain conditions? One answer is that our system doesn't work that way; once a drug is approved, it can be used off-label. But that will not work as a defense of the status quo. It suggests that we should approve some drugs earlier with off-label use prohibited.

There is, however, another way to defend a system that insists on very high confidence in the safety and effectiveness of drugs but makes exceptions for VIPs or other select cases. The argument is based on the value of information. The candid way to make the argument is like this: Based on current information, this drug would improve patient welfare. But we don't know for sure. The population of future patients will benefit if we have reliable data. Once we approve the drug, it will be much harder to perform randomized controlled trials, both because the pharmaceutical company's incentives to perform such trials are reduced and because patients' incentives to participate in trials are reduced. We keep drugs off the market even after we think their benefits exceed their costs because we need guinea pigs. Only by keeping the drug off the market can we coerce people into participating in trials. But we can make a few exceptions without harming any ongoing trials, if sufficiently great interests are at stake. The President's health is one of those exceptions.

This argument makes many people uncomfortable. Medical ethics condemns experimenting on individuals with treatments that we think are likely to harm them, even with their consent. We can justify medical experimentation only when we do not know whether treatments will be harmful, and in this state of epistemic equipoise, we can run randomized controlled trials. That same logic might suggest that once a drug seems more likely to be beneficial than harmful, we should cease experimentation. Refusing someone an apparently beneficial drug to obtain more information harms that person. But status quo bias can avoid cognitive dissonance. There is not an easily definable point where our best estimate shifts from net harm to net benefit. And so we allow experimentation in some broad range of uncertainty, and we comfort ourselves in the thought that we are denying people these drugs for their own good. But when the President takes an experimental drug, we are forced to concede that this isn't always so. Sometimes, we are denying a drug not because of the interest of current patients, but because we want to make sure that the drug is safe before we give the drug to other patients.

Perhaps we would be better off if we were more honest about this. Sometimes we do not allow drugs on the market for genuinely paternalistic reasons (for better or worse), but at other times we insist on more randomized tests because we need the information that will result from experiments. The problem with admitting this, of course, is that the charade may end. The public would not let the government continue to keep a drug off the market if the drug admitted that the only reason it was keeping the drug off the market was that it wanted test subjects. But I am not convinced that randomized controlled trials require dishonesty. Some patients will genuinely be in equipoise about whether to take a drug, and trials can continue. Maybe drug companies will need to provide benefits (if not cash, then medical benefits) to those who agree to participate in trials instead of receiving drugs that are thought more likely than not to be beneficial. This introduces new ethical challenges. But it is hard for me to avoid the conclusion that the medical ethics of human trials is sometimes an elaborate analytical fiction designed to disguise the fact that we coerce people into participating in trials by harnessing the power of the state to keep seemingly beneficial treatments off the market. That seems more ethically troubling to me. If we admit that the public benefits from randomization, then we can confront both the ethical and informational challenges more honestly and directly.

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  1. Sometimes plain old liberty is the best policy. Not very popular among those who have no skills to match their hunger for power.

  2. “It suggests that we should approve some drugs earlier with off-label use prohibited.”

    The problem here is that a lot of drugs have very genuine off-label uses that are valid, beneficial, and unlikely to be pursued by the manufacturers under the current regulatory climate.

    Just suck it up, and free things up. If you really need people to volunteer to maybe get a placebo, perhaps you should pay them for taking that risk.

    1. I like to point out that all the transgender hormones are being used off label.

      1. OK, some of them have stupid, harmful uses, too. But I’ve often said, “If people want to drill holes in the top of their heads, and pour in battery acid, that’s their business. Just don’t force me to pay for the battery.”

  3. Drugs are not kept off the market in order to have test subjects, they are kept off until we have reliable data on safety and effectiveness. You have the logic backwards.

    Until around 1900 there were not regulations on medications. Individuals and companies could sell whatever they wanted, make any claim, and not even disclose what was in it. There was no testing. This lead to a massive mess, some drugs worked (aspirin, heroin), some were outright dangerous (mercury), and many did nothing. The consumer had no way of telling them apart. We do not want to go back to that. Then the Pure Food and Drug Act in 1906 began to change this. The only way to ensure that our medications are safe and effective is to have peer reviewed trials, and not put the drugs out for sale until that process is complete. This is why the US was spared the birth defects from thalidomide, it did not pass our safety checks. One can quibble with the details of the process for FDA approval, but it is vitally necessary.

    1. But thalidomide was basically a one off coincidence coupled with a dramatic over-reaction. (It’s actually a quite useful medication for anyone who isn’t going to get pregnant.) We’ve been much more restrictive than other countries for decades now, without another thalidomide disaster averted. Just lots of people dying prematurely because of delayed access to drugs.

      1. And thalidomide is legal now, with very specific warnings and labels.

        Many of the restrictions are due to insufficient testing on items. If a drug presents a major improvement to people, often the approval process is hastened. If it’s a minor improvement, then the approval process goes through the standard risk-based assessment.

      2. So, a few points.

        1. The FDA looks as safety and effectiveness for its drug approvals.

        2. You may say “well, I should judge whether or not a drug is effective, I shouldn’t have to wait for the FDA to show it is effective”

        3. The issue is, for many of these diseases, there are alternate, effective treatments. And if you’re taking a drug that ISN’T effective for the disease (Because it’s been marketed as effective, but hasn’t gone through phase 3 trials), then you’re effectively shaving years off their life, as they are taking the ineffective drug.

        4. Then there are the safety issues.

        5. Here’s a recent list of drugs that weren’t approved, and the reasoning for it. https://www.fda.gov/media/102332/download

    2. It’s also why we lost Terpin Hydrate which had been widely used since the 19th century as a generic product. No one wanted to pay for the required FDA studies, so we lost it.

      1. You can get it if you want, through a compounding pharmacy

    3. Drugs are not kept off the market in order to have test subjects, they are kept off until we have reliable data on safety and effectiveness.

      So they say, and is generally accepted; but the acception is because it is the regulation, not because it is effective medically. (“It is what it is.”) Nor is the risk-to-benefit balance a binary, as you present it; only the regulations are.

      The approval process is expensive and time consuming. There is nothing wrong with time-consuming in ordinary circumstances; say for sore throat or headache medicines. But the process is binary, it is either approved (or denied) after a long time. In the case of a novel disease a lot of people ‘are going to die’ because the regulatory and health administrative system is not constructed about reaction, but built around certainty. A recent illustration is the thousands killed by ventilators this spring, because “ventilators are the protocol”, but with this flu worsens the lung damage.

      The only way to ensure that our medications are safe and effective is to have peer reviewed trials …

      It’s this attitude that slows effective treatments. When the Ibola virus (AEIOU) starts killing people you will make people die rather than elect to get physician-supervised maple syrup IV which reduces the death rate 25%. (see Marshall and Warren, or Marick) Recent legislation has improved it somewhat, but the average time from FDA application to approval of drugs is 12 years; most plagues or epidemics last a fraction of that time.

    4. Speak for yourself; I would gladly go back to a system in which we are free to make our own choices and live with the consequences. There is no guarantee with your decade-plus approval process. Look at the morning sickness drug DES back in the fifties and all the “DES daughters” like my wife. But like any failed attempt to prevent harm, the solution for some is always more of the same.
      Some chemicals are harmful to you. The fact that the government slowed the official release of a new chemical (while at the same time increasing the cost and establishing a massive barrier to entry to new companies) does not make it safe; it merely makes it a little less likely that it is harmful. Meanwhile, many people die or suffer waiting for the drug. Better, I think, to allow people to evaluate their own risk/benefit. There are always the civil and criminal penalties to keep the drug company honest.

    5. It has been shown over and over that the FDA kills more people by delaying medicines that are saved by avoiding premature approval.

      And it’s not the government’s job to protect me from myself. If I want to chance drugs at risk to myself, that is nobody’s business but mine. If really sick people, terminal or not, want to chance drugs at risk to themselves, that also is nobody’s business but theirs.

      Paternalism sucks only slightly less than dictatorship.

      1. “It has been shown over and over that the FDA kills more people by delaying medicines”

        Please present this evidence….

        1. Maybe not what you want, but recent asthma deaths increased due to coincident with FDA mandated ‘reformulation’ of existing inhalers. Most inhalers used a freon propellant to deliver generic medications, and FDA mandated a change to Green™ propellants. FDA then granted approvals as new medical devices (same medication, same mechanics, different propellant) increasing prices from $60 to $350.
          https://www.cdc.gov/asthma/asthma_stats/asthma_underlying_death.html

          1. Not really what I meant. Besides the whole “coincident” bit (Ever hear about ice cream sales and the rate of crime?) that’s a “Green energy/chemical” mandate.

            Which is an entirely different ball of wax.

          2. I find neither “60” nor “350” anywhere in your reference. As I recall, the actual increase for generic albuterol inhalers was more like from $3 to $30—although a larger percentage increase than you cite, much smaller in real numbers. Also, the mechanism changed too, adding a dose counter (may have been, as you say, coincident to the propellant change).

            I say this as someone with several albuterol inhalers scattered around the house, but without knowledge of their actual cost to the end user (and I’m too lazy to research that right now—anyone have better numbers?).

            The reason I’m not certain of the exact cost is because I’ve been privileged enough have been covered by fully socialistic healthcare throughout my adult life. That consisted of single-provider healthcare for 21 years (UK National Health Service-style: government-delivered in government-owned facilities, by government-paid workers); then another 20+ years Canada-style single-payer supplemented by government single-provider; and now Medicare single-payer backed up with a single-payer Medicare Supplement and government single-providers.

            That was, of course, military hospitals/clinics while active duty; TriCare, plus military facilities and VA after my Air Force retirement with a 40% VA disability; and now Medicare/TriCare-for-Life, plus VA and Madigan Army Medical Center.

            I’m hopeful that all Americans will eventually have the same coverage, thus freeing businesses to make employment decisions based on the potential future value of the individual employee rather without regard to their individual healthcare costs.

        2. There have been repeated comparisons of the FDA’s performance compared to similar agencies in other countries. Yes, here at reason, too. Bottom line has been, the FDA doesn’t do any better at protecting people, they’re just a lot slower. We could save an absurd amount of money, and many lives, by just saying, “Here’s a list of 5 developed countries: If a drug is approved by at least 3 of them, it’s approved here.”

  4. Don’t drug companies have a strong, independent incentive to ensure the drug is well tested before releasing it? If I was to take a drug I would want to know it was well tested. If I was selling drugs I would want to know it is safe before releasing it to the public.

    1. History says “no, they don’t”. The patent medicine industry of the 1800s shows they they will sell anything they can without caring. The modern version is the supplement industry (some of which are dangerous). We want to keep the real drugs and the fake ones quite separate.

      1. “The patent medicine industry of the 1800s”

        Presumably you’re not suggesting that’s the only alternative to the current regulatory regime?

        1. Certainly xhe is. Statists can’t see anything less than full state authority as being at all acceptable.

      2. It isn’t that as much as there is no such thing as a totally safe drug with no side effects. Read the packet insert of any drug sometime — the fistfull of paper that comes with the big bottle that the pharmacist gets.

        1. I take some eyedrops to relieve pressure in my eyeballs. One of the side effects is potentially cataracts, I believe. The alternative, of skipping the eyedrops, is more likely glaucoma, or at least something worse, but less likely, than the potential side effect of taking the eyedrops.

          It is my decision whether to take them or not, but statists don’t think I am responsible enough to make that decision for myself.

      3. Yes, if we give one inch we’ll see horse wagons on the streets carrying snake-oil salesmen. /deserved snark

        Did it ever occur to you that there is a market (an unmet need) the FDA is failing to approve/allow? … or is the 1930s model the only one you can comprehend?

    2. The large multi national drug companies do, but they benefit from the current regulatory scheme since they have the resources to sustain the regime.

      Without the regulations many smaller less responsible companies might release poorly tested drugs on the market. If they made a mistake or were reckless they would go bankrupt, but the damage would already have been done.

      1. I’m more than happy to make that choice myself. Statists do not want anyone to have personal responsibility. It scares the heck out of them to think that anyone should ever be independent of the State.

        1. You, as an individual, would not have the information required to make an informed choice. You don’t have access the testing data (if there is any), nor would you have the ability by yourself to interpret the data. You are flying blind and taking chances with your health.

    3. “Don’t drug companies have a strong, independent incentive to ensure the drug is well tested before releasing it? ”
      Not necessarily.

      Here’s the general issue. Many drug companies are smaller operations. They invest significant funds to getting their first drug out the door. Then they are left with a set off conditions.

      1. Sell the drug as is, without further testing. Either
      a. The drug is safe, and they make a lot of money
      b. The drug isn’t effective, and they make some money
      c. The drug is unsafe, and they are sued. They lose some (most) of the money they make, and the company goes bankrupt.
      2. Do further testing on the drug. Then…
      a. They run out of money, and the company goes bankrupt
      b. They find out the drug is unsafe, and they kill the project and all invested funds, and the company goes bankrupt.
      c. They find the drug is safe and effective, market it, and make a lot of money.

      That’s really the set of conditions. Many times, they’re fiscally better off “not knowing” and selling the drug.

  5. “Maybe drug companies will need to provide benefits (if not cash, then medical benefits) to those who agree to participate in trials instead of receiving drugs that are thought more likely than not to be beneficial.”

    In the US, they do.

  6. How dangerous can it be if they’re giving it to the President of the United States?

    Unless his condition is very bad and they’re becoming desperate.

    1. I’ve seen the initial release of data from the clinical trials. Very impressive results, (Cuts the time to become asymptomatic in half.) and the people getting the treatment had no more negative results than the controls.

      So, not very dangerous. It’s verging into the territory where they have to cut short the trials because it’s unethical to force people to be the controls.

      1. As I’m sure you’re aware, the “initial results” you cite (called “pre-pubs” if formal but not yet peer-reviewed, and “press releases” if not) are very often incomplete and exaggerated, and often end up being wrong.

        That said, yes, these seem pretty good so far. Based on the lack of alternatives and that the side effects don’t yet seem to have killed anyone, probably a reasonable medical decision in this case.

      2. So, this is VERY early in the trial process, especially for the monoclonal antibodies (MAbs). As in the earliest reads in the clinical trial are coming out now. As in the first reads were around September 30th for the Regeneron treatment.

        Now MAbs have some benefit, in that they tend to have less in the way of unanticipated side effects. You still need to prove efficacy, and some odd things have happened there with Eli Lily’s system (It wasn’t effective at the highest dose…but was at the middle dose). And before you begin giving the treatment to everyone, it would be nice to make sure it actually works.

        But the one big downside to MAbs is that they are hard and EXPENSIVE to make. IE, for a 7 gram dose (the highest dose in the Lily trial), that’s $50,000 per treatment on average for a “typical” MAB. These aren’t small molecules (your normal drugs). And it’s not patent costs. It’s not research costs. It’s actual production costs.

        So, it’s not that it’s “unethical” for people to be the controls. It’s the fact they honestly can’t make enough of it for all the patients.

  7. The difference here is that Trump is *so* well medically monitored that any side effects will be caught even without looking for it.

    It’s qualitative research rather than quantitative research, but it has its value as well.

  8. Any doctor can write a letter to the FDA and get a medication for an individual patient, as long as it is not approved by the FDA for the US market. Once approved, the doctor can use any drug off label.

    https://www.fda.gov/drugs/investigational-new-drug-ind-application/physicians-how-request-single-patient-expanded-access-compassionate-use

  9. The notion begs the question that the president should get an untested drug because we expect it to do good, and because the president is so important. Of course we expect any prospective drug to do good, until we know otherwise. But the begged question is whether or not the drug does do good. With that question unresolved, the president’s importance may increase the stakes on both sides of the question, but delivers no net weight to either side of the scales. The president’s importance bears on both sides equally, and thus cannot alter the balance.

    More generally, what applies to the president applies alike to everyone. The president’s health is not more important than the health of any other person.

  10. Many drugs are used “off label” and thanks to the internet there is a lot of anecdotal data out there about possible uses that would never be supported by a clinical trial or almost impossible to develop a methodology that would pass a review board. That does not mean though that some of these treatments don’t work and don’t have real world results for people with frustrating conditions that do not respond to “approved” treatments.

    I had a friend who had this nasty red rash for years. No explanation from doctors and multiple trips to specialists with lab work. Nothing worked to clear it up. Finally after spending a late night on an internet forum someone on the other side of the planet described the exact same condition and recommended a simple supplement. After taking it for 8 weeks the rash disappeared.

    I’m all for providing a system where if someone wants to experiment with a drug, as long as they know the potential side effects, and agree to hold the manufacturer harmless, why not let that individual make their own decision about risks vs. benefits.

    1. If you want to do that, go ahead. There are plenty of sites where you can order whatever chemical or drug you want. They all have big warnings “not for human use, not for human consumption, not for patients”.

      But if you want to ignore all that and try it anyway….well… We can’t stop you.

  11. There is a lot of nonsense in the press about DJT’s risk factors.
    For example in the WSJ. “Being Caucasian puts him at lower risk than if he was a person of color,” said Dr. Griffin. “And people who are diagnosed early, followed closely and have access to the right therapeutics clearly do better than patients without those advantages.”
    Looking at Covid infections on a global basis across ethnic groups in 100 countries with the most cases , this claim cannot be substantiated. As for the issue of weakened immune response in elderly populations one might see a paper published in the last couple of weeks in the New England Journal of Medicine, “Covid-19 and Immunity in Aging Populations.”

    1. I probably should have said “exaggeration” rather than “nonsense;” the correlations are present but are very small.

  12. One question for those who are pro FDA gatekeeping.
    The FDA requires that clinical trial results include all adverse results. Fine.
    The FDA approval process includes reviews by staff, consultants and a formal decision making process. Disagreements occur however it is not clear whether all reports used to reach a decision are made public nor the experience, credentials and track records of each reviewer made available for scrutiny. The result is consumers’ lack of ability to rely on Dr. Expert’s Report as opposed to FDA staff report if they differ.

    https://pharmanewsintel.com/news/disagreements-within-fda-about-novel-drug-approvals-common

    1. Oooh boy… That gets into a rats nest. But here’s the short answer.

      1. Most people don’t have the level of scientific knowledge to meaningfully understand the differences in opinion going on between people having discussions about this.

      BUT (and this is a key but)

      2. If people do have that knowledge (or think they do), the entire clinical trial report is required to be published, and the people can interpret the report for themselves.

      What you’re asking for is for the people be able to make a judgement based on the internal disagreements and discussions of others, and not on the raw data itself (which is made available) and not on the final analysis of that data (by the FDA). Which…is a bridge that doesn’t really make sense.

  13. I think the OP’s reasoning, as well as many of the commenters, miss a key point about US drug regulation. It’s not about preventing individuals from taking unproven drugs. It’s about preventing companies from selling unsafe or inactive drugs.

    I agree with MollyGodiva: history days that drug companies (as a whole) do NOT have adequate incentive to sell only drugs that they reasonably believe are safe & effective. Consider the many cases where pharmas were caught manipulating data, concealing side effects, etc., even with the existing FDA regulations in place. One can certainly question whether the regulations do a good enough job based on that, or whether an entirely different approach would be better. But either way, it’s prima facia evidence that companies are willing to risk monetary & reputational damages to achieve near-term profits.

    I will also echo DaivdBehar’s point. The President is almost certainly (IMO) receiving the Regeneron cocktail under one of the existing FDA-compliant mechanisms that allow single patients to receive un-approved drugs under certain circumstances. These situations are treated very much like single-patient clinical trials. There is considerably more scrutiny of patient suitability, monitoring for side effects, etc., and the patient’s doctors are generally assuming a much higher professional responsibility when they agree to administer such drugs. So IMO, the ethics of administering the drug to an individual in that situation aren’t much different than the ethics of testing it in clinical trials.

    Admittedly, such one-off treatments don’t really contribute to our understanding of a drug’s safety and efficacy the way a clinical trial does. And although such programs are nominally available to anyone, I have no doubt that they are much more available to rich & powerful people.

    Finally, I disagree that “statists” don’t want anyone to have personal responsibility. Once again, the system is not primarily about taking responsibility away from pharmaceutical users. It’s about ensuring that pharmaceutical sellers live up to their responsibilities. It may well be a bad system, and others may well be much better. But mischaracterizing the intent of the current system is at best a distraction and at worst a significant impediment to figuring out something better.

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