Fellow progress blogger Alex Telford and I have had a friendly back-and-forth going over FDA reform. Alex suggests incremental reforms to the FDA, which I strongly support, but these don’t go far enough. The FDA’s failures merit a complete overhaul: Remove efficacy requirements and keep only basic safety testing and ingredient verification. Any drug that doesn’t go through efficacy trials gets a big red warning label, but is otherwise legal.
This was better than the surgery post 😉 I'm not going to write another detailed response because, as you point out, the crux of our disagreement boils down to different (subjective) risk tolerances.
I do think nuance in how regulation is adapted to unmet need is important however. So I'll leave this closing thought (from a response to a comment on my last piece):
"Broadly, you can put new treatments into one of two classes that exist on a spectrum between two extremes:
1. Minimizing downside is preferable (vaccines for healthy people, cosmetic surgery)
2. Maximizing upside is preferable (deadly diseases with no good treatments, transplants)
The FDA grew up during the era of mass-market blockbusters so was designed to deal with class #1-adjacent treatments. We shouldn't have the same approach for both classes, but (in my view) that doesn't mean we scrap the FDA - it has an important function. Accelerated approval etc. tries to deal with the dichotomy of risk-preference but probably doesn't go far enough. I think there are conditions (e.g. n-of-1 rare disease) where there are convincing arguments that you should be able to bring a drug to market based on the judgement of reasonable experts and some preclinical tests."
"Remove efficacy requirements and keep only basic safety testing and ingredient verification"
What does "basic safety testing" mean in the context of cancer drugs? They aren't safe at all! Chemotherapy was literally first discovered when doctors noticed what happened to soldiers attacked by mustard gas. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325736/ If you look at the side effects of any common cancer drug (let's take doxirubicin), it typically looks like this: "May cause infections, sepsis, heart attacks, breathlessness, bruising, extreme fatigue, hair loss, sore mouth, loss of appetite, diarrhea, and more."
In fact, my wife was administered that drug when she had an episode of breast cancer, and it came in an IV bag labeled with a skull and crossbones, with all kinds of warnings for the nurse to "NEVER LET THIS TOUCH YOUR SKIN" and that kind of thing. It's incredibly toxic.
All of which is to say that no cancer drug like this would ever pass a review for "safety." These drugs are not safe whatsoever. They can easily kill you. The only reason to take them is that they (hopefully) kill more cancer cells than healthy cells. Which is about efficacy.
Fair enough. What I tried to show in my argument isn't really about a difference between safety and efficacy testing, it's an argument for significantly relaxing the standards of approval. I just saw the safety-efficacy or Phase I/II - Phase III divide as a convenient signpost for what relaxed standards might look like.
Would just saying "remove Phase III trial requirements" make more sense?
Why doesn't the same argument favor barring off-label prescribing?
I think a key consideration here is what the alternative might be. For instance, I can imagine a system where in exchange for dropping efficacy requirements a tax on pharmaceutical profits is imposed and the FDA then directly funds efficacy studies. This would be alot better than just checking if each medicine gets over a minimum hurdle as you could revisit results and compare treatments.
In the spirit of Chesterton's fence: what happened in 1962 that caused efficacy requirements to be added? Was it just Great Society era trust-the-experts-ism, or were there real problems with useless-but-popular drugs that proponents identified at the time to justify the new requirements? If the latter, is your claim that there were better ways of addressing those problems, or that we should have just let those problems happen as a cost of the freedom to innovate?
Yes the Thalidomide scandal caused the big push for more oversight. It's a bit ironic though because Thalidomide would have passed all of the efficacy tests. It was a very effective nausea drug it just wasn't safe.
Yes, that is ironic-- I don't get why what was very clearly a safety problem, and visible as such even at the time, wouldn't have been addressed just with stronger safety testing requirements.
1. The FDA has a dual mandate to evaluate efficacy AND safety (i.e. the risk-benefit of a new drug) as a result of the 1962 amendments. ~every drug is unsafe in some dose or context of use, so the reasoning is that we also need to look at efficacy to make a full judgement
2. While thalidomide was the catalyst for the 1962 amendments, some were pushing to add an efficacy requirement earlier to address ongoing problems with drugmakers making false/exaggerated efficacy claims. The thalidomide scandal was the 'excuse' to implement existing proposals
3. To say that thalidomide is approved now for some uses (leprosy, multiple myeloma) is irrelevant. What is relevant is the risk-benefit in different contexts of use (thalidomide is no longer used for morning sickness)
Thanks for the additional context. It seems like if the problem was *false* claims of efficacy, one could give the FDA power to evaluate such claims and sanction such falsehoods as fraud, without giving it power to block sales based on what it determined to be lack of sufficiently favorable risk-benefit tradeoff.
Overall the philosophical issue, as I see it, is that a risk-benefit tradeoff is inevitably a value judgment, not only an empirical judgment. Experts (government or otherwise) can have special abilities when it comes to making empirical judgments, but contrary to the ethos that prevailed in 1962, there is no reason to expect them to be particularly good at making value judgments, so it is (on the libertarian view anyway) inappropriate to give them special power to do so.
Imagine I am a shady pharma company, I run 5 low powered clinical trials and one finds my drug has a big positive effect by chance, the other 4 studies fail. I don't publish my failed studies and file them away, but I promote my "success" extensively.
The power of a central government agency is that it can force companies to prospectively define the analysis plan and fully disclose the information as part of an application process, then make a judgement based off the totality of evidence. As a consumer, your problem is that you're likely to get a skewed view of the evidence.
We can reasonably debate over whether the FDA has the balance right for the value judgement question, but it seems clear to me that we need some FDA-like function to address these epistemological issues.
The point is not that the FDA doesn't have the balance right, but that it should not be making these balancing judgments at all. It has no skin in the game! A solution that "protects" consumers from skewed evidence by taking away their freedom to make their own personal value judgments about cost-benefit tradeoffs has not, in fact, helped those consumers.
Funny enough it also caused women to be excluded from clinical trials for a few decades, until the FDA realized this made drugs even more potentially dangerous for women.
"There is no denying that medicine has improved massively over the past 150 years alongside expanding regulatory oversight, but this relationship is not causal." Exactly. Thank you. I'm so tired of this lazy argument for the FDA.
Safety is relative to the problem that a drug is intended to treat - there are side effects that people will accept from a cancer treatment that they won't accept from, say, an acne treatment.
I'd like to propose a slightly different system:
1) If you can establish a drug as meeting a certain safety standard, you can sell it and doctors can prescribe it, but you can't claim it's good for anything, and insurers won't be required by law to cover it.
2) If you can prove efficacy for a drug, you can get a *new* patent on it - even if it's been patented before for a different condition - and insurers can be required to cover it. Otherwise, nobody would actually go to the trouble of proving effectiveness to the FDA's standards if they can just sell the drug without doing that. You can also sell a drug that doesn't meet the "unproven chemical" safety standard if the benefits outweigh the risks. (Figuring out the proper scope of such a patent is a matter for someone who knows more about the economics than I do.)
This was better than the surgery post 😉 I'm not going to write another detailed response because, as you point out, the crux of our disagreement boils down to different (subjective) risk tolerances.
I do think nuance in how regulation is adapted to unmet need is important however. So I'll leave this closing thought (from a response to a comment on my last piece):
"Broadly, you can put new treatments into one of two classes that exist on a spectrum between two extremes:
1. Minimizing downside is preferable (vaccines for healthy people, cosmetic surgery)
2. Maximizing upside is preferable (deadly diseases with no good treatments, transplants)
The FDA grew up during the era of mass-market blockbusters so was designed to deal with class #1-adjacent treatments. We shouldn't have the same approach for both classes, but (in my view) that doesn't mean we scrap the FDA - it has an important function. Accelerated approval etc. tries to deal with the dichotomy of risk-preference but probably doesn't go far enough. I think there are conditions (e.g. n-of-1 rare disease) where there are convincing arguments that you should be able to bring a drug to market based on the judgement of reasonable experts and some preclinical tests."
"Remove efficacy requirements and keep only basic safety testing and ingredient verification"
What does "basic safety testing" mean in the context of cancer drugs? They aren't safe at all! Chemotherapy was literally first discovered when doctors noticed what happened to soldiers attacked by mustard gas. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325736/ If you look at the side effects of any common cancer drug (let's take doxirubicin), it typically looks like this: "May cause infections, sepsis, heart attacks, breathlessness, bruising, extreme fatigue, hair loss, sore mouth, loss of appetite, diarrhea, and more."
In fact, my wife was administered that drug when she had an episode of breast cancer, and it came in an IV bag labeled with a skull and crossbones, with all kinds of warnings for the nurse to "NEVER LET THIS TOUCH YOUR SKIN" and that kind of thing. It's incredibly toxic.
All of which is to say that no cancer drug like this would ever pass a review for "safety." These drugs are not safe whatsoever. They can easily kill you. The only reason to take them is that they (hopefully) kill more cancer cells than healthy cells. Which is about efficacy.
Fair enough. What I tried to show in my argument isn't really about a difference between safety and efficacy testing, it's an argument for significantly relaxing the standards of approval. I just saw the safety-efficacy or Phase I/II - Phase III divide as a convenient signpost for what relaxed standards might look like.
Would just saying "remove Phase III trial requirements" make more sense?
Why doesn't the same argument favor barring off-label prescribing?
I think a key consideration here is what the alternative might be. For instance, I can imagine a system where in exchange for dropping efficacy requirements a tax on pharmaceutical profits is imposed and the FDA then directly funds efficacy studies. This would be alot better than just checking if each medicine gets over a minimum hurdle as you could revisit results and compare treatments.
In the spirit of Chesterton's fence: what happened in 1962 that caused efficacy requirements to be added? Was it just Great Society era trust-the-experts-ism, or were there real problems with useless-but-popular drugs that proponents identified at the time to justify the new requirements? If the latter, is your claim that there were better ways of addressing those problems, or that we should have just let those problems happen as a cost of the freedom to innovate?
Yes the Thalidomide scandal caused the big push for more oversight. It's a bit ironic though because Thalidomide would have passed all of the efficacy tests. It was a very effective nausea drug it just wasn't safe.
And it wasn’t even an approved drug at the time! And now it is!
Yes, that is ironic-- I don't get why what was very clearly a safety problem, and visible as such even at the time, wouldn't have been addressed just with stronger safety testing requirements.
Some important things to clarify:
1. The FDA has a dual mandate to evaluate efficacy AND safety (i.e. the risk-benefit of a new drug) as a result of the 1962 amendments. ~every drug is unsafe in some dose or context of use, so the reasoning is that we also need to look at efficacy to make a full judgement
2. While thalidomide was the catalyst for the 1962 amendments, some were pushing to add an efficacy requirement earlier to address ongoing problems with drugmakers making false/exaggerated efficacy claims. The thalidomide scandal was the 'excuse' to implement existing proposals
3. To say that thalidomide is approved now for some uses (leprosy, multiple myeloma) is irrelevant. What is relevant is the risk-benefit in different contexts of use (thalidomide is no longer used for morning sickness)
Thanks for the additional context. It seems like if the problem was *false* claims of efficacy, one could give the FDA power to evaluate such claims and sanction such falsehoods as fraud, without giving it power to block sales based on what it determined to be lack of sufficiently favorable risk-benefit tradeoff.
Overall the philosophical issue, as I see it, is that a risk-benefit tradeoff is inevitably a value judgment, not only an empirical judgment. Experts (government or otherwise) can have special abilities when it comes to making empirical judgments, but contrary to the ethos that prevailed in 1962, there is no reason to expect them to be particularly good at making value judgments, so it is (on the libertarian view anyway) inappropriate to give them special power to do so.
Here's the core issue that the FDA solves for:
Imagine I am a shady pharma company, I run 5 low powered clinical trials and one finds my drug has a big positive effect by chance, the other 4 studies fail. I don't publish my failed studies and file them away, but I promote my "success" extensively.
The power of a central government agency is that it can force companies to prospectively define the analysis plan and fully disclose the information as part of an application process, then make a judgement based off the totality of evidence. As a consumer, your problem is that you're likely to get a skewed view of the evidence.
We can reasonably debate over whether the FDA has the balance right for the value judgement question, but it seems clear to me that we need some FDA-like function to address these epistemological issues.
The point is not that the FDA doesn't have the balance right, but that it should not be making these balancing judgments at all. It has no skin in the game! A solution that "protects" consumers from skewed evidence by taking away their freedom to make their own personal value judgments about cost-benefit tradeoffs has not, in fact, helped those consumers.
Funny enough it also caused women to be excluded from clinical trials for a few decades, until the FDA realized this made drugs even more potentially dangerous for women.
I think it was safe for everyone except pregnant women.
Thalidomide
"There is no denying that medicine has improved massively over the past 150 years alongside expanding regulatory oversight, but this relationship is not causal." Exactly. Thank you. I'm so tired of this lazy argument for the FDA.
Safety is relative to the problem that a drug is intended to treat - there are side effects that people will accept from a cancer treatment that they won't accept from, say, an acne treatment.
I'd like to propose a slightly different system:
1) If you can establish a drug as meeting a certain safety standard, you can sell it and doctors can prescribe it, but you can't claim it's good for anything, and insurers won't be required by law to cover it.
2) If you can prove efficacy for a drug, you can get a *new* patent on it - even if it's been patented before for a different condition - and insurers can be required to cover it. Otherwise, nobody would actually go to the trouble of proving effectiveness to the FDA's standards if they can just sell the drug without doing that. You can also sell a drug that doesn't meet the "unproven chemical" safety standard if the benefits outweigh the risks. (Figuring out the proper scope of such a patent is a matter for someone who knows more about the economics than I do.)