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Your F.D.A. Is Unsafe and Ineffective A drug passes every safety test your species invented.

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It won't hurt you. Everyone agrees. You still can't have it for another eight point two years.

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There is, however, no waiting list for dying. No one blocks that.

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The testing costs forty-four point one times more than proven alternatives and excludes eighty-six point one percent of

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the patients who'll actually take it. For every one unit of harm prevented, the system creates three thousand and seventy

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through denied access. Here's how to fix it. For every one unit of harm prevented by efficacy delays, the system creates

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three thousand and seventy units of harm through denied access.

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Operational safety ratio: three thousand and seventy-to-one against the patient.

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In nineteen sixty-two, your Congress decided that after proving a drug won't kill you, sick people should wait another eight

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point two years before they're allowed to take it. The drug passed safety testing.

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It won't kill you, won't melt your liver, won't make your hair migrate to your back.

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But you can't have it, because a committee needs to spend eight point two years making sure it works well enough.

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I asked someone why, and they said "we need to confirm efficacy."

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I said, "The patient is dying." They said, "Yes, but we don't know if the drug works."

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I said, "The patient could tell you, if you gave it to them."

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They said that's not how it works. I said, "Dying is how it works?"

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They changed the subject, which I suppose is also how it works.

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You're not allowed to volunteer for the trials that would answer the question faster, either.

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You are, however, allowed to die. Nobody blocks that. There's no eight point two years waiting period on dying.

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On Wishonia, when we confirm something won't harm you, we let you try it.

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On Earth, you lock it in a cabinet and form a committee. The committee meets quarterly.

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You decompose on a different schedule. A Note on Blame. When this chapter says "the F.D.A.

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does X," read it as "the nineteen sixty-two law requires the F.D.A.

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to do X." Congress wrote the rules. The F.D.A. follows them.

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Blaming the F.D.A. is like blaming the gun instead of the person who loaded it, aimed it at patients, and pulled the trigger

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on a sixty-two-year schedule. "But What About Safety?" This is the part where humans panic, so let me be very precise about

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what this chapter is (and isn't) proposing: keep Phase One safety testing (it works, it caught thalidomide, nobody is suggesting

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you skip it). Do *radically more* efficacy testing, on *real patients*, with *transparent results*.

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But stop holding known-safe drugs hostage while you run the trials.

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On Wishonia, we don't have a word for "preventing someone from accessing a safe substance that could help them while they

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die." It would never occur to us to do it, so we never needed a word.

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You have several words for it. My favorite is "the approval process."

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The forty-four point one times inefficiency tax. Compare two real-world systems for testing drugs: The Oxford RECOVERY Trial

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tested COVID treatments on forty-eight thousand patients for five hundred dollars and found a life-saving treatment in three

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months, like a normal species would. The post-nineteen sixty-two system averages forty-one thousand dollars per trial and

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takes over a decade to approve a new drug, like humans would.

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Your efficacy testing system costs forty-four point one times more and takes thirty-two point eight times longer than necessary.

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I showed these numbers to a human and they said "that can't be right."

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So I showed them the sources and they said "well, there must be a reason."

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There is a reason. The reason is that your system costs forty-four point one times more and takes thirty-two point eight

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times longer. That's the reason and also the problem. They're the same thing.

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The eight point two years Efficacy Lag. Here's where your lifespan goes to die: Phase One (Safety Testing) lasts two point

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three years and tests if the drug harms people: death, organ damage, mutations, serious adverse reactions, all the ways

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a molecule can ruin your day. *This part works. Keep it.* Phase Two slash Three (Efficacy Testing) takes eight point two

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years. The drug is now *known safe*. But patients can't have it until the committee is satisfied.

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*This is where people die waiting for a drug that already passed every safety check your species invented.* What the nineteen

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sixty-two Efficacy Requirements Changed. Before nineteen sixty-two, one hundred and forty-four thousand physicians tested

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treatments on real patients and published results. Life expectancy grew three point eight two years every decade for eighty

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straight years. Things were going well. Naturally, Congress intervened.

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Phase One safety testing (added in nineteen thirty-eight) prevented all U.S.

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thalidomide deaths while Europe had thousands. So in nineteen sixty-two, Congress looked at a system that was working and

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thought, "What if we made this much worse?" They added massive pre-approval efficacy requirements via the Kefauver Harris

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Amendment, blocking patient access for years during testing.

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The cost of developing a drug went from twenty-four point seven million dollars to two point six billion dollars, a one

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hundred and five times increase. New drug approvals dropped by seventy percent.

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Life expectancy gains slowed from three point eight two years per decade to one point five four, a sixty percent reduction.

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Time to approval stretched from two to three years to ten point five years.

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Everything got worse at exactly the same time. Every single metric, all at once, the moment the law passed.

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I'm not a statistician so I can't tell you whether that's a coincidence, but I did look at the graph, and it's not a coincidence.

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The one hundred and five times cost increase is rigorously documented.

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See Drug Development Cost Analysis for methodology, sensitivity analysis, and source data.

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The Modern Consequences. Even if you think historical analysis is just opinions with footnotes, the current system's failures

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are happening right now: One. A cure passes safety testing.

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Two. You can't take it (pending efficacy review). Three. You can't join the trial either (too sick, too old, wrong medications).

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Four. You die. Five. The F.D.A. approves the cure. Six. Pharmaceutical companies charge your widow ten thousand dollars

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per pill. I read this sequence several times because I kept thinking I'd got the order wrong.

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I hadn't. That is the correct order. The system works exactly like that, on purpose, and everyone involved considers it

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a success because nobody skipped a step. High Costs Kill Innovation, Reward Monopoly.

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Before nineteen sixty-two: Genius scientist invents cure, raises a few million, tests safety, gives it to people.

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Like a civilization that wants to survive would. Now: Genius scientist must convince one of three mega-corporations to fund

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trials. Those corporations already sell inferior drugs for the same condition, bringing in hundreds of millions a year per

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drug. The math for the mega-corporation: Option one: Develop the better drug Cost: two point six billion dollars on average

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to get a single drug to market. That figure already includes the cost of the nine candidates that fail for every one that

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succeeds, so the ten percent success rate is already priced in.

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Best case, the drug works: you now have a better drug for the same condition.

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But your old drug, which was bringing in hundreds of millions a year, is now obsolete.

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You spent two point six billion dollars to replace your own revenue stream.

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Every year the new drug is on the market, it's earning roughly what the old drug would have earned anyway, minus the two

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point six billion dollars hole you dug getting here. Option two: Buy the patent, put it on a shelf Your inferior drug keeps

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bringing in hundreds of millions a year. Total cost: whatever the patent costs, which is rounding error compared to two

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point six billion dollars. I asked a pharmaceutical executive which option they'd choose and they said "it's more nuanced

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than that." Then I asked which one they chose and they said Option two.

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So it wasn't more nuanced than that. The profit incentive doesn't just fail to reward better treatments.

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It actively punishes them. The best possible outcome of Option one is the same annual revenue you already had, minus two

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point six billion dollars. Curing disease is economically irrational.

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The system doesn't need a conspiracy to suppress cures. It just needs the math.

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I keep waiting for someone to show me where the math is wrong.

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Nobody shows me where the math is wrong. They just look uncomfortable and say "it's complicated," which I've learned is

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what humans say when it isn't complicated and they don't like the answer.

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Off-Patent Drugs and Rare Diseases: Mathematically Doomed. The nineteen sixty-two law made it mathematically impossible

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to cure diseases that aren't profitable enough: Ninety-five percent of diseases are rare: a development cost of two point

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six billion dollars divided by a patient population of about ten thousand patients equals two hundred and sixty thousand

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dollars per patient. No patent equals no funding because off-patent drugs can't attract billion-dollar investments.

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Pre-specification kills serendipity as you must predict what drug cures before testing.

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When something costs more, you get less of it. I looked this up and apparently it's the first thing they teach in economics.

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It is also, somehow, the last thing anyone considers when writing health policy.

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Ninety-five percent of diseases have zero treatments. Not because cures are impossible.

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Because cures are unprofitable. The best thing a disease can do for itself, career-wise, is be popular.

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The Actual Death Toll of "Drug Lag". Economists call it "drug lag," which is a lovely, clinical way of saying "people rotting

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to death in a queue for drugs that have already been confirmed not to hurt them.".

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Early estimates: twenty-one thousand to one hundred and twenty thousand American lives per decade.

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But that was just the U.S. A comprehensive quantitative analysis using W.H.O.

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mortality data estimates the *total* cost of the eight point two years *post-safety* efficacy delay (the lag *after* drugs

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are known safe): four hundred and sixteen million eventually avoidable deaths.

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Including years lived with disability: seven point nine four billion disability-adjusted life years, or D.A.L.Y.s, of healthy

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human life deleted. Economic cost: one point one nine quadrillion dollars (twenty twenty-four U.S.

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dollars), reflecting those seven point nine four billion D.A.L.Y.s valued at one hundred and fifty thousand dollars per

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D.A.L.Y., the standard normative rate used in W.H.O. cost-effectiveness analyses.

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Even if those death estimates are off by a factor of ten, that's still tens of millions of deaths.

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And the inefficiency is independently verifiable: the efficacy testing process costs eighty-two times more per patient and

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takes thirty-two point eight times longer than proven alternatives like the Oxford RECOVERY trial.

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Those numbers don't depend on mortality estimates at all. Here's a news story from the Non-Existent Times by No One Ever,

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without a picture of all the people who die from lack of access to life-saving treatments that might have been.

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You can't photograph millions of people who died from *not* receiving a drug.

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There's no body with a toe tag reading "cause of death: regulatory delay."

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They die of cancer, heart disease, Alzheimer's. The delay that killed them is invisible, so nobody writes the headline.

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Types of Error in F.D.A. Approval Decision If the drug is beneficial and the F.D.A.

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allows it, that is a correct decision. If the drug is harmful and the F.D.A.

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allows it, victims appear on television and the regulator is fired.

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If the drug is beneficial and the F.D.A. does not allow it, victims die at home and nobody is fired.

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If the drug is harmful and the F.D.A. does not allow it, that is a correct decision.

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So the F.D.A. has two kinds of mistakes. One where they give you a bad drug and you die on television.

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And one where they don't give you a good drug and you die at home.

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They've decided the second one doesn't count, which is convenient because it's the one they do most.

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The most infamous case: beta-blockers. Europe used them to prevent heart attacks.

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The U.S. delayed for a decade, killing an estimated one hundred thousand Americans.

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More than died in Vietnam and Korea combined. From one drug.

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That they had. That they knew worked. That they put in a drawer.

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I asked someone if there was a word for killing one hundred thousand people by not doing something, and they said "it depends

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on the context." I think one hundred thousand dead people is the context, but apparently that's not enough context.

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After nineteen sixty-two, U.S. life expectancy diverged from Switzerland's (which didn't introduce the same delays).

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More drug approvals in the eighties narrowed the gap. Fewer approvals in the nineties widened it again.

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The pattern is not subtle. I showed it to a child and the child understood it.

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I showed it to a policy expert and they said it was "multifactorial."

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I think "multifactorial" is what adults say when they can see the same thing the child can see but have reasons not to say

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it out loud. How the Incentives Work. F.D.A. Regulator Decision Tree.

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Approve drug that later shows problems. Congressional hearing (televised).

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"F.D.A. APPROVED KILLER DRUG" headlines. Career ends. Pension threatened.

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Delay drug that could save lives. Nothing happens. Nobody writes a headline.

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Promotion on schedule. Retire to pharma job. To be fair, this isn't a conspiracy.

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It's just a system where the only career-ending move is letting patients access treatments.

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If you approve a bad drug, C.N.N. says your name. If you delay a good drug, nobody dies on television.

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So the rational move is to delay everything, and that's what happens, and everyone who could object is dead, which does

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simplify the feedback process. Dr. Henry I. Miller ran the F.D.A.

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team reviewing recombinant human insulin in the early nineteen eighties.

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Mountains of evidence showed it was safe and effective. His supervisor refused to approve it.

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If someone died from the drug, heads would roll. If people died waiting for the drug?

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Nothing happens. Dead patients don't testify before Congress.

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I checked. The Math: Why Current Regulations Increase Total Harm.

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Even generously crediting ALL drug withdrawals to the nineteen sixty-two changes (ignoring that Phase One safety testing

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already existed), the prevented harm totals approximately two point five nine million disability-adjusted life years, or

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D.A.L.Y.s. The delay harm totals seven point nine four billion D.A.L.Y.s.

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For every one unit of harm prevented, the current system creates three thousand and seventy units of harm through delay.

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The safety net catches one person and drops three thousand and seventy.

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On Wishonia, we'd call that a hole, not a net. Clinical Trial Theater: Excluding eighty-six point one percent of Reality

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Makes Drugs More Dangerous. To be clear: Phase One safety testing should exclude vulnerable populations.

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You don't give an untested molecule to a pregnant woman. But once a drug clears safety, the efficacy trials that follow

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*also* exclude those populations, which means nobody learns whether the drug works for the people who will actually take

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it, or what interactions to expect. Then the drug is approved for everyone, and the post-market surveillance system (the

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Adverse Event Reporting System, or F.A.E.R.S.) catches less than ten percent of adverse events.

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So the exclusions create a data gap, and nothing ever fills it.

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The F.D.A. requires rigorous safety trials. Good. Then it runs efficacy trials on people who aren't sick, aren't old, aren't

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on other drugs, and aren't pregnant. I read this three times.

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They test whether drugs work on people who don't need the drugs, to predict whether they'll work for people who do need

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the drugs, who are different people, with different bodies, taking different medications.

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Then they act surprised when the second group has a reaction.

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I would call this stupid but I think it might actually be something worse than stupid.

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Stupid doesn't usually have a peer-review process. Trials under the current system exclude: Patients over sixty-five: Most

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people who actually take medications (excluded due to "comorbidities").

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Patients under eighteen: All children (metabolism differs from adults).

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Pregnant women: Excluded entirely (then drugs prescribed during pregnancy anyway).

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Anyone with comorbidities: The sickest patients most likely to have adverse reactions.

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Anyone on other medications: Everyone elderly (can't detect drug interactions).

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Anyone too far from trial sites: Poor and rural populations.

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It's like testing whether a car is safe by driving it very slowly into a nice cushion, and then selling it to people who

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drive into walls. And when they die you say "well, it was safe when WE tried it."

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Which is true. It was. Result: In antidepressant trials alone, eighty-six point one percent of real patients are excluded.

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The drugs are tested on the healthiest people alive, declared "safe and effective," then handed to everyone the trial specifically

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avoided. Nobody knows whether the drug works for those populations, what the interactions are, or what the real adverse

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event profile looks like. This is how Vioxx, Fen-Phen, and Bextra all got approved, celebrated, prescribed to millions,

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and then withdrawn after killing people whose demographics the trials had carefully excluded.

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The eight point two years delay didn't make these drugs safer.

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It made them seem safer by hiding the danger behind an exclusion list.

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Testing drugs only on unrepresentative volunteers to prove they work is like testing parachutes only on the ground.

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The parachute worked perfectly, by the way. It just wasn't falling at the time.

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No Long-Term Outcome Data. Data collection can be as short as several months.

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You take the drug for forty years. The gap between these two numbers is where side effects live.

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Nobody checks. It's like reviewing a marriage based on the wedding.

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Pre-Specification Requirements Kill Innovation. The regulations require drug developers to predict exactly what a treatment

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will cure before testing it on humans. You must know the answer before you're allowed to ask the question.

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I asked if this was how science works and they said "it's how regulatory science works," which I think means "no, but we

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gave it the same name.". In two thousand and seven, Dendreon showed that its immunotherapy drug Provenge significantly reduced

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deaths from prostate cancer. The F.D.A. advisory committee agreed it worked.

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Then the F.D.A. rejected it anyway. Not because it didn't save lives.

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Because Dendreon filled out the wrong form about which lives it was planning to save.

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"People stopped dying" wasn't good enough. The paperwork predicting that people would stop dying wasn't filed in the right

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order. Three more years and another trial were required. During those three years, people who could have stopped dying continued

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dying, but at least the forms were correct. On Wishonia, we have a saying: "The gravestone was filed on time."

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It means someone prioritized procedure over the thing the procedure was supposed to protect.

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We retired the saying because it kept applying to too many situations.

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You could use it daily. Due to these additional costs, Dendreon filed for chapter eleven bankruptcy.

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So the approval process killed the patients, then killed the company trying to save them.

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You have a phrase for this: "killing two birds with one stone."

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Although in this case the stone was paperwork and there were considerably more than two birds.

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But you can't count the dead birds who would have been cured by a company you bankrupted.

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The Blinding Catch-22: How Knowing a Drug Works Proves It Doesn't.

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M.D.M.A. was synthesized in nineteen twelve. By the nineteen seventies, therapists were using it to treat trauma, and an

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estimated half a million doses were administered in therapeutic settings.

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In nineteen eighty-five, the government scheduled it. In nineteen eighty-six, Rick Doblin founded the Multidisciplinary

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Association for Psychedelic Studies, or M.A.P.S., to get it approved for P.T.S.D.

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Thirty-eight years and over one hundred and forty million dollars in philanthropic funding later, they ran two successful

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Phase three trials. Sixty-seven percent of participants no longer met the diagnostic criteria for P.T.S.D.

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The drug worked. Veterans with treatment-resistant P.T.S.D.

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got better. The F.D.A.'s own advisory committee reviewed the data.

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They voted nine to two that it wasn't effective. The problem: patients could tell they'd taken M.D.M.A., because M.D.M.A.

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makes you feel things, which is how it treats P.T.S.D., which is the point.

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About ninety percent of participants in the drug group correctly guessed they weren't on placebo.

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The F.D.A. called this "functional unblinding" and said it invalidated the results.

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I want to make sure I understand the logic. The drug works by making you feel profoundly different.

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The F.D.A. requires that you not know whether you feel profoundly different.

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If you notice that you feel profoundly different, the trial fails, because you weren't supposed to notice.

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The drug's mechanism of action is, itself, a protocol violation.

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This is not a fixable design problem. You cannot double-blind a drug whose therapeutic effect is that the patient feels

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it working. The F.D.A. knows this. They granted M.D.M.A. "Breakthrough Therapy Designation" in twenty seventeen, signaling

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that yes, this looks promising, please spend another seven years and tens of millions of dollars on Phase three trials.

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Then they rejected it for a property of the molecule that was evident before the trials began.

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On Wishonia, if you tell someone to build a house and then condemn it for having walls, you owe them a house.

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Here, you owe them nothing. The veterans kept their P.T.S.D.

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The F.D.A. kept its process. Everyone kept exactly what they had, which was the problem in the first place.

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Meanwhile, approximately forty-nine thousand Americans kill themselves every year, including six thousand four hundred veterans

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at twice the civilian rate. About thirteen million Americans have P.T.S.D.

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in any given year, and P.T.S.D. nearly quadruples your suicide risk.

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M.D.M.A.-assisted therapy produced a sixty-seven percent remission rate versus thirty-two percent for standard care.

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Even conservatively, if half of P.T.S.D. patients had accessed the treatment over the forty years since it was scheduled,

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the thirty-five-percentage-point improvement in remission would have prevented something on the order of thirty thousand

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suicides in the U.S. alone, and freed millions of people from a condition that destroys families, drives substance abuse,

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and fills your homeless shelters with veterans. A molecule that Merck synthesized the same year the Titanic sank is sitting

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in regulatory limbo because the people it helped could tell it was helping them.

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I looked for the word that describes letting thousands of people kill themselves each year while a known-effective treatment

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waits for someone to solve an unsolvable blinding problem, and the closest I found was "process.".

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Small Trials Are Dangerous. Phase three trials test one thousand to three thousand patients.

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A one-in-ten-thousand adverse event is mathematically invisible in a trial of three thousand.

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Then the drug goes to millions. After approval, the F.D.A. monitors safety using the F.D.A.

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Adverse Event Reporting System, or F.A.E.R.S., a system where doctors voluntarily report problems if they feel like it.

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It captures less than ten percent of actual adverse events.

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Vioxx killed an estimated thirty-eight thousand to fifty-five thousand Americans before this honor system noticed.

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That's more people than died in the entire Korean War, detected by a system that relies on doctors filling out optional

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paperwork. I want to be clear: the eight point two years delay is supposed to be for safety.

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And then the safety monitoring after approval is a suggestion box.

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You waited eight point two years to get to the suggestion box.

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A decentralized F.D.A. with ten million participants catches one in ten thousand reactions, includes real populations, tracks

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long-term outcomes, and provides automated surveillance instead of voluntary paperwork.

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You have a fax machine and a suggestion box. One of these is a safety system.

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The other is a prayer with an eight point two years waiting period.

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The Negative Results Black Hole. Here's something that would be illegal if anybody important cared: Thirty-seven percent

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of negative trial results are published. Ninety-four percent of positive trial results are published.

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Approximately one hundred billion dollars is wasted annually repeating failed experiments.

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Companies are allowed to hide when drugs don't work. Restaurants can't hide when they fail a health inspection.

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I checked this twice because I thought I was wrong, but I wasn't.

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A sandwich has more regulatory transparency than chemotherapy.

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I don't know what to do with that information but I've had it for three days now and it won't go away.

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Company: "We tested this drug!". Regulator: "Did it work?".

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Company: "...We tested this drug!". Pharmaceutical companies bury negative results deeper than Jimmy Hoffa.

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Other companies waste billions testing the same dead ends. Your insurance premiums fund this magnificent inefficiency.

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It's like casinos only having to report when people win. Actually, I think casinos DO have to report when people win.

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So drugs get less honesty than gambling. I keep finding these comparisons and they keep getting worse.

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Countries That Don't Have Our "Safety". Japan gives conditional approval after Phase Two with real-world data collection.

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Time to patient: two to three years. Americans fly there for treatment.

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The E.U. lets terminal patients access experimental drugs at a doctor's discretion.

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I asked the F.D.A. what might go wrong and they said "the patient could die."

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The patient is already dying. "Yes," they said, "but they could die differently."

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I waited for the rest of the sentence but that was it. Right to Try (U.S.) passed despite F.D.A.

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opposition. The F.D.A. made it effectively impossible to use.

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The law says you can *ask* a manufacturer for their experimental drug.

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The manufacturer can say no. They almost always say no, because the law provides no liability protection, no funding mechanism,

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and no insurance coverage. So "Right to Try" means "Right to Ask a Corporation for a Favor While Dying."

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Corporations said no. Patients helped: fewer than two hundred total.

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Patients who wanted help: tens of thousands. On Wishonia, "Right to Try" is just called "rights."

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The fact that your species needed a special law to allow dying people to take known-safe drugs, and then made the law effectively

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unusable, is the most human thing I've ever observed. You named it "Right to Try."

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The name was accurate, which was so unusual for your species that it should have been suspicious.

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And it was: the law doesn't work. The naming convention holds.

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The COVID Test Fiasco. January twenty twenty: W.H.O. develops COVID test, world starts using it.

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February: F.D.A. blocks all non-C.D.C. tests to "ensure quality."

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The C.D.C. tests were contaminated. Private labs begged to help.

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Late March: F.D.A. finally allows other tests after thousands die.

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The only approved tests didn't work. The unapproved ones did.

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The F.D.A. blocked the ones that worked to ensure the quality of the ones that didn't.

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I've written this paragraph four times now and it keeps sounding like I'm making it up, but I'm not.

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That is what happened. In order. On purpose. The Bottom Line.

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To be fair to the F.D.A., the system does eventually approve most good drugs.

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So if you think about it, the system works. Unless you were one of the people who died waiting, in which case the system

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worked slightly less well for you specifically. But you're dead, so you can't complain, which means the system has a one

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hundred percent satisfaction rate among living participants.

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That's actually quite impressive if you don't think about it.

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It is not a safety system. It is a filing system that produces corpses as a byproduct.

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The only thing missing is the political will to admit that a law signed before the Beatles existed might not be the pinnacle

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of pharmaceutical regulation. The Beatles broke up. The law didn't.

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Draw your own conclusions. Technical Analysis. For the full quantitative analysis including methodology, sensitivity analysis,

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and source data (warning: contains numbers large enough to make you physically ill), see: invisible hyphen graveyard dot

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war on disease dot org. *P.S. The F.D.A. will likely object to this chapter.

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Estimated response time: twelve to fifteen years, pending Phase Three review and proper documentation.*