["The Charlatan," Pietro Longhi, 1757]
An act of madness occurred in Washington last week when the Food and Drug Administration metaphorically stripped itself naked and stood before us as the proud sex toy of the pharmaceutical industry.
At least this full-frontal view of its swollen, ulcerous pudenda allows us to confirm the appropriate pronouns to be applied to it: me, ours, mine-all-mine.
On June 7, the FDA
approved a new medication for Alzheimer’s disease named aducanumab, branded as Aduhelm. The approval came
as a shock to its expert panel, which had voted 8 to 1 (with 2 abstentions)
against it based on the lack of evidence that it does anything. That didn’t
seem to bother the top brass at the FDA, which had huddled with Biogen, the
drug’s peddler, to see whether the data could be resliced and diced to
demonstrate some sort of vague utility.
It’s hard to know
where to begin to dismember this appalling decision given the multiple forms of
horribleness that it embodies. To start, it offers what will probably be false
hope to desperate families dealing with the agonizing impact of dementia in a
loved one. The FDA was created in 1906 precisely to put an end to the
unscrupulous exploitation of sick people and their relatives casting about for a
ray of hope in the face of untreatable ailments. Snake-oil salesmen used to be
able to bottle up any old concoction and push it onto the panicked and gullible—now
they can again.
How could the FDA
approve a drug without solid evidence that it has at least some minimum impact
on the course of Alzheimer’s? The answer lies in that old saw about “lies, damn
lies, and statistics.” Biostatistics is a highly developed science aimed at
answering one key question: do the results of a given trial (such as testing a
new drug) constitute meaningful evidence for a causal effect—i.e., does it work?
Or are superficially promising outcomes merely random artifacts, chance events
that only appear to mean something, like flipping a coin and getting heads 8
times in a row? The logic involved is worth pausing to consider.
Statistical science
originated, not surprisingly, with gambling. If we flip a coin 100 times, we
can calculate the exact likelihood of getting heads 50 times, 60 times, or 99
times, assuming the coin is perfectly balanced and the flip is performed in an exactly
uniform manner each time. By the law of large numbers, more data points will
provide greater evidence: for example, getting heads 9 times out of 10 is
unusual but plausibly random while getting heads 90 times out of 100 suggests
that there is something wrong with the coin—meaning that we are should look beyond
chance for some other more likely cause.
Researchers
conducting a trial of a new drug will recruit thousands of patients and assign
them to either a treatment or a placebo arm, then follow both carefully to see
what happens. If the treated patients improve, they can claim success (depending
on how much improvement is observed). But one can immediately think of dozens
of ways to introduce bias and distortion into the procedures and thus the
outcomes, which good researchers try their best to be aware of and avoid.
Given the billions
of dollars that are at stake if a drug is shown to work, pharmaceutical
companies have built-in incentives to game the system by engineering favorable data.
To avoid corrupting the science, data reviewers have to be extremely rigorous
and skeptical—which the reviewers of Aduhelm were.
One way to guard
against manipulation of data is to set the parameters of what will constitute
persuasive evidence at the outset and not change the rules later to fit the
desired conclusions. But that is exactly what the purveyors of Aduhelm did:
they jettisoned the unfavorable results of one study while highlighting the one
in which their drug performed better. They also hypothesized that one of the study
arms in the favored study had a disproportionate number of patients whose
disease had already progressed beyond the point of being helped by their
medication. The FDA went along with all these mid-stream changes.
In the Journal of
the American Medical Association (JAMA), three physicians laid out the case
against Aduhelm. Two of them (Emerson and Kesselheim) were on the expert FDA panel assigned to
review the data—and resigned in protest after their counsel was ignored. They
write: “Any treatment will appear to be more effective if individuals in whom
it works least are removed from the analysis.”
In addition, one
of the two criteria utilized for demonstrating efficacy of Aduhelm was improved
scores on a provider-administered observational test of things like memory, problem-solving,
and personal care. According to co-authors Emerson and Kesselheim, Alzheimer’s researchers normally look
for an improvement of 1 or 2 points on the 0 to 18 scale as a test of efficacy;
even after all the data massaging, Aduhelm demonstrated only a gain of 0.39.
The other test was
a reduction in Beta-amyloid clusters in the brain—a mostly discredited theory about the causation of Alzheimer’s.
The consequences of
the FDA’s corrupt behavior are quite dire for the health of Medicare and for
the Alzheimer’s field generally. Some of the defenders of this disastrous
decision apparently think that tossing vast sums of public money at Biogen for
its probably useless elixir will incentivize others to do further R&D and
find something better. Dana Goldman & Darius Lakdawalla wrote an article in STAT entitled, “FDA’s
approval of aducanumab paves the way for ‘more momentous’ Alzheimer’s
breakthroughs,” a broad hint that the approved drug is mediocre at best. (The
authors also acknowledge being in the pay of Biogen.)
Patients’ families
will also rush to demand access to the new drug, especially once we start
seeing the predictable tsunami of televised ads showing smiling granddads
bouncing children on their knees and helping them sail kites. As with every
disease in every age, people will desperately try anything that offers a
glimmer of hope for alleviating their agony under the presumption that there is
nothing to lose.
Unfortunately, there is a whole lot to
lose, starting with side effects: “In two clinical trials,
about 40% of clinical trial patients who got the approved dose of Aduhelm developed
painful brain swelling, headache, dizziness, visual disturbances, nausea, and
vomiting; about 17% to 18% of patients had microhemorrhages.” Will lawsuits
follow? Will Biogen care once the bosses in its C-suite make off with
gazillions from the public purse? Will the company even exist when it’s time to
compensate those harmed?
Then there’s the vast billions that Medicare could be
forced to pony up to sustain this travesty. Even though the drug was tested
only on patients at certain stages of Alzheimer’s-related impairment, the FDA
did not limit who will
be eligible for Aduhelm treatment. Because Medicare is prohibited by statute
from negotiating drug prices, Biogen can just say the stuff costs $56,000, so
there. The price
tag for Medicare for just 500,000 patients taking Aduhelm will be $29 billion a
year.
Caitlin Owens at Axios estimated that the
new drug could “blow up health spending.” “If half of the newly eligible Americans in a year began treatment with
Aduhelm, the cost would be $14 billion—roughly equivalent to Medicare Part B
spending in 2019 on the next 8 products combined.” Vast numbers of new patients
enter the Alzheimer’s lists every year. In short, Aduhelm is Pharma’s dream
drug: an insanely expensive product targeted at a huge percentage of the
population who can live sick for years.
Bob Herman, also at Axios, adds that if the drug triggers Medicare’s “significant cost” policy, Medicare Advantage plans would be liberated from paying Aduhelm claims; that is, once people on MA plans start costing real money, they can be sent back to traditional Medicare to be covered on the government dime.
Most experts were dumbfounded at the gross twisting of scientific criteria to pander to patient advocates and line the pockets of yet another pharmaceutical company. (Stand by for news of which FDA employee has decamped to Biogen as Vice President for Government Affairs in the next 12 months.) “Science took a back seat.” “Sham.” “This decision does more than bend standards—it shatters them.” “Unconscionable.” “I won’t prescribe it.” “$56,000 for a sugar pill.”
What to make of this
shameless perversion of our research and public health establishment precisely
at a time of earnest appeals from these same highly credentialed personages to place
our trust in them and bare our biceps for the magic jab? It is impossible to avoid
the conclusion that the impulse among our governing elites to insert their
snouts into the trough of the national treasury has reached stampede
proportions. Our society has succumbed to the addictive pursuit of ill-gotten
gains to such a pathological extent that the beleaguered brain of the body
politic has begun to show clear signs of cognitive deterioration. It is no
longer capable of taking care of itself, exercising sober judgment, handling
its affairs, or functioning independently—although, as the Clinical Dementia
Rating table says for its “mild” score, the patient may “appear normal to
casual inspection.” Is it reversible?
