
People susceptible to the placebo effect may be limiting drug approvals - epistasis
https://www.washingtonpost.com/news/health-science/wp/2016/12/02/people-susceptible-to-the-placebo-effect-may-be-keeping-us-from-getting-new-drugs/
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gus_massa
Looks like someone selling snake oil to the pharmaceutics. Is the method
backed by a double blind study? [1]

From the article:

> _Winkler’s research told him that between 5 and 40 percent of psoriasis
> patients feel their symptoms are alleviated when taking placebo pills._

Between 5 and 40 is a lot of variation!

The placebo effect has many causes, you don't know witch percent of the
general population will react to the no-treatment, you don't know how the
subgroup you selected will react to the no-treatment, you don't know if just
going to the doctor once a week as part of the study will change how the
people fell, how they sleep, eat, whatever. There are too many variables, and
in a serious study it's impossible to eliminate all of them. The best second
option is a double blind control group, so you hope that whatever affect the
subject affect in approximately the same weight to the control group.

[1] Make 100 double blind studies. In half of them use the screening method to
avoid placebo susceptible people and in the other half use the usual mix of
people. But make these selection double blind, so the doctors don't know if
they are running the normal or the filtered study. Then analyze the 100
studies an see if the 50 filtered studies have more success than the 50
unfiltered.

P.S. What about if the drug is better to the people that has no the genes they
are blaming for the placebo effect, but it will kill half of the people with
these genes?

~~~
jessriedel
> P.S. What about if the drug is better to the people that has no the genes
> they are blaming for the placebo effect, but it will kill half of the people
> with these genes?

That's what the phase 2 trial is for. And in any case, you can just require a
genetic test for the drug.

~~~
gus_massa
Less extreme alternative: it's completely ineffective in the people with these
genes.

~~~
jessriedel
As I said: you can just require a genetic test for the drug

There's really nothing special about placebo effect here. Imagine a population
of patients divided into two groups, A and B, with group A smaller but
responding to the treatment much more effectively than B. Then if you can
identify members of A, you can run a study that demonstrates effectiveness on
A much easier than on B, and the drug can be approved for treatment of only
group A (at first). This happens in real life all the time.

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TillE
> In the end, the placebo response was well below 40 percent and the drug
> passed easily, but at a much higher cost than it could have.

This whole article seems like a lot of self-serving bullshit. A real drug
(with real side effects!) absolutely should be expected to perform well above
a placebo. If you can't do way better than a purely psychological treatment,
your drug is crap.

~~~
zzleeper
That would be my first thought, but that's not how it works.

If 50% of people had placebo and the drug had a real effect on 10%, then:

\- Placebo results: 50% \- Drug results: 50% + 10% * 50% = 55%

To detect a difference of 5%, you need way more people than to detect a
difference of 10%, so your testing is now costlier and possibly slower.

In the extreme, drugs that only benefit a few, or with relatively small but
real improvements, will never get tested or fail testing, because of these
placebo-folks

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fgpwd
If I have understood this correctly and the placebo effect is so strong then
maybe more research should go towards hypnosis, self hypnosis for treatment
without drugs. After all if a state of mind can cure a disease then that state
of mind itself is a valid cure if it can be replicated

~~~
costcopizza
No medical background here, but I've had that same thought myself.

I know it's completely unethical to prescribe a placebo (and I assume knowing
it _is_ a placebo erases said effects) but how nice would it be to have the
ability to experience some relief without the cost and side effects of a real
medication!

~~~
sp332
If you believe in the placebo effect, it can still work even if you know
you're taking a placebo. [https://www.psychologytoday.com/blog/all-about-
addiction/201...](https://www.psychologytoday.com/blog/all-about-
addiction/201101/placebo-even-when-you-know-its-fake)

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cortesoft
Isn't it the case that if the strong placebo response is preventing us from
determining with confidence that a drug works, the problem is with our
calculation of confidence and not the placebo effect? Placebo responders
should be equally represented in the test and control groups, so their effect
should be able to be measured. Our calculation for confidence just needs to
take them into account; we already know that our measure of stastical
significance is flawed anyway, we need better statistical models.

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reasonattlm
This is silly. Two things are limiting drug approvals.

The first is that the FDA and similar organizations are demanding ever-
increasing amounts of data and expense. The cost of drug approval has doubled,
accounting for inflation, over the past ten to fifteen years alone.

The second item is that near all drugs have limited cost-benefit ratios - they
simply don't make much of a difference. The reason for this is that most
therapies do not address root causes, but rather proximate causes. Try making
a damaged machine run better and longer without repairing the actual damage.
It isn't easy, and the results are marginal. It is the same in biology. The
reason why most therapies address proximate causes is because most research
starts with the end stage disease and works backwards down the chain of cause
and effect in cellular biochemistry in search of causes. At each new step in
the chain, typically someone tries to build a therapy. And usually fails for
the above reasons.

If a therapy provides an actual cure, no-one is standing on the sidelines
talking about placebo effects. Look at, for example, the very effective cure
for multiple sclerosis achieved through aggressive immune ablation. Is there
anyone in that situation arguing that, oh, we must account for the placebo
effect? Of course not. That would be dumb. Because the effect is very large,
very beneficial, and very robust.

The problem is that too much medical development is aiming at the outset for
results that are small, marginal, and only achieved in some patients.

~~~
briandear
The reason that so much expense has been added is that a faulty drug results
in millions of dollars in lawsuits. Litigation is one of the single largest
contributors to drug costs.

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mattnewton
Interesting article, though given the potential downsides of bad drugs in the
market I am not sure I feel a lot of sympathy for how expensive testing is.
Making the testing cheaper and easier, sure, but we should be optimizing for
the the accuracy above all else. It's not like consumers will see much benefit
from cheaper tests, I imagine the whole process is still cost prohibitive
outside of big pharma.

~~~
trhway
>for how expensive testing is.

having worked in BigCo-s i'm sure it is isn't the testing itself, it is E/S/VP
salaries and travel budget :) For the testing itself : 100 people * $1K/day *
100 days = $10M, i.e. peanuts.

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linsomniac
I've heard but I don't recall the source, that some new drugs they are working
on have an effectiveness rate lower than the placebo effectiveness rate.

There's also the Placebo Paradox: it's unethical for a doctor to prescribe
placebos, but it's also unethical for a doctor not to use a treatment that
works.

Blew my mind!

~~~
richardw
Interesting. How does a drug do worse than a placebo? Surely those who a
placebo works on will also benefit from the drug, since the placebo doesn't
disappear when the drug is real?

So an ethical doctor can just prescribe medicine. It should work through its
intended action + placebo :)

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glup
If the body is conceived of an information processing system, it seems that
one fruitful interpretation of the placebo effect is that it's some sort of
somatic top-down processing to help deal with noise and crappy sensors.
Language and vision research have come to understand that the noisy nature of
the world / our senses necessitates top-down processing (i.e, rich
hierarchical priors) in order to operate, I don't see why it would be
different for the subjective experience of health. Right now we have a rigidly
bottom-up, overly mechanistic understanding of the body, but I think as we go
forward we'll start to appreciate the complexity of the body as an information
processing entity, and move from puzzlement regarding the placebo effect to an
understanding that is an artifact of a far more powerful system that we
previously thought.

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gojomo
Isn't the answer simple?

Make a pill which prevents the placebo effect, among those susceptible to it.
Administer it just before any other placebo/non-placebo medications.

A tic-tac printed with a pharmaceutical company logo should be sufficient as
the anti-placebo-effect pill, as long as a clear explanation of its expected
effect is provided.

~~~
KingMob
Hmmm. Interesting idea, but because beliefs aren't easily conscious or
controllable, it seems unlikely a pill relying on the placebo effect to wipe
out a later placebo effect would work.

Regardless, what if high placebo responders believed they weren't high
responders (aka, "advertising doesn't affect me")? They would expect the first
pill to have no effect, and thus the second placebo would. Or what if they
expect it to wear off by the time of the second pill?

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Lagged2Death
_The team found that those with slick vacuums (about a quarter of the human
population) respond poorly to placebos while those with hinky vacuums (another
quarter of the population) respond extremely well and those with a mix (half
the population) are in the middle._

The placebo effect is well known, understanding it is fundamental to designing
a trial, and it has been studied a lot.

It strains credulity to suppose that a hard partition like this (one quarter
of humans respond weakly, period), if it existed, would not have been
discovered long ago. You wouldn't need to find genes or proteins or any of
that stuff, you'd just need to check if placebo response in individuals is
reasonably consistent over time.

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gwern
"Genetics and the placebo effect: the placebome"
[https://www.gwern.net/docs/nootropics/2015-hall.pdf](https://www.gwern.net/docs/nootropics/2015-hall.pdf)
, Hall et al 2015

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anngrant
Placebo is a psychological phenomenon, and if it makes people feel better, so
let be it. I believe that most of our problems are in our head. You know, my
granny takes vitamins and she believes those are pain relief pills. She
suffers from bad headaches. And they do work for her!!! Btw, let me share with
you a website I get any medication I need for cheap - [http://www.rx-
discountcoupons.com](http://www.rx-discountcoupons.com) .

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chiefalchemist
"A former biotech executive believes he may have the key to do just that.
Gunther Winkler first developed a dislike of the placebo effect in the late
1990s. As head of clinical operations for the pharmaceutical giant Biogen, it
was his job to help choose which new drugs to invest in and shepherd them
through the trials that would prove their effectiveness and clear them with
the Food and Drug Administration for approval."

Gee. I wonder why he didn't like it? Perhaps it called into question his self-
annointed genius?

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chiefalchemist
Question: is the placebo effect factored into the effectiveness of the real
drug? That is, knowing a placebo effect is real, just because I took the drug
doesn't mean I actually responded to it. The drug could have been ineffective,
and my response was more placebo based?

I presume the conventional wisdom is to give the drug the credit but
technically that feels incorrect. Or is this factored in? If so, how?

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Dowwie
Gimlet Media's "Science Vs" latest podcast is about the efficacy of
antidepressants and the placebo effect: [https://gimletmedia.com/show/science-
vs/](https://gimletmedia.com/show/science-vs/)

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kingkawn
those people and their damned unmodelable imaginations getting in the way of
progress

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ranprieur
Could we make a drug that makes everyone highly susceptible to the placebo
effect?

~~~
shrikant
My brain hurts trying to imagine how this drug would undergo a DBRCT.

~~~
groovy2shoes
Easy. You set up a double-blind experiment in which the constituents of a
random sample of the population are randomly assigned to one of two groups:
experimental group or control group. You administer the experimental group the
new drug (dammit, now I've got Huey Lewis and the News stuck in my head...),
while the control group gets a placebo. You then administer both groups
further placebos, and measure their response to those placebos.

