
Are Placebos Really Sugar Pills? - techdog
http://asserttrue.blogspot.com/2013/01/are-placebos-really-sugar-pills.html
======
abtinf
Having worked in the pharma industry, this article is complete bullshit.

For double and triple blind (the third blind comes from not even the pharma
company knowing the blinding details until after the trial) placebo design is
an extraordinarily complex undertaking. A placebo must match the drug in
physical appearance, taste, texture, density, state (liquid/solid/gas), and
anticipated side effects. Any material difference in any of these categories
renders the trial _completely and totally meaningless_ , because at a minimum
it unblinds the doctors on the ground.

Pointing out a few random oversights out of the thousands of clinical trials
that occur every year is not proof of evil on the part of pharma; it is a
testament to the care that goes into their design. It represents a defect rate
virtually unmatched in any other industry.

But sure, go ahead and advocate irresponsible alarmism over a non-issue, as if
though drug trials aren't already expensive enough, retarding scientific
progress and costing millions of lives from drugs that would have been
otherwise developed.

~~~
jarito
I think you may have missed the point. You have stated that the article
'pointed out a few random oversights', but the actual point of the article is
that _there is no data_. How can anyone, including you, know how effective the
choice of placebo ingredients are if they aren't disclosed?

It doesn't seem an undue burden to ask that the placebo ingredients be
documented so that their effect on the study, which is critical by any
measure, can be understood. How can a separate group reproduce the results of
a study if they don't have this type of information?

What you seem to have said is - trust us. We won't tell you what's going on,
you can't evaluate how well we are doing, but this is a totally hard problem
so don't worry about it. This is disingenuous when the drug companies have
vested interests in the outcome of these studies.

If the drug companies are truly doing such a great job, then they should be
recognized for the excellent work. The only way to do that is to release the
ingredients used in the creation of placebos.

~~~
refurb
I don't think he's saying "trust us", he's saying "this is an issue that
everyone knows about, thus it's a non-issue".

When you submit a drug for approval at the FDA, you need to list in exacting
detail exactly how trials were run, including how they were blinded. The
ingredients and form of the placebo are critical for this.

The paper referenced in this blog post examined journal articles to determine
if the composition of the placebo was reported. Journal article are
notoriously lacking in details and they have to be since no one want to read
an article with pages upon pages of details.

If his comment was "Hey, you guys who write papers on clinical trials, it
would be awesome if you'd list the placebo composition, since I'd be more
likely to believe your findings" I would say "fair point".

But the blog post says "Hey! Drug companies are trying to pull a fast on all
of you! Beware of what's in your medicine cabinet" which is a completely
ridiculous statement. This "missing information" is available to the people
that matter (the FDA).

This is truly an example of making a mountain out of a molehill.

~~~
ahoyhere
> _But the blog post says "Hey! Drug companies are trying to pull a fast on
> all of you!…"_

Actually what it says is that placebo ingredients should be documented in
studies, and regulated by the FDA. Why is that such heresy? If placebos are
sugar pills, they don't need regulation. If they are designed to cause side
effects, _they are drugs_. And that will skew the results of the drug tests,
too, and as he describes in the olive oil example, not always in favor of the
drug company.

~~~
tptacek
That's not all the blog post says. Your implicit summary is inaccurate.

The blog overtly implies that drug companies use active placebos to minimize
advertised side effects, and later suggests that active placebos be outlawed.

In fact, active placebos are a requirement for drug trials, because without
them, the trial can't be effectively blinded.

~~~
ahoyhere
He doesn't simply call for active placebos to be outlawed. He lists several
problems with the current system and then says:

 _FDA needs to review its policies on placebos and either outlaw "active
placebos" or rigorously define acceptable conditions for their use._

That's like saying "The US Govt either needs to outlaw medicines OR rigorously
define acceptable conditions for their use." Which is not a statement most
reasonable people would disagree with… hence the FDA. Everybody would
obviously choose the second measure. It's a classic persuasion technique: give
an extreme choice so the other choice will seem more reasonable. It gets
attention. Nobody is going to outlaw active placebos.

As for overtly implying drug companies manipulate their results, he had a
small handful of examples and one of them is a _counter example_ where the
drug company looks to be _undermining_ its own results by using a too-good
placebo (olive oil) that made its drug look _useless_.

Finally he raises the question: If you kick people out of the study when they
improve on placebo, are you still actually testing against placebo?

How can you know, if the trials don't document what's _in_ the placebo, and
the FDA doesn't regulate it?

~~~
tptacek
I'm not sure we read the same article. The one I read said, and this is the
whole graf:

 _FDA needs to review its policies on placebos and either outlaw "active
placebos" or rigorously define acceptable conditions for their use._

That seems like a profoundly ignorant argument. The article doesn't account
for the need to blind studies. Why does it come across as credible to you?

~~~
koide
Why do blind studies need the regulation on active placebos to be non
rigorous?

~~~
tptacek
Who are you arguing with? Surely not me. But the case you're making _isn't the
case the blog post made_. The blog post suggests, with varying levels of
overtness, that there is something shady about active placebos.

~~~
koide
I'm talking about the quote you used on your comment. That quote _by itself_
does not sound particularly outrageous or ignorant.

You should have chosen a different line to illustrate how shady the author
thinks active placebos are.

~~~
tptacek
Outlawing active placebos might be a reasonable course of action?

~~~
bigfudge2
Outlawing active placebos would actually be very foolish. Up to 90% of
patients and 100% of physicians have been found to have broken blinds in
trials of tricyclics, almost certainly because of the side effects. The
original article is extremely weak in failing to address this... in fact, drug
companies really should be adding ingredients with side effects to their
placebos, but won't because it increases the complexity and reduces the
statistical power of the trials they run.

~~~
einhverfr
Agreed, so change advertising requirements. Instead of "compared to a placebo"
(which is highly misleading in this case), make the drug companies disclose
side effects differently. "In clinical trials, this drug had the following
incidents of side effects... An active placebo intended to cause anticipated
side effects had the following incidents...."

This preserves all of what you can currently get, but it frames the issue so
that the average individual does not assume that an on-par comparison means
all side effects are placebo effect.

------
refurb
This seems like a ridiculous blog post.

Only 6% of clinical studies list what their placebo was, so the conclusion
from that is that there is a concerted effort by drug companies to
unscrupulously modified the outcomes of their studies by choosing biologically
active placebos. That's a bit of a stretch.

Typically what is done for a study is that drug company will manufacture the
drug for the study in tablet form, complete with fillers and binders (inert
ingredients used to make the pill). Then they will manufacture the same tablet
without the active ingredient. The drug has to be identical in shape and color
or else the study isn't really blinded, physicians could tell that patients
were getting two different drug. That's the reason why drug companies make
their own placebos.

Also, the example of using olive oil instead of clofibrate has two possible
explanations: 1) clofibrate is soluble in olive oil so they likely gave one
set of patients clofibrate +olive oil and the other just olive oil (negating
the effect of olive oil) OR the study was just poorly done (yes it happens)
and it would be obviously to anyone familiar with clinical trials (including
the people at the FDA).

I could go on, but it doesn't really seem necessary. The article speaks for
itself.

~~~
xenophanes
They should list placebo ingredients after the trial is done so it's possible
to duplicate the trial and get the same results, right?

If you don't provide enough information in your paper to repeat the experiment
(and get the same results!!), then it's not good science. Good scientific
studies need to be repeatable and need to provide enough information to do it.

And even if people don't want to repeat the full experiment, being able to
review the details of how it was done will help them spot mistakes. You can't
have things like "peer review" without saying what you did.

So this is a serious problem, even if the rest is breathless hype.

~~~
refurb
If your argument is that journal article should include more details so that
they are reproducible, that's fine but there is no need to pick on the ones
published on clinical trials. I would say it's a rare paper that is so
exhaustive in detail that you can easily reproduce the results. Many times
I've had to contact original authors to get more details. You'd be amazed at
what gets left out.

~~~
xenophanes
Then it's a rare paper that is good science. This would not really shock me
but it doesn't make it any better.

------
tokenadult
It appears that a lot of participants on Hacker News are interested in the
role of placebos in treatment trials. I have some recommendations for
background articles on the use of placebos in clinical trials and the pitfalls
sometimes encountered in interpreting results from such trials. The articles
are all by expert authors who practice frequently writing on this topic for
general readers.

August 2009 "The Rise of Placebo Medicine" by Steven Novella, M.D.

[http://www.sciencebasedmedicine.org/index.php/the-rise-of-
pl...](http://www.sciencebasedmedicine.org/index.php/the-rise-of-placebo-
medicine/)

December 2010 "Placebo Effects without Deception? Well, Not Exactly" by David
Gorski, M.D.

[http://www.sciencebasedmedicine.org/index.php/placebo-
effect...](http://www.sciencebasedmedicine.org/index.php/placebo-effects-
without-deception-well-not-exactly/)

January 2013 "Is acupuncture as effective as antidepressants? Part 2. Blinding
readers who try to get an answer" by James Coyne, Ph.D.

[http://www.sciencebasedmedicine.org/index.php/is-
acupuncture...](http://www.sciencebasedmedicine.org/index.php/is-acupuncture-
as-effective-as-antidepressants-part-2-blinding-readers-who-try-to-get-an-
answer/)

There are many more good articles about placebos and how they are used in
clinical trials on the site where these articles come from. The issue the
blogger whose post is kindly submitted here seems so upset about is simply an
issue of making a placebo (sham) treatment indistinguishable from the
treatment under investigation, so that doctors and patients are properly
"blinded" during the trial. Another comment already posted here on HN has
pointed out that the FDA does oversee what ingredients are put into placebos,
whether or not those detailed ingredients are published in a peer-reviewed
research study. The blogger's concerns are legitimate, but not proportionate
to the actual problem.

Disclosure: I have been a subject of FDA-regulated medical trials. I was very
impressed by thoroughness of data collection in those trials, and by my
inability to distinguish whether I was receiving placebo or genuine medicine
in one of those trials. My oldest son, now a hacker for a start-up, had work
experience while in college at a medical device company, and he was impressed
that every line of computer code he wrote during his summer job was reviewed
line-by-line by FDA computer scientists as part of the review process for the
medical device he worked on.

~~~
guelo
It makes no sense that the FDA receives extra information that is not
available to peer reviewers. Why would that be?

~~~
kvb
The purpose of the FDA is quite different from that of a journal; why would
you expect the information needed for each to perform its function to be the
same? Among other issues, how much time to you expect a journal reviewer to
spend vetting a study, compared to the amount of effort that the FDA spends
reviewing the same study?

~~~
aneth4
Because how can you have peer review of a study if an essential and
complicated part of the study is not published. If only the pharmaceutical
company and the FDA review placebo technique, then the study has not really
been peer reviewed and placebo techniques are a mysterious black box.

~~~
kvb
Is placebo design actually complicated? Other posts have indicated that you
just have the manufacturer of the drug leave the active ingredient out of the
normal formulation (so that all fillers, etc. are identical). If this is an
important but well-understood aspect of study design (and ultimately vetted by
the FDA), then a reviewer's time is better spent looking at the novel or
error-prone aspects of the study.

Is there any evidence that poor placebo design is a problem in practice, or is
this a theoretical concern?

~~~
aneth4
There is probably not much evidence because that which would constitute
evidence is held effectively in secret. There is no way for the scientific
community to look for flaws in methodology. Flaws in research methodologies
are often found, sometimes years later, so it's to be expected that at least
some placebos are making studies inaccurate perhaps dangerously so, and it's
also to be expected that we will never know which studies are compromised
since the data is not published publicly.

Yes, placebo design is extremely complicated and often involves active
ingredients intended to simulate side effects and treatment experience without
treatment effects.

There is quite a bit written in the comments here.

For instance, it would be quite easy for a company to fake efficacy
accidentally or intentionally by using a placebo that inhibited natural
healing or even made the treated condition worse. The control group would fare
worse than the treated group, and the drug could advance toward the market.
There is a massive economic incentive for this sort of cheating, and I don't
think we can presume pharmaceutical companies are above economic incentives.

------
oneandoneis2
His cited example of a placebo that could skew data is olive oil, which by
reducing heart disease would make the drug appear less effective than it might
actually be.

Pointing out a study where the pharma company might have used a placebo that
made their drug harder to approve is hardly in keeping with the insinuation
that they're using placebos for "disturbing" ends.

Seems more like a case of "throw all the mud and hope some of it sticks" to
me. Sorry.

~~~
gwern
More importantly: if the tested drug can't beat olive oil on the very thing
that the drug is meant to treat, then why should it be approved at all?

(Drugs should be tested against the best existing alternative treatment, not
merely a placebo. We are not interested in whether a new drug has a non-zero
effect - but whether it is an improvement on the state of the art in some
way.)

~~~
kragen
It might be an improvement on the state of the art in some other way. For
example, a new antibiotic might be less effective than existing antibiotics,
but have no cross-resistance with them and therefore be useful in treating
antibiotic-resistant strains in the future (the magainin case), or a new
antipsychotic might be less effective than existing antipsychotics for average
patients, but more effective or less damaging for a few. Finally, you might be
able to get synergistic effects by combining the drug with the best existing
alternative treatment.

------
trotsky
This blog seems to be rather senselessly hyperbolic and misleading. For
example, it attributes an anecdote in which HIV patients are "dropping like
flies" due to lactose intolerance to the research paper it cites. According to
other sources [1] [2] the paper actually discusses a situation in which cancer
patients were administered a lactose placebo in which the author speculates
their predisposition towards lactose intolerance could have influenced the
study. The gap between the two situations could hardly be larger.

 _Certain placebos, they add, may skew results in favor of the active drug.
The researchers referenced a trial for a drug used to treat anorexia linked
with cancer in which a lactose placebo was used. Since lactose intolerance is
common among cancer patients, the fact that some suffered stomach problems
from the placebo may have made the actual drug look more beneficial._

[1] [http://articles.latimes.com/2010/oct/18/news/la-heb-
placebo-...](http://articles.latimes.com/2010/oct/18/news/la-heb-
placebo-20101018)

[2] [https://en.wikipedia.org/wiki/Placebo-
controlled_studies#Pla...](https://en.wikipedia.org/wiki/Placebo-
controlled_studies#Placebo_ingredients)

------
brunorsini
This reminded me of a very good Wired article from a couple of years ago,
"Placebos Are Getting More Effective. Drugmakers Are Desperate to Know Why" -
[http://www.wired.com/medtech/drugs/magazine/17-09/ff_placebo...](http://www.wired.com/medtech/drugs/magazine/17-09/ff_placebo_effect?currentPage=all)

------
hermannj314
From the article: _It's inconceivable (to me, at least) that there are no laws
requiring drug companies to list placebo ingredients._

From CFR 21 Part 312.23 (a)(7)(iv)(c): _A brief general description of the
composition, manufacture, and control of any placebo used in a controlled
clinical trial._ [is required to be supplied for an Investigational New Drug
Application]

What is the difference? It seems the law clearly states that for new drugs,
you must list the composition of your placebo to the FDA. It would seem the
article is mistaken. I am not a lawyer nor do I work in the pharmaceutical
industry. I just did a google search for "placebo composition site:fda.gov"

------
DanBC
Ben Goldacre says that testing against placebo is sub-optimal. You're testing
that a medication is better than nothing. What you want is a medication that
tests better than whatever we're currently using.

I don't know how that fits in with blinding everyone involved. As abtinf and
refurb mention, designing placebo is a difficult process.

And you don't need to include anything to create side-effects; people taking
sugar pills will happily report having a range of side effects.

~~~
quasque
"What you want is a medication that tests better than whatever we're currently
using."

This is also done, depends on the trial. For example, new vaccines are often
tested against the existing one(s).

------
adcoelho
This is not by any means my field of study but i do agree that placebo
components should always be disclosed in order to turn these kind of tests
more transparent.

However, how can we prove that something is 100% biologically inert? We can't
account for all the unknown effects, is there any such 'ingredient'? I guess
that at least the used placebo should be proven to not affect directly
anything directly related to the hypothesis.

~~~
rxmatic
It doesn't appear that anyone actually knows about the field here as this is
really a non-issue for a simple reason (I chose you to reply to because you
were at the bottom).

First of all, most immporant studies don't use a placebo because it would
unethical when there are standard treatments out there already and you have to
show that your new drug is just as good or better than those treatments (the
proper terms are supperior vs. non-inferior trials).

But considering trials that do use a placebo - the whole point is to prove
that their drug is superior to the placebo. If anything, when they design the
placebo, it would have structurally similar molecules that would give the same
side effects, and potentially the same results <\-- which is key. A research
DOES NOT WANT the placebo to do as well as their drug. The placebo can only
hurt their results, not help them cheat.

You could also argue that since it's not regulated, maybe the active component
does actual harm to make the test drug look better! No. There are too many
studies showing what the controlled group should look like (whether they are
on a placebo or on nothing at all).

------
acchow
As an aside, sugars aren't biologically inert either.

~~~
Florin_Andrei
So, is there _anything_ that could be said to be biologically inert in any and
every scenario?

~~~
cotsuka
Chalk?

~~~
josscrowcroft
Calcium, surely..

~~~
masklinn
Calcium can interact with a number of other chemicals, potentially negatively
(for the surrounding organism). Although doses are probably important in
judging that.

[http://en.wikipedia.org/wiki/Calcium_metabolism#Interaction_...](http://en.wikipedia.org/wiki/Calcium_metabolism#Interaction_with_other_chemicals)

------
newishuser
What this article leads me to think is that we need to legally protect the
word placebo. It seems grossly misleading to use the word placebo to describe
non biologically inert ingredients. To do so is to lie and nothing more.

~~~
wiredfool
Just look for homeopathic remedies then. Guaranteed not to have any active
ingredients.

~~~
joshuacc
That's not strictly true. Homeopathic remedies do often include small amounts
of alcohol or sugar.

~~~
hellerbarde
unless it's homeopathic alcohol :P

<http://homeopathicvodka.com/>

------
alayne
The blog title is "Are Placebos Really Sugar Pills?". Was "Or Something
Worse?" editorialized on? The thrust of the article isn't that placebos are
bad, it's that they are inert and not regulated or reported on consistently.

------
rdl
It would be interesting to do placebo vs. placebo trials (telling patient A
he's getting a specific drug and giving him a placebo instead, and telling
patient B he's getting another drug which treats the same condition, and also
giving him a placebo).

i.e. would you subjectively report more pain relief when given ibuprofen
(placebo) vs. vicodin (placebo).

But, pesky IRBs :(

------
kuenx
<http://imgur.com/a/7Vfnc>

Here are some Alzheimer placebo samples (pictures) from Pfizer, handed out to
doctors in Switzerland. Sorry for the bad quality. Pictures taken with a
phone.

------
amund
is this like saying: we use the metric system (small print: but our 0 cm point
starts at 50 cm)?

------
cooldeal
Aren't the side effects mimicked so that participants won't see the lack of
them and then know that they're taking the placebo which will defeat the
double blind study?

For example, if you're testing fish oil, you wouldn't use a sugar pill since
it's easy to know what you're taking by looking at it. You would use something
like olive oil.

~~~
pygy_
Indeed. It is well known that SSRIs studies were biased because of this,
because SSRIs have a lot of early side effects, which break the blinding.
Knowing that you're in the treatment branch increases the placebo effect.

That being said, the opacity of the manufacture process is concerning.

Studies with active placebos should have a third branch with inert placebos,
to assess the incidence of side effects.

~~~
Locke1689
That presents massive ethical issues. One would have to knowingly _not_ give
subjects a drug that we know helps them (i.e., the current standard of care).

~~~
starpilot
There are no ethical issues.

1\. Study participants are told that some of them will receive a "sham"
(placebo) treatment. Participation is voluntary.

2\. It is not known whether the drug they are testing is effective or
comparable to the current standard of care. Determining that is the purpose of
the study.

~~~
refurb
This is not correct and not currently accepted policy by the FDA.

Take oncology drugs for example. Let's say you come up with a great new drug
to treat Non-Hodgkin's lymphoma (NHL). Currently approved drugs already are
very effective, pushing overall survival to close to a decade.

If you're a drug company, there is zero chance you'd get approved (by the
independent IRB board who monitor ethical considerations) to run an NHL trial
using a placebo. Even if patients agreed to take part in the trial, it would
be unethical to deny effective treatments for a potentially fatal disease.

Hence, the FDA has softer data and efficacy requirements for oncology
therapies. There is no requirement for a placebo arm unless there is no
currently effective treatment available.

