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.

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.

and here: http://pharmastrategyblog.com/2010/10/whats-in-placebos-who-...

But all three article (including the Topic) seem to focus on the Journal articles and neglect to write anything about the reports to the FDA. I'd be really interested in more info on that.

EDIT: I have no opinion nor info about the quality of the links i posted, I just found them through cursory duckduckgoing. So beware, they might both be total cranks. :)

Anyway, I found this comment useful. Thanks for replying.

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.

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.

The claim as made by the ads indicates to the average rational person that taking the drug has no higher chance of side effects than simple sugar pills. The reasonable conclusion for anyone who would be willing to take sugar pills is that this medication is safe, when in fact it easily might not be.

And to repeat my point just made in another comment all of it based on "Over the weekend I was reading some medical studies involving placebos.....then I started to wonder..."

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?

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?

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

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.

The idea behind this statement is similar: if the FDA actually pre-commits to a policy saying "either we're going to figure out a huge set of requirements for publishing placebo composition data [huge hassle for us, honestly] or, if we haven't done that by January 2015, no more active placebos"--well, suddenly the drug companies are breathing down the FDA's neck to get those requirements drafted so they can comply with them before it's too late.

But these are accusations made by a man who admits he had never heard of active placebos until a few days ago. He's reading reports that are summaries of the trials and apparently concluding that since the summary doesn't include the ingredients of the placebo then they're undocumented and not regulated by the FDA. How does he know that?

No, that's the entire point of placebos. Placebos are not supposed to be absolutely nothing they are supposed to account for all manner peripheral effects and determine efficacy.

The idea is to test your treatment against something that should have no or very low effectiveness. It's fine for them to be drugs and it's fine for them to have an effect - there's a name for that: placebo effects. People tend to get this confused with the well known "the placebo effect", but that is not the only effect placebos are intended to control for.

The example you point to is dubious to me. The study seems to be working as intended: if you have a drug that doesn't work better than olive oil - you don't have a useful drug.

We're talking about a cholesterol drug here, and it's not that the drug didn't do what it was supposed to do - control cholesterol - better than olive oil; it didn't improve mortality (for a specific subgroup)...something you'd expect with cholesterol control however that doesn't mean it's not effective in it's primary objective.

In fact Clofibrate was taken off the market for precisely that reason; it's effective in lowering cholesterol but it has side effects which lead to increased mortality.

I'm all for increased transparency in placebo use; but this article seems to have done little to clear the confusion about what placebos are and what they are intended for.

Why not?

Yes, I was being a bit dramatic for impact.

According to the OP whose is (just checked) a tech evangelist at Adobe. Additionally the sum of their research is "Over the weekend I was reading some medical studies involving placebos".

What I'm seeing is that someone wrote something (the OP) and made some statements and additionally pointed to one journal article (which I'm sure only a few HN'ers have even bothered to click through and glance at.)

This is interesting to discuss and that's it (at this point at least).

"(a) A sponsor who intends to conduct a clinical investigation subject to this part shall submit an "Investigational New Drug Application" (IND) including, in the following order:

...

(c ) A brief general description of the composition, manufacture, and control of any placebo used in a controlled clinical trial."

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRS...

Once the placebo has been designed to 'match the drug in physical appearance, taste, texture, density, state (liquid/solid/gas), and anticipated side effects' it should still be described in the final paper.

I agree. I think the main issue the author wants the reader to take away is that since the ingredients in placebos are not disclosed, what's to say they can't add ingredients that will skew the results? I'm not saying that this happens, but what is stopping them? They obviously have financial, and other, incentives for their drugs to succeed, so why not take that extra measure to maintain integrity in studies that use placebos?

Another reason for disclosure is the ethical risk assessment. What is to prevent a misguided executive from arranging a placebo with minimal doses of active components that produce adverse effects... just to push the results of a marginally effective drug. I am sure that 99.9% of people in the industry would not do that, but there is no reason to avoid putting checks and balances in place, for the day when some random sociopath decides to push it a little bit and get away with it.

> [...] at a minimum it unblinds the doctors on the ground.

It's very important that the person administering the drug/monitoring the patient can not tell the difference.

There was one study where a drug was designed to improve motor response in patients with retarded motor skills. The doctors had found a way to determine which patient was receiving which drug.

So when it came time for the doctors to measure efficacy of the drug, they would do the motor skills test. If the patient was on the actual drug, and didn't show improvement, the doctors had a tendency to say things like "Well, that can't be right. Let me run the test again."

Disaster. Hundred million dollar trial down the toilet.

But you're replying to a comment that lays out a scenario in which 8-9 figure clinical trials were ruined by the incidental outcome of reasonable honest doctors accidentally unblinding studies.

Also not saying specifically that it was malice, but that it's either malice or stupidity, or both.

Also, I have ethical and intellectual standards of doctors doing things that will impact hundreds of thousands of people.

Not sure why you said "Who cares if doctors will figure out which medication is the placebo?" - Since I didn't even insinuate that.

Isn't testing a vital part of this development, and by extension a crucial part of what you call scientific progress? The fact that we need more and more sophisticated testing techniques is because we understand more about the intricacies of human body and the ways it can interfere with treatment process. Placebo is an obvious example of such interference.

To me, calling a scrupulous testing process a factor that's retarding scientific progress is like saying QA is retarding software progress.

It always made me laugh reading about 'double blinded' trials of cannabis extract for MS... In this and many other cases the blind is a complete fiction.

In fact, there are very few studies in which patients receive an "inert" placebo.

Consider a new drug that claims to treat heart disease. It would be obviously immoral to say, "we are going to take drugs away from the control group and give them sugar pills instead".

So a "Placebo" is usually the current standard-of-care, which might be a very powerful drug.

This works because we are not at all interested in the absolute effectiveness of a drug; we are only interested in whether or not it is better then the current alternatives.

> "Placebo" is usually the current standard-of-care

is correct, either as popularly understood or as actually used during drug trials. Instead, "Placebo" is a device to make the experience of not taking a drug identical to taking a drug, which means both that it's a physical pill and that it causes the appropriate side effects.

Doctor hands patient sealed opaque pill blister pack, tells them to take two, nurse watching on a CCTV or via webcam sends a text message that they've verified the patient taking the pill.

This makes the following statement: "When compared to a placebo, this drug had rare incidents of the following side effects..." translate as "We guessed correctly at the incidents of side effects before we started the trials," correct?

If so, then that's false advertising.

The post we're commenting on made a series of outlandishly ignorant assertions.

That there are reasonable challenges we might make to the way active placebos are handled does not make the article better. You're a great writer. Maybe you should write a good article on the perils of undisclosed/underdisclosed active placebos? Because this particular article doesn't appear to be good.

Doesn't that mean that it's poison by nature if said side effects are negative?

Screw wanting to take part in that.

"Here's a pill that will cause oily discharge and nothing else" Yum!

Let's take DMSO as an example. Treatments with DMSO leave a particular garlic-like taste in the mouth. This is a negative side-effect. But DMSO is not a poison during normal treatments any more than ethyl alcohol is a poison.

A good placebo for DMSO would have the same side-effects as otherwise a patient and perhaps even the doctor could tell the difference based on taste/smell compared to the anticipated taste/smell. I believe this still isn't possible, which makes testing DMSO difficult. One solution, for example, is to look for a dose-response curve, which is a more complicated signal to extract.