Are Placebos Really Sugar Pills?(asserttrue.blogspot.com)
asserttrue.blogspot.com
Are Placebos Really Sugar Pills?
http://asserttrue.blogspot.com/2013/01/are-placebos-really-sugar-pills.html
137 comments
As an aside, sugars aren't biologically inert either.
So, is there anything that could be said to be biologically inert in any and every scenario?
A quote from the press release about the paper the OP cites:
But, according to the paper's author, Beatrice Golomb, MD, PhD, associate professor of medicine at the University of California, San Diego School of Medicine, this standard has a fundamental problem, "there isn't anything actually known to be physiologically inert."
http://www.sciencedaily.com/releases/2010/10/101018174335.ht...
But, according to the paper's author, Beatrice Golomb, MD, PhD, associate professor of medicine at the University of California, San Diego School of Medicine, this standard has a fundamental problem, "there isn't anything actually known to be physiologically inert."
http://www.sciencedaily.com/releases/2010/10/101018174335.ht...
Probably not, but disclosure of placebo ingredients would be enough to determine if it was a wise choice for a particular study.
Chalk?
It has antacid properties.
Cellulose as well? Dicalcium phosphate is also a common tablet filler, though I don't know if it's biologically inactive.
Calcium, surely..
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_...
Everybody consumes a huge amount of sugar every day, so the pill is not even measurable compared to your normal intake.
So on average the effect of this small amount of sugar disappears.
So on average the effect of this small amount of sugar disappears.
Unless you're studying something related to blood sugar, insulin, etc or the user has a condition impacted by sugar, such as diabetes, a small amount of sugar (pills would contain 100-1000mg) isn't going to have any impact.
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.
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.
There are certainly ways to simulate fish oil with biologically inert ingredients.
I think you're missing the point. He was talking about this section of the article:
>That way, of course, they can say things in their ads like "[drug name] has a low occurrence of side effects, such as dry mouth, which occurred about as often as they did with placebo."
cooldeal point is that you need to mimic the side effects to make the control group believable. Whether it is needed to use inert components or not would depend on the nature of the drug in test.
>That way, of course, they can say things in their ads like "[drug name] has a low occurrence of side effects, such as dry mouth, which occurred about as often as they did with placebo."
cooldeal point is that you need to mimic the side effects to make the control group believable. Whether it is needed to use inert components or not would depend on the nature of the drug in test.
There are? What do you have in mind? If you use mineral oil or Olean, you get diarrhea as a side effect in doses of more than a few grams per day.
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.
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.
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).
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.
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.
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.
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.
These issues are already present. You already know that some population of the participants are getting a placebo. You don't know which ones, which possibly dulls the anguish you might feel over it.
I think at best you could say it would amplify already present ethical issues.
I think at best you could say it would amplify already present ethical issues.
The "placebo" mostly is the current standard of care in many cases.
Perhaps the real problem the article should hone in on is that drug companies are (allegedly?) permitted to compare side effect rates to that of the "placebos", when the public will undoubtedly not be aware that the placebos used were manufactured to provide those same side effects.
incidence of side effects can frequently be judged by comparing to incidence rates in the general population. This is indeed how Phase I trials are done to gauge the safety of the molecule and decide what side effects need to be emulated by the placebo in later clinical trials.
I think you're correct. The example given in the linked article mentions dry mouth, but it's arguably important in double-blind studies to have both the controls and test groups develop similar side effects, to prevent both the patient and the administering physician from determining which is the placebo group. I don't think it's entirely due to nefarious motives from the drug company.
>both the controls and test groups develop similar side effects, to prevent both the patient and the administering physician from determining which is the placebo group //
If the physician can effect the trial by knowing to whom they're administering the placebo it seems that the trial lacks in its design. Someone else said that the person administering the drug/control could repeat a test because they felt the result was wrong - why is such a person involved in a drug trial? If they lie about that then it seems they can pervert the trial any number of ways.
How do the patients know how the other members of the study are being affected? If they don't get a dry mouth, but the drug company thinks they should, how does the patient know?
Surely you need the physicians and patients to record exactly what happened, no more and no less.
It seems that you're doomed to fail if you don't know that this is what's happening: suppose you use an active control that dries the mouth (for 95% of patients), if you don't have the side-effect with the drug on test then you know you're part of the active group with a high enough confidence level to alter the results in a qualitatively similar way to using a non-active control (placebo).
So what you need is a placebo that matches exactly the profile of the side-effects of the drug. I'd warrant that's impossible - you don't know the side-effects of the drug that are expected in a wide scale longitudinal study because that's what you're testing isn't it?
What is entirely nefarious is any use of "no significant side-effects beyond that experienced under placebo" when in fact they don't mean placebo but "active-control".
Placebo may be synonymous with active control in Pharma circles but it's not in common usage and so this is still a fraud.
If the physician can effect the trial by knowing to whom they're administering the placebo it seems that the trial lacks in its design. Someone else said that the person administering the drug/control could repeat a test because they felt the result was wrong - why is such a person involved in a drug trial? If they lie about that then it seems they can pervert the trial any number of ways.
How do the patients know how the other members of the study are being affected? If they don't get a dry mouth, but the drug company thinks they should, how does the patient know?
Surely you need the physicians and patients to record exactly what happened, no more and no less.
It seems that you're doomed to fail if you don't know that this is what's happening: suppose you use an active control that dries the mouth (for 95% of patients), if you don't have the side-effect with the drug on test then you know you're part of the active group with a high enough confidence level to alter the results in a qualitatively similar way to using a non-active control (placebo).
So what you need is a placebo that matches exactly the profile of the side-effects of the drug. I'd warrant that's impossible - you don't know the side-effects of the drug that are expected in a wide scale longitudinal study because that's what you're testing isn't it?
What is entirely nefarious is any use of "no significant side-effects beyond that experienced under placebo" when in fact they don't mean placebo but "active-control".
Placebo may be synonymous with active control in Pharma circles but it's not in common usage and so this is still a fraud.
True. Just a happy side effect for the advertising in that example.
Also, I'm not a huge fan of more regulation, but scientific integrity seems to demand the placebo ingredients be disclosed.
From the discussion, it seems clear the doctor-scientists have to think about and carefully consider what to use for the control. A single, simple answer cannot work.
Also, I'm not a huge fan of more regulation, but scientific integrity seems to demand the placebo ingredients be disclosed.
From the discussion, it seems clear the doctor-scientists have to think about and carefully consider what to use for the control. A single, simple answer cannot work.
Is it not possible that, via whatever mechanism placebo drugs have positive intended effects, that they could also cause side effects?
Placebo effect is not a 100% effective substitute for the real deal. If the drug makes you pee more, you could convince yourself of that. If the drug makes your pee turn purple, that'd be harder to achieve just by willing it to happen.
This is a straw man example. Headaches or sinus pressure may be a better way to explain your point.
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.
Actually, I think "Placebo" has always meant "a thing used to make not taking a drug an indistinguishable experience to taking it" (which, it turns out upon reflection, requires it to inflict side effects). Inertness is just a popular misconception.
That said, I think capitalizing on that misconception is wrong and that it might be reasonable to take actions which prevent true but subtle statements like "drug had similar side-effects to a placebo" from misleading laymen.
That said, I think capitalizing on that misconception is wrong and that it might be reasonable to take actions which prevent true but subtle statements like "drug had similar side-effects to a placebo" from misleading laymen.
Just look for homeopathic remedies then. Guaranteed not to have any active ingredients.
That's not strictly true. Homeopathic remedies do often include small amounts of alcohol or sugar.
unless it's homeopathic alcohol :P
http://homeopathicvodka.com/
http://homeopathicvodka.com/
Not everything that claims to be homeopathic actually is. One example is Traumeel. If you look at their ingredients ( http://www.traumeel.us/Products/ProductDetail.aspx?id=190100... ), there's enough active ingredients that are only 1X diluted that the total is over .5% active.
I assume it's just labeled as homeopathic because they failed to fake some clinical trials to get FDA approval (or didn't even try), but maybe it's actually an effective marketing choice.
I assume it's just labeled as homeopathic because they failed to fake some clinical trials to get FDA approval (or didn't even try), but maybe it's actually an effective marketing choice.
is this like saying: we use the metric system (small print: but our 0 cm point starts at 50 cm)?
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...
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.
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.
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).
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).
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.
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.
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.
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.
This is a bit dense with legalese, but if you search for placebo it would seem to indicate that it /is/ required that they disclose placebos ...
"(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...
"(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...
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.
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.
This was discussed 2 years ago here: http://www.doctorslounge.com/index.php/news/pb/14946
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. :)
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. :)
Journal articles are short because journals have limited space. In the year 2013, this is no longer a relevant issue. Just add appendices, online only if necessary, covering placebo composition and other details so that people who want to dive deep can.
I'm a little late responding to this, but there are good points here. It seems like a good compromise might be to have the FDA release the details of the trials / placebo ingredients. That way they can be mapped to the studies that used them (assuming the studies don't just start documenting them). That might be happening already, I don't work in the field, so I don't know.
Anyway, I found this comment useful. Thanks for replying.
Anyway, I found this comment useful. Thanks for replying.
> 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.
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.
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.
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.
Everything else aside, it should be illegal to advertise that your drug "has similar side-effects to placebo" if the placebo has active ingredients deliberately intended to cause the side effects.
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.
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.
Their takeaway is the same one I got, so perhaps you are reading it differently than we are? The piece I read was alarmed that a very important detail can only be found in 8% of the studies they examined and wondered what's up with that.
"and later suggests that active placebos be outlawed."
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..."
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..."
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?
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?
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?
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?
Why do blind studies need the regulation on active placebos to be non rigorous?
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.
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.
You should have chosen a different line to illustrate how shady the author thinks active placebos are.
Outlawing active placebos might be a reasonable course of action?
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.
I take the sentence to mean "If there are no rigorous controls in place on active placebos, they should be outlawed" which doesn't sound unreasonable.
The blog post author may have used the idea of outlawing active placebos as a "door in the face" to make regulating them seem more palatable. At the least, it seems koide is interpreting the second suggestion as having more weight, while you are focusing on the first.
I don't think it would be a reasonable course of action. However, I do think that as long as they are relatively unregulated, a much better approach would be to limit inserts and advertising descriptions on the incidents of side effects to absolute proportions, not comparing side effect proportions to those on active placebos intended to mimic expected side effects.
How can you know, if the trials don't document what's in the placebo, and the FDA doesn't regulate it?
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?
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?
> And that will skew the results of the drug tests, too,
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.
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.
>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.
Why not?
Why not?
because people have olive oil already...
Well, you are assuming they cannot be combined.
That would be a completely different study. You can't make any claims about the effect of a&b if you've only studied a|b.
"This "missing information" is available to the people that matter (the FDA)." - That's right, I'm just too unimportant and stupid to be trusted to look at this stuff, also when the issue a lot of people are having is not being able to trust big pharma and the FDA, well hiding stuff isn't going to fix that.
Yes, I was being a bit dramatic for impact.
Yes, I was being a bit dramatic for impact.
"but the actual point of the article is that _there is no data_"
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).
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).
> (...) 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.
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.
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.
Agreed the article is bullshit. However getting the issue 100% backwards the author actually raises an important point. Active placebos do make for a different comparator than inert placebos --- arguably a much better one. Given that north of 90% of patients and doctors have been found to correctly guess allocation in blinded trials of tricyclic antidepressants and other antipsychotics, it might actually help to add something to the placebo which does generate side effects to make it harder for people to pick which group they are in.
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.
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.
Not necessarily true; The veil of ignorance can be induced for doctors, if some care is taken. Direct psychological effects of the pill's appearance on patients can't be measured, but the effect of the doctors spoiling the study based on that certainly can.
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.
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.
> A placebo must match the drug in physical appearance, taste, texture, density, state (liquid/solid/gas), and anticipated side effects.
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.
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.
"A placebo must match the drug's ... anticipated side effects" --- that's what he is saying too. Placebos are not inert as I had been assuming till date. And then comes the after story...
I encourage you to post that in the comments on the blog itself. There are already comments saying "thank you for this" and "placebos should be regulated" and whatnot. Maybe I'm overly optimistic, but I believe it would be useful to have your comment close to the article text (instead of having to scroll down) to provide balance.
I was about to write something similar. Thanks for formulating it so eloquently. I think it's this part that trips up some people:
> [...] 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.
> [...] 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.
The effects of unblinded doctors can be catastrophic and might not even be discovered.
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.
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.
"The doctors had found a way to determine which patient was receiving which drug." - This implies that they consciously tried to bypass their blindness, physical design of the pill being different would do this sure, but that's not an issue with too much disclosure, that's an issue with people either A) Not doing their job well enough(the pill designers) OR B)Trying to find out which one so they could fudge the results.(Crooked Doctors? Yeah, less disclosure will fix that right up.)
Your argument here basically questions the whole idea of blinded studies ("Who cares if doctors will figure out which medication is the placebo?", it suggests; "After all, that only matters if doctors are crooked.")
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.
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.
I don't mean more disclosure to the doctors on the pills, if that's what you thought, which I'm only assuming because I wasn't attempting to question the validity of clinical trials at all. I was saying given the language the person I was replying to used, it seemed like the doctors were actively trying to figure out what which pills were which, evidenced by the fact that instead of going "dang, we accidentally figured it out and now are susceptible to bias. We should start the trials over right NOW instead of wasting money" They went, lets retest these patients since the outcome isn't coming out like we think it should, something they should know isn't going to fly.
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.
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.
You're attributing to malice what is more likely stupidity. Doctors with patients on experimental trials want the drugs to succeed. They expect the drugs to succeed. That impacts their evaluations.
If I were a doctor participating in a study like this, I'd have a really hard time not trying to figure out who had the drug and who didn't. It's a secret; humans love secrets, and a doctor is extremely well-suited to figure this one out.
Of course we can't know who is telling the truth since ingredients on placebos are not disclosed. That's the part I think is the meat of the issue.
>That's the part I think is the meat of the issue.
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?
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?
You've missed the point.
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.
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.
Yes. If a placebo has active ingredients, you have no chance to replicate the study if you can't tell what those active ingredients are. And if you can't replicate a published study from the details given in the paper, then it's not a scientific study, it's bullshit. Yes, that's right, it's bullshit. And yes most studies fall into this category. Can't be replicated, shouldn't have been accepted for publication in the first place.
OK, but what do you measure the results against then if you distorted the benchmark with active ingredients? Surely the entire point of the control group is that it represents the unaltered baseline?
This is a common misconception.
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.
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.
You're describing an active-control trial, not a placebo-controlled trial. In a trial of drug A (current standard of care) vs. drug B (new agent), there will usually be 2 placebos involved. Participants will be randomized to receive drug A + placebo B or, conversely, placebo A + drug B. Typically the manufacturer of each drug is in the best position to produce an identical appearing placebo for each pill.
What moioci said. I don't believe
> "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.
> "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.
Why does the placebo complexity make a call for regulation and study disclosure "utter bullshit"?
Again: it didn't simply call for "regulation" and "disclosure". It overtly accused pharma companies of using active placebos for marketing purposes, of haphazardly endangering participants in trials, and then later suggested that the whole concept of active placebos might reasonably be outlawed.
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.
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.
While the article might have pulled a few cheap shots at pharma companies, the point stands. We need disclosure of this incredibly complex placebo matching methodology (for lack of a better term), at minimum because the experiments cannot be replicated by a third party without it.
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.
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.
Do we know if it hasn't been disclosed in FDA filings (which are way more detailed), or just that it was disclosed in these research articles? Journal articles are meant to be terse for readability, and standard placebo techniques are just the sort of thing I would expect to be left out.
So didn't you just state that a placebo needs to cause side effects?
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!
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!
Not all side effects are equally negative. Some negative side effects are acceptable and ethical.
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.
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.
Everything is poison by nature. Everything has negative side effects.
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.
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.
>>That's a bit of a stretch.
Can you imagine an "active placebo" for LSD, THK, methamphetamine (for example) ?
"Placebo" must be a potent psychedelic or stimulator itself.
"Placebo" must be a potent psychedelic or stimulator itself.
I'd probably go for 2C-T-7 directly against LSD (but ending the trial after ~4h; after 12+ hours, it would be obvious who had taken what), but I could easily imagine psychedelics as a class having a common effect.
I think that amphetamine has been used as a placebo for LSD in some studies. I've also heard of researchers using threshold doses of the psychedelic as the active placebo. This is probably the best option most of the time.
It's interesting, but amphetamine and LSD are tooo different,
I can imagine amphetamine as placebo for MDMA, but not for LSD.
I can imagine amphetamine as placebo for MDMA, but not for LSD.
Not playing in the conspiracy here, but the lack of transparency is concerning. I know the weight and complexity of the process of designing a clinical study, and I don't doubt that, in most cases, the placebos are well crafted.
However, I'm sure that, in some cases there are oversights in the placebo choice (we do make mistakes), and we don't know which ones.
There are also big financial stakes, and pharmaceutic firms are known to cheat while attempting to bring drugs to the market. The burial of negative studies come to mind.
However, I'm sure that, in some cases there are oversights in the placebo choice (we do make mistakes), and we don't know which ones.
There are also big financial stakes, and pharmaceutic firms are known to cheat while attempting to bring drugs to the market. The burial of negative studies come to mind.
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.
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.
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.
Then it's a rare paper that is good science. This would not really shock me but it doesn't make it any better.
Even above duplication, it's important to document what's in the placebos because these clinical trials are used by the FDA to approve the drug for consumer use… or not.
so the conclusion from that is that there is a concerted effort by drug companies to unscrupulously modified the outcomes of their studies
Did we read the same blog post? The author didn't claim any such thing. In fact, he referenced a study where (if you ascribe intent) it sounds like the drug company was undermining itself by using a placebo that worked better than the drug (the olive oil).
His actual conclusion, for non-readers, is:
Placebos aren't documented, and they're not included in studies, and many times they're active in causing side effects deliberately and yet they're barely regulated -- "current anarchy" -- and this casts doubt on the validity of studies.
His call to action sounds pretty reasonable to me:
> FDA needs to review its policies on placebos and either outlaw "active placebos" or rigorously define acceptable conditions for their use.
Did we read the same blog post? The author didn't claim any such thing. In fact, he referenced a study where (if you ascribe intent) it sounds like the drug company was undermining itself by using a placebo that worked better than the drug (the olive oil).
His actual conclusion, for non-readers, is:
Placebos aren't documented, and they're not included in studies, and many times they're active in causing side effects deliberately and yet they're barely regulated -- "current anarchy" -- and this casts doubt on the validity of studies.
His call to action sounds pretty reasonable to me:
> FDA needs to review its policies on placebos and either outlaw "active placebos" or rigorously define acceptable conditions for their use.
>> so the conclusion from that is that there is a concerted effort by drug companies to unscrupulously modified the outcomes of their studies
> The author didn't claim any such thing.
Actually, the author did claim any such thing:
> Active placebos are designed to mimic the side-effects of drugs under study. So for example, if a new drug is known (or thought by the drug company) to produce dry mouth, the drug company might use a placebo containing ingredients that produce dry-mouth. That way, of course, they can say things in their ads like "[drug name] has a low occurrence of side effects, such as dry mouth, which occurred about as often as they did with placebo."
The author here is accusing drug companies of using active placebos to make the side effects seem less critical, when there's no evidence of that presented.
> The author didn't claim any such thing.
Actually, the author did claim any such thing:
> Active placebos are designed to mimic the side-effects of drugs under study. So for example, if a new drug is known (or thought by the drug company) to produce dry mouth, the drug company might use a placebo containing ingredients that produce dry-mouth. That way, of course, they can say things in their ads like "[drug name] has a low occurrence of side effects, such as dry mouth, which occurred about as often as they did with placebo."
The author here is accusing drug companies of using active placebos to make the side effects seem less critical, when there's no evidence of that presented.
>might use
I feel like the author just provided an example how the drug companies could be exploiting the fact that they do not have to disclose the information about the placebo, not necessarily accusing them of it - I know I wouldn't think of this immediately (especially sleepy me right now).
It is, I agree, unnecessarily alarmist, but the conclusion is true regardless of whether the drug companies are doing that.
I feel like the author just provided an example how the drug companies could be exploiting the fact that they do not have to disclose the information about the placebo, not necessarily accusing them of it - I know I wouldn't think of this immediately (especially sleepy me right now).
It is, I agree, unnecessarily alarmist, but the conclusion is true regardless of whether the drug companies are doing that.
I'd argue these are the main points of his blog posts. Or at least the ones he emphasized.
Active placebos are designed to mimic the side-effects of drugs under study. So for example, if a new drug is known (or thought by the drug company) to produce dry mouth, the drug company might use a placebo containing ingredients that produce dry-mouth. That way, of course, they can say things in their ads like "[drug name] has a low occurrence of side effects, such as dry mouth, which occurred about as often as they did with placebo."
and
The current anarchy that prevails with regard to placebos calls into question the reliability not just of drug-company research but of virtually every placebo-controlled study ever done. Which is a hell of a thing to have to say, or even think about. In fact it's nauseating.
Sounds to me like he's saying drug companies are manipulating the outcomes of studies and implying that any study containing a placebo shouldn't be trusted.
Active placebos are designed to mimic the side-effects of drugs under study. So for example, if a new drug is known (or thought by the drug company) to produce dry mouth, the drug company might use a placebo containing ingredients that produce dry-mouth. That way, of course, they can say things in their ads like "[drug name] has a low occurrence of side effects, such as dry mouth, which occurred about as often as they did with placebo."
and
The current anarchy that prevails with regard to placebos calls into question the reliability not just of drug-company research but of virtually every placebo-controlled study ever done. Which is a hell of a thing to have to say, or even think about. In fact it's nauseating.
Sounds to me like he's saying drug companies are manipulating the outcomes of studies and implying that any study containing a placebo shouldn't be trusted.
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.
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.
"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).
This is also done, depends on the trial. For example, new vaccines are often tested against the existing one(s).
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-...
[2] https://en.wikipedia.org/wiki/Placebo-controlled_studies#Pla...
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-...
[2] https://en.wikipedia.org/wiki/Placebo-controlled_studies#Pla...
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.
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.
Also: The placebo effect is stronger if the placebo used has side effects. Again this works AGAINST drug companies.
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.)
(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.)
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.
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"
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"
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.
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...
December 2010 "Placebo Effects without Deception? Well, Not Exactly" by David Gorski, M.D.
http://www.sciencebasedmedicine.org/index.php/placebo-effect...
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...
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.
August 2009 "The Rise of Placebo Medicine" by Steven Novella, M.D.
http://www.sciencebasedmedicine.org/index.php/the-rise-of-pl...
December 2010 "Placebo Effects without Deception? Well, Not Exactly" by David Gorski, M.D.
http://www.sciencebasedmedicine.org/index.php/placebo-effect...
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...
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.
It makes no sense that the FDA receives extra information that is not available to peer reviewers. Why would that be?
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?
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.
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?
Is there any evidence that poor placebo design is a problem in practice, or is this a theoretical concern?
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.
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.
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.
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.
i.e. would you subjectively report more pain relief when given ibuprofen (placebo) vs. vicodin (placebo).
But, pesky IRBs :(