Wednesday, January 30, 2013

Are Placebos Really Sugar Pills?

Is this really what a placebo amounts to?
Over the weekend I was reading some medical studies involving placebos. The experimental protocols were of the standard double-blind type in which a control group gets a placebo without either the group or their doctors knowing it.

One of the studies involved a medical condition for which sugar (supposedly the main ingredient of placebos) might be anything but biologically inert, and I thought to myself "Okay, certainly the doctors would know that and would choose a sugar-free placebo for the study." But when I read the study I couldn't find an ingredients list for the placebo. Maybe it was a sugar pill. Maybe not. We'll never know.

Then I started to wonder: Who makes placebos? Where do they come from? Is there a widely used "standard placebo" that scientists typically use in studies? What does it contain, exactly? And so on.

Let me skip right to the punch line. It turns out the drug companies (the very people who perform and/or fund the efficacy studies FDA relies on when granting new drug approvals) manufacture their own placebos -- and aren't required to list the ingredients.

One reason this is so disturbing is that drug companies are allowed to use (and do increasingly use) active placebos in their studies. An active placebo is one that is biologically active, rather than inert.

"But wait," you're probably saying. "Isn't the whole point of a placebo that it's biologically inert, by definition?"

You'd think so. But you'd be wrong. 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."

In a 2010 study by Beatrice A. Golomb, M.D., Ph.D. (and colleagues), published in the Annals of Internal Medicine (19 October 2010;153(8):532-535), some 150 recent placebo-controlled trials were examined to see how many of them listed placebo ingredients. Only eight percent of trials using placebos in pill form (the majority of trials) disclosed ingredients. Overall, three quarters of studies failed to report placebo ingredients.

One of the trials in the Golomb study involved a heart drug. Over 700 patients participated, so it was a good-sized study by any definition. In a subgroup of patients that had recently experienced a heart attack, the drug in question (clofibrate) was no better than placebo in extending patients' lives. But the placebo was actually quite effective, reducing the group's mortality rate by more than half. However: the placebo was olive oil. And olive oil is known to fight heart disease.

Carelessly chosen placebos can also have a harmful effect. Dr. Golomb tells of receiving a call from HIV researchers whose drug study had to be aborted because the placebo group was "dropping like flies." The placebo contained lactose. It's well known that lactose intolerance is higher for HIV patients than for the general population.

It's inconceivable (to me, at least) that there are no laws requiring drug companies to list placebo ingredients. The fact that drug companies can formulate their own placebos (some of which are biologically active) and not list the ingredients, in research aimed at getting approvals from FDA, is shocking and outrageous.

It's quite obvious that researchers (whether associated with drug companies or not) need to agree on a standard placebo of some kind (or at least standards for placebos).

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

When I say FDA needs to review its policies on placebos, I'm referring to such (ongoing) practices as letting drug companies de-enroll study subjects from studies based on individuals' sensitivity to placebos. (Drug makers usually begin a study with a two-week "washout period" during which time potential subjects take either a placebo, or nothing. Subjects who respond to the placebo can be summarily taken out of the study before it begins in earnest.)

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.

Someone, please: Pass me the Tic-Tacs.

40 comments:

  1. That's disturbing, to say the least. Unfortunately, it's not surprising given what I understand of pharmaceutical company practices.

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  2. Anonymous11:07 AM

    I agree with your premise - clearly, placebos need to be standardized and regulated.
    However, I can see why a side-effect inducing placebo would be important in a study (besides the clearly misleading purpose of using it for 'comparison' with the drug, as in your dry mouth example). It's important in a blind study that subjects not be aware if they are receiving treatment or placebo. If the treatment is known to widely induce a certain side effect, then if they had none, they might suspect they were receiving the placebo. Or, in a double-blind study, the doctors might be able to tell which group had the treatment and which group didn't leading to potential bias as well. So, basically what you meant with 'rigorous standards for the use of active placebos', just elaborating a bit :)

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    1. Anonymous12:04 PM

      It's more than that. Producing any side effect could give the patient confidence that this is really doing something therefore giving a better effect.

      Delete
    2. Anonymous1:28 PM

      There might be reasons to use certain kinds of active placebos. But there aren't any excuses for not publishing the exact contents of placebos used in the study.

      Delete
  3. Anonymous11:29 AM

    It is worth mentioning that the pill with lactose is actually a sugar pill, since lactose is a sugar ( http://en.wikipedia.org/wiki/Lactose ), even though "sugar" is generally accepted as an alternative name for sucrose.

    This is interesting, because the HIV case highilghts the necessity of having non-sugar placebo pills :)

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    1. Anonymous1:28 AM

      If you wanna get pedantic, the HIV study highlights the necessity of having non-lactose pills. I'm sure some corn syrup concoction with a bitterant would function just as well.

      "Are placebos really biologically inert" also makes for a dumb title.

      Delete
    2. No sucrose and lactose are different. Just like fructose is fruit sugar. Lactose is milk sugar.

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  4. Anonymous11:38 AM

    Do you know if the EU has similar standards viz. placebos? It would be interesting to contrast US vs. EU

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    1. Anonymous3:57 PM

      little grammar nazi input here...

      "viz" means "namely" or "that is to say". It's kinda like "i.e."

      I think you meant "vis-a-vis", which means "with regard to" or "in relation to".

      Delete
    2. Actually, 'face-to-face'

      Delete
  5. Anonymous11:57 AM

    Eu probably does or you are allowed to use fda approval as fast track process.

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  6. You'd say that from Lavoisier's times scientists would have got more careful about considering the implications of the experimentation tools (e.g. back then he found out, after centuries, that the sediment was caused not by the boiling water, but by the flask's erosion). Meh.

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    1. Anonymous4:00 PM

      You mean scientists should be aware of the paradigm within which they are working, and its implications for their results?! Madness. Madness I say.

      Delete
  7. 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.

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    1. You sure did read a lot of your own bullshit into the post, because I never said the pharma industry was evil. Did I? I mentioned actual practices that go on all the time, that can be considered disturbing (like removing placebo-sensitive individuals from a study, to skew the results in favor of a drug). Surely you're not defending such "bullshit practices"?

      Remove chip from shoulder. Just sayin'.

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    2. I wouldn't call it complete bullshit just like I wouldn't say that big pharma is first and foremost looking to help people. Big pharma is first and foremost looking to make a profit and trust me they do some shady things... As you should know among the rigors of passing a clinical double-blind study leniency also exists such as the ability to not publish study results with less than favorable results.

      But let's address the impact of active placebos... Active placebos themselves can interfere with the bodies natural healing abilities. It's why there's such thing as a natural history group but most studies don't use them... Even the active placebo that's chosen can influence the results of the placebo group... I'm pretty sure that companies will take care in not only selecting an appropriate active placebo, but also one that may produce more favorable results.

      The overall point is that there's no regulation of active placebo production and many studies don't list the ingredients of active placebos used. I think that's a very valid point...

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    3. "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."

      But: "Only eight percent of trials using placebos in pill form (the majority of trials) disclosed ingredients" (a published result in a peer-reviewed journal which you do not dispute.)

      So you seem on the one hand to be insisting that placebo design is complex and if it is done wrong the whole experiment is a washout, but on the other hand you do not conclude from this that it is absolutely critical that the detailed ingredients of the placebo used be part of the publication, including a full disclosure of its biological activities and justification for why it was selected (just like you have to justify any other experiment design choice.)

      If you're a paid shill for Big Pharma you really aren't doing a very good job, y'know?

      Delete
  8. I'm confused as to your point.

    You seem to be implying that by sneakily using active placebos, the pharma companies are "disturbingly" able to skew their data. But your olive oil example, whilst it certainly could skew the data, would also make it harder for them to get their drug approved, because it was no more effective than the placebo - I happen to know that even if a drug is completely harmless, if it's no better than placebo it won't get approval for sale.

    This article appears to me to be purely throwing every piece of mud available in the hopes that some of it will stick; rather than making an intelligent and cogent point. Sorry, I'm unimpressed.

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    1. My point was to make a call for standards in the industry, regarding placebos. Are you against that? Or are you just whining for the sake of whining?

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    2. Dominic, it is quite common for pharma companies to run trials on their competitor's products, and these trials are frequently set up to "demonstrate" that the drug does poorly. This is what immediately came to mind on reading about the olive oil trial.

      I have seen this through careful reading of published papers. Pharma companies simply hide this kind of thing in plain sight, knowing that physicians almost never read such papers in detail, even in the rare cases where they have the skills required to do so.

      Delete
  9. Anonymous1:41 PM

    Yet another "oh i just found this out and have done BARELY any research, so OF COURSE i know have the opinon that everyone else is wrong and has overlooked my great insight"


    Really?

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    1. First, don't be a whining Anonymous Coward, leave your name here if you want to be a big boy. Second, I'll pit my scientific and research background against yours if you'll be so kind as to list *your* degrees, institutions, and workplaces. This isn't a subject I came at without credentials.

      Also, I don't "have the opinion that everyone else is wrong."

      What are you, an infant?

      Delete
  10. NO question that the substantive point the blogger makes is of great importance especially if the rigor of the science so undertaken is fundamentally at question. It is like a tainted regulator or judge on the take calling into question all decisions rendered up to that point.

    However all the above not withstanding what strikes me as even more provocative is the story behind the story. One wonder is if this fundamental plank of life science and drug research can so fundamentally called into question then why hasn't it rendered it head before now in the profession and professional publications besides the recognized: In a 2010 study by Beatrice A. Golomb, M.D., Ph.D. (and colleagues)

    Could it be that a fundamental tenet has gone unexamined by the professionals and practitioners whose training would lead them to ask these key methodological questions. The fact that the drug companies might play fast and loose is not surprising. What I find surprising would be the parts that we do not know about the dissemination of this surprising fact and that we then need to infer to fill in the blanks. Beyond my own initial ignorance as to the scope of this being a known issue or not in the related fields, for the moment, let us assume, that their is a significant deficit in this regard then it becomes interesting to wonder why this is the case especially as these are significant matters of how science is conducted. The very essence of science is in its methodology and the methodology goes to the issue of the continued accreation of knowledge.

    This gives rise to my pondering about poking holes into the system and this is not an issue of faith but of epistemology. Or better said to ask what branch of science or philosophy addresses the issue of the quality and criteria of information flow through these complex systems so that one would know that there is sufficiency, comprehensibility, and recursive 'correctiveness' that demonstrates the due diligence of the methods enacted? This is outside the scope of what ends the system is directed which will more or less by definition be within the realm of normative reference i.e. fought out politically and socially.

    Could the same reasoning be applied to the enterprise of education as well as science.

    I do believe that the blog points to a lot more than some idiosyncratic oversight or fudging ploy of the drug company. Not sure where the ball was dropped but poking around to find a cause makes me think about enterprises devoted to pushing knowledge forward and the meta-questions of how it is done is provoking.

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    1. ... consider revising ...

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    2. Anonymous8:58 AM

      People who like to use big words to impress others, really should try to figure out when to use "there" rather than "their".

      Delete
  11. Ricky Bezoomny6:26 PM

    Kas, relax man. Seriously. Take a chill pill ...

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  12. Anonymous8:25 PM

    That certainly is an issue. However, the fact that the clinical studies are made by the pharmaceutical companies themselves, who have extremely high financial interest in seeing them aproved, and who can choose which ones are published or not, how they are conducted, and how the researchers are paid, is a bigger problem.

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  13. Anonymous9:02 PM

    Please consider adding sources to this post - there are a lot of claims here which are not common knowledge, it would be great to know where you learned about them.

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  14. Anonymous9:23 PM

    On the flipside, when inactive placebos are used, patients can often guess whether they are in the experimental or control groups, by noticing whether or not they get the drug side effects. In fact, there was a study done showing that without active placebos patients can guess which group they are in correctly 80% of the time.

    The basic thing here is that the drug companies keep on finding ways to stack the deck in their favor.

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  15. Anonymous11:53 PM

    Also worth noting is the work of Ted Kaptchuk et al. in discovering some stuff about why (normal) placebos actually work sometimes:
    http://www.newyorker.com/reporting/2011/12/12/111212fa_fact_specter

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  16. Anonymous12:42 AM

    The conversation on Hacker News is about 100 times more intelligent than the one happening here. Kas, good God man, don't take everything so personally.

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  17. http://imgur.com/a/7Vfnc

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

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  18. Know how I know this isn't true? Because the FDA's (Food & Drug Administration) own website debunks it..

    Just google § 312.23 and hit the first link to the FDA's (Food and Drug Administration) website listing it's CFR (Code of Federal Regulation) on what is required in new drug applications. It's a pretty long code with lot's of legalese which is why the guy probably never bothered reading it before blogging, but if you search the page for "placebo" the first thing you will find is a sentence saying you must file, among other things, the ingredients used in the placebo for the clinical trial that proves your drug is effective.

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    1. Anonymous10:33 PM

      Are you referring to this passage?:

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

      If so, it hardly seems rigorous - to say the least.

      Delete
  19. It's not computer science, people. Testing should include both types of placebos. It's important to know how a drug acts in a vacuum as well as how it reacts in real life IE alongside common side effects. If there is a notable discrepancy between how the two types of placebos reacted, then additional tests can be performed.1:12 AM

    It's not computer science, people. Testing should include both types of placebos. It's important to know how a drug acts in a vacuum as well as how it reacts in real life IE alongside common side effects. If there is a notable discrepancy between how the two types of placebos reacted, then additional tests can be performed.

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  20. Mantis Tobaggan1:13 AM

    It's not computer science, people. Testing should include both types of placebos. It's important to know how a drug acts in a vacuum as well as how it reacts in real life IE alongside common side effects. If there is a notable discrepancy between how the two types of placebos reacted, then additional tests can be performed.

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  21. homeopathy pills are also known for placebo effect.

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  22. Anonymous6:02 AM

    Mind-body healing practices should always be included in testing against the efficacy of any chemical drug. If you can meditate yourself to wellness (without harmful side effects, or great expense) why not test and put that out there as an option. We are phar too much a pharma-nation. Testing a placebo is a passive test of the mind over body effect; a more active test would be beneficial.

    --LA Rose (btw -- it's not easy to add an identity to the signoff, you are given limited choices and must have a pre-registered ID with a half dozen blog or google accounts)

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  23. Study pills are most familiar drugs which boost the students brain to improve the focus, but not intelligence.It is a good solution for ADHD disorder problems.

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  24. Anonymous8:58 AM

    I am currently in a study for an unnapproved pain medication. I have had digestive problems since starting, with little to no pain relief. I believe I have the placebo capsules. I wonder what I am ingesting.

    ReplyDelete

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