Thursday, July 5, 2012

The Placebo Effect (No Placebo Necessary)

4 out of 5 non-doctors recommend starting
with "regular strength", and titrating up from there...
(Photo from
The modern clinical trial’s Informed Consent Form (ICF) is a daunting document.  It is packed with a mind-numbing litany of procedures, potential risks, possible adverse events, and substantial additional information – in general, if someone, somewhere, might find a fact relevant, then it gets into the form.  A run-of-the-mill ICF in a phase 2 or 3 pharma trial can easily run over 10 pages of densely worded text.  You might argue (and in fact, a number of people have, persuasively) that this sort of information overload reduces, rather than enhances, patient understanding of clinical trials.

So it is a bit of a surprise to read a paper arguing that patient information needs to be expanded because it does not contain enough information.  And it is yet even more surprising to read about what’s allegedly missing: more information about the potential effects of placebo.

Actually, “surprising” doesn’t really begin to cover it.  Reading through the paper is a borderline surreal experience.  The authors’ conclusions from “quantitative analysis”* of 45 Patient Information Leaflets for UK trials include such findings as
  • The investigational medication is mentioned more often than the placebo
  • The written purpose of the trial “rarely referred to the placebo”
  • “The possibility of continuing on the placebo treatment after the trial was never raised explicitly”
(You may need to give that last one a minute to sink in.)

Rather than seeing these as rather obvious conclusions, the authors recast them as ethical problems to be overcome.  From the article:
Information leaflets provide participants with a permanent written record about a clinical trial and its procedures and thus make an important contribution to the process of informing participants about placebos.
And from the PR materials furnished along with publication:
We believe the health changes associated with placebos should be better represented in the literature given to patients before they take part in a clinical trial.
There are two points that I think are important here – points that are sometimes missed, and very often badly blurred, even within the research community:

1.    The placebo effect is not caused by placebos.  There is nothing special about a “placebo” treatment that induces a unique effect.  The placebo effect can be induced by a lot of things, including active medications.  When we start talking about placebos as causal agents, we are engaging in fuzzy reasoning – placebo effects will not only be seen in the placebo arm, but will be evenly distributed among all trial participants.

2.    Changes in the placebo arm cannot be assumed to be caused by the placebo effect.  There are many reasons why we may observe health changes within a placebo group, and most of them have nothing to do with the “psychological and neurological mechanisms” of the placebo effect.  Giving trial participant information about the placebo effect may in fact be providing them with an entirely inaccurate description of what is going on. Bishop FL, Adams AEM, Kaptchuk TJ, Lewith GT (2012). Informed Consent and Placebo Effects: A Content Analysis of Information Leaflets to Identify What Clinical Trial Participants Are Told about Placebos. PLoS ONE DOI: 10.1371/journal.pone.0039661  

(* Not related to the point at hand, but I would applaud efforts to establish some lower boundaries to what we are permitted to call "quantitative analysis".  Putting counts from 45 brochures into an Excel spreadsheet should fall well below any reasonable threshold.)

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