I've always been fascinated by the
placebo effect and the ethical issues
associated with use of placebos in research.
A correspondent in the IRBForum email discussion group
asked about the recent efforts of drug companies to identify patients who are
likely to show a placebo effect and then exclude them from randomized trials.
Here are some excerpts from a June 18 article in the Wall Street Journal (I
couldn't get free access to this article on the web).
Many antidepressant trials fail because the
placebo effect can be so powerful and highly variable. Somewhere between
30% to 50% of patients in depression trials get better when given fake
pills, and that number has increased and become more volatile over time,
making it more difficult to prove that a drug works. In comparison, only
about half of patients taking antidepressants find their symptoms relieved
by 50% or better.
"The placebo response has plagued psychiatric
clinical trials," says Steven Paul, head of research and development at
Lilly. If drug companies could sort out the placebo responders, it "would
greatly help us in the short term in drug development."
But some clinical-trial experts worry that
excluding placebo responders to facilitate drug development could lead to
the approval of ineffective drugs. Kay Dickersin, a Brown University
professor who teaches courses on clinical trials, says such winnowing
"allows bias to enter in" and constitutes "a subtle manipulation" of trial
results.
The companies dismiss the criticism that they
will use the information to gain approval of ineffective drugs. They say
the techniques would be used only in early trials, not for trials done for
FDA approval.
This is a classic example of the tension between
internal validity and external validity. Heterogeneity in the study
population leads to a loss in precision. So drug companies, in an effort to
show efficacy in the most economical way possible, want a nice homogenous
sample.
This isn't just with regards to placebo responders.
They want a sample where everyone complies with the medication. After all,
it's hard to show efficacy in a population where half the people forget to
take their pills.
They also try to exclude troublesome patients,
patients with comorbid conditions or who are taking other medications that
might interfere with the drug being studied. This often leads, by the way, to
an unfair exclusion of elderly patients from studies even though they are
often the target market for the drugs being studied. Older patients are
almost always going to have several things go wrong with them at once, and
they are the ones with frequent flier cards at the local pharmacy.
Once you get a nice squeaky clean sample, all is well
and good for that particular comparison, but can you really extrapolate the
results to patients that you would normally see in your practice? Do you have
the option of saying "I won't treat you because I think that you are unlikely
to take the prescriptions as directed"? Can you refuse to treat a patient
unless they have only the one illness that you are trying to treat?
It seems to me that you should probably start with a
nice clean sample and exclude all those troublemakers. After all, if you
can't show an effect in a small trial with a clean sample, what's the point
in running a larger pragmatic trial?
Of course, when the small trial with a clean sample
shows up significant, you still need to look at the larger trial with a more
heterogenous population.
By the way, I get nervous when people try to hitch
their wagon to the so called placebo effect. I don't think these drug
companies will have much effect in excluding placebo responders. In many
studies the placebo effect is intermingled with other effects, such as the
tendency for some diseases to resolve spontaneously. What's the old
saying--if you don't get treatment for your cold it will last for seven days,
but if you treat it aggressively it will be gone in a week.
Other effects like the cyclical nature of some
diseases and the regression to the mean would not disappear when placebo
responders were excluded. The placebo effect might also just be the greater
level of care and attention that patients get in a randomized clinical trial.
Just getting someone to visit a doctor regularly will probably help that
person's health in a lot of small ways.
I attended a talk about hypnotherapy and I asked the
speaker afterwards about the placebo effect. He argued that the effect of
hypnotism WAS the placebo effect, because the placebo effect was the mind's
ability to control the body. I guess he wasn't familiar with the Hrobjartsson
and Gotzsche review in the 2001 NEJM that showed that the placebo effect was,
for the most part, no different than an unblinded "no treatment" arm.
- Is the placebo powerless? An analysis of clinical trials comparing
placebo with no treatment. Hrobjartsson A, Gotzsche PC. N Engl J Med
2001: 344(21); 1594-602.
[Medline]
[Abstract]
[Full text]
[PDF]
