The
issue is that some of these effects are not obvious in the pre-approval process
in spite of thousands of patients participating in trials. These trials
are powered for efficacy and rare side effects may not be apparent until the
agent is used widely. Remember that the oral hypoglycemic agents were
associated with increased mortality in the university group study in the 70s but
people continued to use them (the trial had some problems) and the controversy
continues (in spite of UKPDS, another less than good RCT). I remember that
in September of 1998 Michael Berger suggested that sulfonylureas should not be
used outside of clinical trials!! So here we are, using them, using
glitazones, and apparently not causing much harm.
Clinicians operate in some areas with very little evidence to guide them
(clinical paralysis is a bad side effect of misinterpreted EBM). Waiting
for evidence to become available before using a drug or a new technology remains
the best strategy, but historically this has only been possible and pertinent
with a few drugs (beta blockers for heart failure, alendronate for osteoporosis)
and not with many others (aspirin, digoxin) and I think the main reason has been
the FDA approval process forcing trials to be conducted before launching of meds
into the market. Anyone knows the ratio of approved to rejected
drugs?
By the
way, a person that has been part of a panel in the FDA once told me that the
evidence available for FDA scrutiny is orders of magnitude larger than that
released to the medical community in publications (I am not talking here about
plain and simple publication bias) - is there some loophole in the industrial
secret protection legislation that will allow this federal agency to
publish their own analyses of drug data to public domain? Any
thoughts?
Victor
In a message dated 3/13/01 2:31:00 PM Pacific Standard Time,
[log in to unmask] writes:
The important question is not so much whether
the treatment
is significantly more likely to cause raised liver enzymes
than placebo
(it is!) but how harmful to patients these raised liver
enzymes are
compared to the benefit they might get from the treatment.
Hello,
I agree with
Toby Lipman. But as physicians here in the US who embraced
Rezulin
without a single POEM (Patient Oriented Evidence that Matters) that
Rezulin improved important clinical outcomes, we bear some blame for the
nearly 400 people (as I understand the number to be) who died from
troglitazone induced liver failure. We assumed that an improvement
in serum
glucose (the only benefit ever demonstrated for troglitazone) was
more
important than a worsening of liver enzymes. Yet no one's life
was saved by
troglitazone's capacity to lower serum glucose, while many
lives were claimed
from its capacity to damage the liver. And we
have not learned. No POEMS
support the use of pioglitazone or the
other glitazone. Yet they are in
widespread use. If we as
clinicians DEMANDED POEMs before utilizing new
medicines the tragedy of
troglitazone would never have happened.
