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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 -----Original Message----- From: [log in to unmask] [mailto:[log in to unmask]] Sent: Tuesday, March 13, 2001 11:12 PM To: [log in to unmask] Subject: Re: Qoute from Warner-Lambert about Rezulin 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.