Normal Limits

"Chance is the very guide of life"

"In practical medicine the facts are far too few for them to enter into the calculus of probabilities... in applied medicine we are always concerned with the individual" -- S. D. Poisson

October 23, 2005

JAMA - Effect of Muraglitazar on Death and Major Adverse Cardiovascular Events in Patients With Type 2 Diabetes Mellitus

In the Pipeline's Dr. Derek Lowe has a interesting post on this. He noted that in the FDA briefing document submitted by GlaxoSmithKline, a noticable association of CV adverse effects could be seen.

His suspicion was confirmed when JAMA rushed out the current article which points out the true magnitude of the CV adverse effect. The accompanying editorial explained that CV risk estimate was diluted by the inclusion of low-dose (hense low-risk) groups. It also points out some other potential sources of bias:

- Selecting a study population unlikely to have adverse outcomes but nonrepresentative of potential future users (eg, exclusion of elderly patients, even though more than one third of type 2 diabetes occurs in this group)

- Conducting underpowered studies increasing the failure rate to detect meaningful safety differences (ie, maximizing rather than minimizing type II errors)

- In contrast to efficacy determinations, reporting individual rather than composite safety outcomes to decrease the likelihood of establishing statistical significance (eg, separate cardiovascular events from CHF)

- Limiting preapproval peer-review publication of results so as to minimize scrutiny and debate of both methods and results (eg, of all submitted data only 1 study of 340 patients has been published8)

- Evoking biological implausibility of safety concerns by the use of surrogate measures (eg, treatment reduces C-reactive protein [CRP]) implying safety, despite no proof that CRP reduction is clinically correlated with improved safety)

- Recording outcomes only in patients who are fully compliant with prescribed treatment because this self-selected group will likely have fewer adverse events (eg, unknown impact of the nonanalysis of the 15% discontinued cases)

- Ignoring the totality of the evidence by excluding consideration of confirmatory safety signals seen in studies of similar molecules (eg, CHF and bladder cancer outcomes with pioglitazone)

- Diverting attention to unproven but potential benefits by concentrating on reductions in surrogate laboratory values (eg, hemoglobin A1C) rather than in meaningful patient health outcomes.

Very intersting....

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