In the yesterday’s JAMA (and captured by today’s new media), cardiologists from Cleveland Clinic, Ohio, called for revoking the approval of a new diabetes drug–Pargluva® (muraglitazar), a dual alpha/gamma PPAR agonist.
PPAR, the abbreviation for peroxisome proliferator-activated receptor, has been extensively examined in biomedicine. PPAR gene is an upstream gene family including alpha, gamma and delta. Through various ways, PPAR can activate fat storage in adipose tissue, stimulate fat oxidation (burning fat) in muscles, and other fat related activities. In short, PPAR genes are thrifty genes which facilitate fat utilization and storage, thus reducing free fatty acids in the blood, increasing insulin sensitivity, and improving lipid profile. They are fine tuned by our millions of years of evolution.
One should note that there are drugs available to activate either PPAR alpha or PPAR gamma such as thiazolidinediones. The novelty of the new drug is to activate both alpha and gamma. However, this time, things get a little bit out of control.
In the JAMA paper, in spite of the limited access to the original data, Dr. Steven E. Nissen and the coauthors managed to pool publicly available documents to compute risk ratios. They warned that the potential risk for combine heart disease and stroke was too folds among the new drug group than among the control group (placebo and thiazolidinediones combined), with a p value of 0.04.
Awakened by the Vioxx mishap (also exposed by Dr. Nissen), clinicians and patients alike are more vigilant to the new drugs. Indeed, the accompanied JAMA editorial summarized eight sins many drug companies may use to favor themselves:
1. 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)
2. Conducting underpowered studies increasing the failure rate to detect meaningful safety differences (ie, maximizing rather than minimizing type II errors)
3. 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)
4. 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 published)
5. 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)
6. Recording outcomes only in patients who are fully compliant with prescribed treatment because this selfselected group will likely have fewer adverse events (eg, unknown impact of the nonanalysis of the 15% discontinued cases)
7. 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)
8. 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.
I would add another sin most people commit—misusing statistical models in favor of the positive results.
More than a third elderly will have type II diabetes during their life. Treating diabetes is also becoming more and more aggressive. However, without the full knowledge of new drugs, patients are nevertheless life time guinea pigs. Adverse outcomes are the price we have to pay. The question is how we can protect these experimental human subjects.
This, I have to say, beyond science and morality.
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Comment by cuntlips — March 22, 2006 @ 4:42 am