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Byetta has had a tough past few days. A lawsuit by a Virginia man alleges that the drug caused his life-threatening bout of severe pancreatitis, and there are rumblings from the U.S. Food and Drug Administration that it may force Byetta's makers to attach a "black box" warning to its container and packaging-a stern, highlighted caution about potentially dangerous, even fatal, side effects.
Both events indicate that the glow may be coming off Byetta (exenatide), which has been hailed since its introduction in 2005 as one of the most powerful and effective type 2 diabetes treatments ever developed, thanks to its weight reduction and A1c percentage-lowering capabilities.
But even as some try to make the case that Byetta might be linked to severe pancreatitis that has led to two deaths, the drug's makers and proponents have taken the FDA to task for allegedly misusing statistics and taking an overly cautious approach.
What Has Been Happening
Virginian Victor Deleon's lawsuit against Amylin and Eli Lilly, Byetta's co-marketers, is seeking restitution for damages from pancreatitis he says was brought on by his use of the drug. Deleon, who was hospitalized for pancreatitis last December, alleges that the companies failed to adequately test and monitor Byetta's potential side effects or to state them forcefully enough on the drug's warning labels.
Deleon came down with the disease, a painful inflammation of the pancreas that can lead to internal bleeding and even death, just weeks after the FDA ordered Amylin and Lilly to provide stronger cautions to prescribers and users that Byetta could be a factor in the onset of pancreatitis.
At the time, the FDA was responding to reports that Byetta usage was suspected in the onset of 30 cases of pancreatitis. Even though that number was miniscule when compared to the number of Byetta users-conservative estimates say 700,000-the form of the disease being reported, hemorrhagic pancreatitis, was more severe than the normal affliction. In hemorrhagic pancreatitis, unlike normal pancreatitis, acute inflammation destroys pancreatic cells and can lead to a patient's death.
On August 18, some time after it had directed Amylin and Lilly to beef up Byetta's warning labels, the FDA announced that it had received news of six more cases of possibly Byetta-related pancreatitis, including two of which the patients had died. As result, the agency indicated that it is considering asking for a "black box" warning label on Byetta that spells out potentially fatal side effects from taking the drug.
Byetta's Defenders Weigh In
Amylin and Lilly weighed in on the controversy on August 26, 2008. In a teleconference with news media, the companies said that since 2006, the prescribing information for Byetta has included information about pancreatitis. "The companies were aware of the pancreatitis cases referenced in the alert, as well as others, and previously reported these cases to the FDA," they said in a press release that preceded the conference.
The co-marketers also pointed to a recent study that said patients with type 2 diabetes run nearly three times the risk of developing pancreatitis as those without diabetes.
David Kliff, publisher of the Chicago-based Diabetic Investor newsletter, mounted a blistering attack on the FDA, questioning its statistics and competence in the matter. He cited the FDA's August 18, 2008, statement that there was no indication of causation between acute pancreatitis and Byetta and that the events were "rare and uncommon."
"Has the FDA ever heard of something called a statistically relevant sample size or incidence rate?" Kliff asked in an e-mail update on the controversy to his subscribers. "Do they understand the concept that patients with diabetes are at an increased risk of pancreatitis?"
He accused the agency of being "hypersensitive to any possible issue after Rezulin, Avandia, and Vioxx-just to name a few of the agency's more recent blunders. Rather than fully investigate and follow their mission to use evidence-based medicine, the FDA overreacted."
He called the agency's actions "careless" and said that the people who will be hurt the most are diabetes patients and their physicians. "Once again government bureaucrats drop the ball and it lands where it does the most damage. Even if the FDA did the unthinkable and actually issued some sort of statement clearing Byetta, the mercury is already out of the thermometer. They cannot undo the numerous press reports on their action or change public perception."
Kliff said he considers it "highly unlikely" that the FDA will require a black box warning for Byetta.
Other Woes: A Threat to Byetta LAR and Questions About Weight Loss Effects
Aside from theoretical links between Byetta and pancreatitis, another potential problem for the drug is whether its users can sustain the often significant weight loss many of them enjoy once they begin using it. The Financial Times of London quotes an article from Pharmawire, "Amylin's Byetta: physicians remain skeptical of drug's real-world benefit," in which some researchers question the drug's weight-loss efficacy beyond a year or two.
However, other doctors and scientists quoted in the article say that a current study that hints at Byetta's loss of weight-control effectiveness is based on too small a sample. They say it will take more than the three and one-half years the drug has been on the market to ascertain its real usefulness as an agent in long-range weight loss.
Possible Effects on Byetta LAR
The suspicions lodged against Byetta by the FDA may come to bear against its long-term version, Byetta LAR, a once-weekly injection that is now in late-stage FDA-approved trials.
Although Amylin has reported no cases of pancreatitis associated with Byetta LAR, a potential problem with the drug is that its active agent remains in patients' systems long after they have ceased taking it. If that agent were later proven to be a causal factor in the onset of pancreatitis, it would have a dampening effect on the long-term drug's marketability.
What Are the Odds?
If a link can be established between Byetta and pancreatitis, what are your chances of developing the disease if you are currently one of the 700,000 people taking the drug?
If the 36 reported cases of pancreatitis reported to the FDA can be linked to the use of Byetta, it means that out of 700,000 people taking the drug, 1 in 19,444—5/1,000ths of 1 percent—have come down with the condition.
(If you use David Kliff's figure of "nearly 800,000" Byetta users, the number of people who may have come down with pancreatitis because of using the drug is 1 in 22,222.)
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