[lou_lou]

http://www.forbes.com/2007/05/21/fda...ech_newsletter

Avandia a diabetes medicine is proven to give heart attacks to it's users...

This is a must read~

if you are able watch the Forbes video!!


http://www.forbes.com/video/?video=f...s&boxes=custom


Avandia
Open-Source Drug Safety?
Matthew Herper 05.22.07, 6:00 AM ET


In fall 2005 and again in August 2006, GlaxoSmithKline shared shocking news with the Food and Drug Administration. When 42 different studies of its diabetes drug Avandia were combined, the drug appeared to raise patients' chances of having a heart attack by 30%.

More than a million Americans take Avandia every year; the risk Glaxo had found would mean thousands of extra heart attacks. But the company argued that the risk only occurred in patients who already had serious heart problems, and that it didn't show up in long-term clinical trials. The FDA made no decision, and no public statement.

Monday morning the New England Journal of Medicine released a study by Steven Nissen, chairman of cardiology at the Cleveland Clinic. Without knowing about Glaxo's own analysis, he had plowed forward with his own evaluation. Using Google, he found a Web site on which Glaxo listed all of its clinical trial results. He looked at 42 clinical trials, and counted the number of patients who had heart attacks.

The patients who got the medicine were 43% more likely to have a heart attack, and 64% more likely to die. Nissen's conclusion mirrored the one Glaxo had found in its own study. While he admits that there are problems with smashing different studies together, he is concerned. "It really is very serious," he says.

Nissen sent the results to the New England Journal of Medicine, which rushed to publish them. The FDA said in a statement that it didn't know if there the data should change the way patients are treated, but would convene a panel of experts to weigh the risks and benefits of the drug. Timothy Anderson, an analyst at Prudential Equity Group, predicts the result will at the least hurt Avandia sales as patients switch to competing medicines from Merck and Takeda.

This story has repeated again and again over the past six years. An independent doctor assembles all the available data on a drug or medical device, and finds it dangerous. Vioxx was among the first drugs felled this way (Nissen co-wrote that analysis.) J&J's Natrecor, for heart failure, saw its sales plummet after to cardiologists called its safety into question. Pargluva, from Bristol-Myers Squibb, was never approved after such an analysis. It was an analysis of published clinical trials that raised the first big questions about drug-coated stents causing heart attacks in rare cases.

Now, this kind of pharmaceutical vigilantism is set to become the order of the day. Both houses of Congress are expected to pass laws that tweak the way the FDA monitors the safety of new medicines after they are approved. Many of the most radical changes, like a proposal to restrict TV ads and a push from Grassley to set up a separate FDA division to monitor side effects, didn't make it into the Senate version. But the bill would compel drug firms to make all of their data available on public Web sites. That, in turn, would let academic watchdogs like Nissen troll for side effects more easily.

It's an open source approach to drug safety.

Some doctors already say that the safety conclusions drawn from such analyses don't necessarily help them decide how to treat their patients. "It's great that they're identifying a potential problem, but to have it as a lead article in the New England Journal is not sensitive to the consequences" for patients who might stop taking their medicine, says Stuart Weiss, an NYU endocrinologist. James Underberg, an NYU cardiologist, complains that drug safety experts are too eager to use studies to answer questions they were not designed to answer.

But drug safety experts say that the problem is that this is the best data available--and that the FDA, because of lack of authority to force drug firms to do anything, has not been able to mandate large studies that would answer safety questions. "This is the best data we have right now," says Bruce Psaty, a drug safety expert at the University of Washington.

The FDA's ability to track drug side effects is "a joke," says David Nathan, a diabetes drug expert at Harvard Medical School who reviewed Nissen's paper. " What Steve Nissen did was appropriate and clever." Adds Curt Furberg, from Wake Forest University: "In the U.S., we don't take action. Drugs are approved and then we discover problems down the road."

GlaxoSmithKline says it disagrees strongly with Nissen's analysis, and with the criticisms being leveled by Grassley and other legislators. It points out that it did share its meta-analysis with regulators both in the U.S. and in Europe--although it declines to comment on the timing of those meetings. And the company says big clinical trials it conducted show no cardiovascular risk.

But the very clinical studies Glaxo is using as its defense are the ones that Nissen says inspired him to look into Avandia's heart side effects in the first place. He also argues that it is not clear all this secrecy is actually helping drug makers in the long run.

Avandia works by hitting a drug target called the peroxisome proliferator-activated receptor (PPAR) gamma. PPAR gamma is one of three PPAR receptors, master switches on the cell surface that control muscle growth, metabolism and the processing of fat and sugar. The first of these PPAR receptors was discovered 17 years ago, and for a long time many researchers, including Steve Nissen, thought drugs designed to hit them might prevent heart attacks.

But a drug that trips a PPAR switch fires up dozens of genes, and side effects for these medicines have proved unpredictable. The first PPAR drug, Rezulin from Pfizer, was pulled from the market in 2000 because of liver side effects. More recent entrants from Bristol-Myers and Eli Lilly have also failed because of side effects. (Nissen did the analysis that showed problems with the first, and the clinical trial of the second.)

Over the past six years, Nissen says, drug firms have started testing 50 drugs that work much like Avandia. Not one has made it to market. If the results of all those failures had been shared, not buried, it's possible that drug companies would have spent a lot less time, brainpower and money on experimental medicines that were never going to work.

[lou_lou]

What was Merck thinking -I bet it was money!
do they really care if the drugs harm us or kill us??




Pharmaceuticals
What Was Merck Thinking?
Matthew Herper, 04.13.07, 10:45 AM ET


Merck's earnings are surging, and it keeps winning battles related to Vioxx lawsuits. So why did the company bother with the quixotic effort to get its Vioxx sequel, Arcoxia, approved, especially at the risk of further tarnishing its image?

Merck kept insisting that its attempt to get approved its painkiller Arcoxia, designed years ago as a follow-up to the then-successful Vioxx, at least had a chance. But when a panel of outside experts convened by the Food and Drug Administration voted on whether Arcoxia deserved to be sold in the U.S., it delivered a resounding "No." The final tally: 20 to 1 against the pill.

In hindsight, Merck's decision to ask the FDA to even consider Arcoxia is baffling. The original FDA application for Arcoxia was pulled in 2002. Two years later, Merck decided to yank Vioxx from the market because it increased the risk of heart attacks and strokes. Arcoxia eases inflammation. Like Vioxx, it was designed to do so while causing fewer ulcers than older drugs, but those benefits are in question.

Merck decided to push forward with Arcoxia after the results of a big study comparing its cardiovascular risk with Voltaren, or diclofenac, from Novartis. But even as those results were released, it was pretty evident that study wouldn't satisfy Merck's critics. They were out in force poking holes in the results even before the study emerged.

The fact that Merck pushed forward despite criticism had some critics nervous. In an interview before the panel met, Steven Nissen of the Cleveland Clinic, one of the more prominent Vioxx critics, worried that there weren't enough cardiovascular experts on the FDA's 21-person panel.

Warren Wexelman, of Maimonides Medical Center in Brooklyn, banned Vioxx at his institution before it was withdrawn; he was unconvinced by Arcoxia. "Why should I think Arcoxia is any safer than Vioxx coming from the same group of people?" Wexelman asks.

By pressing the issue, Merck aroused all the drug safety concerns it had previously raised by withdrawing Vioxx, just as Congress is starting to talk about reforming the drug safety system at the FDA. The Arcoxia decision has probably made it more difficult for any new pain drug to be approved. There are 20 other arthritis pills already available, including ibuprofen, naproxen and diclofenac. Now the FDA and one of its panels have delivered the charge that new drugs must be better or safer than these old options.

That doesn't bode well for Novartis, which is hoping to launch its Prexige in the U.S. someday, or indeed for any new arthritis pain treatment. This is emblematic of the drug industry's larger problem: It is getting increasingly hard to invent new treatments for conditions like high blood pressure or arthritis pain, where the pills we have are pretty good.

"We've moved a long way from the era when the bias was to approve even when there were questions of safety," says Nissen. "It's getting harder and harder to find new drugs that are clean. The easy new drugs to develop have been developed."

The FDA's new message: just providing another option is no longer good enough. This way of thinking could even raise problems for Pfizer, which is currently running ads emphasizing that its Celebrex shares the same safety labeling as other, older arthritis medicines. Some experts argue the drugs are not alike; naproxen, for instance, seems to be safer for the heart than other options.

With Arcoxia, Merck is failing to get its own new drug approved while at the same time dredging up all the bad feelings that came from Vioxx. What is especially strange about this is that, in other ways, Merck is doing great.

Its sales keep beating Wall Street expectations. Last night, after the Arcoxia ruling came in, Merck raised its earnings outlook for the year by 10 cents, to between $2.75 to $2.85 per share, excluding items. The main reason seems to be cost restructuring and the success of diabetes drug Januvia and cervical cancer preventative Gardasil.

On the news, Goldman Sachs raised its rating on Merck from "sell" to "neutral." Analyst James Kelly noted that Merck has dealt with big patent expirations "in a superior manner to other industry participants."

And Merck keeps winning Vioxx cases. It has a winning record in court and has gotten thousands of cases dismissed. This morning, the company said that a New Jersey judge had dismissed a much-watched case filed by investors against the company. Merck still faces tens of thousands of suits, and it is far from out of the woods. But so far, so good.

So why did this company, which had better things to do, press forward with Arcoxia? Merck says it thinks the drug represents a good option for patients, and it will continue to sell it in the rest of the world.

Shares of Merck were up more than 7.6% to almost $50 in early trading this morning.