FDA will reveal on Friday the data it is reviewing ahead of an advisory panel meeting about the safety of the popular diabetes drug.

The meeting, scheduled for July 13 and 14, comes on the heels of two new studies suggesting that Avandia may cause serious or even life-threatening heart problems — and a third study that seems to show just the opposite.

In type 2 diabetes, the body loses the capacity to metabolize glucose — sugar — in the blood. High blood sugar can lead to severe complications. Avandia was approved in 1999 after trials by GlaxoSmithKline (then known as SmithKline Beecham) showed that it could lower blood sugar, by improving the body’s own ability to process glucose.

The tide turned in June 2007, when Dr. Steven Nissen, a respected heart expert at the Cleveland Clinic, published a meta-analysis — a paper looking at all the available research on Avandia — and concluded that the drug not only failed to prevent heart disease in diabetics, but actually raised the risk of heart failure and increased the risk of heart attacks by 43 percent.

Confusion and controversy ensued, along with scrambling on the part of Glaxo. In a series of meetings, e-mails and public statements — detailed in a Senate report released in February — GlaxoSmithKline fought to clear the name of its popular drug. There were allegations of pressure, both public and private, on researchers. And there was the expedited publication of a major clinical trial known as the RECORD study, which compared Avandia with two older diabetes drugs — metformin and sulfonylurea — and found no link to heart problems. A more complete version of theresults was made public last year.

RECORD, however, did not include enough patients — or find enough heart problems — to reach a definite conclusion. Critics, unmollified, accused Glaxo of putting business goals ahead of good science. The Senate report cited internal company documents and dismissed the RECORD study as a marketing tool “to limit competition from Actos,” a competitor’s drug.

A spokeswoman for GlaxoSmithKline says the company welcomes a full airing of the evidence. Dr. Murray Stewart, vice president of clinical development, said in a phone interview that the FDA will need to consider the “totality” of evidence, not just the meta-analyses. According to Stewart, “All the clinical trials show no increase in mortality” when Avandia is compared with other drugs.

A closer look reveals that concerns similar to those raised by Nissen date back to the 1990s. In 2000, the advocacy group Public Citizen successfully petitioned the FDA for a stronger warning label, based on studies in animals before the drug was approved.

Nissen said the FDA should have acted long ago. “There are no unique benefits for this drug that are not provided by other diabetes medications,” he said in a phone interview last week. “I want the FDA to order the company to withdraw the drug. The evidence is there, and it’s been there a long time. It’s a matter of having the political will to do it.”

The FDA would not comment prior to its document release, but such sweeping statements anger Dr. Alan Garber, a diabetes specialist at the Baylor College of Medicine in Houston. Garber has been an investigator on two major clinical trials of Avandia, with funding from GlaxoSmithKline, as well as from the National Institutes of Health and other sources. He says neither study found an increase in heart attacks, although he agrees that patients with heart failure should not take Avandia. Garber says those trials, along with the RECORD study, offer good evidence that Avandia is effective as well as safe for most patients.

“This drug offers the most durable glucose control of anything,” he said. “The more you reduce glucose, the more you reduce the eye disease, the kidney disease and the neuropathic complications.”

In clinical trials, patients on Avandia show a smaller rise in fasting glucose levels — a standard measuring stick for diabetes — than patients taking other drugs. In theory, as Garber points out, this should be good news for patients on Avandia. Critics, though, say there is no evidence of better long-term outcomes — lower mortality or fewer complications.

Garber sits on the board of the American Association of Clinical Endocrinologists. He says the clinical trials — which closely followed several thousand patients, under careful monitoring — constitute a gold standard of evidence for the FDA, compared with broad but less detailed data used in studies such as Nissen’s.

“If there is a [negative] effect, it’s a small effect,” says Garber. “Let’s treat our patients instead of sensationalizing half-truths and conclusions that are not yet formed. Otherwise what happens is that patients stop taking their medicines. I’ve seen data, and a fair number of patients just stop taking medicine, and as a result their blood sugar rises. That convincingly demonstrates harm, whereas all these other things are all unproven.”

hree studies made public in late June will add fuel to what was already shaping up as a potentially fiery debate at the FDA. In the Archives of Internal Medicine, Nissen and colleagues published an update of their 2007 paper, including additional studies, and reported a similar increased risk of heart attacks and heart failure. The Journal of the American Medical Association published an analysis by Dr. David Graham, the FDA scientist who first flagged deadly side effects of the painkiller Vioxx. Graham compared Avandia with Actos, and found patients on Avandia are more likely to suffer stroke, heart failure or premature death. At the same time, doctors who support Avandia got ammunition from a presentation at the scientific meeting of the American Diabetes Association. There, Dr. Richard Bach of Washington University presented data from the BARI-2D study, and said it shows patients on Avandia actually have a lower risk of heart attack or stroke.

Practicing physicians find themselves in a quandary. Since 2006, sales of Avandia have fallen by about two-thirds, with many physicians taking the tack of Dr. Barbara Onumah, a diabetes specialist at Washington Hospital Center in the nation’s capital. After the first reports of trouble, she says, patients began coming into the office with news clippings and anxious questions. Since then she has switched all but one of her diabetes patients to different medications.

Onumah says she just wants some clarity. “I’m looking for a strong statement [from the FDA]. Because right now, there’s a lot of information. But none of it is clear.”

After Nissen’s bombshell, the FDA pushed GlaxoSmithKline to launch a major effort to try to settle the safety issue once and for all. Known as the TIDE study, it’s designed to recruit more than 15,000 patients and be completed by 2015. However, barely a thousand patients have been willing to sign up — a shortfall that seems likely to continue in the wake of ongoing doubt and negative reports. An FDA spokeswoman says the fate of the TIDE study will be on the agenda of next week’s meeting.

Source: CNN

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Correctly interpreted, the study actually supports critics’ contentions that Avandia may cause heart attacks, said the reviewer, Dr. Thomas Marciniak, in a posting on the F.D.A.’s Web site.

The company’s misreadings of the study, known as the Record trial, were so profound, he concluded, that they “suggest serious flaws with trial conduct.”

“One does not have to be a mathematician or to perform calculations,” he wrote, to come to the conclusion that a combined look at all the trials of Avandia would demonstrate that it causes heart attacks.

The review is part of a broad reassessment of Avandia’s safety by F.D.A. medical officers to educate a panel of experts who will gather next week in Gaithersburg, Md., to advise the agency whether Avandia should be withdrawn from the market — after millions of prescriptions, billions of dollars in sales and 11 years of wide use.

The panel’s decision will have broad repercussions not only for GlaxoSmithKline — which recorded $1.2 billion in Avandia sales last year and could face significant liability if the drug is withdrawn — but also for the F.D.A. The agency has been riven for years by fierce internal disagreements about Avandia’s uncertain risks. It was the F.D.A.’s delay in issuing stronger warnings about Avandia that led Congress in 2007 to give the agency greater powers over drug makers.

GlaxoSmithKline said in a statement that Avandia was safe.

“Since 2007, we have seen results from six controlled clinical trials looking at the cardiovascular safety of Avandia, and together they show that this medicine does not increase the overall risk of heart attack, stroke, or death,” said Dr. Murray Stewart, the company’s vice president for clinical development.

Avandia helps patients get better control of blood sugar levels, but its known risks are substantial: it can increase the risks of bone fractures and can cause swelling that can leads to heart failure and eye problems. And a number of studies, including some by GlaxoSmithKline, suggest that it could increase the risks of heart attacks, stroke and death.

Within the F.D.A., some officials insist that the evidence is mixed and others say it is strong enough to merit the drug’s withdrawal. An advisory meeting in 2007 concluded that Avandia did increase the risks of heart attack but that it should remain on the market.

In response, Avandia’s sales fell sharply, to $1.2 billion last year from a peak of $3.2 billion in 2006. But while endocrinologists have advised against its use, Avandia remains popular — with nearly two million prescriptions last year.

During that 2007 advisory meeting, the Record trial — specifically designed to assess Avandia’s heart risks — was a significant source of reassurance for Avandia’s supporters. GlaxoSmithKline insisted that the trial had proven that the drug was safe. In a news conference on Thursday, Dr. Janet Woodcock, director of the F.D.A.’s drug center, called the Record trial one of the “most germane because it’s a study of cardiovascular outcomes.”

Avandia’s critics have long asserted that the Record study was both weakly designed and too short to prove anything. And an investigation by the Senate Finance Committee found that GlaxoSmithKline may have improperly influenced the independent experts in charge of the study.

Now, Dr. Marciniak has found that even the study’s underlying data were misinterpreted. Instead of little risk to the heart, the Record study actually hints at substantial risks, Dr. Marciniak concluded.

Along with a host of observational studies concluding that Avandia is riskier than a similar drug — Actos, made by Takeda — the review by Dr. Marciniak could prove crucial, since it seems to kick away one of the final pillars supporting Avandia’s use.

Another issue the expert committee will be asked to resolve is whether a GlaxoSmithKline study being done at the F.D.A.’s request, comparing the safety of Avandia and Actos, is ethical. Some F.D.A. officials argue that the trial must be stopped, because observational studies — which use health records to measure how patients fared while taking a particular drug — have already proved that Avandia is dangerous.

Others within the F.D.A. say that observational studies are not good enough and that a well-controlled “prospective” study, like the one being conducted by GlaxoSmithKline, is the only sure way to answer whether Avandia is truly dangerous.

In a report released Friday, the Institute of Medicine, the nation’s leading medical advisory group, seemed to side with those who have argued that observational studies are adequate. Indeed, the group seemed to describe almost exactly a study of 227,571 Medicare patients conducted by an F.D.A. reviewer and published June 28 in The Journal of the American Medical Association concluding that Avandia increased the risks of stroke, heart failure and death compared to Actos.

The institute concluded that such studies “can sometimes provide higher-quality safety evidence than randomized controlled trials.”

Still, no matter how the experts vote next week, a final decision about Avandia is the responsibility of the F.D.A. commissioner, Dr. Margaret Hamburg, a public health expert who has shown clear signs that she is more concerned about drug risks than her predecessors in the Bush administration. Her decision could reshuffle the balance of power within the agency and is almost certain to influence hundreds of smaller decisions by staff members on scores of other products for years to come.

“F.D.A. is going to make a decision on behalf of the public,” said Dr. Joshua M. Sharfstein, the agency’s principal deputy commissioner, at a news conference on Thursday.

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The Justice Department also contends that the company violated the federal anti-kickback statute by making illegal payments to physicians. They were allegedly recruited by AstraZeneca to present themselves as authors of articles the company had written about the drug.

The civil settlement was the latest step in an Obama administration crackdown on health-care fraud. “We will not let such actions stand,” Attorney General Eric H. Holder Jr. said at a news conference. “This administration is committed to recovering taxpayer money lost to health-care fraud.”

Glenn Engelmann, the company’s U.S. general counsel, said AstraZeneca denies the allegations but “takes its obligations very seriously under its agreements with the government. . . . It is in the best interest of AstraZeneca to resolve these matters and to move forward with our business of discovering and developing important, life-changing medicines.”

Source: WP

The senate report by the Senate Finance Committee also criticized the FDA, saying that the agency overlooked or overrode safety concerns found by its staff.

“Americans have a right to know there are serious health risks associated with Avandia and GlaxoSmithKline had a responsibility to tell them,” said U.S. Senator Max Baucus, a Democrat and committee chairman. “Patients trust drug companies with their health and their lives and GlaxoSmithKline abused that trust.”

GlaxoSmithKline rejected any assertions Saturday that the drug is not safe. ”We disagree with the conclusions in the report,” company spokeswoman Nancy Pekarek told CNN. “The FDA had reviewed the data and concluded that the drug should be on the market.”

Seven clinical trials on the drug prove that it is not linked to heart attacks, Pekarek said. ”None of that data shows a statistically significant correlation between Avandia and myocardial ischemia or myocardial infarction [heart attack],” she said.

Ischemia is a condition in which blood flow and oxygen are blocked from going to certain parts of the body.

The Senate report was developed over the past two years by committee investigators who reviewed more than 250,000 pages of documents provided by GlaxoSmithKline, the FDA and several research institutes. Committee investigators also conducted numerous interviews and phone calls with GlaxoSmithKline, the FDA and anonymous whistleblowers.

“GSK executives attempted to intimidate independent physicians, focused on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk and sought ways to downplay findings that a competing drug might reduce cardiovascular risk,” the report says.

As an example, committee investigators say they found that GlaxoSmithKline experts verified an outside study showing the cardiac problem, but the company publicly attacked the findings as incorrect.

• Two FDA safety officials sounded a clear alarm in October 2008 writing, “There is strong evidence that rosiglitazone [Avandia] confers an increased risk of [heart attacks] and heart failure compared to pioglitazone [rival drug on market].” They concluded and trials comparing the two would be “unethical and exploitive.” Yet, the trial is still under way, the senators say.

The Senate report does not address the issue of whether Avandia should be removed from the market.

In the letter, the FDA said that it reviewed two Sotradecol web pages located on the Bioniche Pharma website (www.sotradecolusa.com or “Bioniche web page”) and the AngioDynamics, Inc. website (www.angiodynamics.com/pages/products/Sotradecol.asp or “AngioDynamics web page”) as part of its routine monitoring and surveillance program.  The agency found that these two web pages were misleading because they (1) presented efficacy claims for Sotradecol but failed to communicate any information about the risks associated with the brand, (2) broadened Sotradecol’s approved use, and (3) overstated Sotradecol’s efficacy.

Specifically, the FDA said that the Bioniche and Angiodynamics web pages “entirely omit risk information for Sotradecol.”  The letter also states that these web pages made claims that “entirely avoid mention of the actual indication, which is for the treatment of a very limited subset of varicose veins, and misleadingly suggest that Sotradecol is appropriate for use in all sclerotherapy patients and procedures.  The Contraindications and Precautions sections of the product label lists numerous conditions in which Sotradecol is either inappropriate or should be used with extreme caution, and these two web pages failed to present such material limitations and thus broadened Sotradecol’s FDA-approved indication.  Third, the FDA said that a graphic contained in one of the web pages “overstates the efficacy of Sotradecol” and “fails to provide any information regarding the ranges of the results patients may achieve depending on [several] variables.”

The FDA also expressed concern over Bioniche’s “continued violative promotion of this product,” because this is not the first time the agency sent Bioniche a letter like this.

In an earlier letter dated April 14, 2006, the FDA told Bioniche Pharma to immediately cease the dissemination of violative promotional materials for Sotradecol and to respond to the agency within four days.

In the 2006 letter, the FDA said that it reviewed a product brochure for Sotradecol that was submitted by Bioniche Pharma Group and made available on the product website.  The agency found it to be misleading because it presented numerous claims about how safe and effective Sotradecol, but failed to reveal material facts, minimized the risks associated with Sotradecol treatment, broadened the indication, included unsubstantiated claims, and presented misleading graphics.

If you have been treated with Sotradecol on or before September 14, 2009, you may be entitled to compensation.

This notice applies to all residents of Arkansas, California, Connecticut, Florida, Kansas, Missouri, New Jersey, New Mexico, New York, Ohio, South Carolina, Vermont, Washington, and Wisconsin.  If you live in one of these states, you may be eligible for compensation if you were prescribed and purchased Sotradecol on or before September 14, 2009.

The law firm of Bailey Perrin Bailey is actively reviewing potential Sotradecol cases of deceptive advertising against Bioniche Pharma USA, LLC and Angiodynamics, Inc.  Please click here to contact an attorney.

FDA scientists estimated in July 2007 that Avandia was associated with approximately 83,000 heart attacks since the drug came to market.

Unfortunately, since its release in 1999, Avandia drug has been shown to increase patients’ risk of developing the following, potentially fatal side effects:

• congestive heart failure
• heart attack
• pulmonary embolism (a condition in which blood clots congest the lungs and impede breathing)
• stroke

Other serious, non-fatal Avandia side effects include bone fractures (namely in the hands and feet) and pulmonary hypertension (increased blood pressure in the lungs’ arteries).

In 2007, an FDA panel recommended by a vote of 22-1 that Avandia should remain on the market despite an analysis showing links to increased risk of heart attack. The vote was not binding, but a suggestion to FDA regulators.

The panel also voted 20-3 at the same meeting in support of data that showed Avandia increased the risk of cardiac ischemia in patients with the most common type of diabetes.

After years of litigation, a comprehensive settlement was proposed in November under which Merck agreed to compensate plaintiffs who can show, under certain conditions, that taking Vioxx is connected to their having suffered a heart attack or stroke.  More than 48,500 of about 50,000 people—about 97 percent of all eligible claimants—registered, exceeding the 85 percent required threshold.  In addition, Merck extended the enrollment deadline to October 30, 2008 for eligible plaintiffs.  According to the Associated Press, “payouts are expected at a minimum of $5,000 up to a few million dollars” to “former Vioxx users, or their survivors.”  To be eligible, “They must have had pending lawsuits or tolling agreements, which suspend the statute of limitations, as of November 9, 2007, the date the settlement was reached.”

Merck pulled Vioxx from the market on September 30, 2004 after its study showed that long-term Vioxx users had twice the risk of heart attack and stroke.  Merck also agreed to a $58 million settlement with Washington, the District of Columbia and 28 other states in May over deceptive marketing of Vioxx.  In April, two reports published in the Journal of the American Medical Association (JAMA) found that two Merck-funded studies investigating the benefits of Vioxx in Alzheimer’s minimized death rates.  The reports also revealed that Merck hired outside firms to write Vioxx studies, paying prominent researchers to list their names as research authors.

A consent judgment against Merck, filed in Suffolk Superior Court, prevents the New Jersey-based drug maker from misleading consumers in future advertising and mandates full disclosure of all known risks of Merck drugs.  The judgment bans the deceptive use of scientific data when marketing doctors and “ghost writing” articles and studies and addresses conflict of interest issues.  Also, Merck must obtain Food & Drug Administration (FDA) approval for direct to consumer television drug advertisements and must comply with regulatory recommendations if the FDA calls for a delay in such advertising.  In 2000, Merck spent $160.8 million on direct to consumer Vioxx marketing.

Vioxx—refecoxib—is in a class of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs) and works by reducing substances that cause inflammation, pain, and fever.  A three-year study aimed at showing that Vioxx—at a 25-milligram dose—prevents recurrence of polyps in the colon and rectum was ceased when Merck discovered a higher heart risk compared to patients taking placebos.  Prior to the Vioxx withdrawal, the FDA announced that patients taking Vioxx had a 50 percent greater chance of heart attack and sudden cardiac death and patients taking the highest recommended daily dosage of Vioxx had three times the risk of heart attack and sudden cardiac death as those not taking standard painkillers.

The Public Citizen consumer group thinks the FDA has not adequately warned physicians and Zyprexa patients of the Zyprexa risks. Hyperglycemia, diabetes, and ketoacidosis have been reported amongst Zyprexa patients. Ketoacidosis, associated to Zyprexa adverse effects reports end up fatal in about 50% of the cases. The last time the Zyprexa labeling was updated in the U.S. the FDA only made a quick reference to the risk of Zyprexa diabetes and hyperglycemia in the middle of the adverse reactions section of Zyprexa labeling.

The move to pull the COX-2 inhibitor off the market on September 30, 2004 shocked the arthritis world and rocked the stock value of Merck.

The Reason

The decision to recall Vioxx followed a three year trial, known as APPROVe (Adenomatous Polyp Prevention on Vioxx), which was a multi-center, randomized, placebo-controlled, double-blind study to determine the effect of Vioxx on the recurrence of neoplastic polyps of the large bowel in patients with a history of colorectal adenoma.

The trial which begain in 2000, involved 2,600 patients and compared Vioxx 25 mg. to placebo. The study revealed that an increased risk of cardiovascular complications began 18 months after patients started taking Vioxx.

The History

Merck CEO Rymond Gilmartin said, “We are taking this action because we believe it best serves the interests of patients.” Vioxx, which was launched in the United States in 1999 for the treatment of arthritis has been marketed in 80 countries and used by 84 million people worldwide.

What Lies Ahead?

Acting FDA Commissioner Dr. Lester M. Crawford stated in a press release that the FDA will closely monitor other drugs in this class for similar side effects. Crawford added, “All of the NSAID drugs have risks when taken chronically, especially of gastrointestinal bleeding, but also liver and kidney toxicity. They should only be used continuously under the supervision of a physician.”

There are existing lawsuits filed against Merck because of Vioxx and some analysts predict there will be more provoked by the recall. What will this mean for other COX-2 inhibitors? It is expected to impact them in some way. Will it cause a surge in the popularity and use of Celebrex (Celecoxib) and Bextra (Valdecoxib)? Will Novartis’ yet-to-be approved Prexige (Lumiracoxib) be affected? Even Merck has another COX-2 inhibitor, Arcoxia (Etoricoxib) , which has been highly-anticipated and expected to get FDA-approval soon.

The Vioxx Recall was prompted after a three year trial known as Adenomatous Polyp Prevention On Vioxx conducted a double blind study to determine Vioxx Side Effects. The trial discovered through 2,600 patients using a Vioxx 25 mg. tablet that there was a serious risk of cardiovascular problems in patients using the drug.

Currently, FDA Commissioner Dr. Lester M. Crawford has stated that the FDA will monitor drugs in this class action lawsuit for similar side effects. The FDA has concluded that Vioxx Side Effects can include gastrointestinal bleeding, liver, and kidney toxicity. The Vioxx Lawsuits filed against Merck are expected to impact the company in some way.