FDA may not ban Avandia

Editor's note: This is an update. Diabetes patients should know that while it is uncertain whether Avandia boosts risk of heart attack, it is certain that a drug called ACTOS in the same class is much safer.

A joint meeting of two FDA advisory committees is scheduled for July 13 and 14 to decide whether avandia should remain on the market.  The drug is used to help diabetics to control blood sugar, but has been found associated with increased risk of heart attack.

A similar meeting was held in 2007 leading to addition of warnings on the label for avandia.

On Thursday, FDA officials told reporters that the agency experts remained split over the drug.

"There's not complete unanimity within the FDA about interpretation of these data, and that's one of the reasons we're going to the advisory committee," said Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research.

To be exact, Ellis Unger, a deputy director in the FDA's drug division and Thomas Marciniak, a medical team leader have conflicting assessments on the largest trial ever on avandia called RECORD.

Dr. Marciniak said in his slides expected to be presented at the meeting that the trial was not adequately designed and the drug increased risk of heart attack.

Unger did not come to the same conclusion.

It is not just Dr. Marciniak who has found that avandia or Rosiglitazone boosts the heart attack risk in diabetes patients on the pill.

Steven Nissen, a famous cardiologist at world-famous Cleveland Clinic and well known industry consultant, will also present his findings against avandia.

Dr. Nissen concludes as expected at the meeting that it is unethical to keep avandia on the market now that studies showed that avandia was linked to heart risk and a much safer drug called ACTOS, made by Japan-based Takeda Pharmaceuticals is available.

London-based GlaxoSmithKline, the drug's maker said results from six trials indicate that avandia does not raise heart risk. 

Avandia was the second biggest money maker for Glaxo with $2.6 billion in sales in 2006. After studies revealed its link to elevated heart attack risk, the sales dropped to $520 million in 2009, according to media reports.

In Europe, The European Medicines Agency said its Committee for Medicinal Products for Human Use will also discuss the safety of avandia from July 19 to 22 to decide whether avandia should be taken off the market.

Below is the report published early on foodconsumer.org

Two advisory committees of the Food and Drug Administration are scheduled to make their decision as to whether Avandia, a diabetes drug that has been linked for years to increased risk of heart attack, should be allowed to stay in the market.

The Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on July 13 and 14 will hear a series of presentations by about a dozen of shareholders, focusing on the safety of Avandia or rosilitazone maleate tablets made by GlaxoSmithkline, which is approved to help type 2 diabetics to control blood sugar.

At the meeting, the FDA will also present its meta-analysis of several trials of ACTOS or pioglitazone hydrochloride tablets made by Takeda Pharmaceuticals North America Inc, according to a statement released on July 8 on the FDA website. The trials compared Avandia with ACTOS.

The increased risk of heart attack and death associated with Avandia has been widely publicized.  The FDA did not pull the drug off the market even though warnings have been added to alert patients to the risk.

Among others, one study led by Dr. Wolfgang C. Winkelmayer and colleagues at Harvard medical School showed death rates for patients on Avandia were 15 percent more likely and congestive heart failure rates were 13 percent higher than those who took  ACTOS.

Dr. Winkelmayer et al. came to the conclusion after they meta-analyzed 42 studies involving 28,361 patients who had been tracked for up to five years.

The study was published in the Nov 24, 2008 isue of Archives of Internal Medicine.

Dr. Steven Nissen, a prominent heart specialist and chief of cardiovascular medicine at the Cleveland Clinic, one of the best heart clinics in the world, early analyzed data from 42 clinical trials of Avandia and found Avandia patients were 43 percent more likely to have a heart attack or be hospitalized for blocked coronary arteries than others in the studies.

His findings were reported in the New England Journal, a prestigious medical journal.  

The FDA held a hearing in 2007.   Dr. David Graham, a veteran drug safety reviewer of the FDA's Office of Surveillance and Epidemiology told FDA advisory panelists that the Glaxo's diabetes drug should come off the market, according to USA Today.  

Dr. Graham also said Actos does not increase heart risk like Avandia and suggested that there should be no reason for the Glaxo's drug to stay on the market.   But the FDA panel did not heed Dr. Graham's suggestion and voted 22 to 1 to keep the drug on the market.

At the scheduled meeting, Drs. Nissen, Graham and Thomas A. Marciniak, medical team leader of Division of Cardiovascular and Renal Products, a FDA division all will give a presentation regarding the safety of Avandia.

In his presentation, Dr. Nissen is expected to give his conclusion as follows:

"Rosiglitazone increases the risk of ischemic myocardial events iin a highly vulnerable population, 70 percent of whom will eventually die of cardiovascular disease. And with an alternative in the same class (pioglitazone) with favorable effects on CV outcomes, continued marketing of rosiglitazone cannnot be medically or ethically justified."

Dr. Marciniak has reviewed the contraversial open-label trial called RECORD and found the trial is full of bias, errors and mistakes. 

He concludes as showed in his slide presentation that "RECORD was inadequately designed and conducted to provide any reassuarance about the CV (cardiovascular) safety of rosiglitazone; RECORD confirms and extends the recognized concerns regarding increased HF (heart failure) and HF deaths with rosiglitazone; RECORD suggests the rosiglitazone increases the risk for MI (myocardial infarction or heart attack)."

Dr. Marciniak asks "Why should you believe my numbers rather than GSK's?"  His answer to this question is "Neither my job nor (for me) $100,000,000's are riding on the results." 

In his presentation, Dr. Graham concludes that

In older adults, compared to pioglitazone, rosiglitazone (Avandia) 

increased risk of hospitalized heart failure

increased risk of stroke

increased risk of death

increased risk of composites for AMI (acute myocardial infarction) or death, AMI, stroke, or death, AMI stroke, heart failure or death,

increase all-cause death most likely due to increase in out-of-hospital SCD (sudden cardiac death).

At the meeting, Glaxo's representatives will present their case.  Media reports say that Glaxo claims based on six trials that Avandia does not raise the risk of heart attack and death.

The American Diabetes Association and the European Association for the Study of Diabetes have already stopped recommending rosiglitazone for type 2 diabetes. 

A health observer suggests that when given Avandia, diabetes patients may ask their doctors to give them ACTOS, which is indicated for the same  treatment, but much safer than Avandia.

By David Liu