The Canadian physician whose research escalated safety concerns about the Type 2 diabetes drug rosiglitazone (marketed as Avandia) is urging the U.S. Food and Drug Administrationto call a halt to a major international trial designed to compare the safety of Avandia against another diabetes drug in the same class.
Dr. David Juurlink, chief of clinical pharmacology and toxicology at Sunnybrook Health Sciences Center in Toronto, was the lead author of a 2009 study that found that compared to elderly diabetics taking a drug called pioglitazone (marketed as Actos), those taking Avandia were about 30% more likely to suffer heart failure or death. On Tuesday, Juurlink joined with Dr. Sidney Wolfe, director of health research for the consumer watchdog group Public Citizen, in calling a further clinical trial pitting the two diabetes drugs against each other "unethical" and "dangerous."
In 2007, the FDA issued two separate safety warningson Avandia and required the drug's maker, GlaxoSmithKline, to post "black box" warnings on the medicine's patient instruction sheet indicating the drug might put patients taking it at higher risk of ischemic heart attack or heart failure. The agency also ordered GSK to conduct a post-marketing safety trial of Avandia. That planned trial is expected to draw from sites in 14 countries, including a number of newly-added developing countries such as Pakistan, India, Latvia, Chile, and Mexico, and to enroll 16,000 subjects. Called the TIDE trial, or Thiazolidinedione Intervention in Vitamin D Evaluation, was the subject of Tuesday's appeal from Juurlink and Public Citizen.
In act, both drugs have been tagged with safety issues: In addition to raising rates of cardiovascular events, the class of Type 2 diabetes drugs known as thiazolidinediones (or TZDs) have been linked in studies to higher rates of edema, macular edema, bony fractures, anemia and acute liver injury. Older diabetes medicine such as metformin and sulfonylurea are widely believed to be safer alternatives.
At the same time, the drugs are widely used and have many defenders in the care of Type 2 diabetes -- an obesity-related condition that has exploded in the U.S. population in recent decades. But extensive financial ties between the drug companies that make the medicines and many of the clinicians and researchers who have defended them have prompted some -- including leaders of the Senate Finance Committee -- to ask whether the safety debate has been tainted by industry influence.
There is scant evidence that the proposed clinical trial will yield more reliable evidence of Avandia's relative safety profile than existing research has done, Juurlink and Wolfe wrote in a Tuesday letter to FDA Commissioner Margaret Hamburg. Nevertheless, it will expose "thousands of high-risk patients with diabetes to a drug with an unfavorable safety profile and clinical advantage over its comparator," they wrote. The "price of definitive proof" of the drug's safety hazards, they added, "will almost certainly be measured in the lives of study subjects who have been incompletely informed about the risks and benefits of participation" in the trial, they added.