FDA-Sanctioned International Diabetes Drug Trial Is Unethical and Dangerous, Must Be Stopped
Public Citizen and Leading Canadian Researcher Call on FDA to Immediately Halt TIDE Trial
WASHINGTON, D.C. - The Food and Drug Administration (FDA) should immediately halt an international trial (including sites in six developing countries) designed to assess the cardiovascular risks associated with the diabetes drug Avandia because enough research has been done to show that the drug is more dangerous than its comparator Actos, Public Citizen and a leading scientific expert in Canada said today.
In a letter sent to the FDA, Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, and Dr. David Juurlink, a Toronto researcher who led a large study in 2009 that found Avandia to be more dangerous than Actos, said that continuing the Thiazolidinedione Intervention in Vitamin D Evaluation (TIDE) trial is unethical and should be stopped.
The trial, which began in May 2009 by GlaxoSmithKline at the request of the FDA, involves 137 sites in 14 countries, including 19 sites in the U.S and 34 in Canada. During April 2010, many new sites were added in developing countries, including Chile, Mexico, Colombia, Latvia, Pakistan and India, presumably to compensate for poor enrollment elsewhere. Eighty-three sites are already recruiting subjects for the trial, which has an anticipated sample size of 16,000 subjects and a targeted completion date in 2015.
A major objective of the trial is to compare the safety risks of Avandia (the generic name of which is rosiglitazone) with those of Actos (the generic name of which is pioglitazone). But that question has been studied in several jurisdictions using different methodologies, and the results are in: Evidence has steadily accumulated showing the increased dangers of Avandia compared to Actos, and both drugs are more dangerous than older diabetes drugs, Wolfe and Juurlink said.
Both drugs have been associated with a host of side effects including macular edema, anemia, edema, congestive heart failure, myocardial infarction, bony fractures and acute liver injury, some cases of which have been fatal. Strong evidence suggests that both drugs cause edema and congestive heart failure.
However, a large body of research has shown Avandia to be more dangerous than Actos. It is more likely to cause heart failure; even FDA scientists estimate that the risk of heart failure with Avandia is roughly 50 percent higher than with Actos. Avandia also is associated with a higher risk of death than Actos.
In 2008, the American Diabetes Association and the European Association for the Study of Diabetes advised against using Avandia, and the Saudi Arabian drug regulatory agency has recently removed Avandia from the market. The FDA has ordered a black box warning to be placed on Avandia (but not Actos) because of concerns about heart attacks.
"It really does not make sense that this trial should continue," Juurlink said. "Given the gathering cloud of data regarding the risk of rosiglitazone as compared to pioglitazone, what really is the ‘big picture' purpose of this trial? To see if the previous studies are right, and that rosiglitazone - which has no advantage over pioglitazone - really is more dangerous than pioglitazone? The need for certainty is not a reason to do a trial. These are patients, not guinea pigs."
Juurlink led a study published in 2009 comparing adverse effects in 39,000 people who used either Avandia or Actos starting between 2002 and 2008. Juurlink and colleagues found a significantly higher risk of congestive heart failure and death from any cause in patients taking Avandia. The authors estimated that one additional hospitalization for heart failure would occur annually for every 120 patients prescribed Avandia rather than Actos, and that one additional death would occur each year for every 269 patients treated with Avandia rather than Actos.
"Surely no patient would willingly participate in a trial in which they have a substantial likelihood of taking a drug that, in the opinion of a large group of experts, has no role in present day therapeutics because of its risks," Wolfe said. "The trial shouldn't continue because the question has been answered. If the trial continues, the health of thousands of patients will be jeopardized. It is unethical to continue this trial. As unethical as it is in developed countries such as the U.S. and Canada, it is even more unconscionable to subject people in developing countries such as Chile, Mexico, Colombia, Latvia, Pakistan and India to a drug known to be more dangerous than the drugs it is being compared to."
Identifying information for David N. Juurlink MD, PhD, FRCPC
Head, Division of Clinical Pharmacology and Toxicology
Sunnybrook Health Sciences Centre
Scientist, Institute for Clinical Evaluative Sciences
Medical Toxicologist, Ontario Poison Centre