A medical doctor and former consultant to Takeda Pharmaceuticals is charging in a whistleblower lawsuit that the company failed to report serious adverse events related to the antidiabetes drug pioglitazone (marketed as Actos).
Helen Ge states in her lawsuit that Takeda “instructed medical reviewers not to report hundreds of non-hospitalized or non-fatal congestive heart failure cases as ‘serious’ adverse events and thus avoided its responsibility of accurately analyzing and reporting these hundreds of serious adverse events to the FDA [US Food and Drug Administration].”
She also claims that the company failed to report 28 of 100 cases of bladder cancers to the FDA, which she called a “serious discrepancy,” and that Takeda told her to change her notation that the cancers were “related” to “unrelated.” The suit says that she was fired after she complained to her supervisors about the company’s failure to report all serious adverse events.
The suit was originally filed in June 2010 but wasn’t publicly disclosed until 24 February, when the federal government declined to join the suit.
Dr Ge charges that Takeda “orchestrated” the downfall of its main competitor drug, rosiglitazone (GlaxoSmithKline’s Avandia), which is in the same class of drugs. In her suit she claims that after the New England Journal of Medicine published a study in 2007 (2007;356:2457-71) showing that rosiglitazone increased heart attacks and congestive heart failure, the FDA asked GlaxoSmithKline and Takeda in May 2007 to add warnings about heart failure for both drugs.
According to the suit, in November 2007 Takeda “began to run print advertising in 82 major market newspapers and national publications such as Time and Newsweek, advising readers with type 2 diabetes that ‘Actos has been shown to lower blood sugar without increasing your risk of a heart attack or stroke.’” At the same time Takeda stopped reporting non-fatal or non-hospitalised heart failure events as “serious,” while GSK continued to report all heart failure events as serious, unfairly positioning pioglitazone as safer than rosiglitazone.
Whether pioglitazone is actually safer than rosiglitazone is controversial. A 2010 meta-analysis by Steven Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic in Cleveland, Ohio, reported that when compared with control treatment rosiglitazone increased heart attacks but not the rate of heart failure or cardiovascular mortality (Archives of Internal Medicine 2010;170:1191-201, doi:10.1001/archinternmed.2010.207). David Graham, a safety officer with the FDA, conducted an observational, retrospective, inception cohort study of 227 571 patients aged more than 65 years to compare rosiglitazone and pioglitazone and reported that rosiglitazone was associated with “an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of AMI [acute myocardial infarction], stroke, heart failure, or all-cause mortality” (JAMA 2010;304:411-18, doi:10.1001/jama.2010.920). However, a retrospective cohort study published in 2010 in Circulation that assessed 36 628 patients taking either rosiglitazone or pioglitazone found no differences in overall heart failure, acute myocardial infarction and all cause mortality (2010;3:538-45, doi:10.1161/CIRCOUTCOMES.109.911461).
Dr Nissen told the BMJ that FDA statisticians “showed unequivocally that pioglitazone is less likely to cause ischaemic events than rosiglitazone.” He said, “These findings were confirmed by the analysis published in JAMA” and that “since several of these analyses” did not rely on data reported by Takeda “the differences are likely [to be] real.” He added that both drugs, however, “can precipitate congestive heart failure and cause fractures.”
France suspended pioglitazone in June 2011 over concerns about bladder cancer. Rosiglitazone is available in the United States with severe restrictions (BMJ 2010;341:c5287, doi:10.1136/bmj.c5287), and the European Medicines Agency has suspended its marketing approval (BMJ 2010;341:c5291, doi:10.1136/bmj.c5291).
Takeda said that it can’t comment on the allegations while the lawsuit is pending but that it “complies with all laws and regulations regarding the reporting of adverse events.” Dr Ge declined to comment.
Cite this as: BMJ 2012;344:e2002
By Jeanne Lenzer