Actos (pioglitazone hydrochloride) was approved by the FDA in July 1999 for the treatment of patients with type 2 diabetes mellitus. Originally, Takeda Pharmaceutical Co. and Eli Lilly & Co. partnered in a marketing agreement for the medication and launched Actos jointly. A little over a year after its introduction to the U.S. market, in October 2000, Actos was approved by the European Medicines Agency (EMA).
In 2005, a PROactive Study demonstrated an increase in the presence of bladder cancer associated with Actos compared to competitor drugs, although the information was not published until 2009 and again in 2011. In 2006, Takeda and Eli Lilly ended their joint marketing agreement, with Eli Lilly retaining marketing rights for Asia, Canada, Europe, and Mexico, and Takeda retaining U.S. rights, although Takeda would buy back the rights in seven countries in 2009.
In 2007, the FDA issued a blackbox warning to Takeda as well as GlaxoSmithKline, which manufactures the primary competitor medication, Avandia. This safety alert brought attention to the connection between pioglitazone and heart failure. As of 2008, Actos was the nation’s 10th-most prescribed drug and netted worldwide sales of approximately $4.6 billion, followed by $3.4 billion in 2009.
The year 2010 — in which an estimated 2.3 million patients filled prescriptions for Actos or another medication containing Actos — saw the arrival of legal controversy. A former medical reviewer filed a suit under the False Claims Act against Takeda Pharmaceutical Co., alleging that cases of congestive heart failure were not adequately reported to the FDA. Shortly thereafter, a study was published in Circulation: Cardiovascular Quality and Outcome Journal that outlined the risk of acute heart failure and heart attack associated with both Actos and Avandia. In 2010, the FDA also began its investigation into a possible connection between Actos and bladder cancer.
In 2011, another whistleblower complaint was filed in the U.S. District Court, District of Massachusetts — same as the 2010 suit. That same year, the American Diabetes Association (ADA) published a report analyzing the association of Actos and bladder cancer, and the EMA announced its decision to suspend Actos from the market — it was subsequently banned in France and Germany.
At the end of 2011, Bloomberg Businessweek published that Takeda would potentially face more than 10,000 lawsuits. Although the medication’s warning label was updated to reflect the risk of bladder cancer, controversy continued in 2012 with more research linking Actos to bladder cancer.
In 2013, the first Actos trial began in California Superior Court and was brought to conclusion within a little more than two months when the plaintiff, who was diagnosed with bladder cancer after taking Actos for more than four years, was awarded $6.5 million.
In January 2014, the first federal Actos Bladder Cancer bellwether trial began in the U.S. District Court for the Western District of Louisiana, also concerning the development of bladder cancer after taking Actos for a number of years and the failure of Takeda to reveal the medication’s risk to consumers. In April 2014, Takeda and Eli Lilly were ordered to pay a combined $9 billion as a result of masking cancer risks associated with Actos. It is the seventh-largest jury award in U.S. history.