The FDA approval of 23-mg donepezil (Aricept) conflicted with the opinions of its own reviewers and breached the agency's own regulatory standard, authors write in a BMJ article, leading to misleading consumer and physician ad campaigns that put patients at risk.
The authors assert that the 23-mg dose of the Eisai drug, which was approved four months before the 5- and 10-mg formulations went generic in November 2010, failed to show that it provided a significant improvement on two fronts: cognitive and global function, measures laid out by the FDA itself as the regulatory standard for approval of an Alzheimer's med. In fact, the authors say the drug had a lopsided impact, affecting only cognitive function and did so insignificantly. They also add that the higher dose caused significant side effects.
The authors contacted the FDA about the erroneous claims made in the label, and the agency soon requested the label be changed.The FDA had said the offending phrase had "slipped by" reviewers. A new one was approved March 1, more than a year-and-a-half after the original label was posted.
According to Dartmouth's Lisa Schwartz and Steven Woloshin, however, Aricept 23's ability to clear the FDA was just the beginning of a disaster. Because the FDA approved a label stating that the new dose improved cognition and function, professional media ads went on to perpetuate that same language, and the drug's sales took off.
DTC ads took a soft approach to side effects. The higher dose's untoward effects are said to include a higher level of nausea and vomiting compared to the lower doses. Consumer ads brush these aside with the claim “side effects may get better after the patient takes Aricept for a while,” according to the authors.
Despite these drawbacks, government and private insurance now cover the drug, and it continues to sell. In an earnings report, Eisai said the 23-mg dose brought in ¥3,002 million ($35.4 million) in US sales for the third quarter of fiscal 2011 (ending December 31), while sales of the off-patent Aricept fell 92.8%, to ¥9,414 million ($112.4 million) during the same period, compared to the third quarter of fiscal 2010. An authorized generic version had sales of ¥2,808 million.
When asked about Aricept 23, an Eisai spokesperson said the FDA approved the initial package insert. As to whether insurance companies will continue to reimburse for the higher dose, or relegate it to a lower tier on their formularies, several did not return calls for comment Thursday.
The story doesn't end there. The label for Aricept 23 still contains the erroneous statement: "This study showed that patients on 23 mg/day experienced important clinical benefit on both measures compared to 10 mg/day." And that's why Aricept 23 mg ads that make that claim don't break any laws. (It's contradicted by text elsewhere in the label.)
Woloshin told MM&M that one way to avoid sending physicians and patients distorted messages in the future would be to have the FDA write drug labels, as opposed to leaving it up to the drugmakers. "The FDA's role is to
review and approve the draft label, often after a period of negotiation over specific wording or content," he and Schwartz noted in their article. He added that Aricept 23 is just one example of a broader problem about “how information gets out to doctors and nurses.”