Nearly two years ago, the FDA approved a higher dose of the Aricept treatment for Alzheimer's, just a few months before the drug, which is sold by Pfizer and generated some $2 billion in annual revenue, was due to lose patent protection. At the time, Pfizer sold two versions of Aricept - a 5 mg dose and a 10 mg dose - but wanted to sell a 23 mg pill.
Although 23 mg may seem like an odd dosage, the move was designed to provide an advantage over forthcoming generics that would allow patients to combine two 10 mg pills more cheaply. And so Pfizer and the FDA agreed that approval would be granted if its 23 mg dose was superior to the existing 10 mg dose on both a cognitive and a global functioning measure.
Now, though, an article in BMJ charges the approval was made "only over the objections of the FDA’s medical and statistical reviewers” and, therefore, "breached the FDA’s own regulatory standard" and led to "incomplete and distorted messages" about the drug. And they also argue that the higher dose of Aricept offers “no meaningful added benefit, just more harm.”
Why? The FDA documents indicate the higher dose did improve cognitive functioning, but not overall functioning, which would suggest the cognitive difference was actually not meaningful. Moreover, the higher dose also caused more side effects, such as nausea and vomiting. Just the same, Pfizer won an additional three years of marketing exclusivity for a dosage that was marketed aggressively.
In fact, the BMJ authors, Lisa Schwartz and Steven Woloshin of the Center for Medicine and the Media at The Dartmouth Institute for Health Policy and Clinical Practice, cite a "stunningly erroneous statement" in an ad that was aimed at doctors and claimed patients on the 23 mg dose "experienced important clinical benefit on both measures," a reference to cognitive and overall functioning.
“Nowhere - not in the direct to consumer or the physician advertisements, nor even in the FDA approved label – are the great uncertainties about this drug acknowledged, uncertainties that led the FDA’s own medical and statistical reviewers to recommend against approval of the 23 mg dose,” they say (here is the BMJ paper).
Similar concerns led the Public Citizens consumer watchdog group and a Johns Hopkins University professor last year to file a Citizen's Petition with the FDA in which the agency was urged to immediately ban the 23 mg dose (back story and the petition). The approval, by the way, was granted by Rusty Katz, who oversees the neurology products division.
“Rarely do we see such a dangerous difference between what pretty much everyone in the neurological division thought and what its leader thought,” Sid Wolfe of Public Citizen tells The New York Times. “That’s a huge slap in the face to all the people who spent much more time reviewing this drug than he did.”
The petition argued the only clinical trial submitted to the FDA for approval of the 23mg dose compared it to the 10mg dose, but failed to prove the higher dose was more effective. And in three of four tests, there was no significant difference between the doses on a cognitive or functional level. Improvement shown in the fourth test for the 23mg dose was only two points higher on a 100-point scale.
The FDA has not yet acted on the petition. We have asked Pfizer for comment and will update you accordingly. [UPDATE: Since Eisai developed Aricept, a Pfizer spokesman directed us to the Japanese drugmaker. So, we have asked Eisai for a comment and will post convey any response.]
[AND NOW... EISAI REPLIES: A spokeswoman tells us that "we can't comment on the FDA process... A Phase III used for submission showed a statistically significant improvement in cognition compared with the 10 mg dosage, but not global improvement when copmared with the 10 mg dosage." As for the ad, "the language in the ad was consistent with the label at that time, and is no longer in use... it is Eisai policy to revise marketing materials to reflect label changes when appropriate."]