By Dan C. Bolton, Keller, Fishback & Jackson LLP.
With the clock about to run out on patent protection for their blockbuster drug Aricept, prescribed to treat symptoms of Alzheimer’s Disease (AD), two pharmaceutical giants, Pfizer, Inc. and Eisai Inc., came up with a brazen idea to dodge patent expiration and continue to reap profits.
The plan was a new 23 mg dose of Aricept (Aricept 23) that could not be reached by combining the soon to be generic and less expensive 5 mg and 10 mg doses. This scheme would ensure three more years of exclusivity and sole marketing rights for the pharmaceutical companies, along with a continued revenue stream, for the new 23 mg dose.
Aricept 23, however, failed three of the four efficacy measures in the single clinical study submitted by Eisai (the one it barely passed was clinically meaningless), and was panned by FDA reviewers, who found that the 23 mg dose was no more effective than the 10 mg dose, and were especially alarmed by the increase in dangerous, and potentially fatal, risks for elderly patients in the grip of advanced AD.
Despite the recommendation by the reviewers that Aricept 23 not be approved, and its lack of efficacy and increased dangers over the lower dose, Aricept 23 was approved. With this approval, Pfizer and Eisai revved up a relentless marketing and advertising campaign that continues to this day, the core of which is to misrepresent the safety and efficacy of the clever new dose, and prey on a vulnerable elderly patient population, their families and caregivers, who are desperate to try anything to help their loved ones.
The History of Aricept
Aricept is the best-selling drug in the world to treat symptoms of AD. Aricept was also the best-selling drug for Eisai, accounting for 60% of its revenue in the United States before the loss of patent protection for the 5 mg and 10 mg doses. The drug is co-marketed in the United States with Pfizer, Inc. It is a blockbuster drug that has generated billions of dollars in revenue for Pfizer and Eisai since its approval in the United States.
Aricept was first approved by the FDA on November 25, 1996, for the treatment of mild to moderate AD, at a dose of 5 mg or 10 mg once a day. On October 13, 2006, Aricept was approved for severe AD at a dose of 10 mg once a day.
On July 23, 2010, just a few months before patent expiration in November 2010, Aricept 23 was approved for moderate to severe AD. This occurred even though Aricept 23 received highly critical reviews from both the FDA clinical and statistical reviewers (both clinical and statistical reviewers recommended against approval). And the one clinical study submitted to support the efficacy of Aricept 23 failed to establish that the dose had any clinically meaningful benefit beyond a lower dose, and in fact, presented more serious and life threatening risks to AD patients.
Aricept 23 study fails to meet multiple efficacy endpoints
Under federal law, new doses of previously approved drugs, not reproducible from currently marketed doses, may be given a three year period of exclusivity during which generic competitors are not permitted to manufacture and sell the same new dose. Eisai sought approval for an unusual 23 mg dose—a dose that would be entitled to marketing exclusivity since it could not be reached by combining the 5 mg and 10 mg pills.
When the FDA met with Eisai in March 2007, it agreed to Eisai’s request for the submission of a single efficacy study. The FDA and Eisai both agreed that the proposed 23 mg dose of Aricept would be considered effective, and would be approved, only if it was shown to have statistically significant superiority over the 10 mg dose on both cognitive and global functioning measures. The global functioning measure is important since it confirms that any cognitive measure is clinically meaningful; that is, an improvement that patients, healthcare professionals and/or caregivers notice.
In support of its NDA, Eisai submitted the results of a single efficacy study (Study 326) that compared the safety and efficacy of Aricept 23 against 10 mg Aricept. The study did not have a placebo control, and significantly, did not include a group taking 20 mg of Aricept (which would not be entitled to marketing exclusivity since the dose is reproducible from existing dosages).
The study showed a small but statistically significant difference on a cognitive measure, but no statistically significant difference in global functioning. The improvement in the cognitive measure was only 2.2 points over the 10 mg dose on a 100 point scale.
The study also had two secondary endpoints that were designed to provide support for the primary endpoints. The study showed no statistically significant treatment difference on the two secondary measures. Thus, in three of four tests comparing Aricept 23 to 10 mg Aricept, no significant difference was found between the two doses on a cognitive or functional level, and the fourth test resulted in patients on Aricept 23 scoring a meager two points higher on a 100-point scale. In sum, the only “evidence” of efficacy was, as the FDA described it, a “numerically small” two-point increase on a large 100-point scale, and on every other measure Aricept 23 was no more effective than the lower dose.
Aricept 23 study shows increase in dangerous risks
Not only was Aricept 23 without meaningful clinical benefit in comparison to the 10 mg dose, the study established that the dose was associated with an alarming and significant increase in risk to patient safety. Study subjects taking the 23 mg dose had a higher incidence of all adverse events. In particular, the use of Aricept 23 was associated with a much higher incidence of vomiting, which in patients with AD, can lead to pneumonia, massive gastrointestinal bleeding, esophageal rupture, or death.
There was a significant increase in adverse events with Aricept 23, compared to the 10 mg dose. Vomiting occurred in 2.5% of patients on 10 mg, and climbed over three-fold to 9.2% of patients on the 23 mg dose. Nausea occurred in 3.4% of patients in the 10 mg group, and jumped to 12% of patients on Aricept 23. Diarrhea occurred in 5.3% of patients on 10 mg, and increased to 8.3% of patients on the higher dose. Fatigue occurred in 0.8% of patients on 10 mg and rose to 2.4% of patients on Aricept 23. In fact, all eight of the most commonly occurring adverse events increased in frequency with the 23 mg dose. More than twice the percentage of patients in the 23 mg dose group (19%) discontinued participation in the study because of adverse effects compared to the 10 mg dose group (8%).
The FDA’s medical reviewer concluded that “the results of Study 326 did not satisfy the pre-specified criteria for demonstrating the efficacy of the higher dose…I recommend that this application, which seeks approval of Aricept in a new dose strength of 23 mg administered once daily, for the treatment of moderate to severe dementia of the Alzheimer’s type not be approved.” The FDA statistical reviewer concurred, stating that “…the data from this trial does not seem to provide enough support for the efficacy of [Aricept 23].”
Despite the failure of Study 326 to demonstrate the efficacy of Aricept 23 on the agreed upon criteria, and the FDA staff recommendation that approval be denied, the Director of the FDA’s Division of Neurology Products approved the application for Aricept 23 on July 23, 2010. He did so even though he agreed that Aricept 23 did not show greater efficacy on the global measure, in comparison to the 10 mg dose, “I also believe the results do not support a conclusion that the 23 mg dose group offers a greater benefit on overall functioning that the 10 mg dose.”
Experts outside the FDA who treat AD have also recognized the lack of efficacy and increased risk of Aricept 23. A researcher at the Mayo Clinic wrote that “not only does donepezil 23 mg/day increase the likelihood of unacceptable gastrointestinal side effects, it provides no clinical benefits. Aricept 23 mg is about 10 times more costly per pill than donepezil 10 mg.”
Since the approval of Aricept 23, and its launch in August 2010, Pfizer and Eisai have embarked on an aggressive marketing campaign to collect as much revenue as possible from the 23 mg dose. This is in spite of the fact that it has no more efficacy than a lower, less expensive dose, and poses substantially more risks, including death, to elderly and disabled AD patients. AD patients, families and caregivers who were duped into spending money for an expensive drug, with no more efficacy and much more risk than generic Aricept, should be entitled to restitution for the conduct of Pfizer and Eisai in marketing Aricept 23.
Dan C. Bolton is Of Counsel in the Los Angeles office of Keller, Fishback & Jackson LLP. The firm represents plaintiffs nationwide in pharmaceutical and medical device litigation, including Aricept 23, hernia and transvaginal mesh, hip implant, and power morcellation cases. Mr. Bolton oversees the pharmaceutical and medical device practice.