Experts Challenge FDA Approval of New Donepezil Dose

Fran Lowry

April 02, 2012

April 2, 2012 — Approval for the new 23-mg dose of the Alzheimer's disease (AD) drug donepezil (Aricept, Eisai) "breached the FDA's own regulatory standard" and has led to "incomplete and distorted messages" about the agent, experts say.

Steven Woloshin, MD, and Lisa Schwartz, MD, both of the Center for Medicine and the Media at the Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire, note that the head of the US Food and Drug Administration's (FDA's) Division of Neurology Products went against the recommendations of his own medical and statistical reviewers when he decided to grant approval for a 23-mg dose of donepezil for the treatment of AD.

Drs. Lisa Schwartz and Steven Woloshin

In an article published in the British Medical Journal, Drs. Woloshin and Schwartz provide their view on the approval of the 23-mg dose of donepezil, which is manufactured by Eisai and is co-promoted by Pfizer and Eisai as Aricept, and challenge claims that it is more effective than the 10-mg dose.

The decision to approve the higher dose of the drug despite lack of evidence that it was superior to the lower doses of the drug that were currently on the market is indicative of a bigger, underlying problem, which is how the FDA communicates what it knows to the public, Dr. Woloshin told Medscape Medical News.

"We spend a lot of time watching how the FDA communicates drug information to doctors and patients," he said in an interview. "We saw a small news brief in the BMJ about a petition that Syd Wolfe of Public Citizen had, wanting the 23-mg dose of donepezil pulled from the market."

Dr. Woloshin was referring to Sidney Wolfe, MD, a physician who is the director of Public Citizen's Health Research Group, a consumer and health advocacy lobbying group.

"We didn't see any American media coverage about it, and so we started looking into it, and the more we delved into the FDA documents, the more amazing things we found," he said.

Blockbuster Drug

Specifically, Drs Schwartz and Woloshin discovered claims on the label of donepezil 23 mg that the 23-mg dose was superior to the 10-mg dose on both a cognitive and global measure.

With over $2 billion in sales annually in the United States alone, donepezil was a blockbuster drug. Just 4 months before its patent expired, the FDA approved the new higher dose for moderate to severe AD.

When marketing of the new dose began, "the marketers had to overcome some inconvenient facts," Drs. Schwartz and Woloshin note. "The drug had been approved only over the objections of the FDA's medical and statistical reviewers. In fact, approval breached the FDA's own regulatory standard."

Russell Katz, MD, leader of the FDA's Division of Neurology Products, approved the 23-mg dose of donepezil "for reasons that are hard to understand," Dr. Woloshin said.

The 23-mg dose of donepezil is associated with more nausea and vomiting — side effects that can lead to significant morbidities and even death.

"Russell Katz, in his comments, actually pointed out that these are not trivial problems. He says there's a clear increase in incidence of adverse events in the 23-mg dose compared with the 10-mg dose. So I don't understand his logic," Dr. Woloshin said.

No Comment

Medscape Medical News asked the FDA's Office of Public Affairs for an interview with Dr. Katz, but the request was denied.

"We have a citizen petition in house on this issue that we are in the process of reviewing and responding to, and we cannot comment," FDA press officer Sandy Walsh said.

Instead, Walsh indicated that Dr. Katz's approval memo can be read online.

"I believe that the sponsor has demonstrated that the 23 mg dose of Aricept is effective, and that there is sufficient reason to believe that it may produce an increased benefit compared to the 10 mg dose in some patients. For these reasons, then, I will approve this application, with the agreed upon labelling, and with the PMRs [post-marketing requirements] discussed above imposed," Dr. Katz concluded.

Dr. Woloshin said he would like to see the uncertainties about donepezil explained and brought to the public's attention.

"The drug companies write the labels. And for this label for donepezil, there is no way to know that there was any controversy or any concern about whether this drug actually had more benefit than harm, or any internal debate about whether the drug should be approved. There is no attention being paid to the way labels are written. We think the FDA should be writing the label and not the drug company," he said.

Dr. Schwartz and Dr. Woloshin have disclosed no relevant financial relationships.

BMJ. Published online March 22, 2012. Abstract


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