A professional marketing promotion for Novartis' Exelon (rivastigmine) capsules and oral solution is misleading because it makes unsubstantiated superiority claims for the Alzheimer's medication over Pfizer's Aricept (donepezil) based on an "inadequate study," FDA's Division of Drug Marketing, Advertising and Communications says in a warning letter issued to Novartis and posted online Aug. 14.

A two-page spread in a multi-page file card given to health care providers includes the claims: "In an open-label study, the majority of donepezil nonresponders responded to Exelon" and "70% of donepezil nonresponders responded to Exelon in this open-label study - Response defined as no change or improvement in [Clinician's Global Impression of Change]."

These statements suggest Exelon is superior to Aricept at treating patients with mild to moderate Alzheimer's disease, which is misleading, FDA says, because the claims are based on the results of an open-label, 26-week, single arm, uncontrolled study that is inadequate in many respects.

For example, the open-label design of the trial is not appropriate to evaluate a subjective endpoint like CGIC, and the study relied on a questionable definition of "response," including patients who demonstrated no change in CGIC, the agency notes.

"This design presumes, however, that patients could not have improved spontaneously, and does not evaluate what would have happened to patients given another treatment, such as placebo, or more pertinently in this case, donepezil," FDA states. "There is good reason to believe patients' historical responses might be different from their response in a formal study, either because conditions are different or because of observer expectations."

Additionally, FDA points to the tagline, "Efficacy matters most," included with the product name and logo in the promotion, as leaving a misleading impression that Exelon is more effective than donepezil.

Beyond the comparisons to Aricept, the promotion further overstates the efficacy of Exelon by highlighting data showing the mean change in the effect on the Progressive Deterioration Scale with treatment, a secondary endpoint in the study for which no method of analysis is specified in the protocol.

"Furthermore, the PDS was used as a secondary efficacy measure in several major studies of Exelon (other than the referenced study), with inconsistent results," the agency notes. FDA says the issue of the PDS data is particularly "troubling" because the agency's Division of Neurology Products already communicated its concerns over the data to Novartis as part of its initial review of Exelon in 1999 and again when the drug was approved in 2000.

FDA also cites Novartis for using claims like, "Significantly reduced aggression at 26 weeks," because the drug has not been shown to manage behavioral aspects of Alzheimer's disease in substantiated studies.

Additionally, statements such as, "Turn to Exelon for a favorable safety profile" and "no increased incidence in cardiac adverse events as measured by electrocardiogram," fail to accurately portray risk information for the drug, FDA says. Labeling includes several warnings such as gastrointestinal adverse events, including severe vomiting in 2 percent of patients treated.

DDMAC is requesting that Novartis immediately cease disseminating the promotion and submit a written response to the agency before Aug. 22.

FDA recently approved a once-daily patch formulation of Exelon for the treatment of Alzheimer's disease. Patients given the target dose of the Exelon Patch had three times fewer reports of nausea and vomiting than with the capsule form of the drug, according to Novartis (¹ Also see "Novartis Adds Patch Formulation To Exelon Franchise" - Pink Sheet, 9 July, 2007.).

Exelon is approved for the treatment of dementia related to Alzheimer's disease and Parkinson's disease.

- Jessica Merrill (j.merrill@elsevier.com)

Novartis Exelon Promotion Cited By FDA For Unsubstantiated Superiority Claims To Aricept

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