Tuesday, March 27, 2012

Patents versus patients? Revisiting the Journal Club on donepezil 23 mg

In the March 15, 2011 issue of AFP, Drs. Mark Graber, Robert Dachs, and Andrea Darby-Stewart analyzed an industry-funded trial that compared the effects of two daily doses of the Alzheimer's disease drug donepezil (Aricept): a new 23 mg version and the existing 10 mg version that would soon lose its patent protection. Despite the trial authors' finding that the higher dose of donepezil slightly improved cognitive outcomes, AFP Journal Club commentators determined that this difference was clinically unimportant, and was greatly outweighed by the higher frequency of adverse effects in patients using the higher dose:

First, the authors did four comparisons. Three were negative and only one was positive. And the one that was positive was only two points different on a 100-point scale. So, although this is statistically significant, it is clinically meaningless. There is no discernible benefit for the patient or caregivers. ... Also, the drop-out rate in this study was an astounding 30 percent in the higher-dose group and 18 percent in the lower-dose group.

Adverse effects of donepezil include bradycardia, falls, nausea, diarrhea, and anorexia. In fact, a recent study demonstrated that community-dwelling older persons with dementia who are taking currently available cholinesterase inhibitors have higher rates of hospitalization for syncope, bradycardia, pacemaker insertion, and hip fractures compared with similar patients with Alzheimer disease who are not taking these medications. So, the idea of increasing the dose to 23 mg, potentially resulting in more serious adverse events while achieving no clinical gain, is ill-conceived at best.

Nonetheless, based on this study, the U.S. Food and Drug Administration eventually approved the 23 mg dose of donepezil against the advice of its own medical reviewers. One year later, though, the Journal Club on donepezil has proved to be prescient. Last week, in a scathing editorial published in BMJ, noted physician-researchers Lisa Schwartz and Steven Woloshin echoed AFP's earlier critique. They also rebuked the FDA for allowing Eisai, the manufacturer of donepezil, to include a false statement on the drug label and physician advertisements that touted "important clinical benefits" on measures of cognition (which, as noted, were clinically meaningless) and global function (which were not even statistically significant). Schwartz and Woloshin concluded by calling on the FDA to exercise greater oversight of such ethically questionable practices:

Alzheimer's is an awful disease. Sadly, the available drugs don't work well. But that is no excuse for emotionally manipulating vulnerable patients, desperate family members, and their doctors to use a product that is more likely to add harm than benefit. 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 explained. ... That it is so easy to send doctors and patients incomplete and distorted messages about drugs is depressing. To make good decisions about drugs, doctors and patients need the evidence. The FDA should not forget to give it to them.