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PUBLIC CITIZEN HEALTH RESEARCH GROUP SIDNEY M. WOLFE, M.D., EDITOR March 2004 + VOL. 20, N0 . 3 Overselling Donepezil (ARICEPD and Exploiting Patients v1ith i\lzheimers Disease: Why Isn't the FDA Stopping These Ads? n the 1999 Edition of Worst Pills, patients. The ads proclaim that If this conclusion were based on a Best Pills, we urged patients not patients with Alzheimer's disease randomized, placebo-controlled trial I to use donepezil (ARICEPT), who "persistently" use donepezil are (RCT) (the scientific gold standard for made by Pfizer/ Esai, because of a able to stay in the community and medical research) wherein 50 percent combination of adverse effects such avoid going into a nursing home for of the patients got donepezil and the as nausea, diarrhea and vomiting almost two years more than patients other 50 percent of exactly the same along with serious questions about who have only limited treatment or kinds of patients were randomly clinically significant effectiveness. no treatment with the dmg (see assigned to be given a placebo, it We quoted the prestigious Medical advertisement on page 2 for an would be a major public health Letter, an independent evaluation for example). The implication is star­ breakthrough and a cause for cele­ physicians of newly approved dmgs, tling. The families and other friends bration. Unfortunately, it is not based which stated "There is no evidence who are caring for patients with on such a study and is not any cause that use of... donepezil... leads to Alzheimer's disease will have a for celebration. substantial functional improvement substantial amount of extra time to The study cited as the basis for this or prevents the progression of the have their loved ones in the commu­ seemingly remarkable improvement disease." Since then, Pfizer/ Esai has nity before they have to go into a is flawed. The group on donepezil mn ads that claim the dmg delays nursing home if only the patients are and the group not on donepezil the time to nursing home placement. lucky enough to be persistent users appear to have been as dissimilar as The claim is misleading and an exag­ of donepezil. continued on page 3 geration of the drug's extremely modest efficacy. We wish to rein­ CONTENTS force this recommendation and high­ light the need for the Food and Dmg Product Recalls Administration (FDA) to take action: January 15- February 17, 2004 the ads should be halted and Batteries, fitness machines, and footballs are on our list Pfizer/Esai should issue a retraction. this month ......................................................................................... ... ... 4 In order to boost the sales of this dmg, for over a year Pfizer/Esai have New jersey Slow to Police Problem Physicians mn extraordinarily misleading and Doctor convicted of manslaughter and still allowed to practice .. ... ... 8 predictably highly successful full­ Protecting Yourself from Mad Cow Disease Infection page ads in leading medical journals Tips on what to avoid ........................................ .................................. lO such as the journal of the American Medical Association and the journal Outrage of the Month of the American Geriatrics Society, a Kidney dialysis facilities face serious problems of compliance with journal widely read by geriatricians Medicare quality standards .................................................................. 12 and others taking care of older VISIT HEALTH RESEARCH GROUP'S WEB SITE AT WWW.CITIZEN.ORG/HRG/ The Strength to Meet Dementia* Head On Persistent ARICEPT treatment helped Delayed Time to First Dementia-Related Nursing Home Placement keep Alzheimer's disease (AD) patients in the community nearly 2 years longer 121 Persistent ARICEPT Treatment !n•31Dl s.;l 1 Data are from 2 cohorts ol patients in a prospective, observational follow-up of 671 AD patients from ARICEPT clinical trials for v.llom reason for and time of nursing home placement Umited ARICEPT Treatment !n·l13l were obtained Persistent group-at least 9 to 12 months of ARICEPT; 209 received >2 )<'ars 3.7 of ARICEPT. Um~ed group-s 6 months of ARICEPT. See adjacent page for a detailed study description As with all studies of this type, results may be anributed to various factors ARICEPT treatment was one such factor. Other analyses (sensitivity analyses) varying the length of exposure, ~ •.,. lknt shown Years definitions of compliance (80% and 100%). and double-blind study completion status were conducted. Tllese results were consistent with the study findings shown ARICEPT is indicated for mild througll moderate Alzheimer's disease. The most common adverse events in clinical trials with ARICEPT were nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and anorexia. In clinical trials, syncopal episodes have been reported (2% for ARICEPT versus 1% for placebo}. Clinical studies of ARICEPT have shown no increase. relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal ~, bleeding. Nevertheless, cholinesterase inhibitors may be expected to increase gastric acid secretion. Therefore, patients (especially those at increased risk for developing ulcers-eg, having a history of ulcer disease. receiving concurrent nonsteroidal anti-inHammatory drugs} should be monitored closely for gastrointestinal bleeding Responses to ARICEPT include improvement, stabilization, and less than expected decline. (done~~~.i,l" ~,~,~) • The ma}Oiity of all dementia is caused by Alltleimer's disease · Please see brief summary of prescnbmR mformarion on i'HJjacent page. STRENGTH TO FIGHT DEMENTIAN 2 +March 2004 DONEPEZIL, from page 1 prove conclusively that taking effec­ misleading because it is not support­ the proverbial apples and oranges tive doses of donepezil delayed nurs­ ed by scientific evidence. These rather than being identical in every ing home placement." The article exploitative ads should have been way except for the drug they were further stated that the only way to stopped long ago. Where has the being given, as would have been the prove this finding of delayed nursing FDA been? Why have these mislead­ case in a properly done randomized home placement would be to do a ing ads, clearly exploiting patients placebo-controlled study. randomized double-blind placebo­ with Alzheimer's disease and their The major flaw is what has been controlled prospective trial that families and friends through the referred to as "drop-out-bias", a flaw would assure that the two groups medium of misleading doctors, not in many previous studies claiming to were completely comparable. been stopped long ago? prove meaningful improved social Similarly buried in the copy of the As we have mentioned before, the outcomes with drugs such as ads is the statement that in all "stud­ past five years have seen the virtual donepezil. The study used as the ies of this type, results [delayed nurs­ demise of FDA enforcement of the basis for the misleading ad was a ing home placement] may be attrib­ laws and regulations governing follow-up to previous studies that uted to various factors." prescription drug advertising. False were themselves randomized. The In addition to the drop-out bias and misleading advertising, typically drop-out after this first phase occurs described above, factors such as overstating the benefits and/or when patients were told whether they spousal relationship and willingness understating the risks, constitutes a had been given a drug or a placebo. to stay in research are factors that health hazard because it may result The bias occurs because people drop have themselves (without drugs) in a patient getting a prescription for out based at least in part on how they been shown to improve patient a drug thought to be safer or more felt they did in the RCT and this drop­ outcome and lessen the chances of effective than it actually is. Therefore out almost certainly occurs in an needing to go into a nursing home. there is a relative danger inherent in extremely unbalanced way. Many of the characteristics of the such a "misprescription" compared How does this bias work? If you caregiver and the interaction between to a safer drug that might have other­ are told you got a placebo in the the caregiver and the patient with wise been prescribed. Consequently, earlier study, you are more likely to Alzheimer's disease could well be FDA enforcement of prescription volunteer for the continuation of the quite different in the group getting drug advertising, whether the kind study, regardless of how you "did" "persistent" treatment from the other directed at doctors or at patients, is a on the placebo, because you would group. Hence, exposure to donepezil crucial part of the agency's regula­ like to see how you might do on a may have had nothing to do with the tion of the pharmaceutical industry. "real" drug. If, instead, you were in delay to nursing home. In 1998, the FDA stopped 157 ille­ the group who got drug treatment Indeed, a randomized, placebo­ gal prescription drug ads but in 2003, and you think your short-term controlled study in the United they stopped only 24: an 85 percent improvement was caused by the Kingdom, known as AD (Alzheimer's decrease in enforcement. This is drug, you will be more likely to Disease) 2000, done by Dr. Richard despite the lack of any evidence that continue taking the drug. Conversely, Gray and his colleagues at the the quality or accuracy of such ads if after having taken the drug in the University of Birmingham Clinical has improved. In the face of a previous study you do not perceive Trials Unit, examining the effect of massive increase in prescription drug an improvement, or even got worse, donepezil on outcomes such as nurs­ advertising since 1998 that would, if you are more likely to drop out. ing home placement, was presented anything, argue for an increased Thus, the drop-outs selectively occur almost two years ago at a medical number of FDA enforcement actions in the group who got the drug, not meeting in Stockholm and has been rather than the sharp decrease that the placebo, in the first part of the submitted for publication.

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