Observations Not So Stories

How the FDA forgot the evidence: the case of donepezil 23 mg

BMJ 2012; 344 doi: http://dx.doi.org/10.1136/bmj.e1086 (Published 22 March 2012) Cite this as: BMJ 2012;344:e1086
  1. Lisa M Schwartz, professor12,
  2. Steven Woloshin, professor12
  1. 1VA Outcomes Group, Department of Veterans Affairs Medical Center, White River Junction, Vermont 05009, USA
  2. 2Center for Medicine and the Media, The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire, USA
  1. Steven.Woloshin{at}dartmouth.edu

In the first of a new occasional series highlighting the exaggerations, distortions, and selective reporting that make some news stories, advertising, and medical journal articles “not so,” Lisa M Schwartz and Steven Woloshin challenge the claims made for the new 23 mg dose of donepezil

What is the difference between 20 and 23? If you said three, you are off by millions—of dollars in sales, that is—at least from the perspective of Eisai, the manufacturer of donepezil (marketed as Aricept by Pfizer).

A little context helps make the maths clearer. Donepezil, the biggest player in the lucrative market for Alzheimer’s disease treatments, was a blockbuster, with over $2bn in annual sales in the United States alone. But the drug, first approved in 1996, had reached the end of the road: the patent expired in November 2010. Investors call this “going over the cliff,” an anxious reference to plummeting sales as market share is lost to generic competitors. Necessity, however, is the mother of invention. Just four months before the expiry of the patent, the US Food and Drug Administration (FDA) approved a new dose for moderate to severe Alzheimer’s disease: donepezil 23 mg. Is 23 an odd number? Not really, when you consider that you cannot get to 23 mg using the 5 mg and 10 mg doses that were going generic. The “new” 23 mg product would be patent protected for three more years.

Now it was time for the marketing to begin. In addition to their sales force, the manufacturers deployed dedicated teams of “Aricept 23 mg clinical nurse educators” to reach prescribers. They focused particularly on “priority targets”—neurologists and high volume facilities for the long term care of people with Alzheimer’s disease—to promote the idea that “there are no ‘stable’ AD [Alzheimer’s disease] patients—therefore aggressive treatment is required.”1

But the marketers had to overcome some inconvenient facts. The drug had been approved only over the objections of the FDA’s medical and statistical reviewers.2 3 In fact, approval breached the FDA’s own regulatory standard. In study planning meetings, the director of the FDA’s Division of Neurology Products (the division that oversaw drug approval) told Eisai that the regulatory standard for approval of a drug for Alzheimer’s disease required superiority on both a cognitive and a global measure.4 The rationale for the global measure is to ensure that any statistically significant cognitive difference (for example, performance of tasks such as the correct repetition of a series of three, four, or five digits) represents a real clinical benefit (that is, an improvement that patients or care givers notice). The FDA and Eisai explicitly agreed that the 23 mg dose would be approved only if the drug were shown to be superior to the 10 mg dose on both measures.

But it didn’t. In the approval trial of more than 1400 patients, there was a small statistically significant improvement in cognition (a 2.2 improvement over the lower dose on a 100 point scale) but no statistically significant difference in global functioning (a 0.06 improvement on a seven point scale).5 Further, the higher dose was not superior on either of the pre-specified secondary outcome measures, which, as the FDA medical reviewer pointed out, argues that the cognitive difference was not meaningful.2 (See table.)

Findings of study comparing 10 mg and 23 mg donepezil*

View this table:

The other problem was side effects of the 23 mg dose, including substantially more nausea and vomiting. Russell Katz, director of the FDA’s neurology products division (who ultimately approved the drug), said that “there is a clear increase in the incidence of adverse events on the 23 mg dose compared to the 10 mg dose . . . These are not trivial events; in these patients, these could lead to significant morbidities and even increased mortality.”6

And yet the drug was approved. Why? The same FDA division director (who signed the correspondence stating the regulatory standard for approval, of superiority on both a cognitive and a global measure) said, “In my view, this strongly argues for a conclusion that the 23 mg dose is very likely to also have an effect on overall functioning, despite this not having been demonstrated directly in this study . . . I believe that the sponsor has demonstrated that the 23 mg dose of Aricept is effective . . . I will approve this application.”6

How do you sell a drug at a dose that offers no meaningful added benefit, just more harm? Here’s how.

The manufacturers began a high profile Aricept 23 campaign aimed directly at consumers. The print advertisements, like the drug’s website, make a strong emotional appeal, with loving scenes of people with a spouse or parent with Alzheimer’s disease. The take home message seems clear to us: truly caring people will ask the doctor to prescribe Aricept 23 mg for their loved ones. The advertisement says that the drug improves cognitive symptoms but not overall functioning. But there is no explanation of why that matters. It does warn that more patients taking the 23 mg dose experienced side effects but doesn’t provide any sense of how frequent or serious they are. It does state that “side effects may get better after the patient takes Aricept for a while.”

The advertisement aimed at doctors is worse (Fig). It contains a stunningly erroneous statement in a large bold font: “Patients on Aricept 23 mg/day experienced important clinical benefit on both measures [cognition and overall functioning],” which is simply not true. In fact, this statement is directly contradicted by a statement in a smaller plain font that says that the results for global function “did not show statistical significance.”

Figure1

Part of advertisement for donepezil 23 mg aimed at doctors

FDA regulations stipulate that drug advertisements must be truthful and not misleading. To ensure this, advertisements can make only those claims that appear in the FDA approved drug label. The label (also called the professional package insert) informs clinicians about when and how to use the drug. Although it is often assumed that the FDA writes the label, it is in fact the drug company that drafts it. The FDA’s role is to review and approve the draft label, often after a period of negotiation over specific wording or content. Drugs cannot be marketed in the US until the FDA has approved the label.

Unfortunately the process does not always work well. Labels may be missing important information about the benefits, harms, and uncertainties of drugs.7 Shockingly, the erroneous statement in the advertisement actually appears, nearly word for word, in the label: “This study showed that patients on 23 mg per day experienced important clinical benefit on both measures compared to 10 mg per day.”8 Again, this is directly contradicted by text elsewhere in the label stating that the results for global function were not statistically significant.

Paradoxically, even though it contains the false statement, the Aricept 23 mg advertisement does not break any laws. That is because it simply quotes the label—highlighting the importance of FDA oversight. If the FDA signs off on a label containing exaggerated (or in this case false) claims, these claims may show up in advertisements.

After we contacted the FDA about the erroneous statement, the agency reviewed the Aricept 23 mg label. Dr Katz said, “The offending phrase was in the original label, and we don’t recall how it slipped by, but we contacted the company as soon as it was brought to our attention, and they readily agreed to remove it. We are always interested in improving the content and clarity of our labeling, and appreciate being informed of any misleading or inaccurate statements that anyone may notice.”

The corrected label was approved on 1 March 2012 (more than a year and a half after the original label was posted). When we contacted Eisai for comment the company repeatedly emphasised that the FDA approved the original label.

The 23 mg marketing strategy seems to be working. Government and private insurance programmes now cover the drug. And in the first six months after approval more than 68 000 prescriptions were written for it.1 This number may expand dramatically in the next few years: the 23 mg dose is or will soon be under consideration for approval in 16 countries in Asia and South America.

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, uncertainties that led the FDA’s own medical and statistical reviewers to recommend against approval of the 23 mg dose.

The fact that it was approved—and is still on the market, despite a call by the prominent US consumer advocacy group Public Citizen to have it removed—is disappointing. 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.

Notes

Cite this as: BMJ 2012;344:e1086

References