Healthy Skepticism Library item: 1566

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Publication type: news

Davis A.
'Postmarketing' by Makers of Alzheimer's Pill Raises Questions About the Uses of Research
The Wall Street Journal 2002 Jan 7
http://online.wsj.com/article/SB1010364361294762440.html?mod=googlewsj

Full text:

Doctors attending an Alzheimer’s disease conference in Orlando, Fla., last January heard some encouraging news: Studies suggested that a drug approved for mild to moderate Alzheimer’s could help even at late stages of the disease.

That would mark a major advance for the drug, known as Aricept, in fighting the debilitating, mind-robbing disease. It surprised listeners such as Walter DeArmitt, an Indiana family doctor. “It was generally felt that it didn’t do any good” for the severely ill, he says. Since hearing about the studies, he says, he has become “more aggressive” in prescribing Aricept.

But these studies won’t win FDA approval to sell Aricept for advanced Alzheimer’s. Its marketers, Pfizer Inc. and Eisai Co. of Tokyo, are years away from having research solid enough to submit to the Food and Drug Administration for permission to make that broader claim. The results outlined to the doctors came simply from so-called postmarketing studies — limited research on already-approved drugs, driven by marketing objectives as well as by science.

Many of these studies wouldn’t pass muster with the FDA because they involve too few patients, aren’t tightly focused or, in some cases, don’t even involve a control group given a placebo. But this doesn’t stop pharmaceutical companies from sharing the results with doctors. Companies sponsor conferences at which the researchers discuss their work, funding honoraria for the speakers and sometimes for doctors who attend. They mail brochures to doctors. Public-relations firms help spread the word about results and coach doctors in how to discuss them with the media.

‘Off-Label’ Issue

The upshot: Postmarketing studies have emerged as a powerful tool for drug makers to get their medicines used more broadly and for longer periods. The companies aren’t allowed to promote approved drugs for unapproved uses, known as “off-label” use. But dissemination of postmarketing research can have the same effect. The way Pfizer — the largest drug maker and one known for especially sophisticated marketing — handles studies of Aricept opens a window on this research practice.

The FDA permits drug companies to sponsor medical conferences where researchers discuss limited or preliminary studies and off-label uses, so long as the companies don’t dictate what is said. The agency treats this as continuing medical education. Claudia Kawas, a University of California scientist and head of an FDA advisory panel, believes a key impetus for postmarket research is companies’ wish to win more customers without the cost and delay of winning a label change from regulators. She considers this research valuable because it helps to fill gaps in knowledge.

Besides, says Russell Katz, director of neuropharmacological products at the FDA, “off-label use is extremely common in all areas of medicine. … That’s the practice of medicine, and we don’t regulate practice of medicine.” The FDA would consider a company to be marketing unapproved uses only if it paid someone to deliver a scripted message recommending such uses.

A Learning Process

Pfizer and Eisai, the marketers of Aricept, deny any effort to promote off-label use of Aricept or to do an end run around the FDA’s drug-approval process. Pfizer says the limited postmarketing studies are simply part of a gradual process of understanding approved drugs better, one that sometimes leads to full-fledged clinical trials that could be submitted to the FDA.

“As you learn more … as science evolves in an area, you start finding potentially other indications,” says Pfizer’s senior vice president for medical and regulatory operations, Joe Feczko. “It’s totally appropriate for the medical staff of Pfizer, for the physicians who’ve been involved in a trial or other consultants who are aware of the data to talk about it.”

Critics see this as a slippery slope. “The problem,” says Lon Schneider, professor of neurology, psychiatry and gerontology at the University of Southern California, “is that Pfizer and its competitors selectively report some of the statistics and sometimes overstate the case. If you’re not careful, you buy into the mantra.” The effect, he says, can be to raise optimism about drugs that are effective, but only modestly so.

In a joint editorial in The New England Journal of Medicine in September — about the industry, not specifically Pfizer or Eisai — editors from 13 leading medical journals said that for companies to use clinical trials primarily for marketing “makes a mockery of clinical investigation and is a misuse of a powerful tool.”

Pfizer and Eisai say the presentation of their studies is faithful to the data. They note that many conferences where their studies are discussed are overseen by academic screeners, that doctors in the audience aren’t shy about challenging them, and that much of the research eventually is published in peer-reviewed medical journals. In addition, company-funded researchers who discuss their work with medical audiences commonly disclose study limitations.

Alzheimer’s is a progressive and largely untreatable disease. The benefit that drugs can have is subtle, often hard for anyone but a trained researcher to detect. Only a minority of those patients who respond show marked improvement. Most, after brief initial gains, merely decline a bit more slowly.

Aricept and competing drugs act by helping preserve the brain’s supply of a key chemical, called acetylcholine. They block an enzyme that breaks it down. Aricept and its main rival drugs — Exelon from Novartis AG and Reminyl from Johnson & Johnson — are known as “cholinesterase inhibitors,” after the enzyme they block.

They are approved only for mild to moderate cases. Some experts doubt that advanced patients have enough intact brain machinery left for the drugs to perform their function. The label for Aricept states that its “effect may lessen as the disease process advances.”

But lately, other scientists have challenged that pessimistic view, and a few long-term cases provide hope. Herb Farr of Chagrin Falls, Ohio, started taking Aricept during a 1994 clinical trial and never stopped. His wife, Janet, says he regained the ability to slowly read a newspaper and write his name. “I’m just really sure that Herb would be a lot worse off” without it, she says of her husband, who is 69.

Pfizer acknowledges some uncertainties, which are partly due to the difficulty of measuring any improvement in a severely demented patient. “There’s not a lot known about the usefulness of these tests in the more severe” cases, says Dr. Feczko. “It’s not even clear whether you can show good impact in severe disease. We’re trying to understand that better.”

Despite the uncertainty, Aricept’s marketers have sought to keep patients on the drug as long as possible, say some former Eisai executives. Eisai originally discovered the drug and sought out Pfizer for aid in marketing it. Around the time Aricept won U.S approval, Pfizer told Eisai the drug would never be a big seller unless patients took it long term, says Sharon Rogers, a former Eisai scientist who had a key role in developing it.

“Everyone felt a sense of urgency … to keep the [patients] on and to make sure we didn’t lose them,” she says, adding that Pfizer called this strategy the “evergreening” of Aricept. Dr. Rogers says her own patient experience convinces her the drug continues working past the moderate stage of Alzheimer’s.

Patrick Kelly, a top Pfizer marketing executive, says “evergreening” is a term “that some have used.” But both Pfizer and Eisai say that “there has not been any promotion of Aricept data in severe patients.”

The medicine, which costs $4 or more a day, met resistance from insurers. Some restricted payment to six months, the length of the trials used to win FDA approval. Some European governments that pay for medicines also resisted long-term coverage. British medical experts argued that gains that showed up statistically didn’t necessarily translate into better quality of life.

Early Postmarketing Study

To combat skepticism, says Dr. Rogers, Pfizer and Eisai approached high-profile academics, known in the drug industry as opinion leaders, to do company-sponsored postmarketing studies and explain the results to medical audiences. One study involved behavioral problems that advanced patients often develop, such as delusions and nighttime wandering. It looked at 208 nursing-home patients, primarily to see whether Aricept reduced such symptoms. Pierre Tariot, a psychiatrist at the University of Rochester (N.Y.) Medical Center, helped design the study and led it.

It was a disappointment. Aricept-treated patients didn’t appear significantly less delusional, anxious, irritable or depressed than a control group. “The primary hypothesis was negative,” Dr. Tariot says.

Still, he found positive things to say about the study. Dr. Tariot told the American Geriatrics Society’s 1999 annual meeting that on traditional measures like memory, Aricept’s “results in this severe population are essentially the same as what you see in mildly impaired outpatients.” Tapes of the meeting show he also said that one behavioral symptom, agitation, when analyzed “under a microscope,” improved enough on Aricept to conclude the effect wasn’t due to chance.

His talk got a frosty reception. One skeptic in the audience said he had found Alzheimer’s agitation actually worsened on Aricept. He also noted that only about a quarter of the patients in the study actually had severe Alzheimer’s.

But the study took on a life of its own. Larry Tune, an Emory University psychiatrist who ran one of the test sites, says he has continued to brief doctors on it, and he believes nursing homes are starting to try Aricept for behavioral problems. “We can’t wait for the absolutely definitive study,” Dr. Tune says. “There’s pressure to do as much as possible for our patients.”

The study was published last month in the Journal of the American Geriatrics Society. A Pfizer-Eisai news release said the study showed Aricept “maintained or improved cognition and global function” in nursing home patients.

The mere fact Aricept was tested on nursing-home residents heightened expectations, says Concetta Forchetti, medical director of a Chicago- area Alzheimer’s center called the Wealshire. She says patients’ relatives “really twist my arm” to continue using the drug, even when she sees no improvement. Sales of Aricept to long-term-care facilities have nearly tripled in four years and now make up a fifth of the drug’s $562 million yearly sales, according to research firm IMS Health.

Widespread Practice

Meanwhile, rivals Novartis and Johnson & Johnson also were doing postmarketing research of their own Alzheimer’s drugs and sharing results with doctors. For instance, a Novartis-funded researcher told a gathering of psychiatrists in Chicago in May 2000 about a study suggesting that nursing-home patients given Novartis’s Exelon had fewer delusions and hallucinations and less nighttime wandering. The study had only 76 patients when it ended and used no placebo controls.

J&J’s Janssen Pharmaceutica unit, meantime, sponsored meetings where doctors were told about postmarketing studies of its drug, Reminyl. One study said patients who had tried and quit other drugs could still benefit from this one. Janssen financed $1,000 stipends for several dozen doctors to attend a “national speaker training” meeting in Dallas last March. After hearing about the studies, the doctors filed into “coaching workshops,” where they were videotaped and critiqued on how best to present study data to colleagues when they got back home. Novartis and Janssen say they are careful not to overstate results.

Throughout the drug industry, postmarketing studies are growing more popular. The industry is increasing its research spending on already- approved drugs faster — by 17% to 18% a year — than its spending to research potential new drugs, says CenterWatch Inc., a clinical-trial monitoring firm in Boston.

Another study that Pfizer and Eisai sponsored — billed as a study of “moderate to severe” Alzheimer’s patients — found improved scores on cognition, behavior and the activities of daily living among patients who took Aricept. “This shows us that the anticipated ‘trap- door’ — that point after which we would be inclined to say the patient can’t be helped — is not a valid assumption,” researcher Howard Feldman of the University of British Columbia said during an Alzheimer’s conference in Sweden in April 2000. Yet of the 290 patients in the study, only about 80 actually had severe dementia.

Small samples raise red flags. Zaven Khachaturian, former head of Alzheimer’s research for the National Institutes of Health, says that given the modest effects of the Alzheimer’s drugs and the difficulty of measuring symptoms, any study with fewer than several hundred to 1,000 people would be problematic.

John Ieni, Eisai’s senior director for medical affairs in the U.S., acknowledges the study’s limits, including the fact that subjects were at varied stages of the illness. “It would be a supportive study but not a pivotal trial,” he says. Dr. Feldman says that when he and the companies ran the results for just those patients who had advanced Alzheimer’s, no conclusions could be drawn about Aricept’s effect, partly because the sample was so small. The study was published in August in the journal Neurology.

Staying Out of Nursing Homes

A third Aricept study that Pfizer and Eisai have been describing to doctors suggests the drug might keep Alzheimer’s patients out of nursing homes longer. Patients who took Aricept during clinical trials and stayed with it long afterward, the study found, were able to function at home about 21 months longer than patients who took Aricept for a shorter time or not at all.

The study proves little, say some clinical-trial experts. The companies had offered patients a free drug supply after the trials ended in the mid-1990s. Years later, the companies looked at those who stayed on Aricept — at least those they could locate — and found that, on average, they remained out of nursing homes longer.

What can’t be determined is why, says Kenneth Davis, psychiatric chairman at Mount Sinai School of Medicine in New York. Citing just one problem with the study, he notes that patients who had dedicated care-givers might have been more likely to stay on Aricept. And these same patients might have been more likely to stay at home longer — simply because they had a dedicated care-giver.

Pfizer’s chief of Alzheimer’s research, Tom McRae, agrees that the study doesn’t show cause and effect. But he says the association is “very strong” between the drug and a delay in entering a nursing home, adding: “We tried to make sure we were eliminating any kind of ‘selection bias’ by doing a variety of analyses.”

The main way drug makers disseminate results of postmarketing studies like this is by sponsoring medical-society meetings at which researchers present their data to other doctors. But sometimes, drug makers also target the general public.

P.R. Initiative

Last spring, a public-relations firm coordinated an Alzheimer’s media campaign, recruiting doctors to talk to the news media about the disease and about Aricept. One “message point” the doctors were expected to relay was that Aricept could delay entry into a nursing home, says Michelle Rabil, who worked on the project for Hill & Knowlton.

“As our spokesdoctor, you will be expected to mention the product as appropriate during all media interviews,” including “the benefit of long-term treatment,” said a recruitment letter Hill & Knowlton sent to a doctor on March 8. It added: “We do NOT want the interview to come across as a commercial for Aricept — quite the contrary, since mentioning the product excessively lowers credibility.”

Asked about this, Pfizer and Eisai said the mass media are a good way to raise the public’s awareness of how Alzheimer’s disease can be treated.

Sales Tactics

The FDA, while permitting dissemination of postmarket-study results to doctors at medical gatherings, doesn’t allow drug-company salespeople to mention them unless doctors inquire. Yet Eric Buchalter, a psychiatrist in Mineola, N.Y., says that Aricept sales representatives are “definitely pushing the fact that … no matter what the stage of the disease is, it can be of assistance.”

Pfizer and Eisai say their salespeople promote Aricept “only in adherence with current product labeling.”

The limited studies raise a puzzling question: Why didn’t the companies start research years ago on severely ill patients that would be hefty enough to take to the FDA for a wider marketing mandate? Pfizer and the researchers say one reason is that diagnostic tools haven’t been sensitive enough to measure severely ill Alzheimer’s patients’ conditions.

Now, Pfizer and Eisai do plan to enroll 440 severely ill patients in a test of Aricept. It is a step toward possibly applying for the right to label the drug for such patients.

The study will be overseen by Rachelle Doody, a Baylor College of Medicine professor who worked on some of the initial clinical trials and appears frequently on Pfizer- and Eisai-sponsored medical panels. It was she who described Aricept’s promise for all stages of the disease to the Orlando conference, a meeting to which Pfizer and Eisai had invited several hundred doctors and clinical researchers.

Dr. Doody stresses in her presentations — as do all of the company- sponsored Aricept researchers — that more needs to be learned about how the drug works. That’s what postmarketing studies are for, she says.

In the interim, Dr. Doody says, “It’s fascistic to try to control information and say, ‘Because this local doctor might overstate the case, let’s not tell him about this.’ “ She says her own clinical practice with Aricept and severely ill Alzheimer’s patients convinces her that Pfizer and Eisai are onto something. If her saying so publicly “improves their sales and their marketing,” she says, “so be it.”

Write to Ann Davis at ann.davis@wsj.com

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