[Ip-health] Ann Davis in WSJ on weak R&D as marketing tool for off label use

[James Love]

http://interactive.wsj.com/articles/SB1010364361294762440.htm

January 7, 2002
'Postmarketing' by Makers of Alzheimer's Pill
Raises Questions About the Uses of Research

By ANN DAVIS
Staff Reporter of THE WALL STREET JOURNAL

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.

[[Go]] Should pharmaceutical companies market drugs for potentially 
beneficial but unapproved uses? Participate in the Question of the Day.

"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

-- 
James Love
Consumer Project on Technology
P.O. Box 19367, Washington, DC 20036
http://www.cptech.org, mailto:love@cptech.org
voice: 1.202.387.8030 fax 1.202.234.5176 mobile 1.202.361.3040