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Another Part of the Battle:
Keeping a Drug in the Store
By JEFF GERTH and SHERYL GAY STOLBERG
New York Times, December 13, 2000
Adell Buggs walked into the federal courthouse in
downtown Rochester on a cold and snowy Tuesday in December 1999, not knowing
quite what to expect. She walked out with a promise from one of the world's
biggest pharmaceutical manufacturers to pay her $1.3 million.
Six years earlier, Ms. Buggs, then a 28-year-old
counselor for needy children, had suffered a stroke that her doctors attributed
to an ingredient in her over-the-counter decongestant, Tavist-D. She sued
the manufacturer, the pharmaceutical giant Novartis A.G., saying its cold
pills had left her with brain damage.
Novartis, based in Switzerland, had a strong defense:
the ingredient, phenylpropanolamine,
or PPA, was in dozens of cold remedies, as well as appetite
suppressants, and had been taken in billions of doses with no ill effects.
But by the time Ms. Buggs arrived in court, Novartis
knew something the public did not:
Yale University researchers had tentatively concluded that PPA was linked
to a slight risk of stroke in young women. The company
offered to settle, and Ms. Buggs accepted. But there was a condition:
she could not discuss specifics of the settlement.
Ms. Buggs had initially hoped that a trial would
lead to publicity about PPA. Instead, she remained silent - until last
month, when the Food and Drug Administration announced plans to ban phenylpropanolamine.
The Yale study had led the agency to estimate that PPA
caused 200 to 500 strokes each year; it said the risk, while
slim, outweighed the drug's benefits as a decongestant and a diet pill.
Drug companies protested, saying that the Yale scientists
were wrong and that the drug was safe. But nonetheless, they removed the
products from store shelves. Ms. Buggs was elated. "Now," she
said, "people will see."
The Buggs case offers a glimpse into how companies
marketing PPA worked aggressively to assuage concerns about the safety
of a drug that for six decades was a staple in American medicine cabinets.
It also sheds light on a larger issue: pharmaceutical
companies, which spend more than $20 billion a year researching and developing
medicines, devote far less attention to examining how their drugs are
used by consumers.
In the case of PPA, safety questions simmered for
two
decades on three fronts: in scientific circles,
the courts and in Washington. In each arena, an examination of court records
and other documents shows, pharmaceutical companies or their representatives
tried to tamp down the public debate.
In scientific circles, a university pharmacologist
acted as a reviewer for medical journals considering whether to publish
reports on PPA, while he was on the payroll of the leading diet pill manufacturer,
Thompson Medical Company. His anonymous critiques helped relegate some
articles that questioned PPA's safety to little-known journals.
In the courts, PPA makers faced more than two dozen
lawsuits, but the cases were not widely publicized because they were usually
settled with confidentiality agreements. In two cases,
patients had died. In another, the court record was sealed. And in Washington,
Sandoz Pharmaceutical Corporation, a predecessor to Novartis and the original
manufacturer of Tavist-D, pressed regulators to keep cold medicines out
of the PPA safety review.
Thompson Medical no longer exists; it sold its diet
pill line to Chattem Pharmaceuticals, whose officials declined comment.
Novartis officials, citing pending litigation, also would not discuss
the issue.
Keeping PPA on the market was especially important
for diet pill manufacturers, because virtually all other weight loss ingredients
were withdrawn by the F.D.A. in the wake of a congressional inquiry in
1990. But in any event, Dr. R. William Soller, senior vice president of
the Consumer Healthcare Products Association, the trade group that represents
manufacturers of over-the- counter medicines, said there was no need to
withdraw PPA because the companies had ample evidence of its safety, which
they had submitted to the F.D.A. throughout the 1980's and early 1990's.
In 1992, the F.D.A. demanded a more thorough investigation,
which resulted in the Yale study. The industry helped design it, and paid
for it, at a cost of more than $5 million.
Such research is rare, said Dr. Louis Lasagna, an
expert on drug development at Tufts University who helped oversee the
Yale study at the request of Dr. Soller's group. Dr. Lasagna said drug
manufacturers do not devote enough research to looking at what makes their
drugs "more effective or more tolerable." He added, "There's
very little money spent on it; the
emphasis is on getting the drug to market."
Even as questions were being raised about the potential
dangers, at least one company, Sandoz, declined to pay for additional
research.
"The only advantage for funding this study
is that we may be able to get an early read on the results," Mark
B. Gelbert, a company official, wrote in June 1994, as the Yale study
was about to begin. In recommending against financing the study, Mr. Gelbert
noted that the company might get an early look at the results anyway,
"if the study begins to turn sour."
The
Yale study bought PPA six additional years. Had it not been underway in
1994, said Dr. Charles Ganley, director of the F.D.A.'s division of over-the-counter
drugs, "the agency probably would have proceeded to take PPA off
the market back then."
Meanwhile, drugs containing PPA generated hundreds
of millions of dollars in sales. Senator Ron Wyden, the Oregon Democrat
who as a congressman in 1990 held hearings on the diet industry, said
in a recent interview that he was troubled by the delay.
"This is a textbook case," Mr. Wyden said,
"for how a powerful industry that is willing to pull out the stops
can be successful in preventing an objective evaluation of an important
drug ingredient."
Concerns Emerge in 1970's
Phenylpropanolamine
had already been used as a decongestant for two years when, in 1938, Congress
gave the F.D.A. authority to regulate the safety and effectiveness of
medicines. Like other drugs already
on the market, it was grandfathered; its manufacturers never had to satisfy
the rigorous testing requirements for new medicines.
PPA works to clear nasal passages by constricting
blood vessels, which become inflamed during infection. Later on,
it became commonly used in weight loss drugs because it resembles amphetamine,
which as a stimulant helps suppress appetite.
Safety concerns about PPA did not emerge until the
late 1970's, when some marketers packaged it with caffeine and ephedrine,
another stimulant, in black capsules to look like amphetamine. Soon, these
"look-alike black beauties" were landing patients in emergency
rooms.
Some doctors theorized that PPA caused strokes by
raising blood pressure. In 1981, the advocacy group Public Citizen warned
against PPA's use, as did an editorial in The Journal of the American
Medical Association. The next year, consumer advocates asked for PPA to
be withdrawn.
But some pharmacologists were not convinced. Among
them was Dr. John P. Morgan, a professor of pharmacology at City University
of New York who has conducted studies of PPA for the industry. Dr. Morgan
said PPA was only a weak stimulant, and he was skeptical of the blood
pressure theory. With so many people taking PPA, Dr. Morgan has long argued,
some were bound to have strokes, just by coincidence.
In the early 1980's, Dr. Morgan's research caught
the attention of Danny Abraham, the chairman of Thompson Medical, and
he was hired as a consultant.
Mr. Abraham is best-known for creating Slim-Fast
foods. But he also, almost single-handedly, created the PPA diet pill
market, naming his pills Dexatrim, Dr. Morgan said, to echo that of a
popular amphetamine, Dexedrine.
Mr. Abraham, now retired, did not respond to requests
for interviews. But Dr. Edward Steinberg, Thompson's former vice chairman,
said, "The company was very open-minded and interested in gathering
as much information as possible."
The relationship between Thompson and Dr. Morgan
lasted more than 15 years; he served as the company's part-time medical
director. Thompson paid a retainer to his academic employer, the City
University of New York. Dr. Morgan said he took some of the money as salary
and used the rest for expenses. And when Dr. Morgan organized a conference
on phenylpropanolamine, Thompson paid the $100,000 bill.
The session, which at Dr. Morgan's insistence featured
proponents and critics of PPA, led to a 1985 book. "The F.D.A. was
quite impressed," Dr. Morgan said, "and the pressure let up."
Lawsuits in the 1980's
But the pressure was not off in the courts.
In 1988, Brian Glaser, a 20-year-old Dexatrim user,
collapsed while in line at a Detroit bank and suffered a stroke. Mr. Glaser
sued Thompson; in its defense, the company tried to bar the testimony
of Dr. Gary Zaloga, an emergency room physician whose research questioned
the safety of PPA. But the company settled after a federal appeals court
ruled in 1994 that Dr. Zaloga was an expert.
Also in the late 1980's, Rose Gorskow, a Minnesota
nurse, filed suit, claiming that Dexatrim caused her to suffer a stroke.
The case settled, her lawyer, Ed Natonich, said. "I can't tell you
the outcome," Mr. Natonich added, "because of confidentiality
agreements that, I believe, are contrary to public policy."
Dr. Morgan said he reviewed more than two dozen
lawsuits for Thompson and most settled out of court. He also published
his own research on PPA, often rebutting studies by two critics, Dr. Zaloga
and Dr. C. Raymond Lake, now a professor of psychiatry at the University
of Kansas, who was interested in the drug's effects on the brain.
In
1989, Dr. Lake published a review of 142 reported reactions to PPA, a
study often cited as evidence that PPA might be unsafe.
That same year, Dr. Morgan helped write a study led by Dr. George Blackburn,
a nutrition expert at Harvard Medical School, that found the rise in blood
pressure caused by PPA was "clinically unimportant."
The Blackburn-Morgan study, which the industry trade
group cites as evidence that PPA is safe, appeared in The Journal of the
American Medical Association. Drs. Lake and Zaloga, however, were unable
to achieve such notice. Unbeknownst to them, Dr. Morgan was the reviewer
of their work, and he persuaded journal editors - he would not say whom
- to reject it.
Professionally, Dr. Morgan said, he thought his
criticism was well-founded. Even so, he said, he has recused himself on
one occasion. And on a personal level, he felt badly for his fellow researchers.
"That poor Dr. Lake published five papers
in a short time," Dr. Morgan said in a court deposition last year.
"They were, most of them, turned down from the first journal, because
I disagreed with them."
Hearings in the 1990's
There was a time, around 1990, when Ron Wyden joked
he was "one of the few people in America who could pronounce phenylpropanolamine."
That year, Mr. Wyden, as head of a House subcommittee
on small business, held hearings on the diet industry, and PPA emerged
as an issue. An Iowa couple testified that their daughter died after overuse
of PPA diet pills, and other witnesses, warning that PPA was dangerous,
bemoaned the lack of independent research. The industry responded with
stronger warning labels. But Mr. Wyden pressed the food and drug agency
to investigate.
Until then, questions about PPA revolved largely
around diet pills; now an entirely different category of medicines - cold
and cough remedies - was about to get dragged into the fray.
Standing anxiously on the sidelines was Sandoz,
the maker of Tavist-D. The drug, used widely for allergies, also contained
a prescription antihistamine. Sandoz wanted to sell the drug over the
counter, but they worried that a PPA inquiry would complicate their plan.
They asked their Washington lawyers to quietly inquire about the F.D.A.'s
plans.
In memorandums on record as part of the Buggs case,
the lawyers reported that the "agency initially hoped to respond
to Rep. Wyden's concerns quietly and without public attention." But
by early 1991 the agency had a new commissioner, Dr. David A. Kessler,
who ordered a public hearing on PPA. The Sandoz lawyers learned the agenda
contained a small mention of decongestants. So they recommended "no
further effort to interfere with or restructure" the agency's plans.
The hearing on May 9, 1991, explored the agency's
concern about hemorrhagic stroke, a type caused by bleeding in the brain.
Reports of these strokes had been emerging in young women and first-time
users of PPA for reasons that are still unclear. A review of reported
reactions found that 14 percent of those with PPA involved stroke, compared
to 1 percent for other drugs.
But only 8 out of 100,000 people from age 18 to
49 suffer hemorrhagic strokes each year. With millions of people taking
PPA, documenting any association could only be accomplished through a
large, carefully conducted study that might take years.
Over-the-Counter Sales
in 1992
Meanwhile, Sandoz was working to keep PPA out of
an F.D.A. review of whether Tavist products could be sold without a prescription.
"PPA should not be a factor," Gregory
Torre, the company's top regulatory officer, told an F.D.A. official,
according to Sandoz documents.
The company got its wish. When the panel convened
in March 1992, Sandoz provided the F.D.A. with scientific data demonstrating
the safety of its product, and PPA did not become an issue.
The
Tavist line went over-the-counter in August
1992. After a year, and a $40 million advertising campaign, Tavist products
had become the company's top-selling nonprescription brand. Court records
show they exceeded $100 million in sales - about 80 percent was profit.
But the seeds of PPA's eventual demise were planted
a few months later, on Nov. 9, 1992.
On that day, F.D.A. officials, who by this time
were demanding more safety research on PPA, met with members of the nonprescription
drug trade group and two Yale scientists, Dr. Ralph I. Horwitz, an epidemiologist,
and Dr. Lawrence M. Brass, a stroke expert. They gathered to work out
the details of a plan by Drs. Horwitz and Brass to examine whether PPA
was associated with an increased risk of stroke among young women and
first-time users.
"My bias at the time," Dr. Brass said,
was that "the data for an association is pretty weak."
The study began in September 1994. Thompson Medical
and Ciba-Geigy, which manufactured the diet pill Accutrim and later merged
with Sandoz to form Novartis, paid for it. The industry played a hands-off
role, although Dr. Brass said Mr. Abraham routinely expressed interest
in the safety of PPA. Dr. Brass remembered that "He said, `Listen,
if you guys tell me that you really think there is something going on,
I'll take it out.' "
By the time the Yale study was over, Mr. Abraham
was out of the diet pill business.
Ms. Buggs's Stroke in
1993
Odell Buggs was just the type of stroke victim the
Yale investigators were interested in. She was young, and had never taken
a decongestant before her stroke in February 1993.
That month, Ms. Buggs was fighting a cold. Determined
to finish a grant application for the neighborhood youth center where
she worked, she took Tavist-D for three days. On the fourth day, Feb.
12, she woke up with a headache.
Her next memory was of lying in a hospital bed with
a shunt in her head, inserted by doctors to relieve bleeding. A medical
toxicologist suggested that PPA might be to blame. It took Ms. Buggs three
years to sue.
The first lawyer she consulted said "it was
not a winnable case." The second was Robert Brenna, a Rochester sole
practitioner who had represented Ms. Buggs in a dispute with a car dealer.
He persuaded Terrence McCartney, a New York lawyer who had experience
in PPA litigation, to help. They filed suit against Sandoz on March 4,
1996.
The case dragged through the courts for two years,
as Mr. Brenna and his partners repeatedly pressed Sandoz, and later Novartis,
for documents relating to Tavist-D. The company denied holding back records,
but the judge appointed a special master to investigate. Ms. Buggs' legal
team, meanwhile, reached out to other lawyers suing the company.
They learned that in New York, Novartis had put
forth a highly interesting defense in a case involving allegations that
another drug, Parlodel, had caused a stroke. The company offered experts
saying PPA might have been the cause.
And in Annapolis, Md., a young stroke victim who
had taken Tavist-D was also suing. Her lawyer was helpful at first, Mr.
Brenna said, but backed off last year when his case was about to settle.
"The door was being shut on him," Mr. Brenna said.
The lawyer, Thomas McCarthy Jr., said he could not
discuss his suit. A clerk at the county courthouse in Annapolis explained
why: the entire record is sealed.
The Yale Report in 2000
The Yale University team reported their final results
to the Food and Drug Administration in May, nearly six years after their
study began. Dr. Brass said he was surprised by the findings: women aged
18 to 49 who took PPA for weight loss were roughly 15 times as likely
as others to suffer hemorrhagic stroke, and first-time PPA users were
three times as likely.
The Consumer Healthcare Products Association, the
over-the-counter trade group, disavowed the Yale results, and hired some
of the nation's leading epidemiologists to critique the study. At a a
hearing in October, before a panel of advisers to the Food and Drug Administration,
they said the study was not statistically significant, noting that its
findings rested on fewer than a dozen cases of stroke.
In response, agency scientists said they looked
at the raw data from the Yale study - the largest ever on hemorrhagic
stroke - and confirmed its conclusions. Given the rarity of such strokes,
they said, the small numbers were not surprising.
Dr. Morgan was in the audience that day, as was
Dr. Lasagna of Tufts; both said they could see the handwriting on the
wall. At one point, Dr. Lasagna said, Dr. Morgan leaned over and whispered,
"It's doomed."
His prediction was correct; the panel voted overwhelmingly
that day to recommend PPA be withdrawn. Dr. Soller complained later that
it was "a preordained result." Even so, the company moved quickly
to take PPA out of pharmacies. Some decongestant manufacturers said they
would reformulate with pseudoephedrine. Chattem Pharmaceuticals, the maker
of Dexatrim, has already begun marketing the pills using ephedra, an herbal
stimulant.
Scientific debate continues over whether PPA should
have been withdrawn. In
the final analysis, the F.D.A. said, the drug's benefits are limited:
it has not been proven to reduce weight over the long-term, and there
are other decongestants available.
Dr. Blackburn, the Harvard nutrition expert whose
study the industry cites as evidence PPA is safe, said the agency did
the right thing. Dr. Morgan disagrees. But a tiny part of him has doubts.
"I'm still thinking and still worried,"
he said, "worried that I could be wrong."
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