Bayer: "Delay mandatory implementation of FDA recommendation. Blunt PR impact
by highlighting questionable study conclusions as they pertain to
cough/cold products. Begin shipping PPA-free product as soon as
A Dose of Denial
How drug makers sought to keep popular cold and diet remedies on store shelves after their own study linked them to strokes.
By Kevin Sack and Alicia Mundy
March 28, 2004
Tracy Patton had just arrived at a community theater rehearsal in August
2000 when she felt such a searing explosion in the back of her head that
it knocked her to her knees.
DIMINISHED: Tracy Patton, 41, has had difficulty with simple tasks since
her stroke in 2000.
At the hospital in Louisville, Ky., doctors said Patton, then 37, had
suffered a catastrophic stroke, and they predicted she wouldn't survive
Patton defied the odds. But nearly four years later, she is so
overwhelmed by simple tasks that she must post a "personal hygiene
checklist" in her bathroom to remind herself to brush her teeth and
flush the toilet.
At 15, Tricia Newenham was full of promise when she suffered her stroke
in October 2000 while hanging out in her bedroom with a cousin. A Down
East Mainer from a family of woodsmen and lobstermen, she had been named
her middle school's student of the year and was on track to become the
first Newenham to attend college.
LIVES CHANGED FOREVER: Tricia Newenham, 18, is embraced by her mother,
Patricia Bybee, three years after a stroke left Tricia blind and
mentally disabled. Shortly before her stroke, she had taken a cold
product containing PPA.
She spent a month in a coma, and emerged totally blind and profoundly
mentally impaired. When reminiscing about her former self, about her
prom dates and nights at the movies, she dissolves into inconsolable
sobbing, condemned to remember just enough of what her life was like
then to understand how much less it is now.
Only hours before these devastating strokes, each victim had washed down
a seemingly innocuous over-the-counter cold medicine, one of billions of
doses consumed annually nationwide. The medicines contained
phenylpropanolamine, or PPA, the active ingredient in scores of popular
nonprescription decongestants and diet aids until November 2000, when
the Food and Drug Administration declared PPA unsafe and asked drug
companies to stop selling it.
By then, the drug industry had spent more than two decades fending off
growing evidence of a possible link between PPA and hemorrhagic stroke.
But Patton and Newenham were among hundreds of PPA consumers who
suffered attacks after a landmark study -- sponsored by the drug
industry itself -- concluded in October 1999 that the use of PPA was
associated with an increased risk of that deadliest form of stroke.
Recently obtained internal company documents show that rather than
alerting the public during cold season, drug makers launched a yearlong
campaign to keep the results quiet and stall government regulation. By
the time the FDA acted, 13 months and hundreds of strokes later, the
companies had reformulated their brand names with little interruption in
sales. The market for PPA has been estimated at $500 million to $1
In the interim, Americans continued to purchase PPA products right off
the shelf and assume they were safe.
"It was in the store. Everyone uses it. It must be all right."
-- Tim A. Bybee, stepfather of Tricia Newenham, who suffered a stroke
after taking Triaminic cold syrup
"It never even dawned on us," said Tim A. Bybee, Newenham's stepfather,
speaking of the Triaminic cold syrup Tricia took shortly before her
stroke. "It was in the store. Everyone uses it. It must be all right."
The Times reviewed thousands of pages of documents produced through
discovery in PPA lawsuits and obtained from the FDA through a Freedom of
Information Act request. The documents demonstrate that the
pharmaceutical industry consistently challenged any notion that PPA
could be dangerous and dismissed evidence to the contrary. They also
show that the manufacturers assured the public that PPA was safe even as
some FDA scientists and industry officials were raising concerns.
. FDA Draft Report on Risk of Stimulants, February 1982
. Sandoz Medical Services Department Analysis of Parlodel Cases, April
As early as 1982, an FDA report warned that PPA had "the ability to
cause cardiovascular effects, cerebral hemorrhage and cardiac
arrhythmias." Two years later, a memo from the medical services
department at Sandoz Pharmaceuticals, which made the PPA products
Triaminic and Tavist-D, referred to PPA as "an agent known to cause
hypertension and stroke."
Yet the drug companies accelerated their marketing of PPA, winning FDA
approval to sell prescription PPA products on an over-the-counter basis
and introducing flavorful new formulas for children.
Upon learning that the 1999 study had found a stroke link, the drug
makers opened a relentless assault on its methodology and on the
integrity of the Yale University researchers who conducted it. They did
so despite having paid for the five-year, $5-million study themselves,
approving its protocol and handpicking investigators who had previously
expressed skepticism about a link between PPA and stroke.
Some documents show that the companies hoped to survive the 2000 cold
season without pulling PPA products. Rarely do the internal memos
indicate concern by corporate officials that PPA might pose a threat to
Draft of Bayer PPA Crisis Action Plan, Nov. 5, 2000
Early in November 2000, for instance, two weeks after an FDA advisory
panel concluded that PPA could be hazardous, an official with Bayer,
which made Alka-Seltzer Plus with PPA, drafted a proposed "PPA Crisis
Action Plan." Its stated objectives: "Delay mandatory implementation of
FDA recommendation. Blunt PR impact by highlighting questionable study
conclusions as they pertain to cough/cold products. Begin shipping
PPA-free product as soon as possible."
Terry O. Tottenham, a lawyer for Bayer, said the plan was not
implemented. But records and interviews show the industry largely
followed that course.
The FDA eventually recommended the withdrawal of more than 100 PPA
products, including popular cough and cold brands such as Robitussin CF
and Dimetapp, and appetite suppressants such as Dexatrim and Acutrim.
FDA officials said they did not move faster because the industry's
efforts to discredit the Yale results effectively delayed the delivery
of a final report.
"There were obvious concerns that we weren't getting the data because it
was being held up by the people who sponsored the study," said Dr.
Charles J. Ganley, director of the FDA's Division of Over-the-Counter
Left in the Dark
Once the FDA stepped in, the manufacturers issued press releases, posted
notices on websites and wrote letters to doctors, pharmacists and
retailers advising them of the agency's action. But after the products
were withdrawn, neither the companies nor the FDA mounted major
advertising or direct-mail campaigns to warn Americans they might have
dangerous products in their handbags and homes.
A survey commissioned by plaintiffs in lawsuits over PPA estimated that
3.5 million U.S. households still possessed PPA formulations a full 15
months after the withdrawals were requested in November 2000.
The wife of a Mississippi stroke victim says she purchased Alka-Seltzer
Plus with PPA from a convenience store in April 2001, six months after
it was supposed to have been removed. Her 45-year-old husband took two
packets over two days, began convulsing, and now is confined to a
wheelchair, according to his lawyer. Both the retailer and the
wholesaler have testified in depositions that they were never alerted by
Bayer or the FDA. The couple are suing Bayer and Double Quick Inc., the
Even now, the industry's attacks on the study it commissioned are its
primary defense against more than 2,500 lawsuits filed by plaintiffs who
say they suffered strokes shortly after taking products with PPA.
Spokespersons for each of the major manufacturers of PPA products said
in interviews or written responses that they continued to believe PPA
was safe, despite the study's findings.
"We did not believe then, nor do we believe now, that PPA was dangerous."
-- Terry O. Tottenham, lawyer for Bayer
"We did not believe then, nor do we believe now, that PPA was
dangerous," wrote Tottenham, the Bayer lawyer. "In fact, we believe the
PPA in those medications was safe and effective and did not, in any way,
cause or contribute to hemorrhagic stroke or any other circulatory
disease, when used as directed." Tottenham said that there was "no valid
scientific evidence" of an association and that the Yale study, when
"properly analyzed, does nothing to change this conclusion."
The Consumer Healthcare Products Assn. (CHPA), the leading
nonprescription drug trade group, declined to comment for this article.
But its former longtime president, James D. Cope, who took a previously
scheduled retirement shortly after the study's completion, said the drug
companies would have been well-advised to accept the findings. "Industry
was convinced that if a proper study would be done, the results would
come out where they wanted them: safe and effective," he said. "It
didn't. And since it didn't, and they designed the best study they
could, I think they have to live with it."
The manufacturers include some of the largest drug companies in the
world -- Bayer; Novartis, which absorbed Sandoz in a merger; Wyeth,
which makes Dimetapp and Robitussin CF; GlaxoSmithKline, which makes
Contac; and the former Thompson Medical Co., which made Dexatrim until
Chattem Inc. bought the line late in 1998.
Doctors and scientists cannot say for sure that PPA caused Patton,
Newenham or any other victim to have a stroke. Many of those who
suffered strokes after taking PPA were particularly susceptible to blood
pressure spikes because they suffered from one of several conditions
affecting tens of millions of Americans.
A LIFE OF HOPE: Tricia Newenham in 1999, a year before a stroke ruined
her dreams of college and a career in design.
Some had hypertension, which afflicts one in five Americans. Patton was
among the estimated 3% of Americans with cerebral aneurysms, which can
pop if blood pressure rises suddenly. Newenham had an arteriovenous
malformation, a circulatory defect that can make vessels prone to
rupture. Neither Patton nor Newenham knew about their conditions before
If PPA had been a lifesaving drug, the benefits might have more clearly
outweighed the risks to such a large segment of the population. But
though it unclogged countless stuffy noses and helped millions of
dieters shed a few pounds, PPA was neither essential nor irreplaceable.
What made it worth fighting for were its sales, estimated at several
billion doses a year. In a deposition, Robert G. Donovan, the former
head of Sandoz Consumer Health Care, said the profitability of the
company's two PPA products was about 75% to 80% of revenue.
Years before the Yale Hemorrhagic Stroke Project, clinical studies and
individual cases published in medical journals began to raise concerns
Sandoz was among several companies that considered reformulating their
cold products with comparably effective ingredients, primarily
pseudoephedrine, which had been used safely for years and gained final
FDA approval in 1994. But pseudoephedrine cost more than PPA. And it had
a bitter taste that was more difficult to mask, an important
consideration for the pediatric market. The manufacturers concluded
there was no reason to switch.
Memo from Sandoz Marketing Director, Oct. 13, 1988
"There appears to be little, if any, upside business potential in
reformulating from both a consumer and professional standpoint," wrote
the marketing director of pediatric cough and cold products for Sandoz
in a 1988 memo included in litigation records.
"Few consumers are aware of [over-the-counter] cough/cold products'
active ingredients," he wrote. "Fewer still would be aware of any safety
issues with PPA."
In depositions, many industry officials have tried to shift
responsibility to the FDA.
"My assumption was that if there was an issue of safety, supported by
sound evidence, that the Food and Drug Administration would exercise
their responsibility and take the product off the market," Donovan
testified. But FDA officials said that until they received the final
results of the industry study, there was not sufficient evidence of
PPA's dangers to take it off the market or demand prominent stroke
warnings on labels.
The agency does not require manufacturers to report cases of adverse
reactions to certain drugs, like PPA, that have long been available over
the counter. That makes it virtually impossible to track potentially
dangerous trends as they develop.
Some companies provide such data voluntarily, but research has shown
that underreporting is widespread.
FDA Estimate of Strokes Attributed to PPA
As a result, there are no reliable figures for how many strokes may have
been associated with PPA use. But in 2000, FDA epidemiologists estimated
that between 200 and 500 hemorrhagic strokes a year could be attributed
to PPA in people 18 to 49.
Although products with PPA are no longer for sale, Sen. Ron Wyden, an
Oregon Democrat who held hearings on PPA safety as a congressman in
1990, said in an interview that he hoped FDA officials would learn from
the PPA experience.
"In 1990, there was already essentially a decade of evidence that PPA
could be causing health problems, and it was 10 years after I opened up
these hearings that PPA came off the shelf," he said. "There are real
human consequences of slow, stalling tactics. Loved ones don't come
back, disabilities don't disappear, just because PPA is off the shelf
after years of foot-dragging."
The 'Big Soldier'
Tracy Patton could never have imagined such a tentative life.
FAITH: Prayer and family have sustained Tracy Patton. She has recurring
nightmares, often about brains.
Though only 5 feet 2, she was the first player off the bench for her
Scottsburg, Ind., high school basketball team when it went to the state
semifinals. She held the town's high school long jump record -- 16 feet,
8 inches -- and won a track and field scholarship to college. Before her
stroke, she mowed the yards at seven of her father's rental properties
Whenever Patton faced adversity as a child, when she skinned a knee or
was dragged to the dentist, her father would tell her to "be a big
soldier," and she took his instruction to heart. Within her family and
in her job as the director of a foster care agency, she had a reputation
for determination and grit.
Patton says that on the drive to nearby Louisville for her play
rehearsal that night, she took a single tablet of Tavist-D to unclog her
sinuses. She hemorrhaged an hour later.
At the hospital, Patton's doctor told family members to expect the
worst, and advised them to say their goodbyes. "She'll probably bleed
out," he said. "We'll try to make her as comfortable as we can." To
their astonishment, just before sunrise, she began to wake from her coma.
The surgeons cut a scythe-shaped incision in her head, repaired her
aneurysm with two metal clips and inserted three metal plates in her
skull. She lost 85% of the vision in her left eye, leaving her to view
the world as if through Vaseline-smeared glasses.
"Shopping for brains, brains of all shapes and colors and sizes, brains
-- Tracy Patton
These days, Patton struggles with simple math and the concept of time.
She keeps a printed inventory of her own odd behaviors: "I have been
found talking to pictures on the wall. I have 'thanked' myself after I
have poured myself a drink." One day, she thought she saw a reindeer
driving a car.
Patton, who is single, tries to present a patina of normalcy, but her
daily routine taxes her strength. She has recurring nightmares, often
about brains. "Shopping for brains, brains of all shapes and colors and
sizes, brains in jars," she said. "And then there's brain surgery. They
want me to go in and look at other people having brain surgery. I wake
up in a panic."
Patton still holds down her job, where her office computer has been
programmed with large-print type. But she acknowledges she is able to
work only because a colleague has assumed many of her responsibilities.
"She does it all and acts like I did it," Patton said. "We hide it
ADAPTATION: Because Tracy Patton lost some of her sight, her office has
been equipped with large-type computers and machines that magnify
documents. Still, she struggles with basic math.
On the day she came home from the hospital, a month after her stroke,
Patton celebrated her 38th birthday with family and friends. She held an
ice pack to her head as her sister, Kim, read her cards aloud and handed
her gifts -- a scented candle, a collectible race car, and, most
utilitarian, a collection of hats. Then Kim presented the cake she had
baked in the shape of a brain. "Can you imagine how many times it took
me to make gray icing?" she asked with a laugh.
But the day's most meaningful gift came from her father. It was a simple
sliver of silver, and he had had it engraved: "#1 Big Soldier."
Researchers estimate that hemorrhagic strokes, which occur when blood
vessels rupture and bleed into the brain, kill more than a third of all
victims within a month and leave more than a third of survivors severely
disabled. They account for only 12% to 17% of the 700,000 strokes in the
U.S. each year, according to the American Stroke Assn., but play a
disproportionate role in making stroke America's third leading killer.
Phenylpropanolamine, which was first synthesized around 1910, is one of
a class of drugs that stimulate the sympathetic nervous system, not
unlike amphetamine and cocaine. It also can constrict blood vessels and
increase the force of heart contractions. By narrowing blood vessels in
nasal mucous membranes, PPA allows air passages to open up. The very
same mechanism can, according to the FDA, produce transient spikes in
Whether PPA can raise blood pressure to dangerous levels has been the
subject of extensive debate. After dozens of studies and case reports,
the cumulative weight of scientific evidence suggests that PPA is not
necessarily dangerous to everybody, but that it can trigger lethal
reactions in some.
Studies found that the degree of blood pressure elevation attributable
to PPA depended on the type and quantity of product taken, whether it
was taken in combination with stimulants like caffeine, whether the
patient was otherwise susceptible to high blood pressure, and whether it
was consumed while upright or lying down, when the impact apparently is
Of particular concern was that PPA could produce adverse effects in
quantities that were only two or three times the FDA's recommended
dosing limits -- 150 milligrams per day for decongestants and 75
milligrams per day for diet drugs.
The FDA takes the position that over-the-counter drugs, while not
risk-free, should be "relatively hard to get in trouble with," said Dr.
Robert J. Temple, the agency's associate director for medical policy.
Some researchers, many of them bankrolled by drug manufacturers, have
held that PPA has minimal effects on blood pressure. Most prominent is
Dr. George L. Blackburn, whose chair in nutrition medicine at Harvard
was endowed by the founder of Thompson Medical Co., which created
Dexatrim. Another is Dr. John P. Morgan, who was Thompson Medical's
part-time medical director and who defended PPA in a 1985 text that was
heavily underwritten by the company.
Morgan acknowledged in an interview that he was paid "an enormous amount
of money" over the years by Thompson. "I know some people thought that
influenced the research, but that was not the case," he said. He added
that he still did not believe PPA caused strokes. "But I've always been
afraid I'd be proved wrong," he said. "Maybe it does."
When the FDA began evaluating PPA in the 1970s, the agency's expert
panels recommended it be categorized as safe and effective, while also
noting reports of "idiosyncratic reactions of central nervous system
stimulation and/or blood pressure rise." There was enough uncertainty
about safety to keep the agency from issuing a final ruling, placing PPA
in a regulatory limbo that allowed its continued marketing.
Proprietary Association Statement on PPA, May 1989
As the body of research about PPA's potential hazards expanded, the
industry maintained there was no health risk. In 1989, the Proprietary
Assn. -- a forerunner of the CHPA -- declared in a statement that PPA
was safe, and asserted that "clinically recommended doses of PPA produce
no clinically significant changes in blood pressure, heart rate or EKG."
But even as the companies were publicly defending PPA, one internal
report after the next referred to its potential dangers.
. Sandoz Memo on PPA and Pseudoephedrine, Jan. 19, 1989
. Sandoz Safety Update on PPA, Nov. 25, 1996
In 1989, for instance, a manager in the Sandoz medical services
department wrote that both PPA and pseudoephedrine were "viable for use"
in over-the-counter products but that "each have had dire outcomes in
small doses." The manager then added: "It isn't only abuse or overdoses
which cause problems. Adverse effects are rare but can be serious."
By 1996, a confidential Sandoz "safety update" warned: "It is
conceivable that the intake of drugs containing this active ingredient
predisposes to or even causes cerebrovascular accidents."
Dorsey Laboratories Memo on Cost of Reformulating with Pseudoephedrine,
March 25, 1983
Some manufacturers had begun exploring the possibility of reformulating
their brands with other ingredients in the early 1980s. But at Dorsey
Laboratories, a division of Sandoz, officials calculated in 1983 that a
switch to pseudoephedrine, which was more than twice as expensive as
PPA, would cost $1.4 million. Furthermore, a company marketing survey
concluded that awareness of PPA's possible side effects was not yet
widespread among physicians and pharmacists.
Dorsey Laboratories Memo on Awareness of PPA's Possible Side Effects,
"Based on the reaction of these professionals, reformulation to
pseudoephedrine is not an urgent matter," wrote a staffer in Dorsey's
marketing research division.
Birth of a Study
In 1990, prompted by reports of PPA's dangers and its growing use in
diet drugs, then-Rep. Wyden held his hearings. Some of the testimony was
After enumerating a laundry list of ailments, including cerebral
hemorrhage, that had been associated with PPA in medical literature, Dr.
Thaddeus E. Prout, then the chairman of medicine at Greater Baltimore
Medical Center, issued a challenge: "I defy anyone to find another
unregulated drug that has such a record of disaster." Prout, an
authority on drugs, blamed the FDA for not moving against PPA.
"Thousands of people will suffer as a result of our negligence," he
From the FDA's vantage point, the only way to truly determine whether
PPA users were at disproportionate risk of stroke was to conduct an
extensive epidemiologic study. But since the agency does not itself
sponsor research for drug reviews, it had to rely on PPA manufacturers
to investigate the safety of their own products.
There was incentive for the companies as well. A long-term study would
keep PPA on the market, at least temporarily.
The industry sponsors -- Thompson Medical and Ciba Consumer
Pharmaceuticals (then the maker of the diet drug Acutrim) -- were
involved in all major methodological decisions, as was the CHPA. They
chose investigators who were highly credible with the FDA, but who also
were known to be skeptical of any connection between PPA and stroke.
Lawrence M. Brass, the Yale neurologist initially enlisted for the
study, said in an interview that he told the industry sponsors in an
early meeting that he "really didn't see a lot of evidence for an
Similarly, the sponsors approved Dr. Louis C. Lasagna, who had endorsed
PPA's safety in a 1988 textbook, as chairman of the study's three-member
In April 1994, as the investigators and the companies applied the
finishing touches to the study's design, Timothy R. Dring, Ciba's
assistant director of regulatory affairs, wrote to one of the Yale
researchers that the protocol "will serve our research purposes quite
At the same time, Dexatrim's maker, Thompson Medical, broke with the
rest of the industry by disclosing on labels that there had been reports
that stroke and other conditions "might be associated" with PPA.
Letter from Thompson Medical President Daniel N. Horwitz, May 24, 1994
It seemed a purely defensive move. Thompson's president, Daniel N.
Horwitz, stressed in a letter to the FDA that the company "in no way
believes that these reports are correct." And CHPA officials made it
clear that they disagreed with the decision.
The companies not only continued to sell their products, but also
introduced new PPA brands, like Bayer's Alka-Seltzer Plus children's
cold medicine with "fizzy fresh cherry taste."
To the astonishment of the drug companies, the study conducted by its
handpicked researchers using their industry-approved protocol produced
An examination of 702 stroke cases in people 18 to 49 years old
identified 27 victims, mostly women, who had taken PPA shortly before
their attacks. Their experience was compared to a control group of 1,376
The most significant finding was that women who had taken an appetite
suppressant with PPA were 16 times more likely to have a stroke within
three days than those in a control group who had not taken any.
The study also found that the risk of stroke was three times greater for
women who had used PPA products for the first time in the last 24 hours.
"First use" meant that the subject had not taken a PPA product in the
previous two weeks. All the first-users in the study had taken PPA cough
and cold remedies.
In their final report to the FDA, the investigators concluded that "the
association of PPA with risk for hemorrhagic stroke is present for both
customary indications for PPA (as a cough-cold remedy and an appetite
For all subjects -- regardless of gender, the type of product taken or
the timing of ingestion -- the risk of stroke increased by 50%. But that
finding, like some others, fell short of statistical significance.
Upon learning the results on Oct. 17, 1999, the members of the study's
oversight committee -- including Lasagna, who had previously written so
confidently about PPA's safety -- unanimously approved the findings and
instructed the researchers to notify the FDA immediately.
The next day they did, placing telephone calls to officials at the
agency and to the leaders of the trade association. Industry officials
feared that the study would prompt FDA action against all forms of PPA,
and began mounting a counteroffensive.
E-mail from Whitehall-Robins' John Incledon, Oct. 6, 1999
Even before the Yale results were disclosed, the industry had started
considering worst-case scenarios. "We need to be thinking offense here
not just defense," wrote John Incledon, vice president of the
respiratory business unit of Wyeth's Whitehall-Robins Healthcare
division, in an e-mail to a colleague on Oct. 6, 1999. "The timing of
this is ideal for news stations to pick up on it in droves. It's Yale,
it's cold season and it's in children's products."
. Letter from CHPA Senior Vice President R. William Soller to Dr. Ralph
I. Horwitz, Oct. 26, 1999
. Letter from Soller to Horwitz, Oct. 27, 1999
. Letter from Novartis lawyer, Oct. 29, 1999
Once the study was finished, the FDA asked the doctors to summarize
their findings in a letter. Dr. R. William Soller, then the senior vice
president of the CHPA, wrote to one of the researchers to insist that
any report to the FDA stress PPA's overall safety record. The next day,
he wrote again, this time warning that the Yale investigators may have
violated their contract by communicating results to the FDA before fully
vetting them with the industry sponsors. Two days later, a lawyer for
Novartis accused the Yale doctors in a letter of committing "a serious
breach" by prematurely disclosing the results.
The doctors were taken aback. "We contend that we were in full
compliance with the contract," Dr. Walter N. Kernan, one of the Yale
researchers, said in an interview. "Neither the university nor the
investigators were going to allow anything to get between us and what we
perceived as the best interest of the public."
The FDA, meanwhile, told the researchers that any communication with the
agency would have to be public. It quickly scheduled an open meeting of
its Nonprescription Drugs Advisory Committee, a panel of experts whose
recommendations were almost always endorsed by the FDA commissioner.
But the doctors said their data needed further refining and analysis
before public release. And the industry told the FDA it could not
prepare a public defense so quickly.
In the end, the panel's meeting was pushed off by more than 10 months,
with much of that time marked by parrying between the Yale doctors and
the industry over the research methods they had agreed to five years
earlier. In the meantime, the public remained unaware of the study's
findings, and products with PPA stayed on the market.
"I think the companies wished that we'd never reach the final stage,"
said Dr. Ralph I. Horwitz, a clinical epidemiologist who helped lead the
Yale team, "because the longer the process was underway, they were able
to avoid finally dealing with the consequences of the research."
Horwitz, who is now dean of the Medical School at Case Western Reserve
University, said the delay left issues of consumer safety in suspension.
"I do think that had they been able to see the study findings as soon as
the data were available, that the FDA would have felt obliged to issue a
warning in the interest of public health and safety," he said.
The FDA's Ganley said the agency could not act without a final report.
"Why would we put out something like that when we didn't really have the
data in hand?" he asked. "We would be criticized, and justifiably so."
Circling the Wagons
Ruder Finn Draft Public Relations Advisory, Feb. 29, 2000
As the clock ticked toward some form of FDA regulation, the companies
enlisted a battalion of consultants to analyze the study. They hired a
public relations firm, Ruder Finn, which suggested in a draft memo that
the industry argue that PPA-related jumps in blood pressure were "within
the range of increases associated with routine daily activities, such as
climbing stairs or mowing the lawn," according to correspondence from
Bayer E-mail Summarizing Industry Meeting on Yale Study, Jan. 24, 1999
One Bayer memo about a meeting of an industrywide PPA task force said it
had been noted that the FDA's Temple had an unfavorable position on PPA
and that "efforts should be made to steer the media away from him."
Letter from Chattem President A. Alexander Taylor II to CHPA Senior Vice
President R. William Soller, Oct. 25, 1999
At Chattanooga, Tenn.-based Chattem, which had just bought Dexatrim,
President A. Alexander Taylor II wrote to Soller that he feared "an
avalanche of negative publicity" if the study were to become public
before it could be reviewed by the industry sponsors.
Letter from Chattem President A. Alexander Taylor II to Sen. Bill Frist,
Feb. 4, 2000
Taylor appealed to his home-state senator, Tennessee Republican Bill
Frist, a physician, to intervene with the FDA. Taylor began a Feb. 4,
2000, letter by mentioning that a prominent Frist donor served on the
Chattem board of directors and that the company's chief executive
officer was the brother of a Frist county reelection chairman. "I am a
very proud contributor to your current campaign," Taylor continued.
"A few more months of study before any public release of this data will
not harm the public health, and may benefit it," he wrote.
Frist never responded. "It fell on deaf ears," Taylor said in a deposition.
As the months passed, the companies saw that it was time to reformulate.
In December 1999, Novartis had kick-started its efforts to remake
Triaminic with pseudoephedrine. Wyeth also set a quick timetable for
reconstituting Dimetapp, then slowed down as the FDA postponed its
advisory committee meeting.
Wyeth Memo About Delaying the Reformulation of Dimetapp, April 11, 2000
"It appears that we have a bit more time than we originally expected on
a decision from the FDA on PPA," wrote Wyeth's senior product manager
for Dimetapp in an April 2000 memo. "By launching in January 2001
instead of September 2000 (the peak of the cough/cold season), we will
be able to better manage open stock and display inventories."
Whitehall-Robins Draft Memo About Returns of Robitussin CF with PPA, May
In May, a draft memo from Wyeth's Whitehall-Robins division addressed
whether retailers should return stocks of Robitussin CF when they began
receiving shipments of PPA-free replacements. The answer: "NO. Again,
the decision to reformulate was voluntary. Therefore, current stock is
perfectly safe and effective for use. We will not be accepting returned
product for the new formula."
David E. Dukes, a lawyer for Wyeth, stressed in an interview that the
companies and the FDA were still evaluating the Yale study at that
point. "At the senior levels, where decisions were being made about
Dimetapp and Robitussin CF, safety was the primary concern," he said.
Meanwhile, even the consultants brought in by industry found it
difficult to dismiss the study's conclusions.
Report by Bayer Consultant on Yale Study, Nov. 10, 2000
Dr. James Lewis, a University of Pennsylvania epidemiologist who had
been commissioned by Bayer, wrote that the Yale researchers showed
"fairly convincing evidence of an association between PPA use and the
risk of hemorrhagic stroke."
Like other consultants hired to critique the study, however, he also
guided his client toward a strategy for attacking the fragility of the
findings. With such a small number of PPA-related stroke cases, he
wrote, any methodological bias could affect the statistical significance
of a result.
"We came out and said we don't like our own study."
-- James D. Cope, former president, Consumer Healthcare Products Assn.
The industry seized on that approach. "We came out and said we don't
like our own study," said Cope, the former CHPA president. "It's
predictable: If the results don't come out the way you like, since
there's no such thing as a bulletproof study, you point out the
weaknesses in it."
Under increasing pressure from the FDA, the Yale doctors submitted their
final report on May 10, 2000. Though they stopped short of saying PPA
could cause hemorrhagic stroke, they later emphasized that "causation is
one explanation for that association."
. FDA Statistical Review of Yale Study, Sept. 26, 2000
. FDA Epidemiologists' Analysis of Yale Study, Sept. 27, 2000
The FDA staff quickly sided with the researchers. An FDA statistician
praised the study as one of the best he had reviewed in the last decade.
A pair of FDA epidemiologists were so persuaded that they took the
unusual step of recommending that PPA-containing appetite suppressants
be banned as over-the-counter products.
"The study demonstrated a statistically significant increased risk of
hemorrhagic stroke among both appetite suppressant users and first time
users of PPA as a cough/cold remedy," their report concluded. The
recommendation for a ban infuriated industry officials, who complained
it would unfairly sway the advisory panel, now scheduled to meet on Oct. 19.
At the advisory committee meeting, Dr. Noel S. Weiss, a University of
Washington epidemiologist who had been hired by the CHPA, honed in on
the disparity in the study's findings for different types of products.
"Why an association with appetite suppressant drugs and not for colds
and such when the typical doses given for colds are higher than for
appetite suppressants?" he asked.
But the attack on the study was so broad that it ultimately undercut the
industry's cause, FDA officials said. "They essentially trashed the
study, even though they are the ones who designed it and financed it,"
FDA Request that Manufacturers Stop Marketing PPA, Nov. 3, 2000
The advisory panel voted unanimously, with a few abstentions, that PPA
could not be considered safe. A few weeks later, the agency told
manufacturers it expected to classify PPA as not safe for
over-the-counter use and asked that they voluntarily discontinue
marketing the products. The evidence of an association, while not
conclusive, had been persuasive.
"If someone wanted you to swear it must be true, I wouldn't do that,"
said the FDA's Temple. "But we thought it was enough. Look, if the drug
were lifesaving, if it was something of immense value and had no
replacements, you'd have to think about it. But it wasn't."
A LIFE IN THE BALANCE: Slowly, Tricia Newenham began awakening from her
monthlong coma in a Maine hospital.
Tricia Newenham suffered her stroke the week before the advisory
committee met. As her neurosurgeon prepared to remove the damaged tissue
from her brain, he warned her parents she might not survive her eight
hours on the table. Three days later, before a second operation to
remove a blood clot, her mother had her baptized, just in case.
Tricia made it through, but she would never be the same.
Before her stroke, she stood a gangly 5 feet 6 and weighed 106 pounds.
She was becoming a woman, and had developed a serious case of the
boycrazies (login: kissable98; password: puckerup). She never left her
house in Steuben, Maine, without her hair and makeup just right. She had
given up basketball and softball and swimming in vanity over her skinny
Now 18, Newenham weighs 196 pounds, the consequence of medication and a
captive life in which junk food provides a rare escape. Once a promising
artist who had imagined a career in design, she passes the time rocking
gently in a blue recliner, listening to the drone of soap operas.
Newenham can brush her teeth and wash her hands, but she does not always
know when to stop. Clinging fast to her femininity, she insists on
shaving her own legs, but leaves them scabby with cuts.
She hears a lot and comprehends much, but she has difficulty processing
thought and even more in communicating it. When asked a question, she
struggles to find the most economical answer, usually a word or two,
often a guttural "I don't know," with little intonation.
A LIFE OF BOREDOM: Tricia Newenham spends much of her time at home in a
recliner, listening to the drone of soap operas. Once a joyful, outgoing
teenager, she now leads a life with few friends and little stimulation.
Is she in physical pain? "No." Is she angry? "No." Is she sad? "No." Is
she frustrated? "Yeah."
What are her favorite things to do? "Sleep and eat." What does she like
to eat? "Chop suey." What else? "I don't know."
What does she remember about her old life? "Boys."
Is she content or bored with her life? "I get bored." What does she wish
she were doing? "I don't know. Going out with friends."
And then she begins to cry. And cry and cry.
While Newenham lingered in a coma after her stroke, the doctors advised
her parents to consider a nursing home. Even if Tricia came to, she
would not be the daughter they had known.
But ever so slowly, Tricia started waking up. First, a tear would form
in the crease of her eye. Sometimes, when her mother talked to her,
Tricia would reward her with a muffled, choking cry.
HELPING HAND: Tricia Newenham carefully navigates the steps at her home
in Steuben, Maine. A stroke left Tricia reliant on others just as she
was asserting her independence. "We have grown to love her and accept
her the way she is," her stepfather says.
Patricia Bybee told the doctors she was taking her daughter home. "I
just sensed that she was in there," she said. Two months later, Tricia
had spoken her first word: "M-m-m-om." Three months after that, she
When the paramedics came to the house on the day of the stroke, they
asked Bybee what medications Tricia had taken. "Only Triaminic," she
said. It was months later, after the FDA had asked drug companies to
withdraw their PPA products, that she learned of the possible connection
between cold medicines and stroke.
Bybee, a nurse's assistant, and her husband, Tim, a plumber, went deep
into debt to pay off medical bills. They say a settlement reached last
year with Novartis will relieve their debts and cover the cost of
Tricia's attendance at a school for the blind near Boston.
After three years, they have slowly adapted to their new reality, and
lowered their expectations.
"We would give anything to have her back the way she was," said Tim
Bybee. "But we have grown to love her and accept her the way she is."
Softening the Blow
The withdrawal of PPA was a tough loss for the companies, but they had
succeeded brilliantly in minimizing the impact. The study's long
duration bought five years to market PPA products without restriction.
And the post-study delay provided time to formulate products without
PPA, which began shipping within days of the withdrawal.
Throughout, the manufacturers remained defiant.
As late as Oct. 25, 2000, six days after the FDA advisory committee
voted that PPA was unsafe, Novartis' director of medical affairs sought
to reassure doctors about the safety of PPA, particularly for children,
who he pointed out were not included in the Yale study.
"As you know, hemorrhagic stroke is exceedingly rare in the pediatric
population," Dr. Geoffrey Ross wrote.
Letter from Novartis to Doctors About PPA, Oct. 25, 2000
"Particular to the pediatric population, PPA plays a significant role in
reducing missed school days and in promoting effective symptom relief."
The researchers submitted a scientific article on their PPA study to the
New England Journal of Medicine, reporting a statistically significant
risk of stroke for women taking PPA diet drugs and a possible
association between decongestant use and stroke in women. The journal
considered the findings important enough to post the article on its
website Nov. 6, six weeks before it came out in print.
FDA Public Health Advisory, Nov. 6, 2000
The same day, the FDA issued a public health advisory that consumers
should not use PPA products. Health officials in a number of countries,
from Canada to Malaysia, quickly followed suit.
Finding herself stuck with millions of dollars' worth of useless pills
Chattem's Dexatrim brand manager suggested to a colleague in an e-mail
-- produced by the company for litigation -- that they sell the
inventory to a sampling and promotion company known as Box of Brands.
Chattem Email Exchange About Dexatrim Inventory, October 2000
Andrea M. Crouch, the vice president of toiletries marketing, responded
enthusiastically. "I think using Box of Brands is an excellent idea!"
she wrote. "I see no downside -- so what if they divert! I will be
surprised if they don't have a problem with PPA but let's go for it!"
Crews Townsend, a lawyer for Chattem, called the proposal "part of the
brainstorming process" and said the company never sold its Dexatrim
inventory to Box of Brands. Instead, he said, it was destroyed.
Draft Remarks Prepared for Delivery to Whitehall-Robins/Wyeth Banquet,
Dec. 5, 2000
At Wyeth, gallows humor set in. When a speech was drafted for an
executive to deliver at an awards banquet several weeks before Christmas
2000, it included a line about the need to dispose of large quantities
of Dimetapp and Robitussin CF: "When you're sorting this year's holiday
gift list by 'naughty and nice,' don't think 'lump of coal,' think
'product with PPA.' " By the time a final draft had been prepared, that
opening had been replaced by an off-color joke about the 2000
presidential campaign, according to a copy provided by lawyers for Wyeth.
Virtually all of the firms took one-time accounting losses because of
the withdrawals -- $80 million for Wyeth, $54 million for Bayer, $50
million for Novartis and $8 million for Chattem, according to corporate
filings and statements.
But for the most part, the losses were short-lived. Thanks to the quick
reformulation and shipment of PPA-free Dimetapp, domestic sales of the
product rose 50% in the first quarter of 2001. Meanwhile, 2001 sales of
Dexatrim Natural, the non-PPA version of Chattem's diet aid, "more than
made up for lost sales" due to the discontinuation of Dexatrim with PPA,
according to an annual report.
The Battle Continues
Chattem announced in December that it would seek to settle most of its
332 PPA lawsuits. It had already agreed last year to pay $3.5 million to
Jennifer Villarreal, a Texas hairstylist who collapsed at a gym on March
6, 2000, allegedly after taking a Dexatrim pill.
The company also said it had reached settlements with insurers who
alleged in lawsuits that Chattem had applied for liability policies
without disclosing the Yale results. Townsend, the Chattem lawyer, said
the settlements did not indicate that the company had changed its belief
that Dexatrim with PPA was a safe and effective product.
Novartis agreed to make payments to Tricia Newenham and her family last
year on the condition that the terms remained confidential, according to
her mother. Novartis would not answer questions about Newenham, and
neither Novartis nor the other companies would disclose details about
WILLPOWER: Tracy Patton continues to work as director of a foster care
placement agency but only because colleagues have assumed many of her
duties. Doctors and scientists cannot say for sure that PPA caused
Patton or any other victim to have a stroke.
Thousands of plaintiffs, including Tracy Patton, have lawsuits pending
against PPA drug makers, but only a few of those cases have made it to
trial. This year, juries in New Jersey and California rejected claims by
plaintiffs that Novartis products had caused their strokes. In both
trials, the victims had had a variety of risk factors for stroke, and
their strokes occurred before the Yale study was completed.
"Our company is extremely gratified that two diverse juries, from
opposite ends of the country, reached the same conclusions after an
exhaustive airing of all the evidence," said Nancy Fitzsimmons, vice
president for global communications of Novartis Consumer Health.
The industry's efforts to discredit the Yale study have continued in
court, with defense lawyers trying to poke holes in enough of the
study's PPA-related stroke cases to negate its findings.
The dispute has become increasingly personal. Drug company lawyers have
hypothesized a conspiracy that has the Yale doctors manipulating data to
strengthen their chances of finding an association. Such a finding, the
industry lawyers suggest, would help the researchers win promotions and
publication in a top journal.
"Those investigators were very vulnerable to human frailty, to human
desires and human error; driven by a desire to succeed, to obtain
recognition," said Jan E. Dodd, a lawyer for Novartis, in her closing
argument in the California trial.
In constructing their theory, defense lawyers have focused on a
midcourse shift by the researchers in defining when a stroke begins.
E-mail from Dr. Walter N. Kernan, Oct. 15, 1998
In one case, the investigators set the onset of a stroke one hour after
the patient had taken PPA, even though the patient had begun suffering a
headache -- potentially an early sign of stroke -- six days earlier. The
companies have made much of a 1998 e-mail sent by Yale researcher Kernan
to his colleagues saying the strategy of shifting the time of onset
"effectively increases our likelihood of finding an association" between
PPA and hemorrhagic stroke.
Kernan said in an interview that he was just stating the obvious, and
not suggesting that data could be tweaked to produce a desired result.
"Sloppy research does not get you promoted at Yale," he said. "Lack of
integrity gets you fired. The investigators had no stake in the outcome
of the research."
Brass, the Yale neurologist, joked that given the drug industry's
financial support for friendly scientists, the researchers would have
had more incentive to skew the study in PPA's favor. "If we were
thinking payoff, we should have shown PPA as safe," he said. "I would
have had a chair. Yale would have a whole division dedicated to the
study of obesity. But we don't fix studies. We just do them."
Some in academic medicine worry that the industry's attacks on the Yale
doctors might discourage researchers from pursuing similar studies.
"With the amount of hassle and harassment that they had to endure, I'm
sure the next time they're asked to undertake something like this,
they'll wonder if it's worth the cost," said former FDA Commissioner
David A. Kessler, now the dean of medicine at UC San Francisco.
The Yale doctors, said Horwitz, clearly were naive about the industry's
willingness to assail their integrity. "I love arguing about the
science," he said, "but this is outrageous, especially considering who
was making the accusations. It was their study."
Kevin Sack is a Times staff writer based in Atlanta; Alicia Mundy is a
special correspondent based in Virginia.
Researcher Janet Lundblad in Los Angeles contributed to this report.
. Left in the Dark
. The 'Big Soldier'
. Hidden Dangers
. Birth of a Study
. Unexpected Findings
. Circling the Wagons
. Stolen Youth
. Softening the Blow
. The Battle Continues
Example of drug makers' strategy
A library of some of the supporting materials used in this article
Copyright 2004 Los Angeles Times