During the last decade, more than 1,500 Americans died
after accidentally taking too much of a drug renowned for its safety:
acetaminophen, one of the nation’s most popular pain relievers.

Acetaminophen – the active ingredient in Tylenol
– is considered safe when taken at recommended doses. Tens of millions of
people use it weekly with no ill effect. But in larger amounts, especially in
combination with alcohol, the drug can damage or even destroy the liver.

Davy Baumle, a slender 12-year-old
who loved to ride his dirt bike through the woods of southern Illinois, died
from acetaminophen poisoning. So did tiny five-month-old Brianna Hutto. So did Marcus Trunk, a strapping 23-year-old
construction worker from Philadelphia.

The toll does not have to be so high.

The U.S. Food and Drug Administration has long been aware
of studies showing the risks of acetaminophen – in particular, that the
margin between the amount that helps and the amount that can cause serious harm
is smaller than for other pain relievers. So, too, has McNeil Consumer
Healthcare, the unit of Johnson & Johnson that has built Tylenol into a
billion-dollar brand and the leader in acetaminophen sales.

Yet federal regulators have delayed or failed to adopt
measures designed to reduce deaths and injuries from acetaminophen overdose,
which the agency calls a “persistent, important public health problem.”

The FDA has repeatedly deferred decisions on consumer protections
even when they were endorsed by the agency’s own advisory committees, records
show.

In 1977, an expert panel convened by the FDA issued
urgently worded advice, saying it was “obligatory” to put a warning on the drug’s
label that it could cause “severe liver damage.” After much debate, the FDA added
the warning 32 years later. The panel’s recommendation was part of a broader review
to set safety rules for acetaminophen, which is still not finished.

Four years ago, another FDA panel backed a sweeping new
set of proposals to bolster the safety of over-the-counter acetaminophen. The
agency hasn’t implemented them. Just last month, the FDA blew through another deadline.

Regulators in other developed
countries, from Great Britain to Switzerland to New Zealand, have limited how
much acetaminophen consumers can buy at one time or required it to be sold only
by pharmacies. The FDA has placed no such limits on the drug in the U.S.
Instead, it has continued to debate basic safety questions, such as what the
maximum recommended daily dose should be.

For its part, McNeil has taken steps to protect consumers,
most notably by helping to fund the development of an antidote to acetaminophen
poisoning that has saved many lives.

But over more than three decades, the company repeatedly fought
against safety warnings, dosage restrictions and other measures meant to
safeguard users of the drug, according to company memos, court records,
documents obtained under the Freedom of Information Act, and interviews with
hundreds of regulatory, corporate and medical officials.

In the 1990s, McNeil tried to create a safer version of
acetaminophen, an effort dubbed Project Protect. But after the initiative
failed, the company kept its experiments confidential, even when the FDA
inquired about the feasibility of developing such a drug.

Later, McNeil opposed even a
modest government campaign to educate the public about acetaminophen’s risks,
in part because it would harm Tylenol sales.

All the while, it has marketed
Tylenol’s safety. Tylenol was the pain reliever
“hospitals use most,” one iconic ad said. The one “recommended by
pediatricians,” said another. “Safe, fast pain relief,” its packages promised.

In written
responses to questions for this story, as well as a pre-recorded statement 
by its vice president for medical affairs, McNeil said it has always acted to
ensure its products were used safely.

“McNeil takes acetaminophen overdose very seriously,
which is why we have taken significant steps over the years to mitigate the
risk,” the company wrote. McNeil has engineered safety packaging and spent
millions on research, education and poison control centers that advise people
who have overdosed.

The company said that science on acetaminophen had evolved over time and that it had implemented safety
measures accordingly. Most recently, it announced it will soon add red
lettering to the caps of medicine bottles saying they contain acetaminophen and
that users should read the label.

In several cases, after FDA advisors recommended the
agency enact safety measures over McNeil’s objections, the company adopted them
before the agency forced it to do so. The company then said it was taking such
steps voluntarily. McNeil also stressed that it has always followed FDA
regulations.

McNeil objected to the thrust of questions from ProPublica
and This American Life, saying they indicated “a clear bias” in favor of
plaintiff’s lawyers who are suing the company.

The company declined to answer questions about individual
cases of death or injury. “Our hearts go out to those who have suffered harm
from acetaminophen overdose, and to the families of those who lost their lives
as a result,” McNeil wrote in its statement.

FDA officials said the agency
saw the benefits of keeping acetaminophen widely available as outweighing the “relatively
rare” risk of liver damage or death. Some patients cannot tolerate drugs such
as ibuprofen, and for them acetaminophen may be the best option, said one
agency official.

The FDA has bolstered
acetaminophen warnings as new science about the drug emerged, the agency said
in a statement.

But FDA officials acknowledged
the agency had moved sluggishly to address the mounting toll of liver damage
caused by acetaminophen. They blamed changing research, small budgets, an
overworked staff and a cumbersome process for changing rules for older drugs such
as Tylenol slowing them down.

The agency has greater
authority over prescription drugs, and it has already slapped medications
containing acetaminophen with a “black box warning” that says overdosing can
lead to “liver transplant and death.” Paradoxically, the same medicine sold
over the counter does not tell patients that death is a possible side effect.

“Among over-the-counter
medicines, it’s among our top priorities,” said Dr. Sandy Kweder,
one of the FDA’s top experts on acetaminophen. “It just takes time.”

Many doctors believe in acetaminophen
and some medical associations advise patients to take it for mild to moderate
pain or reducing fever. “Given the number of doses given annually, the track
record is incredibly safe,” said Dr. Bill Banner, a pediatrician and the
medical director of the Oklahoma Poison Control Center.

Every over-the-counter pain
reliever can cause harm. Even without overdosing, aspirin and ibuprofen can lead
to stomach bleeding. In extremely rare cases, according to the FDA, recommended
doses of ibuprofen and acetaminophen can provoke a skin reaction that can
kill.

But the FDA says acetaminophen
carries a special risk. About a quarter of Americans routinely take more
over-the-counter pain relief pills of all kinds than they are supposed to,
surveys show. That behavior is “particularly troublesome” for
acetaminophen, an FDA report said, because the drug’s narrow safety margin places
“a large fraction of users close to a toxic dose in the ordinary course of use.”

The FDA sets the maximum
recommended daily dose of acetaminophen at 4 grams, or eight extra strength acetaminophen
tablets. That maximum applies to both over-the-counter and prescription drugs
with acetaminophen.

Taken over several days, as
little as 25 percent above the maximum daily dose – or just two
additional extra strength pills a day – has been reported to cause liver
damage, according to the agency. Taken all at once, a little less than four
times the maximum daily dose can cause death. A comparable figure doesn’t exist for ibuprofen, because so few people have died from overdosing on that drug.

About as many Americans take ibuprofen as take acetaminophen, according to consumer surveys from the mid-2000s.

The U.S. Centers for Disease Control and Prevention and the American Association of Poison Control Centers collect data on the number of deaths associated with each drug, but the figures are incomplete, making comparisons subject to question. McNeil contends the databases do not contain the information needed to draw conclusions about the relative risks of different medicines. The company and some epidemiologists maintain that these data sets undercount deaths resulting from chronic use of naproxen, ibuprofen and similar pain relievers. (More on the numbers can be found here.)

Still, the data show that acetaminophen is linked to more deaths than any other over-the-counter pain reliever.

From 2001 to 2010, annual acetaminophen-related deaths amounted to about twice the number attributed to all other over-the-counter pain relievers combined, according to the poison control data.

In 2010, only 15 deaths were reported for the entire class of pain relievers, both prescription and over-the-counter, that includes ibuprofen, data from the CDC shows.

That same year, 321 people died
from acetaminophen toxicity, according to CDC data. More than half – 166
– died from accidental overdoses. The rest overdosed deliberately or
their intent was unclear. For the decade 2001 through 2010, the data shows,
1,567 people died from inadvertently taking too much of the drug.

Acetaminophen overdose sends as many as 78,000 Americans
to the emergency room annually and results in 33,000 hospitalizations a year, federal data
shows. Acetaminophen is also the nation’s leading cause of
acute liver failure, according to data from an ongoing study funded by the
National Institutes for Health.

Behind these statistics are
families upended and traumatized and, in the worst cases, shattered by loss.

Just before Christmas 1999, 12-year-old
Davy Baumle came down with a sore throat. For a week,
his parents, David and Udosha Baumle,
gave him Maximum Strength Tylenol Sore Throat, measuring out doses of
the thick syrup.

But instead of getting
better, Davy became listless. On Christmas Day, he threw up blood. His father
took him to a local emergency room wrapped in a fuzzy brown blanket. A few days
later, the boy was declared brain dead.

The Baumles later sued McNeil, claiming the company had failed to warn
consumers of its product’s lethal danger. At trial,
they testified they never gave Davy more than the recommended dose, 4
grams per day, or eight tablespoons. An expert for the company testified that
lab work suggested the boy had ingested more, 6 to 10 grams, over several days.

The difference amounted to as little as 4 tablespoons a
day, but the company prevailed, persuading the jury
that the Baumles had not used Tylenol precisely as
specified.

David Baumle said he would
never have given his son the drug if he knew it was potentially lethal. At the
time, the label simply warned of “serious health consequences” in case of
overdose.

“They tell you it’s medicine,” he said. “They don’t tell you it can kill
you.”

Tylenol was born in 1955, when the family-owned McNeil
Laboratories introduced a liquid for children called Tylenol Elixir.

The drug’s key ingredient, acetaminophen, was developed in
the late 1800s in Germany’s coal tar industry. McNeil seized on the drug’s
potential after American research suggested that the medication does not cause stomach
bleeding, as aspirin can. McNeil named the product based on letters in the
chemical term for acetaminophen, N-acetyl-p-aminophenol.

Johnson & Johnson acquired McNeil in 1959, the same
year that Tylenol was approved for over-the-counter sales. Soon thereafter, the
first adult version of Tylenol rolled off the company’s production line in Fort
Washington, Pa., the site of McNeil’s current headquarters.

Unlike companies that develop prescription drugs, McNeil
has no patent on acetaminophen, and so no right to sell it exclusively. Virtually
every drug store stocks generic acetaminophen, usually on the same shelf as
Tylenol. To sell Tylenol at a premium, the company had to persuade customers
they were getting extra value.

Tylenol has had “generic competition for 40 years,” said
Ashley McEvoy, then the president of McNeil, in a
webcast interview
posted in 2008. “If I look back at what’s garnered success for McNeil, it’s the
enduring value of brands.”

The company aimed its early sales pitches at doctors, according
to a company history, working to persuade them to recommend Tylenol as a
safer alternative to aspirin. To this day, the company’s formula for success
hinges on positioning Tylenol as safer than other painkillers and more
trustworthy than generics.

Perhaps the most famous chapter in McNeil’s corporate history
is its response when several people in the Chicago area died in 1982 after
taking Tylenol laced with cyanide.

The mysterious deaths terrorized the country — and
raised questions about the safety of the company’s products. But in what later
became a business school case study, McNeil removed Tylenol from the market, offered
refunds and eventually developed tamper-resistant pills. By the end, it had
transformed a disaster into a public relations coup.

McNeil’s marketing campaigns for its master brand were also
skillful, burnishing Tylenol’s image while usually avoiding claims of absolute
safety or zero side effects. One slogan: “The brand of pain reliever that doctors
recommend more than any other.” Another: “Trust TYLENOL. Hospitals do.”

“We never use the word ‘safe’ in our advertising,” said
Anthony Temple, McNeil’s longtime medical director, in a legal case in 1993. “We will say ‘a superior safety profile’ or some language to suggest its relative safety to other” over-the-counter pain relievers.

McNeil’s advertising budget for Tylenol has frequently
exceeded $100 million per year: $115 million in 2003, according to Brandweek; $138 million in 2005, according to Advertising
Age; and $162 million in 2008, according to Adweek. In
2004, marketing was the largest department in the company, employing about 150
professionals, McEvoy said in a court deposition.

McNeil’s recent chief executives have often come from
marketing backgrounds. Johnson & Johnson, a conglomerate of more than 250
companies, does not even place McNeil into its pharmaceutical division, which
is responsible for prescription drug products. Instead, the company is part of
the consumer division, along with shampoo, mouthwash and skin care products.

Johnson & Johnson does not release sales figures for
individual products, but Tylenol is the dominant acetaminophen brand in the U.S.
Although the drug is available in cheaper generic forms, McNeil accounted for nearly half
of all over-the-counter sales of acetaminophen, according to a 2010 McNeil
presentation.

Sales of acetaminophen by all companies have also grown.
It became the nation’s most-used drug in the mid-2000s, according to
surveys. In 2009, more than 27 billion
doses of acetaminophen were sold in the U.S., most over the counter.

One way McNeil has reached ever-more households is
through a marketing strategy known as line extension: targeting market niches
by adding products, all under the halo of the Tylenol brand. Between 1988 and
2002, the company notified the FDA of plans to introduce 54 different kinds of
packages, ranging from chewable tablets to coated pills, packed into bottles,
pouches, cartons and blister packs.

In the webcast interview, McEvoy,
a marketing expert who rose into Johnson & Johnson’s corporate ranks,
called Tylenol “a billion-dollar brand.”

Internally, company officials refer to it simply as “the
Brand.”

The first reports of deaths from acetaminophen emerged in the late 1960s.

Researchers subsequently learned that when the drug is
broken down in the liver, it produces a potentially toxic byproduct. In an
overdose, the liver can no longer safely dispose of the byproduct and can fail
in a matter of days, shriveling like a deflated balloon.

The concerns with acetaminophen emerged at a time when
the American system for drug oversight was undergoing a sea change. Congress
had passed a law in 1962 requiring the FDA to institute more rigorous testing
for new drugs and to review the safety and efficacy of those already on the
market.

In 1972, as part of the review of existing drugs, the FDA
assembled a group of doctors and scientists to assess painkillers, including
acetaminophen. Over five years, the panel held 50 meetings, heard from scores
of witnesses, and scoured thousands of pages of research – much of it
submitted by drug makers themselves.

As the panel’s work was going on, one of the world’s most
prestigious medical journals weighed in on acetaminophen. The
London-based Lancet declared in a 1975 editorial that if the drug “were
discovered today it would not be approved” by British regulators. “It would
certainly never be freely available without prescription.”

The journal’s editorial board called the drug’s apparent safety “deceptive.” They pointed
out that “not much more than the recommended maximum daily dosage” could cause
liver damage and that acetaminophen poisoning was already “one of the commonest
causes” of liver failure in Britain. (The drug is known there and in many countries as paracetamol.)

Relatively few cases of acetaminophen poisoning had been documented in the
United States. But an American study published in 1975 identified four acetaminophen-related
deaths in one year in one city, Denver. The article suggested a reason why so
few cases had previously been found: “If you do not look for something you will
not diagnose it.”

McNeil dispatched a top official to meet with one of the study’s authors. The company then gave
him funding to help develop the acetaminophen antidote.

Two years
later, in 1977, the FDA’s expert panel delivered its 1,200-page report on pain
relievers.

While the committee
found that acetaminophen was generally safe when used as directed, it warned that
“some advertising for acetaminophen gives the impression that it is much safer
than aspirin.” So the panelists urged the FDA to add a clear, specific warning
to the acetaminophen label.

The language the panel suggested: “Do not exceed recommended dosage because severe
liver damage may occur.” The panel had only advisory power, but it felt so
strongly that it told the FDA the warning was “obligatory.”

Committee members wanted to drive home the potentially devastating consequences of taking
too much acetaminophen, said Ninfa Redmond, a
toxicologist who served on the panel.

“We felt very strongly the evidence was conclusive,” Redmond
said.

For McNeil, the proposed liver warning put a lot at
stake. Just the year before, Tylenol had become the No. 1 brand in the
over-the-counter pain medication market, according to a company history.

As McNeil prepared its response to the advisory panel’s
recommendation, new reports of harm from the drug emerged.

In September 1977, the Annals of Internal Medicine published articles about patients
who suffered liver damage after taking acetaminophen for an extended period of
time at or slightly above therapeutic doses, underscoring what the Lancet had said
about the drug’s narrow margin for error.

That December, McNeil filed a voluminous response to the
FDA opposing the recommendation for a liver warning. It’s not known if the
individuals who drafted the company’s filing were aware of the journal
articles, but the company asserted that people who overdosed were “almost
invariably” trying to kill themselves. Indeed, McNeil maintained it had never
seen a “documented case” of a person harmed while taking the drug for medical
reasons.

A liver warning “is unnecessary and serves only to
confuse and frighten the vast majority of consumers who use acetaminophen in a
rational and appropriate fashion,” the company concluded. It also wouldn’t help
consumers, the company said, because signs of liver damage often don’t emerge until
it’s too late to get help.

McNeil raised another objection: The warning would put it
at a competitive disadvantage.

Bayer, one of the world’s largest aspirin makers, had
started running advertisements citing acetaminophen’s potential to harm the
liver, based on the advisory panel’s recommendation. “Losses are already in the
millions of dollars,” McNeil stated in its submission to the FDA.

Almost a decade would pass without the FDA coming to any
decision. While the label advised consumers to seek medical assistance if they
overdosed, McNeil was able to sell its drug without warning that it could harm the
liver. The agency’s decision was delayed, at least in part, because regulators extended
deadlines to review new research.

Redmond called such additional review unnecessary because
the basic facts about the drug were well-established. She said she was mystified by regulators’
failure to act on the panel’s recommendation. “It’s very surprising, and it’s
sad,” she said. “How many people might have died because of that?”

Finally, in 1988, the FDA announced a “tentative” ruling.
The agency agreed a warning was necessary but said there was no need to specify
that the drug could injure the liver.

The agency explained that it didn’t want people who were
considering suicide to know what an overdose could do. And, it said, liver
damage didn’t produce telltale symptoms for several days, when it was often too
late for doctors to intervene.

So it mandated a catchall warning: In case of overdose,
consumers should seek prompt medical attention “even if you do not notice any
signs or symptoms.”

McNeil had won a reprieve from having to put a phrase on its
bottles that company officials believed scared off buyers: “severe liver
damage.” And the FDA would not return to the issue until many, many years
later.

As the FDA’s deliberations over the label crawled on,
research began to emerge about the risks of drinking alcohol and taking acetaminophen
— and McNeil took steps to counter the research.

As early as the 1970s, an FDA panel had examined whether
to put an alcohol warning on the acetaminophen label. In 1978, according to an
internal McNeil memo, the company had been “successful in convincing” FDA
officials “that such a warning was not indicated.” But the issue had not gone
away.

According to a corporate memo from February 1986, McNeil had test-marketed
how consumers would interpret different versions of an alcohol warning. No
matter how the warning was phrased, consumers reacted negatively: Most
respondents concluded that drinkers should reduce or discontinue using Tylenol,
even at recommended levels.

The following month, the Annals of Internal Medicine
published a study
describing alcoholics who developed liver damage after taking “apparently
moderate” amounts of acetaminophen.

Two weeks after the article’s publication, a McNeil
official issued a memo to Tylenol’s sales force warning representatives to “not
initiate discussions with your physicians” about the danger of mixing alcohol
and acetaminophen. A senior McNeil official would later testify in a deposition
that the issue was controversial and complex. Sales reps, he said, were “not
equipped” to discuss it.

Then, in August 1987, a relatively obscure Swedish journal
published a study on the dangers of drinking and taking acetaminophen.

Thomas Gates, then McNeil’s medical director, shot off a memo to the chief executive of Johnson & Johnson, the president of McNeil
and other top officials, laying out a detailed “plan of action” for “diffusing media
interest” in the research and “limiting the extent and duration of the
coverage.”

Gates
envisioned two possibilities: “Low Level of Publicity (most probable scenario)”
and “High Level of Publicity (worst case scenario).” For the latter, Gates
suggested a series of responses: a letter-writing campaign to medical
societies, doctors, pharmacists and academics; a coordinated public relations
response with the FDA; even placing on retainer scientists whose research the
company favored.

“If there is another wave of publicity,” Gates warned,
“the FDA might be compelled to reconsider the matter and require a specific
warning regarding a possible risk of toxicity in chronic alcohol abusers.”

Gates, long retired from McNeil, was too ill to respond
to questions, his wife said.

Ultimately, the Swedish study received little attention.

Gates’ memo summarized cases in the scientific literature
over the previous decade that documented acetaminophen’s risk for drinkers. He wrote
that 38 “chronic alcoholics” had reportedly suffered liver and/or kidney damage
while taking acetaminophen. In just over half the
cases, users substantially exceeded dosing limits.

However, there were 18
instances in which they took less than 6 grams a day, not much more than the 4
grams considered safe, Gates noted. 

He stressed that “the amount of
acetaminophen ingested is open to question since alcoholics are notoriously
unreliable informants.”

But “if accurate,” he wrote, the amount of acetaminophen that harmed those 18 patients “bring us uncomfortably
close” to the maximum recommended daily dose.

Although McNeil had been preparing for the possibility that the FDA would require an alcohol warning, it took years before the agency publicly
grappled with the issue.

In 1993, the FDA convened an advisory panel to look at
the risk of mixing alcohol and acetaminophen. Such panels are made up of
outside experts. While the FDA does not have to follow their recommendations,
it usually does.

McNeil argued against the warning, saying the scientific
evidence did not justify it and that it would frighten customers into taking
other pain relievers that the company claimed were riskier.

But the panel found that an alcohol warning was warranted.
The chairman called the science behind it “unusually strong and
well-supported.”

At the same time, McNeil was seeking FDA approval for a
new product, extended release Tylenol. Because it was a post-1962 drug, the
agency could push for a warning with less red tape. It moved to do so on the
new product, raising the possibility that regular Tylenol would have no alcohol
warning but that the time-release product would have one.

After the FDA approved extended release Tylenol with an
alcohol alert in 1994, McNeil voluntarily added the warning to all Tylenol
products.

“After careful deliberation and discussion with the FDA,
McNeil has made several label changes to Tylenol over the years — all for
the purpose of eliminating potential confusion by consumers and protecting
consumer safety,” the company wrote in response to questions. “A label change
does not mean that a prior label was inadequate, and in fact label changes are
an indication that our medical understanding is evolving.”

Four years after McNeil acted, the FDA required all
acetaminophen manufacturers to add an alcohol alert to their products. People who drank three or more alcoholic drinks every day were advised to consult their doctors and were warned that liver damage could occur.

The warning label came too late for Antonio Benedi.

Benedi, who worked as a special
assistant to President George H.W. Bush, often drank two or three glasses of
wine with dinner. On a Friday in February 1993, just weeks after Bush left
office, Benedi came down with the flu. Over the next
several days, he said, he took Tylenol, never exceeding the maximum dose.

Benedi said he was careful to
read labels. At the time, nothing on his box of Extra Strength Tylenol warned
about the risk of drinking or liver damage.

Several nights later, he woke up, confused and
incoherent. His wife called an ambulance to rush him to a hospital near their
home in the Virginia suburbs of Washington, D.C.

By the time he arrived, Benedi
had slipped into a coma. Tests showed his liver enzyme levels were high, a sign
of organ damage. He had brain swelling, so doctors drilled a hole in his skull to
relieve the pressure.

After his third day in a coma, Benedi
got a second chance at life. Doctors declared a young man taken to Benedi’s hospital after a motorcycle accident to be brain
dead, and Benedi received the man’s liver.

Benedi spent two months in the
hospital, more than 200 surgical staples holding his abdomen together in a raw
wound that looked like the Mercedes-Benz symbol.

Almost two decades later, he still suffers from those few
days of taking Tylenol. To keep his body from rejecting his transplanted liver,
he had to take powerful medications that eventually destroyed his kidneys,
requiring a kidney transplant.

He sued McNeil. In court, the company argued that a virus
had destroyed his liver and that the warnings on Tylenol’s label were adequate.
The jury found for Benedi, awarding him an $8.5
million judgment in 1994. To this day, he will have nothing to do with Tylenol —
he always tells doctors and nurses not to give him any.

“I have nothing against corporations. They do a lot of
good, employ a lot of people,” said Benedi. But “when
a company omits a known danger to them that could hurt people, they’re lying to
us. I think that is outrageous.”

As Benedi’s case unfolded, McNeil
was pressing ahead with a program dubbed Project Protect to create a safer
version of acetaminophen.

But the company kept the program, which has never been
reported, confidential. Even when the government specifically asked for
scientific information on developing a safer acetaminophen, the company didn’t
mention its own research.

The concept of such a drug was not new. The 1975 Lancet
editorial had called for the development of a version of acetaminophen that
wouldn’t harm the liver. In the United Kingdom, companies had developed drugs combining
acetaminophen with one of its antidotes. But sales never took off — the
drugs were too expensive, the pills were too large, and there were questions
about the drugs’ safety.

In the early 1990s, McNeil embarked on a series of experiments to combine acetaminophen with various protective agents. The effort
involved almost 20 different lab and animal studies lasting several years, according
to internal company documents and court records.

As the experiments progressed, however, one official
worried that the research could be a double-edged sword.

A Johnson & Johnson manager based in Europe wrote to
Ralph Levi, the head of Project Protect for McNeil, according to court
documents. In his June 1994 note, the manager cautioned that a new, improved
product touched on “a sensitive point,” because the company would be acknowledging
that its existing product “isn’t so safe as we’ve always said before.” Levi has
since died, and the court documents identified the manager only by his first
name, Geert.

To help keep Project Protect hidden, the company signed a
confidentiality agreement with Rutgers University, where some of the research
was conducted. A key clause: The publicly funded university agreed not to
publicize “the identity or interest of McNeil in this area of technology.” Rutgers
said such agreements were standard when researchers worked with companies.

At least one line of research showed early promise,
according to Rutgers documents, but there’s no public evidence that it or any Project
Protect compound made it beyond laboratory or animal studies.

McNeil’s work remained confidential even after the FDA became
interested in that field of research. In 2006, as part of a larger review of acetaminophen,
the agency solicited information about combining the drug with antidotes.

In response, McNeil submitted a
lengthy report citing 51 studies to document the drawbacks of such combinations.
But the company did not mention that it had extensively researched the topic.

FDA officials said McNeil wasn’t required to disclose its
research in that response. Asked if the company had ever told the agency of its
project, the FDA did not answer. “Those are the kind of things that we are
always interested in knowing about,” said Kweder, the
FDA’s acetaminophen expert. She added that even “if they didn’t show anything,
it’d be useful to us to know if didn’t work scientifically.”

In response to questions about Project Protect, McNeil
acknowledged “research into acetaminophen overdose antidotes” but did not provide
details. The company noted that confidentiality clauses are standard industry
practice. It also said that the firm had complied fully with FDA reporting
requirements.

The company said it halted the research after discovering that the most promising agent
“posed a cardiovascular risk for individuals with a particular genetic defect.”
The company did not disclose the name of the agent.

“Had the research yielded a viable discovery, our
intention was to launch a product,” the company statement said. It continued:
“Despite the outcome, we consider this type of research a responsible action on
our part, and are proud of the many scientists who worked on it.”

Lee’s research spurred the FDA to re-examine if the label on over-the-counter acetaminophen
should explicitly warn about the risk of liver damage.

The agency invited a grieving mother to tell her story at a public hearing.

Kate Trunk’s 23-year-old son Marcus had hurt his wrist in 1995 while working on a
construction job in Pennsylvania. Over the next two weeks, he took Tylenol with
Codeine and Extra Strength Tylenol. He started to feel sick and started on Theraflu
— apparently not realizing that it, too, contained acetaminophen.

Soon, Marcus felt bad enough to check himself into a hospital, where he lapsed into a
coma. Eight days after Marcus entered the hospital, Kate and her husband
decided to end life support.

“We stayed with him and held him and talked to him and kissed him and petted him,” Trunk
said. “He finally just went. It was total shock, walking around in a daze, not
knowing, angry at God, angry at everything.”

The mystified family did not find out the cause of Marcus’ death until the autopsy
came back: liver failure caused by acetaminophen. The Trunks sued McNeil and
settled for an undisclosed amount. McNeil did not respond to questions about
the case.

When the Trunks took their concerns to the FDA hearing, Kate was so nervous that her
husband kept checking her blood pressure. But she delivered a call to action:
She wanted acetaminophen clearly labeled to warn that the drug could poison and
even kill.

“If our son or my husband and I even had an inkling that acetaminophen toxicity
existed, I feel that the outcome of our story would be totally different,” she
said. She ended her testimony by saying that “death is not an acceptable side
effect.”

The committee recommended adding a warning aimed at all
users, not just drinkers, that overdosing can damage the liver.

This time, McNeil gave ground, agreeing with the need for
a liver warning. “We believe with you that the American consumer is smart,
responsible and can self-manage medications,” Dr. Debra Bowen, McNeil’s vice
president of research and development, told the panel.

By 2005, McNeil began placing labels on Tylenol warning that
taking too much could result in “liver damage” for anyone, not just people who drank alcohol.

In 2009, the FDA imposed stronger language, requiring all over-the-counter acetaminophen
products to warn that overdosing may cause “severe liver damage.”

The FDA’s wording was nearly identical to what its expert
panel had recommended 32 years earlier.

Asked about this time lag, the agency replied, “While we
acknowledge that there has been some delay between available scientific
information and the translation to labeling instructions for consumers, FDA has
strengthened warnings on the acetaminophen label accordingly as science has
evolved.”

While McNeil agreed on the need to warn consumers of
acetaminophen’s potential to harm the liver, it vigorously objected to the FDA’s
plans to raise public awareness of that very risk.

In 2004, the
agency launched a modest public service advertisement initiative. The slogan: “Why is it important to know that all these medicines contain acetaminophen? Because too much can
damage your liver.”

A key problem the campaign hoped to address: double
dipping, or overdosing by inadvertently taking more than one medication that
contains acetaminophen.

That risk had grown as McNeil and its competitors expanded the number of acetaminophen
products on drugstore shelves. The drug was in medications targeted at consumers
suffering all manner of ills, from colds to arthritis aches to insomnia caused
by pain.

The FDA didn’t have a lot of money for the 2004 campaign, just $20,000, according to an
Associated Press story from the time.

During this period, McNeil was spending more than $100 million a year to advertise
Tylenol, trade publications reported.

Nevertheless, McNeil launched an intense and lengthy effort to overhaul the campaign.

The company sent a 79-page complaint demanding that, if left unchanged, the FDA’s
educational campaign would “negatively affect
McNeil, the world’s largest marketer of OTC acetaminophen products.”

Indeed, the complaint said, the FDA should speed up its
review “in order to limit the damage that is being done” by the nascent
campaign.

McNeil wanted the FDA to include warnings about other
over-the-counter pain relievers, arguing that they posed risks at least as
serious as acetaminophen. The FDA’s initiative, the company contended, created the
false impression that “acetaminophen products are less safe” than other over-the-counter
painkillers and could spur consumers to switch to other pain medicines,
resulting in more injuries and deaths – a frequent McNeil argument.

The FDA’s Steven Galson, then
the acting director of the agency’s Center for Drug Evaluation and Research, disagreed.

Doubling the maximum daily dose of over-the-counter pain
killers such as aspirin or ibuprofen “may slightly increase a person’s risk for
bleeding,” in the stomach and gastrointestinal tract, he wrote, but “it is not
even close to the seriousness presented by doubling the dose of acetaminophen,”
which can lead to liver failure.

McNeil took its case all the way to the FDA commissioner,
who turned down the company’s final appeal, saying the agency had “refuted
each example to respond to your allegation.”

McNeil did not respond directly to questions about its
opposition to the campaign. But it stressed that it had launched numerous
acetaminophen safety education efforts, both on its own and with industry and government
partners. Altogether, McNeil said, these “acetaminophen awareness messages have
been seen over one billion times.”

Although the agency had prevailed, its safety initiative fizzled.
Major media outlets were reluctant to run the public health announcements.
Magazine publishers told agency officials that they “did not want to antagonize
potential advertisers,” according to an
FDA report.

The FDA concluded that its campaign “did not appear to
have a significant impact on the problem.”

Indeed, a nationwide poll this year shows that many
Americans don’t recognize the risk of double dipping.

Thirty-five percent of respondents said it was safe to take the maximum recommended dose of Extra Strength Tylenol with NyQuil, a cold remedy that also contains acetaminophen. The margin of error was 3.5 percentage points.

Among parents, 35 percent thought it was safe to give a child the maximum dose of Children’s Tylenol with Children’s Tylenol Plus Multi-Symptom Cold, both of which contain acetaminophen. The margin of error for the parents’ subgroup was 6.7 percentage points.

In both these examples, mixing the two medicines would not be safe, according to the FDA.

(The survey of 1,003 respondents – conducted by Princeton Survey Research Associates International and commissioned by ProPublica and This American Life – was completed in March.)

With the public education campaign faltering, the FDA regrouped in 2006 and convened a
team to examine the agency’s handling of acetaminophen — including what a
former top official described as “the interactions between the FDA and McNeil
over this 30-year history.”

Officials reviewed the science, the reports of deaths and side effects, and the long
history of regulatory delays. The 265-page report that emerged was both a blunt
assessment of the drug’s dangers and a plan for mitigating them.

Officials concluded that deaths from acetaminophen
poisoning had risen dramatically over the decade between 1995 and 2005. They zeroed
in on how the drug differed from other over-the-counter pain relievers.

“The 4 gram per day recommended dose is also the maximum
safe dose, one that must not be exceeded, an unusual situation for any drug,
particularly an OTC drug, one placing a large fraction of users close to a
toxic dose in the ordinary course of use,” the report said.

Officials proposed more than a dozen solutions, including
several aimed at widening the drug’s safety margin, such as lowering the
maximum recommended daily dose and reducing the amount of the drug in each pill.
The report also suggested removing an entire class of pediatric products to
reduce the
potential for dosing mix-ups.

Taken together, the proposals constituted a blueprint for
sweeping safety reforms.

At the same time, the FDA officials who wrote the report
gave a candid assessment of the fierce resistance they expected from drug makers
to certain proposals.

To the notion of lowering the recommended daily dose, the agency expected a “possible
industry challenge.”

To the proposal to decrease the amount of acetaminophen per pill, the report
anticipated “possible industry resistance to costs related to reformulation”
and to “possible loss of revenue from elimination of 500 mg products.”

In June 2009, the agency gathered nearly 40 experts in a
Maryland Marriott to weigh in on its recommendations. Everyone in the room,
including executives from McNeil and other companies, knew the stakes.

Edwin Kuffner, McNeil’s medical
director, had prepared for the meeting by attending some 100 practice sessions
with a consulting company that specialized in readying corporate clients to speak
before the FDA, according to a court deposition.

Kuffner objected to dropping
the daily recommended dose below 4 grams. For decades, the company’s labels had
advised users to take no more than 1 gram, or the equivalent of two Extra
Strength Tylenol pills, at a time. He suggested directing consumers to take one pill at a time until they felt pain relief, gradually easing up to a maximum of
4 grams a day only as necessary. Even though a company document calls this practice “good medicine,” McNeil
has not added this instruction to Tylenol labels.

When it came time to vote, Judith Kramer, a physician and
professor of medicine at Duke University, reminded her fellow panelists of the
opportunity before them, noting that attempts to make acetaminophen safer had
foundered for decades.

“There is an elephant in the room that we really should
talk about explicitly,” she said. “There are tremendous cost and commercial
implications to some of the recommended changes. These conditions frequently
can overshadow the public health considerations. And I think that we can’t let
that happen.”

The panel handed McNeil a defeat, endorsing most of the
FDA’s proposals.

But then, the agency’s momentum stalled.

Four years later, the agency has not enacted any of its
own suggestions for over-the-counter acetaminophen.

In fact, the FDA has still not completed the review of
the drug that began back in the 1970s, as part of the agency’s larger mandate
to assess the safety and efficacy of older medicines.

In interviews, FDA officials acknowledged that it has taken longer than it should. They blamed a
combination of science and bureaucracy.

Despite 50 years of
sales and more than 30,000 published papers, there remain unknowns about
acetaminophen. In a little-publicized 2011 announcement, the FDA acknowledged it was still unable “to identify precise toxic
thresholds and/or specific populations for whom currently recommended dosages
are not safe.”

A Canadian government study found
six people had suffered serious liver damage after taking less than the maximum
recommended dose. By contrast, a case report described
a man who survived after ingesting as much as 60 grams all at once. In response
to questions, McNeil first wrote in an email that 8 grams, or double the maximum daily dose,
over several days can damage the liver. Later, when asked to confirm this figure, the company declined to do so. It pointed to data showing that at least 10 grams a day for at least 2 to 3 days can threaten the liver.

Setting the right dose “has been one of the big
challenges for us,” the FDA’s Kweder said. “There is
so much disagreement among experts who are well respected and can present data
on where they’d draw that line.”

Agency officials also said that McNeil has often resisted changes.

McNeil was “more aggressive than most,” a former top FDA
official said. “It’s a company that feels very strongly about the competitive
nature of the marketplace.”

McNeil countered: “Our marketing practices are
appropriate and align with the regulatory standards for our industry.”

It also added that the company had a “deep
respect for the Food and Drug Administration (FDA) and its role in establishing
and enforcing regulations” and noted that it has voluntarily implemented some
safety measures before the agency required it to do so.

The FDA delays are, at least in part, self-inflicted.

The agency said that the procedure it set back in the
1970s for revising rules for older drugs “was not rapid, but there were
many fewer steps to the process that today is long.” Indeed, actions that
were supposed to take months have dragged on for years or even decades.

For prescription drugs, the FDA can act more swiftly, and it has limited the amount of acetaminophen in
such medicines.

In 2011, the FDA limited
the amount of acetaminophen that can be put in prescription drugs to 325 milligrams
per pill, and gave companies until January 2014 to implement the change.

Yet the agency continues
to allow the sale of over-the-counter pills that contain up to 650 milligrams
of acetaminophen — twice as much.

Asked why it permits
such potent pills to be sold directly to consumers, an FDA official said the
agency “believes there is a benefit to having acetaminophen available.”

In addition to lowering the dose per pill, the FDA
slapped prescription acetaminophen with a so-called black box warning, the
agency’s most serious. It states that “acetaminophen
has been associated with cases of acute liver failure, at times resulting in liver
transplant and death.”

The label for the
over-the-counter version of the drug, taken by far more Americans, mentions
neither of those potential consequences.

The agency’s disparate actions on prescription and over-the-counter acetaminophen have
given rise to glaring inconsistencies.

Tylenol with Codeine No.
3, made by a Johnson & Johnson company, combines acetaminophen with
codeine, which can be bought only with a prescription. Tylenol 3, as it is
commonly known, carries a black box warning about acetaminophen, and each pill
contains 300 milligrams, less than the new limit of 325 milligrams.

By contrast, a single pill
of Extra Strength Tylenol — sold at newsstands, gas stations and big-box retailers
across the land — delivers 500 milligrams of acetaminophen. The bottle
carries no black box warning.

Two pills, containing
the same medication, made by the same corporation, carrying the same brand
name, regulated by the same agency – but subject to different standards.

While the FDA remains stuck on rules for over-the-counter
acetaminophen, McNeil has reversed course on one major proposal.

Just a month after adamantly opposing dosing reductions
at the 2009 advisory committee meeting, McNeil wrote top FDA officials, offering a plan that recognized the will
of the advisory committee.

Although the company had insisted for half a century that
4 grams of medicine per day was the most appropriate dose for pain relief, the
company said it was ready to recommend taking no more than 3 grams a day (or
six pills) of its flagship product, Extra Strength Tylenol. The company
implemented the change in 2011.

The move echoed other instances, such as the alcohol
warning, in which the company opposed safety proposals until the FDA signaled
its intent. Then the company adopted measures voluntarily as the agency plodded
toward final rules.

Kuffner, McNeil’s vice president for medical affairs, said in an interview that the company changed its
dosing instructions “after hearing the discussion” at the 2009 advisory
committee. The lower dose is “intended to increase the margin of safety,” he said.

McNeil hasn’t standardized the new daily dose across all
its products, however. For Tylenol Arthritis Pain, the company’s label puts the
daily limit at 3.9 grams. And the company didn’t change the dose for customers
worldwide. In Canada and other countries, the company still instructs users of
Extra Strength Tylenol that they can take up to 4 grams a day — eight
pills.

Kuffner said the “root causes” of
acetaminophen overdose differ from region to region.

“The safety of consumers in every region is important to
us. When you really go back and look at root causes, some of the root causes
weren’t as prevalent as in other regions,” he said. “There are
differences in the prevalence of acetaminophen overdose and liver injury.”

“At the end of the day, when people take 4 grams or 3 grams,
both of them are safe doses,” Kuffner said.

The FDA had said it would issue proposed rules for
over-the-counter acetaminophen by the end of August. But the agency missed that
deadline, pushing it back to December.

Dr. Thomas Garvey, a former FDA official and drug
industry consultant who has testified against McNeil in trials, called the
amount of time the FDA had taken to reach a final ruling “remarkable and
unusual.”

“There are still many questions about this drug,” Garvey
said. “It’s still killing people.”

  

In many other countries, authorities have taken a very
different approach to regulating acetaminophen.

At least 10 other industrialized countries —
including Australia, New Zealand, Germany, Finland, Denmark, Sweden and
Switzerland — have placed some kind of restrictions on the drug, a 2008
FDA report said. Most limit how much can be sold at one time or
require pharmacies to be the only outlets that carry it.

Some European countries with strict regulations have remarkably few deaths.
Switzerland’s national toxicology center reported only four deaths due to
acetaminophen poisoning from 1998 through 2012. Even accounting for
Switzerland’s much smaller population, that’s a fraction of the U.S. toll.

The German government reported four deaths from acetaminophen poisoning in 2010, the same
year the CDC put the American total at 321. The U.S. population is four times
that of Germany.

Both Switzerland and Germany limit sales to pharmacies, which sell packages with a maximum of 10
grams, the equivalent of 20 Extra Strength Tylenol pills.

In many nations, authorities were focused more on reducing suicides than on preventing
accidental overdoses. In the U.K., for example, acetaminophen had become a
common suicide method by the 1990s. The drug was easy to get: In drug stores,
it could be purchased in unlimited quantities.

In 1998, the U.K. cracked down on several types of pain relievers, including acetaminophen.
At pharmacies, people could buy the equivalent of only 32 Extra Strength
Tylenol pills. At other stores, they were limited to half that.

Here was a real-world experiment of the effect of restricting acetaminophen. Early studies
were somewhat contradictory, but this year, a large study concluded that the
number of deaths linked to acetaminophen had plunged by 43 percent. In the 11
years since the restrictions took effect, the researchers estimated, 765 fewer
people had committed suicide using the drug.

While the new regulations may have saved lives, they hurt sales. The amount of
acetaminophen sold in the U.K. plunged by 60 percent from 1998 to 2000,
according to a study by the FDA. The agency noted that such restrictions would be
more difficult to implement in the U.S. because it has a different commercial, regulatory
and medical culture than Britain and many European countries.

Indeed, here there has been only limited debate about restricting the amount of
acetaminophen consumers can buy.

A proposal to limit package sizes — how many pills could be put in a bottle, for
example — was considered by the advisory panel convened by the FDA in
2009. In a close vote, it failed. Some of the experts worried that patients
suffering from arthritis would be inconvenienced by having to make repeated
trips to buy the drug.

Several committee members said they had struggled with their vote.

“I hope the FDA doesn’t consider this ‘no’ vote to mean that we support selling 1,000
acetaminophen tablets in Costco,” said Kramer, the Duke University professor.

Over the past several years, McNeil and Tylenol have suffered a series of body blows related not to
acetaminophen’s risks but to the company’s ability to manufacture its drugs
safely. The headlines might have killed a lesser product, but have only
underscored the extraordinary resiliency of the Brand.

Between 2008 and 2010, federal regulators discovered an
array of troubling manufacturing violations at McNeil’s plants, triggering a
series of recalls of Tylenol and other products such as the company’s Motrin brand of ibuprofen.

For example, to make Tylenol syrup for infants and
children, the company used an ingredient that was possibly contaminated by
dangerous bacteria. The company said “a thorough investigation” showed the
bacteria had not reached its medicine. However, the FDA found that McNeil’s
tests — skimming a teaspoon off the top of a container of liquid — were
inadequate.

Later, agency investigators also discovered that Tylenol
and other products had been contaminated by tiny bits of cadmium, nickel,
chromium, iron and other metals, most likely shavings that fell into the
medicine from machines on the production line.

Again, McNeil officials saw little cause for concern. “We
are talking minute particles,” one McNeil employee told FDA officials. “We are
talking contaminants you don’t want to be there!” an inspector replied, according
to previously unreported notes taken by McNeil.

The company itself determined that it had manufactured batches
of what the FDA called “super potent” Infants’ Tylenol with up to 23 percent
more acetaminophen than was supposed to be in it. It is not known if any
reached the market.

On April 30, 2010, the FDA issued a formal inspection
report with a litany of deficiencies. The same day, McNeil pulled 136 million
bottles of pediatric Tylenol and other medicines off the market.

It was the largest recall in the history of pediatric medicine.

Subsequently, the Department of Justice launched a civil
investigation that effectively gave the FDA power to direct the cleanup of McNeil’s
troubled plant in Fort Washington, Pa. The FDA has not tied any recalled
product to individual cases of harm.

Congress hauled in company executives for two public
hearings. William C. Weldon, then chairman and chief executive of Johnson &
Johnson, told lawmakers the company had “let the public down” by not
maintaining high quality control standards.

“We are working hard to restore the public’s trust and
confidence in Johnson & Johnson and to strive to ensure that something like
this never happens, ever again,” Weldon said.

By the end of 2010, the recalls had cost McNeil approximately
$900 million in sales, it reported. Many Tylenol products vanished from the
shelves for months. The company recently
acknowledged that it faces federal investigations related to the recalls;
it said it is cooperating with the probes. The company’s Fort Washington plant
remains closed.

Meanwhile, McNeil has faced new court challenges about
the risks of its billion-dollar brand.

In the past few years, about 100 lawsuits have been filed,
contending that McNeil has failed to adequately warn the public about the true
danger of Tylenol. Most of the lawsuits have been consolidated before a federal
judge in Philadelphia. McNeil is fighting the claims, saying its warnings were
adequate. Many of the cases allege that consumers suffered injury or death
after taking Tylenol at or near the maximum recommended daily dose.

After enduring all the negative headlines about its manufacturing
plant, getting hit with scores of lawsuits, and even being removed from some markets
for months, Tylenol retains its power as a brand — a testament to the
decades of skillful marketing.

In Johnson & Johnson’s July earnings call, top
officials said McNeil’s over-the-counter revenue had surged
by 26 percent. Children’s Tylenol was one of the top two brands in over-the-counter
pediatric pain relief.

And the company’s flagship product?
Extra Strength Tylenol had doubled
its market share in the first half of 2013.

Once again, it was America’s No. 1 over-the-counter adult
pain medicine.

Additional reporting by Jannis Brühl, Cora Currier, Liz Day, Sergio Hernandez, Olga Pierce, Hanna Trudo

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