Another FDA Cover-up ... Uncovered Propulsid

http://www.nytimes.com/2005/06/10/bu...gewanted=print

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June 10, 2005
Lucrative Drug, Danger Signals and the F.D.A.
By GARDINER HARRIS and ERIC KOLI

Dozens had died and more than 100 patients had suffered serious heart
problems by March 1998 after taking Propulsid, a popular medicine for
heartburn. Infants, given the drug to treat acid reflux, seemed
particularly at risk. Federal officials told Propulsid's manufacturer,
Johnson & Johnson, that the drug might have to be banned for children,
or even withdrawn altogether. Instead, the government and the company
negotiated new warnings for the drug's label - though not nearly as
tough as regulators had wanted.

Propulsid had a good year anyway. Sales continued to surpass $1
billion. Johnson & Johnson continued to underwrite efforts that
promoted Propulsid's use in children. A survey that year found that
about 20 percent of babies in neonatal intensive care units were being
given the drug.

Two years later, as reports of heart injuries and deaths mounted,
Johnson & Johnson continued defending the safety of Propulsid, but
then pulled it from the market before a government hearing threatened
to draw attention to the drug's long, largely hidden, record of
trouble.

That record, pieced together from newly obtained corporate and
government documents, provides an in-depth view of a pharmaceutical
company trying to save a lucrative drug in the face of growing
evidence of harmful side effects. It is a story that has particular
resonance now, as troubled arthritis painkillers - Vioxx, Celebrex and
Bextra - have again focused attention on what critics say is the
federal Food and Drug Administration's inability to monitor and
regulate pharmaceuticals effectively once they are on the market.

Documents from lawsuits against Johnson & Johnson show that the
company did not conduct safety studies urged by federal regulators and
their own consultants that could have revealed Propulsid's danger
early on. The F.D.A., moreover, did not disclose company research that
cast doubt on Propulsid's effectiveness against digestive disorders it
was being used to treat, since the studies are considered trade
secrets.

Propulsid's history has striking parallels with the painkillers now at
the center of controversy. Dozens of studies sponsored by Johnson &
Johnson that might have warned doctors away were never published, just
as the pharmaceutical manufacturer Pfizer failed to publish an early
study of Celebrex that indicated a heart risk. And Johnson & Johnson
was able to delay and soften some proposed label changes, just as
Merck later did with Vioxx.

An F.D.A. advisory panel concluded in February that the three
painkillers increased the risk of heart attacks and strokes.

In April, Pfizer, under pressure from the F.D.A., withdrew Bextra and
placed severe warnings about heart risks on the label for Celebrex, a
sister pill. That followed a decision in September by Merck to
withdraw Vioxx after years of insisting that it was safe.

Members of a federal advisory committee on those painkillers cited
Propulsid as an example of how even the strongest warnings - known as
black box warnings - do not stop physicians from prescribing a drug
inappropriately.

Dr. Alastair Wood, the chairman of the panel, said in an interview
that label warnings of a drug's potentially lethal effects do not
protect all patients. Eventually, Johnson & Johnson made five
significant changes to Propulsid's warning label and sent five letters
to doctors across the country.

But Dr. Wood, an associate dean at Vanderbilt University Medical
Center, said, "The case of Propulsid proves this: When people are
falling off a cliff, you don't put up more signs; you put up a fence."

Despite these public warnings about Propulsid, much of the
conversation between the company and regulators remained private as
the drug thrived. With evidence mounting that Propulsid could
interfere with the heart's electrical system, government regulators
became increasingly confrontational with Johnson & Johnson executives.

But physicians were never made aware of the full depth of the agency's
concerns. And even though Propulsid was never proved effective in
children, the company helped finance programs that encouraged the
drug's pediatric use, according to internal company documents.

Johnson & Johnson agreed last year to pay up to $90 million to settle
lawsuits that eventually involved claims that 300 people died and as
many as 16,000 were injured from taking Propulsid.

Many of the documents relating to Propulsid obtained by The New York
Times were filed under seal in the lawsuits.

The company declined repeated requests to make executives available to
be interviewed for this article. In written responses, Johnson &
Johnson defended the safety of Propulsid and said that the marketing
of the pill was appropriate.

The company said it removed the drug from the market because
physicians continued to prescribe it inappropriately despite repeated
attempts by the company to warn them against that.

Jason Brodsky, an F.D.A. spokesman, said that the Propulsid case had
been unique because doctors insisted on having access to the drug,
despite its side effects, and because its label was unusually
confusing. Although the F.D.A. has the power to declare a drug
mislabeled and order it off the market, it has done so only once in
the last 30 years. Short of that, any label change sought by the
agency has to be negotiated with manufacturers, a process that
sometimes takes more than a year.

Testifying before Congress in March, Dr. Sandra Kweder, the F.D.A.'s
deputy director of the office of new drugs, bemoaned such delays and
said having the power to mandate label changes "would be very
helpful." Even without that power from Congress, the F.D.A. has
recently made moves to disclose concerns about drugs' adverse effects
before label negotiations with drug makers are complete.

The government and Johnson & Johnson negotiated for five years before
the company pulled Propulsid. By then, the federal government had
reports of 80 heart-related deaths and 341 injuries among patients
taking Propulsid.

First Signs of Trouble

The first signs of trouble emerged soon after Propulsid was approved
in 1993 for the treatment of nighttime heartburn in adults. By January
1995, the F.D.A. received reports of 18 Propulsid patients who had
developed serious heart arrhythmias; one patient, an infant, had died.
At a private meeting that month, agency officials told Johnson &
Johnson executives that the drug was causing life-threatening
arrhythmias, according to F.D.A. minutes of the meeting.

Company executives insisted that such problems occurred only in
patients who took Propulsid with other drugs or who had heart
problems. The company sent two letters to doctors and added warnings
to the drug's label listing drugs that should not be used with
Propulsid.

But by July 1996, regulators had reports of 57 Propulsid patients,
including seven children, who had developed serious arrhythmias or
other heart problems. In August 1997, after the company told the
F.D.A. that two more children taking the drug had died, a top agency
official wrote to the company that Propulsid's growing number of
cardiac problems among infants and children "suggests that pediatric
patients may be at greater risk for them."

Johnson & Johnson had previously conducted pediatric studies of
Propulsid that failed to demonstrate that the drug was effective. In
January 1995, the F.D.A. told the company that without studies showing
that the drug worked in children it would not receive approval for
pediatric sales. Johnson & Johnson never applied for such approval and
the label did not recommend it for use in children.

But doctors are free to prescribe medicines beyond the confines of
labels, and Propulsid became popular among pediatricians. By 1998,
doctors were writing more than half a million prescriptions a year for
children and infants, according to internal company estimates. The
company has said that its cherry-flavored liquid Propulsid was
developed for geriatric patients, but company documents show that as
much as 90 percent of it went to children.

Without approval for pediatric use, Johnson & Johnson could not
directly promote Propulsid for children. But F.D.A. rules did allow
the company to support educational efforts among doctors. A crucial
player in that effort was Dr. Paul Hyman, a pediatric
gastroenterologist who is now at the University of Kansas.

Dr. Hyman said in an interview that he was the first doctor in the
United States, in 1984, to treat a child experimentally with
Propulsid. Dr. Hyman became a Propulsid proponent. Johnson & Johnson
financed some of his work and put him on its Propulsid advisory board.
When he edited a textbook about childhood digestive problems that
recommended Propulsid, the company paid for the press run of 10,000
copies and distributed them to doctors. In December 1997, he also made
a 15-minute presentation at a Johnson & Johnson seminar where 240
doctors were trained to speak to health care professionals about the
drug.

While Dr. Hyman acknowledged that Propulsid had some potentially
dangerous side effects, he said they were rare. The drug was so safe,
he said, that it could be used to treat "happy spitters" - infants who
frequently spit up but are not ill.

"I was fairly vocal about how silly the whole death thing was, and how
it was one in a million," he said.

Although the company said educational efforts were legal, Dr. Stephen
B. Fredd, who oversaw Propulsid for the F.D.A., said that he had been
unaware that Johnson & Johnson was supporting programs advocating the
drug's use in infants.

"I had no idea they were doing anything in any way to support
off-label use in pediatrics," said Dr. Fredd, former director of the
F.D.A.'s gastrointestinal and coagulation drugs unit. Instead, he
said, "I wanted them to warn doctors that there were dangers in using
the drug."

Growing Concerns

Reports of patients who died while taking Propulsid were recorded in
stark language on federal forms.

"Pathologist reports that a three-month-old female died while on
Propulsid therapy," reads a July 3, 1998, report on F.D.A. MedWatch,
the agency's Web site for posting potential safety problems.

Her parents reported that the child, who had undergone cardiac
surgery, was sitting in her swing chair and was "fussy" at 7:50 a.m.,
the F.D.A. form says. "When the parents rechecked her at 8 a.m., the
infant was unresponsive," it reads. "Attempts to revitalize her were
futile."

Three weeks later, the mother of an 11-week-old premature boy who had
had stomach surgery and was taking Propulsid "noticed her son not
breathing," another report said. Attempts were made to revive him. He
was declared dead at the hospital.

Johnson & Johnson later concluded in both those cases that the
patients had no risk factors that would have indicated not to use
Propulsid. In a statement yesterday, Johnson & Johnson said analysis
of the cases "strongly suggests" other factors may have contributed to
the infants' deaths.

As injuries mounted, concern inside Johnson & Johnson about side
effects among the youngest patients was growing. Johnson & Johnson
researchers and executives made plans to ban sales for premature
infants in the United States, an action it had taken in some European
countries, according to documents obtained by The Times.

But there was internal debate. On March 16, 1998, a Johnson & Johnson
regulatory affairs director, Gaetan Rouleau, sent an e-mail message to
other executives saying that Propulsid could be used for premature
babies and that further discussion of its use in them be delayed until
after an F.D.A. meeting that month on the drug's safety.

Dirk Reyn, a Johnson & Johnson executive, wrote back to support the
decision to ban Propulsid for premature babies, saying, "We do have
cases and there is a scientific rationale for this."

Mr. Rouleau, however, responded that if the company agreed to ban
Propulsid in premature children, it might be forced to stop selling
its cherry-flavored liquid form of the drug. Unless Johnson & Johnson
could justify the use of Propulsid in premature babies, he wrote, "We
have very little to support the use of the suspension in children at
this time."

Ultimately, the drug was not banned for premature babies. In the March
1998 meeting between the F.D.A. and company representatives,
regulators expressed increasing concern about Propulsid's risks.
During a presentation, an F.D.A. official projected a slide that
asked, "Is it acceptable for your nighttime heartburn medicine (i.e.,
something for which you could take Tums) to have the potential to kill
you?"

Johnson & Johnson's minutes of the meeting stated: "In F.D.A.'s
opinion, cisapride is only minimally efficacious therefore no safety
risk is acceptable."

In May 1998, the F.D.A. proposed major changes to the label, including
adding a paragraph stating, "Despite more than 20 clinical trials in
pediatric patients, safety and effectiveness of cisapride (Propulsid)
have not been demonstrated in pediatric patients for any indication."

An internal company memo examined 15 of the proposed label changes and
estimated that they would cost over $250 million a year in lost sales.

Since federal regulators cannot order changes to labels, the F.D.A.
and the company negotiated. In the end, 13 of the 15 major proposed
changes were either scrapped or softened. Instead of mentioning the
results of the 20 clinical trials, the F.D.A. agreed to simply state
that "safety and effectiveness in pediatric patients have not been
established." The label said some pediatric patients had been injured
and others had died while taking Propulsid, "although causality has
not been established."

Financing Questions

Throughout the negotiations and label changes, the company kept up its
support of doctors and patient groups that were promoting the drug as
safe for use in children.

During the late 1980's and the 1990's, for example, Johnson & Johnson
said it gave $1 million to the American Pseudo-Obstruction and
Hirschsprung's Disease Society. The society began as a support group
for parents of children with rare digestive diseases for which
Propulsid was a treatment.

By 1996, with financing from Johnson & Johnson, the group's focus had
shifted to common childhood acid reflux. Dr. Hyman was the chief
medical adviser to the group, which helped to train speakers who, over
three years, made presentations to 6,000 to 8,000 pediatric doctors
and nurses about the treatment of reflux, recommending Propulsid, said
the group's founder, Andrea Anastas.

Ms. Anastas said the company had no influence over the group's
activities. (Some details of the company's financial support of groups
promoting Propulsid were reported in a 2003 documentary
"MAMA/M.A.M.A.," by Nonny de la Peña.)

After the June 1998 label changes, the North American Society for
Pediatric Gastroenterology Hepatology and Nutrition, a medical group
for pediatric gastroenterologists, announced that it was going to
study whether pediatricians should continue using Propulsid.

Johnson & Johnson sent the group a confidential report conceding that
placebo-controlled studies, many of them never published by the
company, failed to show it was effective in treating children for
reflux disease. The company, which had begun financing the group
before the study was announced, eventually donated $450,000 to the
society. The group report, released in May 1999, concluded that
Propulsid "has a place in pediatric therapeutics."

Dr. Robert Shulman, a professor at the Baylor College of Medicine and
the lead author of the report, said Johnson & Johnson's money had no
influence on the group's conclusions, although he said that he
regretted that its financial support was not disclosed in the paper.

Asked how his group's recommendation squared with the company's
admission that the drug had not been proved effective in infants and
children, Dr. Shulman said his group understood acid reflux in
children better. "We treat these kids every day," he said.

By January 2000, the F.D.A. had reports of 80 deaths and 341 serious
heart problems in patients taking Propulsid. The agency scheduled a
meeting to discuss its concerns with a panel of outside experts. This
meeting, unlike the others at which Propulsid's safety record was
discussed, would be public.

Preparing for the hearing, Janice Bush, a Johnson & Johnson executive,
wrote a note during what a company spokesman said was a
"brainstorming" session: "Do we want to stand in front of world and
admit that we were never able to prove efficacy!" The words "never
able" were underlined.

Three weeks before the scheduled hearing, Johnson & Johnson announced
it would stop selling Propulsid in the United States. The hearing was
canceled.

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