PRACTICE
AREAS:: ORTHO EVRA CONTRACEPTIVE
PATCH:: Attorney
Gingerly, Kathleen Thoren's
family gathered around her
in the intensive care unit,
unable to speak to their beloved
sister, daughter, wife, or
even stroke her hands. The
slightest stimulation might
create a fatal amount of pressure
on the 25-year-old woman's
swollen brain, warned the doctors.
"We were horrified, but we tried to just quietly be
with her," said her sister Erika Klein. "In the end,
it didn't help."
The mother of three died last fall, just after Thanksgiving,
after days of agonizing headaches that the coroner's
report said were brought on by hormones released into
her system by Ortho Evra, a birth control patch she
had started using a few weeks earlier.
She was among about a dozen women, most in their late
teens and early 20s, who died last year from blood
clots believed to be related to the birth control patch.
Dozens more survived strokes and other clot-related
problems, according to federal drug safety reports
obtained by The Associated Press under a Freedom of
Information Act request.
Several lawsuits have already been filed by families
of women who died or suffered blood clots while using
the patch, and lawyers said more are planned.
Risk three times higher
Though the Food and Drug Administration and patch-maker
Ortho McNeil saw warning signs of possible problems
with the patch well before it reached the market, both
maintain that the patch is as safe as the pill.
However, the reports obtained by the AP appear to indicate
that in 2004 - when 800,000 women were on the patch
- the risk of dying or suffering a survivable blood
clot while using the device was about three times higher
than while using birth control pills.
The women who died were young and apparently at low
risk for clots - women like Zakiya Kennedy, an 18-year-old
Manhattan fashion student who collapsed and died in
a New York subway station last April. Or Sasha Webber,
a 25-year-old mother of two from Baychester, N.Y.,
who died of a heart attack after six weeks on the patch
last March.
Some doctors, reviewing the Food and Drug Administration
reports at the request of The AP, were alarmed. "I
was shocked," said Dr. Alan DeCherney, editor-in-chief
of Fertility and Sterility and a UCLA professor of
obstetrics and gynecology.
But other doctors said they would have expected some
deaths and no investigation is warranted. They point
to more than 4 million women who have safely used the
patch and note that the FDA reports are called in voluntarily,
rather than gathered scientifically.
"It doesn't jump out at me to say, 'Let's look at this
any further,"' agreed Dr. Steven J. Sondheimer, professor
of obstetrics and gynecology at the University of Pennsylvania. "I
don't feel that these need to be looked at in any detail."
No cause for alarm?
Ortho McNeil, a subsidiary of Johnson & Johnson, says
none of the deaths can be directly attributed to the
patch.
"Although we are investigating each and every one of
the reports that we get, we have not drawn any causal
relationships to the medication," said Dr. Katherine
LaGuardia, Ortho McNeil's director of women's health
care.
Not one? "Right," she said. "It's difficult to reach
a definitive answer, and privacy laws prevent us from
investigating as thoroughly as we wish."
Blood clots are an accepted risk from hormonal birth
control because estrogen promotes blood coagulation.
But how many clots are too many?
The AP found that before the patch was approved, the
FDA had already noticed nonfatal blood clots from the
patch were three times that of the pill. The AP then
examined what has actually happened since the patch
came on the market and found that deaths also appear
to be at least three times as high.
If you are a woman taking the pill who doesn't smoke
and is under 35, the chance that you are going to have
a blood clot that doesn't kill you is between 1 and
3 in 10,000. Your risk of dying from a blood clot while
using the pill is about 1 in 200,000.
By contrast, with the patch, the rate of nonfatal blood
clots was about 12 out of 10,000 users during the clinical
trials, while the rate of deaths appears to be 3 out
of 200,000.
Clots usually form in the legs, and become serious
problems if they travel to a woman's heart, lungs or
brain.
Early warning signs
In 2000, doctors at the FDA reviewing clinical trials
of the wafer-thin, plastic patch warned that blood
clots could be a problem if it was approved.
In those trials, two of the 3,300 women using the patch
were treated for blood clots that traveled to their
lungs. Ortho McNeil says one of those women shouldn't
be counted because she had undergone surgery. But an
FDA reviewer, using capital letters and underscoring
his comments, took issue with Ortho McNeil.
"THE REVIEWER DOES NOT AGREE WITH THE SPONSOR'S ABOVE
CONCLUSIONS. The two cases of pulmonary embolus, a
serious and potentially fatal condition, must be counted
as two cases ...," said the report. "The incidence
rates quoted by the sponsor may be misleading."
The reviewer said "the label should clearly reflect
this reviewer's safety concern about a potential increased
risk." It would be important to study users after the
patch came on the market for clot problems, he wrote.
But when the patch was approved in the U.S. in 2001,
there were no requirements for follow-up studies beyond
routine FDA reviews of reports called in by consumers,
doctors and manufacturers.
The label's safety warning says two different and seemingly
contradictory things: First, it says the patch is expected
to be associated with similar risks as the pill. Then,
it says it is unknown if the risk of blood clots from
the patch is different from the pill.
The AP reviewed what has happened since the patch came
on the market in 2002.
Hormones enter bloodstream directly
The FDA responded to a FOIA request by providing the
AP with a database that contained about 16,000 different
reports of adverse reactions associated with the patch.
These ranged from mild rashes to deaths, and there
were many duplicate reports. Within this collection
of reports, the AP found 23 different deaths associated
with the patch. The primary cause of death in those
reports isn't always clear - some mention suicide,
others abortion. Doctors who reviewed the 23 cases
found about 17 that appeared to be clot-related, including
12 from last year.
"That number of deaths certainly sounds suspicious," said
Dr. Pamela Berens, associate professor of obstetrics
and gynecology at the University of Texas Medical School
at Houston. "There may be something about the way the
drug is metabolized that could increase the risk for
clots."
Although the estrogen levels are similar in the patch
and the pill, the hormones in a pill must be processed
through the intestinal tract before they enter the
blood stream. Hormones in the patch, on the other hand,
go directly into the bloodstream.
Dr. Sidney Wolfe, director of Public Citizen's Health
Research Group, a consumer advocacy organization founded
by Ralph Nader, said that the deaths and high rate
of clots are "worrisome" and should be investigated.
"These days, more often than not the problems with
a drug show up after they're approved," he said.
But Dr. Daniel Shames, the FDA's director of the Division
of Reproductive and Urological Drug Products, who approved
the agency's medical review, said he has reviewed cases
of women who died using the patch and saw no cause
for alarm.
"We think the death rate here is of concern, but it's
not different than what we expect," he said. "As of
right now we still believe there's nothing that would
precipitate our doing anything additional to follow
up on these reports."
And other doctors who prescribe the patch warned that
women should not overreact to news of deaths. It is
more risky to remove the patch and become pregnant,
several pointed out.
'You can use a patch safely'
Dr. Philip Darney, a professor of obstetrics and gynecology
at the University of California, San Francisco, and
a leading contraceptive researcher, cautioned that
the FDA's adverse event reports tend to be inflated
for newer products like the patch.
Patients and doctors are more likely to contact the
FDA when they have a bad reaction to a new drug than
for something that has been on the market for a long
time, he said. In addition, women using the patch are
likely to either be new to hormonal birth control or
have reacted poorly to the pill and are looking for
a change. The result is that the pool of women using
the patch are at higher risk than birth control users
at large.
He tells patients, "If you can use a pill safely, you
can use a patch safely, and we're going to know a lot
more later as more women use patches," he said.
Ortho McNeil recommended that the AP speak to two doctors,
Dr. Hilda Hutcherson, co-director of the NY Center
for Women's Sexual Health and a professor at Columbia
University Medical Center, and Dr. Vanessa Cullins,
vice president of medical affairs at Planned Parenthood
Federation of America. Both doctors have served in
the past as paid advisers to Ortho McNeil.
Hutcherson said the risks of blood clots from hormones
are well known, and that "what has happened with the
patch is consistent."
Cullins said she did her own comparison of data for
the pill and patch and found the patch is safer than
expected.
"My research was to determine whether or not the expected
number of deaths from the pill was lower than what
was seen with the number of deaths reported with Ortho
Evra. I found the opposite," said Cullins, who has
done research, consulted for and been a speaker for
Ortho McNeil and other drug companies.
Cullins said she reviewed the deaths looking at "women
years" rather than current users. Women years is a
measure that takes into account that different people
use a particular contraceptive for different periods
of time. For example, if three women each used a patch
for four months, that would count as one woman year
rather than three current users.
Cullins reviewed patch users from 2002, when the patch
came on the market, until late 2003. For that period,
Cullins said she would have expected 22 deaths and
found only 6.
The AP reviewed the deaths looking at both women years
and current users, but used more recent data, focusing
on 2004 when the patch had been much more widely adopted.
© 2005 The Associated Press. All rights reserved.
This material may not be published, broadcast, rewritten
or redistributed.
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