Drug Makers Near an Old Goal: A Legal Shield ... NY Times April 6, 2008

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NY Times April 6, 2008 Drug Makers Near an Old Goal: A

Legal Shield By GARDINER HARRIS and ALEX BERENSON For

years, &

obscured evidence that its popular Ortho Evra birth

control patch delivered much more estrogen than

standard birth control pills, potentially increasing the risk of blood clots

and strokes, according to internal company documents. But because the Food and

Drug Administration approved the patch, the company is arguing in court

that it cannot be sued by women who claim that they were injured by the product

— even though its old label inaccurately described the amount of estrogen

it released. This legal argument is

called pre-emption. After decades of being dismissed by courts, the tactic now

appears to be on the verge of success, lawyers for plaintiffs and drug

companies say. The Bush

administration has argued strongly in favor of the doctrine, which holds that

the F.D.A. is the only agency with enough expertise to regulate drug makers and

that its decisions should not be second-guessed by courts. The Supreme Court is to

rule on a case next term that could make pre-emption a legal standard for drug

cases. The court already ruled in February that many suits against the makers

of medical devices like pacemakers are pre-empted. More than 3,000 women

and their families have sued & , asserting that users of the

Ortho Evra patch suffered heart attacks, strokes and, in 40 cases, death. From

2002 to 2006, the food and drug agency received reports of at least 50 deaths

associated with the drug. Documents and e-mail

messages from & , made public as part of the lawsuits

against the company, show that even before the drug agency approved the product

in 2001, the company’s own researchers found that the patch delivered far

more estrogen each day than low-dose pills. When it reported the results

publicly, the company reduced the numbers by 40 percent. The F.D.A. did not

warn the public of the potential risks until November 2005 — six years

after the company’s own study showed the high estrogen releases. At that

point, the product’s label was changed, and prescriptions

fell 80 percent, to 187,000 by last February from 900,000 in March 2004. Gloria Vanderham, a

& spokeswoman, said the company acted responsibly. “We have

regularly disclosed data to the F.D.A., the medical community and the public in

a timely manner,” Ms. Vanderham said. “Ortho Evra is a safe and

effective birth control option for women when used according to the

labeling.” But Janet Abaray, a

plaintiff’s lawyer from Cincinnati ,

said that & took advantage of an agency overwhelmed by its

many responsibilities. “ &

knew that F.D.A. does not have the funding or the manpower to police

drug companies,” Ms. Abaray said. A series of

independent assessments have concluded that the agency is poorly organized,

scientifically deficient and short of money. In February, its commissioner,

C. von Eschenbach, acknowledged that the agency faces a crisis and may

not be “adequate to regulate the food and drugs of the 21st century.” The F.D.A. does not

test experimental medicines but relies on drug makers to report the results of

their own tests completely and honestly. Even when companies fail to follow

agency rules, officials rarely seek to penalize them. “These are scientists,

not cops,” said Vladeck, a professor at

town Law School . Last month, at a trial

over the schizophrenia

drug Zyprexa, Dr. Gueriguian, a scientist who worked at the F.D.A. for two

decades, testified that the agency did not always ask for strong warnings even

if it believed a drug was risky. Companies typically oppose warnings, and the

agency knows it must compromise on its requests or face years of delay, Dr.

Gueriguian said. “We at the

F.D.A. know what we can obtain and we cannot obtain,” Dr. Gueriguian

said. “We have many, many problems, and we have a management system

— what we can’t obtain we will not ask.” For years, top

officials at the agency acknowledged that lawsuits could aid the agency’s

oversight of safety issues. In the last decade, suits over Zyprexa, the

withdrawn pain pill Vioxx, the withdrawn diabetes

medicine Rezulin, the withdrawn heartburn

medicine Propulsid and several antidepressants

have shown that companies played down the risks of their medicines and failed

to disclose clinical trials to the public even as they have aggressively

marketed their drugs. But now, the agency

says a proliferation of lawsuits could lead to an overlapping patchwork of

rules that would burden companies and might discourage patients from taking

useful medicines. The Ortho case,

however, suggests that & , like other drug makers, is not

always quick to tell the F.D.A. about potential problems with its medicines. In 1996, the company

told the agency it planned to develop the Ortho Evra patch in part because it

would be likely to expose women to less estrogen than pills. The company

suggested that the body would not break down hormones delivered via the patch

as readily as the pill, so lower doses could be used to achieve contraception.

And unlike the pill, which must be taken daily, the patch is changed weekly. High doses of estrogen

are known to raise the risk for blood clots that can cause heart attacks and

strokes. But a crucial trial

completed in 1999 showed that the patch delivered 30 to 38 micrograms of

estrogen into the bloodstream each day, according to company documents. Because up to half of

the estrogen in pills is lost in the digestive tract before it reaches the

blood, the study suggested that the patch delivered an amount of estrogen that

could be as high as a pill containing 76 micrograms of estrogen. In 1988, the

F.D.A. banned birth control pills with more than 50 micrograms of estrogen. But the study’s

author, Dr. Larry Abrams, who has since retired from & ,

decided to apply a “correction factor” to the results of the 1999

trial, according to documents. He claimed that the patch actually delivered

about 40 percent less estrogen than the trial results showed — about 20

micrograms a day. Dr. Abrams made the

change, according to his deposition, to adjust for the different ways the body

metabolizes hormones from pills and patches. This adjustment was never part of

the study protocol, a plan filed with the F.D.A.. “The judgment

was made by the pharmacokeneticists at the time that in doing the calculation,

it was probably appropriate to make that correction,” Bob Tucker, a

lawyer representing & , said in an interview Thursday.

“Later on when people looked at it in a different time frame, they

concluded that probably the correction shouldn’t be applied.” The

company mentioned its decision to use the “correction factor” only

once in a 435-page report filed with the F.D.A., and then only in a complex

mathematical formula. When the study was published in 2002, there was no

reference to the alteration. Mr. Tucker said that

the F.D.A. was aware of the “correction factor.” Clinical trials

conducted before the patch was approved raised other red flags, as patients

complained of breast soreness and nausea. “The side effects seem

related” to high estrogen doses, one company scientist wrote in an e-mail

message. Two other studies, one

conducted in 1999 and another in 2003, confirmed that the patch released more

estrogen than the pill. Still, & delayed reporting those

results to the food and drug agency, according to documents that have been made

public in lawsuits. After the patch was

approved, the company marketed it as releasing 20 micrograms of estrogen to the

blood every 24 hours, a figure it now acknowledges was inaccurate. It also

acknowledges that the patch releases more estrogen than the pill but says that

the estrogen released under the two methods cannot be directly compared. The New York Times

provided the drug agency with a copy of a court brief and asked whether agency

medical reviewers were aware of the “correction factor.” Rita Chappelle, an

F.D.A. spokeswoman, replied, “At present, we are reviewing the

allegations and cannot comment further at this time.” Prescriptions for the

patch grew rapidly after its introduction, reaching more than 900,000 by March

2004, according to data from Wolters Kluwer, a company that tracks prescription

trends. But as the use of the patch rose, so did reports of side effects. By 2004, after the

death of Zakiya Kennedy, an 18-year-old college freshman in

New York , food and drug officials had become

concerned. In November 2005, the

agency announced that it had placed a warning that the patch “exposes

women to higher levels of estrogen than most birth control pills.” Since then, an

epidemiological study has shown that women on the patch can have as much as

double the risk of blood clots than those taking pills. And prescriptions for

the patch have fallen 80 percent. Still, lawyers for

& say that patients should not be allowed to sue the

company because the F.D.A. approved the patch and its label. “F.D.A. is

responsible for making those decisions,” said Winter, a lawyer for

the company. Judge A. Katz of

Federal District Court for the Northern District of Ohio is expected to rule soon on whether any of

the lawsuits against & can go forward. In the fall, the

Supreme Court will hear a separate pre-emption case involving Wyeth, another

drug company. Seeger, a plaintiffs’ lawyer who has about 125 Ortho

Evra cases, said he expected the court to rule in Wyeth’s favor. “Our lawsuits

are the ultimate check against the mistake made by the government, or fraud

made by the companies against the government, or just an underfunded

bureaucracy stretched thin,” he said. Janet

contributed reporting.

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