FDA MOVING TO REVIVE DEADLY DRUG

Health: Agency Director Works With Manufacturer To Bring Back
Lotronex Despite Fatalities.

WASHINGTON-- Senior Food and Drug Administration officials are
planning how to bring back to market a pill for a common bowel
disorder despite new evidence that the risk of a life-threatening
complication is far higher than thought when the drug was withdrawn
in November, government documents show.

The FDA began reconsidering the withdrawal amid an outcry from
patients who say they benefited from the prescription drug, called
Lotronex. In early clinical studies, as many as 1 in 5 participants
showed improvements that doctors attributed to Lotronex.

Dr. Janet Woodcock, director of the FDA's drug evaluation center, has
privately voiced support for the drug to executives of
GlaxoSmithKline, the manufacturer, according to the documents and
people familiar with the matter. Woodcock and her aides have
discussed with the company how best to orchestrate the drug's return
to pharmacies--including how to structure a public advisory committee
meeting so as to minimize the effect of criticism of the drug.

The flurry of activity over Lotronex once again puts a spotlight on
the FDA's handling of a drug with demonstrated lethal risk and modest
proven benefits. Lotronex is one of 11 prescription drugs withdrawn
for safety reasons in the last four years.

Eight of those drugs were approved from 1993 through 2000--an era
when the FDA came under pressure from members of Congress and the
White House to become more of a partner than an adversary of the
$100-billion pharmaceutical industry.

Aside from one antibiotic pill, none of the 11 withdrawn drugs was a
proven lifesaver.

Lotronex could be returned to U.S. pharmacies as soon as this summer.

It has not been sold in any other country.

During eight months on the American market last year, Lotronex was
approved for use by women with diarrheal symptoms of what is known as
irritable bowel syndrome.

The condition can cause pronounced abdominal bloating and pain and
other vexing inconveniences, such as the need to go to the bathroom
on a moment's notice.

Irritable bowel syndrome, however, is not life-threatening, and
Lotronex was withdrawn after being cited as the primary suspect in
dozens of cases of ischemic colitis, a complication that can be
lethal.

It results from inadequate flow of blood to the colon.

At the time of the withdrawal, voluntarily filed reports linked five
deaths to the drug.

When Lotronex first went on the market one year ago, the product
labeling said ischemic colitis had occurred "infrequently" in
clinical studies.

In August, after reports of bowel surgeries and death, the labeling
was changed: Doctors were told that 1 in 700 women taking Lotronex
were at risk of ischemic colitis.

But within the last several months, FDA scientists have found that a
patient who took Lotronex for three months would actually have a 1 in
218 chance of developing the complication.

"The longer a woman is on the treatment, the more likely it is that
she will develop an episode of ischemic colitis," concluded Dr. Zili
Li, an FDA epidemiologist, in an April 2 memo to his superiors.

Li termed "inaccurate and misleading" the original 1 in 700
calculation, which was based on data submitted by the manufacturer.

In a more recent memo, Dr. John R. Senior--an FDA bowel specialist
who warned in vain of Lotronex's link to ischemic colitis before the
agency granted a fast-track approval in February 2000-- again urged
caution.

"It is NOT clear that the benefits of [Lotronex] outweigh its risks,"
Senior wrote on May 6. Nonetheless, Woodcock has told subordinates
this spring that she believes the drug's benefits do outweigh its
risks.

In an e-mail on April 26 to three top aides, Woodcock described
assurances that she had just voiced to a GlaxoSmithKline executive,
Dr. Tadataka Yamada:

Woodcock wrote that Yamada told her that the company was concerned
about holding a public hearing on the return of the drug. Yamada, she
wrote, feared that an advisory committee meeting "would be a media
circus and 2. that the advisors may disagree with what we have
negotiated and put us back at square 1, and 3 that it would slow
things down."

According to her e-mail, Woodcock assured the company executive that
"we can manage" the media.

As for the prospect that the advisory committee might disagree with
what Woodcock and GlaxoSmithKline have already negotiated, "I said I
agree that 2 is a real liability and we have to consider the
vulnerability vs. the benefits," Woodcock wrote. "For 3, I said we
could do it in a hurry."

On May 3, Dr. David Wheadon, a subordinate to GlaxoSmithKline's
Yamada, called Dr. Florence Houn, a senior aide to Woodcock, to
follow up on a conversation between their bosses.

Wheadon inquired about which advisors the FDA might assign to the
upcoming meeting on Lotronex.

"He stated they were reluctant to go [before an advisory committee]
because the statements that come from an AC meeting can be used to
increase their product liability and are used inappropriately in
other ways that are detrimental to the company," Houn wrote in an
e-mail summarizing her conversation with Wheadon, adding: "I stated
that FDA does not want to have unintended consequences. . . . I told
him that we would work w/ them on developing the agendas and
questions." Indeed, officials who are preparing for the advisory
committee meeting, tentatively planned for July 13, told The Times
that they do not expect the panel will be allowed to vote on the
central question of whether Lotronex should be allowed back.

Rather, the advisory committee would be instructed by Woodcock's
staff to recommend the best conditions under which to reintroduce the
drug. Advisory committee recommendations are not binding on the FDA,
but the agency follows them more often than not.

'Progress Is Being Made' on Lotronex's Return

Woodcock declined to be interviewed and refused to answer written
questions concerning the FDA's reevaluation of Lotronex. An FDA
spokesman, Jason Brodsky, would not comment on Woodcock's
conversations with the company or other details.

He provided this prepared statement: "FDA is committed to resolving
the issues surrounding Lotronex. From the agency's perspective,
progress is being made."

A spokeswoman for GlaxoSmithKline, Ramona DuBose, said the company
has been "in discussions with the FDA" since January. She said "the
nature of those discussions would guide the timeline" for returning
Lotronex to the market.

"We are hoping that through our discussions with FDA, that we can
come up with a risk-management plan that will allow the medicine to
be available to patients who can derive some benefit from it while
minimizing any potential risks," DuBose said.

DuBose declined to discuss the company's privately expressed concerns
about the composition of the advisory committee and the structuring
of a public meeting. "It would be the FDA's call--100%--as to who was
on that advisory committee and what their role would be," she said.

Regarding the FDA epidemiologist's conclusion that the risk of
ischemic colitis is far higher than doctors and patients were warned
previously, DuBose said GlaxoSmithKline stands behind the estimate of
1 in 700 patients.

In addition to ischemic colitis, nearly 30% of patients in clinical
studies experienced mild to severe constipation. This is noteworthy,
doctors say, because for some who were struck with ischemic colitis,
their only early symptom of impending danger was constipation.

As for benefits, 10% to 20% of patients in clinical studies gained
improvement in their symptoms that could be attributed to Lotronex,
according to FDA medical officers who reviewed the drug before the
first approval.

It was just six months ago that the FDA gave Lotronex's manufacturer,
then known as Glaxo Wellcome, a choice: Agree to safety controls that
would severely limit distribution, or withdraw it from the market.

Glaxo announced its withdrawal of Lotronex on Nov. 28. One executive
said then that the company regarded the FDA-proposed controls as
"no-gos."

However, within weeks after the withdrawal, scores of patients--some
aligned with GlaxoSmithKline, some acting independently--implored
Woodcock to allow the drug back. Some said they worried that the
withdrawal of Lotronex, the first new drug in years for irritable
bowel syndrome, would serve to stifle research of the malady.

"I, as many, was having panic attacks before Lotronex," said Carol A.
Clay of Sun Lakes, Ariz., one of about 60 patients who e-mailed The
Times in favor of the drug. "I was afraid to leave my house lest I
could not find a bathroom quick enough.

Lotronex made my life normal.

I desperately need it back." Clay said Tuesday that her symptoms have
since improved while using other medicines. "I'm better now," she
said, but added: "Nothing was as good as Lotronex."

Others, including Dr. Sidney Wolfe of the consumer group Public
Citizen, caution that the anecdotal claims of patients are to be
expected, and do not equal scientific proof.

Wolfe called for withdrawal of Lotronex last summer and he opposes
the reintroduction being considered by Woodcock. "That storm [of
e-mails from Lotronex patients] is her fault, because that drug never
should have come on the market," Wolfe said.

Woodcock's handling of Lotronex also was denounced this month by the
editor in chief of the Lancet, a leading British medical journal.

"This story reveals not only dangerous failings in a single drug's
approval and review process but also the extent to which the FDA, its
Center for Drug Evaluation and Research in particular, has become the
servant of industry," wrote the Lancet's Dr. Richard Horton.

Horton, whose specialty is internal medicine, said he felt compelled
to speak out because the Lancet had earlier published results from
one of the studies used to boost Lotronex's original approval.

"Irritable bowel, while disabling, is not life-threatening," Horton
said in an interview. "The calculus of risk and benefit is so clearly
weighted towards risk when you're having people dying and requiring
major surgery, that it defies belief that this drug should be allowed
back on the market now."

Yet with no sure-fire remedy available, sufferers of irritable bowel
have held high hopes for Lotronex. Among them was Thecla "Terry"
Romeo, who managed a doctor's office in Beaver, Pa., a suburb of
Pittsburgh. Romeo, now 57, first heard about Lotronex from a
drug-company saleswoman while attending a medical society meeting.

According to Romeo and a lawsuit that she and her husband have filed,
she began taking a twice-daily course of Lotronex on March 31, 2000.
She began to experience constipation, however, and stopped taking the
drug about April 21.

She then took a sharp turn for the worse.

"Out of the blue one night [April 25], I was awakened by some pretty
severe abdominal pain," Romeo said. She quickly called her family
doctor.

By 8 the next night, Romeo said, she remained severely constipated,
the pain intensifying.

"It was unbelievably bad," Romeo said. "I was doubled over with it."

At the urging of her daughter, a neighbor drove Romeo to the
emergency room at Beaver Medical Center.

At noon the next day, Romeo's husband was told by the hospital that
she needed surgery.

The surgeons found that she had ischemic colitis, that her bowel was
gangrenous. Her life in jeopardy, they removed her colon, resulting
in three weeks of hospitalization.

Romeo wore a colostomy bag for six months until undergoing a
follow-up procedure in October. During that time, she said, she
suffered urinary tract infections and chronic diarrhea. "My life is
just completely altered," she said.

'It's Not Worth Risking Your Life For'

Romeo shudders that Lotronex might return to the U.S. market.

"By the time I was hospitalized, it was too late," she said. "This is
not a drug that you want to play games with. . . . As far as I'm
concerned, that drug is lethal, and it should never be allowed back
on the market. Irritable bowel syndrome is an annoyance, but it's not
worth risking your life for."

Romeo and her husband filed the lawsuit Dec. 21 in a Pennsylvania
court against the drug manufacturer, alleging that it "misrepresented
the safety and risks of Lotronex with respect to the risk of ischemic
colitis and severe constipation." The physician and medical practice
that oversaw Romeo's care also are named as defendants.

DuBose said GlaxoSmithKline would not comment on Romeo's case, citing
company policy against discussing "ongoing litigation."

Based on reports filed with the FDA through February 2001 and
reviewed by The Times, Lotronex was cited as the "primary suspect"
drug in 11 deaths and, overall, 72 cases of ischemic colitis. (At the
time of the November 2000 withdrawal, five deaths had been reported.)
The reports, filed voluntarily by doctors and others, linked 296
patient hospitalizations to the drug.

Experts believe that as few as 1% to 10% of adverse-drug reactions,
including deaths, are reported to the FDA. Approximately 514,000
prescriptions for Lotronex were filled or refilled, according to data
collected by IMS Health Inc., a private firm. Lotronex generated
sales topping $50 million.

The symptoms of irritable bowel syndrome occur during the lives of
about 1 in 5 U.S. residents and mostly among women, according to the
American College of Gastroenterology.

Woodcock, in a Feb. 13 e-mail to a Lotronex backer in Ventura,
Calif., advised the woman, a former schoolteacher, how best to help.

"We are working with GlaxoSmithKline to resolve the issues," Woodcock
wrote. "The most important contribution that people with IBS can make
is to make sure your voices are heard on the severity of the
condition. Apparently, there are a lot of people out there who don't
believe it, for some reason."

And in remarks this month to an Internet outlet, Dickinson's FDA
Webview, Woodcock attributed criticism of her handling of Lotronex
and other drugs to unnamed "very angry" dissidents within the agency.

Woodcock also suggested that her actions are shaped in part by
politics "I have to work in the real, political world," Woodcock told
Dickinson's, adding: "There are limits to government power,
especially right now. It's unlikely that this administration, like
the Clinton administration before it, is going to support a wide
expansion of FDA control over medical practice and other matters."
Times researchers Janet Lundblad in Los Angeles and Sunny Kaplan
in Washington contributed to this article.
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