http://www.latimes.com/news/nation/updates2/lat_lotronex001102.htm
Thursday, November 2, 2000
FDA Minimized Issue of Lotronex's Safety
Health: Times study finds officials sided with drug maker on
regulatory concerns. Agency reevaluation is underway.
By DAVID WILLMAN, Times Staff Writer
WASHINGTON--In the drug's first eight months on the market, five
people who took it died. Several others underwent bowel
surgeries--one had a colon removed. A total of 49 patients developed
ischemic colitis, a potentially life-threatening complication.
As a result, the Food and Drug Administration is now
"reevaluating" the safety of Lotronex, a drug intended to treat women
with a nonfatal disorder, irritable bowel syndrome. But a Los Angeles
Times investigation of the FDA's handling of Lotronex found that over
the last year agency officials repeatedly played down questions about
the drug's safety while siding with the manufacturer, Glaxo Wellcome
Inc., in important regulatory decisions.
The FDA officials disregarded the significance of concerns
raised by an agency medical officer who examined the drug before its
approval. They chose a paid consultant to Glaxo to serve with an
advisory committee that recommended approval of the drug. They agreed
with Glaxo not to place a highly visible "black-box" warning on the
label of Lotronex. Rather than wait for Glaxo to conduct a major new
study of the drug's link to ischemic colitis, the agency approved the
pill on a condition that the study would take place after the drug
entered the market. The study has yet to begin.
And for the last several months, the officials have declined, in
the face of data gathered by FDA epidemiologists, to seek withdrawal
of the drug.
The FDA's handling of Lotronex is the latest example of how the
pressure to get new drugs to market can clash with the agency's
mandate to protect public health and safety. Since 1993, the agency
has dramatically stepped up approvals of new drugs submitted by the
$100-billion pharmaceutical industry, with fortunes rising or falling
on sales of a single medication.
In the last three years, the FDA has been forced to withdraw
nine drugs from the market after reports of deaths and injuries
linked to the compounds.
An FDA administrator, Dr. Florence Houn, on Wednesday defended
the agency's decisions on Lotronex but added, "FDA is concerned about
the serious adverse event reports of ischemic colitis and severe
constipation associated with Lotronex." When the agency approved
Lotronex, Houn said, officials suspected that the ischemic colitis
seen with the drug was nonfatal and reversible.
3 Deaths Not Linked to Drug, Firm Says
A representative of Glaxo, Dr. Allen Mangel, said the company
has investigated three of the five deaths and believes those events
were not caused by Lotronex. Mangel said Glaxo has not been able to
adequately probe the remaining two deaths. He said the company "will
absolutely want to meet with the FDA very soon" to discuss the drug's
future.
As for Glaxo's pledge to launch the major new study regarding
ischemic colitis and Lotronex, Mangel said the company and the FDA
are still negotiating details of how to conduct the research. A
spokeswoman for Glaxo, Ramona Dubose, said the company stands behind
Lotronex.
"We have complete confidence in the safety profile of this
drug," Dubose said. "We believe that any risks can be managed."
The FDA takes into account whether other treatments are
available when deciding whether to approve or withdraw drugs. For
irritable bowel, there are five drugs on the U.S. market, including
Lotronex. Doctors say that none is effective at easing all symptoms
of the disorder, which can include abdominal pain, diarrhea and
constipation. However, a search by The Times of records maintained by
the FDA since 1993 found that only Lotronex has been cited as the
"suspect" in a case of ischemic colitis.
It was last November when an FDA medical officer named John
Senior tried to sound an alarm about Lotronex. Time was short. The
FDA had agreed to conduct a "fast-track" review of Lotronex, on the
basis that it would treat a "serious" disease. Dr. Senior, while
stopping short of recommending rejection or approval of Lotronex,
deplored Glaxo's approach to the safety concerns surrounding the drug.
"It is very disturbing that the applicant has chosen to downplay
so strongly the important issue of constipation, induced commonly and
predictably by [Lotronex], and has totally ignored the [problems] of
ischemic colitis," Senior, a bowel specialist, wrote in his review.
Senior identified four cases within Glaxo's clinical studies of
ischemic colitis--the potentially lethal complication that results
from inadequate blood flow to the colon. He noted that no patient
taking a placebo had developed it.
"This finding represents a signal of a potentially serious
problem," Senior warned in his review, adding that drug-induced
ischemic colitis can be "mild and transient" but can also result in
gangrene of the bowel and death.
He found that 27% of the patients taking Lotronex experienced
constipation.
Improvement in Patients Cited
As for the drug's potential benefits, the FDA medical-review
staff concluded that 10% to 20% of patients in Glaxo's clinical
studies gained improvement in their symptoms that could be attributed
to Lotronex. The drug is intended for women whose predominant
irritable-bowel symptom is diarrhea. Once a drug is approved by the
FDA, doctors can prescribe it for anyone or any purpose they deem
appropriate.
After Senior apprised the Gastrointestinal Drugs Advisory
Committee of patients' risk for ischemic colitis, Dr. Houn asked
panelists whether more safety studies "should be performed prior to
approval, or after approval?"
The question was crucial to Glaxo because withholding approval
until more safety data could be examined would have knocked Lotronex
off the fast track and delayed, if not dimmed, sales. Only one
committee participant, Dr. Arnold Wald of Pittsburgh, responded
directly to Houn's question:
"I think we could approve the drug with the caveat that we
monitor it very carefully. . . . So I would not hold up the approval
pending that data," said Wald, who recalled that he participated at
the meeting as a temporary special government employee paid by the
FDA.
Wald, it turns out, was no stranger to Lotronex or Glaxo,
according to FDA records and interviews.
Wald at the time of the meeting had a grant from Glaxo, the
panel's secretary announced, "on a matter unrelated" to Lotronex. He
also had helped conduct one of the early studies of Lotronex on
Glaxo's behalf, as an intestinal specialist at the University of
Pittsburgh.
In an interview, Wald acknowledged that it was also around
November 1999--the same month as the FDA advisory meeting--that he
and several faculty colleagues began teaching a series of courses for
Glaxo's sales representatives, honing their familiarity with
irritable bowel syndrome.
The Gastrointestinal Drugs Advisory Committee voted unanimously
to recommend prompt approval. The FDA formally approved Lotronex on
Feb. 9, completing a review that took seven months. Securities
analysts predicted Lotronex would generate sales for Glaxo of up to
$2 billion within five years.
When the FDA approved Lotronex, Glaxo retained Wald to make
presentations to physicians who might prescribe the drug. Wald said
that his financial ties to Glaxo did not taint the advice he gave to
the FDA.
"We do have that relationship," Wald said of his work with
Glaxo. "That's a potential conflict. But personally, it wouldn't be
enough to misrepresent the drug in terms of my professional
reputation."
Wald said that he holds no regret about advising the FDA to
approve Lotronex quickly--instead of waiting for additional safety
data concerning the drug's capacity to induce ischemic colitis.
"They proved their efficacy; it seemed to be safe," Wald said,
adding: "I don't really have any concerns about the drug."
Lotronex began arriving on pharmacy shelves in March. And in
April, the FDA received the first voluntarily filed reports of
serious side effects among the new patients, according to records
reviewed under the Freedom of Information Act. In one case, a
59-year-old woman was hospitalized and the health professional who
filed the report listed Lotronex as the "primary suspect" drug.
By early June, a total of eight new ischemic colitis cases had
emerged. Six other Lotronex patients were hospitalized with
constipation-related complications, and three of them required
surgery.
On June 27--less than five months after the FDA approved
Lotronex--the agency convened a special meeting of the advisory
committee.
Another FDA medical officer, Dr. Hugo Gallo-Torres, told the
advisory committee that "there is a causal relationship" between
Lotronex and both ischemic colitis and constipation. Gallo-Torres a
few months earlier had recommended approval of Lotronex, despite
saying it was "a hard to explain/accept coincidence" that no patient
taking placebos in the clinical studies suffered ischemic colitis.
'Black-Box' Warning Opposed by Glaxo
Glaxo representatives suggested that preexisting medical
complications or patients' use of other drugs may have caused some of
the hospitalizations. A company executive, citing competitive
considerations, said Glaxo opposed the FDA staff's proposal to place
a "black-box" warning in the drug's labeling. This black-bordered
feature signifies pronounced risk and is more noticeable to patients
and their physicians.
"We don't feel . . . that this drug is a dangerous drug and
merits a black box," said Dr. Richard S. Kent, Glaxo's chief medical
officer and vice president.
With a black box, Kent said, "patients and physicians may end up
making inappropriate decisions around whether to use this drug. I
think there is a duty to warn that we all have; I think there is a
great duty not to over-warn. We have to put the risks and benefits of
all these products in proper perspective."
The FDA dropped the proposal for a black-box warning.
The first fatality of a Lotronex patient was reported to the FDA
on July 17, a 50-year-old woman who suffered "mesenteric occlusion,"
a severe blockage of blood to the colon. This report, filed
voluntarily by a health professional, identified Lotronex as the
"primary suspect" drug in the death. Glaxo denies that Lotronex
caused this death.
On Aug. 24, the FDA and the company announced a safety-labeling change.
In a letter to doctors and pharmacists, Kent acknowledged
reports "of serious complications of constipation, including
obstruction, perforation, impaction, toxic megacolon, and secondary
ischemia, in patients treated with Lotronex. In some cases these
complications have required intestinal surgery, including colectomy,"
the removal of the patient's colon.
Records kept by the FDA show that, through Oct. 30, the agency
had received 93 reports of patients being hospitalized after taking
Lotronex. In each of the reports, the doctor or other party cited
Lotronex as the "primary suspect" drug in the event.
In an interview on June 30, the FDA's drug center director, Dr.
Janet Woodcock, cited Lotronex as an example of what she termed a
fresh commitment to pro-actively monitor the risks of newly approved
drugs. She praised a leaflet, called a "medication guide," that the
FDA and Glaxo had agreed to develop for Lotronex patients.
Why, given the warnings of potentially fatal ischemic colitis
for a drug that is not lifesaving itself, did the FDA approve
Lotronex?
"We can't not approve drugs because they have certain side
effects," Woodcock said. "They're all going to have side effects. We
have to determine, are they going to be adequately managed?"
Lotronex generated $42.1 million in sales through August for
Glaxo, according to IMS Health, an information-services firm. During
this period 334,000 prescriptions were written, some to the same
patients.
---
Times researchers Janet Lundblad in Los Angeles and Sunny Kaplan
in Washington contributed to this story.
Copyright © 2001 Los Angeles Times
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