FDA Moving to Revive Deadly Drug

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despite new evidence that the risk of a life-threatening complication is far higher than thought when the drug was withdrawn in November, government documents show.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 Lotronex is one of 11 prescription drugs withdrawn for safety reasons in the last four years.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 Aside from one antibiotic pill, none of the 11 withdrawn drugs was a proven lifesaver.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Irritable bowel syndrome, however, is not life-threatening, and Lotronex was withdrawn after being cited as the primary suspect in dozens of cases of ischemic colitis, a complication that can be lethal.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.”

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Times researchers Janet Lundblad in Los Angeles and Sunny Kaplan in Washington contributed to this article.

Previous articles by David Willman on how the FDA handled Lotronex and other prescription drugs are on The Times’ Web site athttps://latimes.com/fda