GlaxoSmithKline, Lotronex and the FDA
A Case of Insider Collusion
Almost the whole of history is but a sequence of horrors.
—Sébastien Roch Nicolas Chamfort
Maxims and Considerations
What went on "behind closed doors" in the months leading up October 5th, 1992 — the date when Paxil's new drug application was reviewed (approved shortly thereafter) by the United States Food and Drug Adminstration? Clues can be found in the horrifying history of Lotronex; the "usual suspects" include GSK's Drs. David Wheadon and Tadataka Yamada.
Sidebar search the FDA web site for:
With Lotronex, even though there was strong evidence in the pre-approval clinical trials of a problem with ischemic colitis, OND approved it. When cases of severe constipation and ischemic colitis began pouring into FDA’s MedWatch program, the reaction was one of denial. When CDER decided to bring Lotronex back on the market, ODS safety reviewers were instructed to help make this happen. Later, when CDER held an advisory committee meeting to get support for bringing Lotronex back on the market, the presentation on ways to manage its reintroduction was carefully shaped and controlled by OND. When it came to presenting the range of possible options for how Lotronex could be made available, the list of options was censored by OND. The day before the advisory meeting, I was told by the ODS reviewer who gave this presentation that the director of the reviewing office within OND that approved Lotronex in the first place came to her office and removed material from her talk. An OND manager was “managing” an ODS employee. When informed of this, ODS senior management ignored it. I guess they knew who was calling the shots.
— Dr. David Graham
Associate Director of Science
Office of Drug Safety
Center for Drug Evaluation and Research
Food and Drug Administration
Nov. 18, 2004
Lotronex: A Timeline
November 16th, 1999
Gastrointestinal Drug Advisory Committee Meeting
NDA 21-107, Lotronex (alosetron) Tablets.
Glaxo: "We conclude there is no evidence for a causal relationship between the development of ischemic colitis and alosetron treatment."
A transcript of this hearing is available in a PDF (three part) or RTF (single) document format; scroll down to date after clicking on link above to access.
February 9th, 2000
The FDA gives Lotronex its official "safe and effective" stamp of approval.
April 28th, 2000
FDA Warning Letter to Glaxo Regarding Lotronex
For the "dissemination of violative promotional material." Eight citations are enumerated.
June 27th, 2000
Gastrointestinal Drugs Advisory Committee Meeting
The topic of this meeting was risk management of post-advertising adverse events associated with Lotronex tablets. Transcripts, briefing information, and questions for discussion are available.
Glaxo: "Our overall conclusion is that ischemic colitis appears more frequently than at least was recognized by us." The company emphasized that the harm is "acute, transient and self-limiting."
November 18th, 2000
FDA Letter Regarding Lotronex by Dr. Janet Woodcock
"FDA worked closely with Glaxo Wellcome both before and after Lotronex’s approval...."
November 28th, 2000
Glaxo pulls Lotronex from the market after the FDA is inundated with reports of serious intestinal conditions, including severe constipation and ischemic colitis. Hospitalizations, blood transfusions, surgeries, and even death occurred.
November 28th, 2000
FDA Lotronex Talk Paper
Glaxo "voluntarily" withdraws Lotronex from the market.
May 30th, 2001
"FDA Moving to Revive Deadly Drug"
Los Angeles Times expose
Excerpts from "FDA Move to Review Deadly Drug":
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.
Nonetheless, Woodcock has told subordinates this spring that she believes the drug's benefits do outweigh its risks. In an email 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 email, 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 email summarizing her conversation with Wheadon, adding: "I stated that FDA does not want to have unintended consequences. . . . I told him that we would work with 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.
....in remarks 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."
J.P. Garnier, GlaxoSmithKline's CEO is quoted in a Reuters article, saying "It's not going to be a major event for GlaxoSmithKline one way or the other, because if we were to put it [Lotronex] back on the market it would be under very cautious conditions." Click here for a reprint of that story (the link is no longer available at Reuters.)
April 23rd, 2002
FDA Advisory Committee Meeting
The committee discussed risk management for Lotronex (alosetron). Glaxo: "Our results show that there is a five-fold increase in the risk of developing ischemic colitis in alosetron-treated subjects."
June 7, 2002
GSK's "Do More, Feel Better, Live Longer" video
FDA announced the approval of a supplemental New Drug Application (sNDA) that allows restricted marketing of Lotronex (alosetron hydrochloride), to treat only women with severe diarrhea-predominant irritable bowel syndrome (IBS). The approved sNDA for Lotronex includes "a risk management program to ensure patients and physicians are fully informed of risks and possible benefits of Lotronex."
(Windows Media Player or RealOne Player required to view)
According to a Jan.-Feb., 2002 FDA Consumer magazine article entitled "Why Drugs Get Pulled Off the Market": "The FDA and drug companies share a common interest in getting drugs that are safe and effective to the market and in conducting well-designed trials that are persuasive. 'We believe the many meetings and other forms of advice that we give help assure that,' says Robert Temple, M.D., director of the FDA's office of medical policy. 'Naturally, once they submit an application, the companies want our answer to their drug application to be 'Yes,' he says, 'but we are completely neutral, having no preferred answer except the right one.' The FDA's mission is to protect the public health fairly and consistently. Decisions are scientifically-based...."
Believe it or not....
Articles to Browse
A Lotronex Victim Speaks Out
Drug Lotronex Pulled Over Safety Fears (2001 Pulitzer Prize)
FDA Enraging Everyone
FDA Minimized Issue of Lotronex's Safety
(2001 Pulitzer Prize)
Lotronex: A Case Study in Regulatory Capture....
Lotronex and the FDA: A Fatal Erosion of Integrity
Lotronex: Officer Foresaw Deadly Effects (2001 Pulitzer Prize)
Problems in the New Drug Approval Process: A Case Study of Lotronex