Problems in the New Drug Approval Process: A Case Study of Lotronex


Unprecedented Number of Drug Withdrawals Point to Problems in FDA Drug Approval Process

Congressional Hearings Needed on Approval of Lotronex & Other Dangerous Drugs

The Prescription Drug User Fee Act (PDUFA), first enacted in 1992 and reauthorized in 1997, allows the FDA to collect user fees from the drug industry in exchange for meeting specified timeframes for the review of new drugs. The agency uses the additional funds it gets from user fees to augment the resources it has available for the review of new drugs. PDUFA was reauthorized in 1997 as part of the Food and Drug Administration Modernization Act. However, that iteration included more stringent "performance goals" requiring that the FDA meet very tight review deadlines. These faster deadlines were insisted upon by the pharmaceutical industry, which argued that these "measurables" were necessary to ensure that the user fees they paid were not dispersed to fund other agency activities. For the first time, PDUFA II also included stipulated time frames for the scheduling of meetings and responses to industry requests ("management goals").

Under PDUFA the agency has delivered on its commitment to industry for timely review of new drugs. In the late 1980s median times for the agency to approve a new drug were approaching 30 months. After the passage of PDUFA, median approval time fell consistently until it reached 11.6 months in 1999. However, there are signs that PDUFA may have contributed to a troubling redefinition of the relationship between the agency and the industry. Because the industry pays fees to the agency for the review of new drugs the FDA has come to see the drug companies more as "clients" than a regulated industry. This may have made it harder for the agency to deny approval for new drugs that pose a threat to the public s health. While it is not possible to prove that the passage of PDUFA has caused a lowering of standards, the following are some of the troubling signs that we believe warrant aggressive Congressional oversight hearings, or, at the very least, an independent investigation of the FDA s new drug approval process:

1. An unprecedented number of drugs withdrawn since the passage of PDUFA

Since the passage of PDUFA in 1992 there have been an unprecedented number of drugs approved and then withdrawn for safety reasons. Nine of the drugs (Baycol, Raplon, Lotronex, Propulsid, Rezulin, Raxar, Duract, Posicor, Redux) approved during the eight-year period from 1993 to 2000 have been withdrawn because of safety concerns. By comparison, only five of the drugs approved during the eight-year period from 1985 through 1992 later had to be withdrawn. In the case of several of the drugs approved since 1992, their approval and the subsequent loss of life they are suspected to have caused was entirely needless. At least five of these nine drugs (Raplon, Raxar, Duract, Posicor, Redux) were approved despite known safety problems and the availability of multiple treatment options in other, older (and safer) drugs approved for the same medical uses.

2. FDA reviewers pressured to approve new drugs

Former FDA employees interviewed by the Los Angeles Times have said that while they were at the agency they felt under pressure to approve new drugs. Bill Schultz, former deputy commissioner at the FDA said, "You can meet the [performance] goal by either approving the drug or denying the approval. But there are some who argue that what Congress really wanted was not just decisions, but approvals. That is what gets dangerous." Dr. Solomon Sobel, the former director of the FDA s metabolic and endocrine drugs division told the Los Angeles Times that deadline pressure under PDUFA was not just to make decisions: "The pressure to meet deadlines is enormous. The basic message is to approve."(1)

Public Citizen's late 1998 survey of FDA Medical Officers, who are in charge of reviewing new drugs, revealed that many feel they are under inappropriate pressure to approve new drugs. Fifty-three out of 172 Medical Officers contacted responded to Public Citizen's survey. Of these, 19 identified a total of 27 new drugs that they reviewed that they believed should not have been approved but were approved. In contrast, five Medical Officers identified only a total of six new drugs that they believed should have been approved but were not. One Medical Officer said, "We are told that approvability is our goal with problems to be addressed in labeling."(2)

Aggressive Oversight Hearings Needed

Congress has a crucial responsibility for ensuring the safety of prescription drugs that has been neglected for over 15 years. Holding meaningful FDA oversight hearings is one of the most important, if not the most important, thing Congress could do to protect the public s health against the threat presented by exposure to dangerous prescription drugs through the FDA s drug approval process and delays from the agency in removing dangerous drugs from the market. Aggressive oversight hearings would send a signal to the upper management of the agency that patient safety, which conflicts with the drug industry s desire for a shorter total drug development time, must be the agency s top priority. Congressional hearings should focus on the following:

Approval of a substantial number of the drugs that have recently been approved and then withdrawn from the market as a result of safety problems.

Delay in the removal from the market of some recently approved drugs.

Drugs banned in other countries for safety reasons, including recently approved drugs, which remain on the market in the U.S.

The conflict of interest created by the existing structure at the agency in which the same personnel responsible for approving drugs have a central role in deciding if a drug should be withdrawn or undergo significant labeling changes as a result of safety concerns.

Hearings conducted on the approval process of Lotronex would be most revealing of underlying problems in the agency s review process.


How the FDA Approved a Dangerous and Ineffective Drug Despite Mounting Evidence of Harm to Women s Health


On February 9, 2000 the Food and Drug Administration (FDA) approved Lotronex to treat women suffering from Irritable Bowel Syndrome (IBS) despite questions raised during the clinical trials regarding patient safety. The drug was withdrawn on November 28, 2000 as a result of the serious nature and number of adverse events reported. After only 8 ? months on the market, more than 70 women suffered serious complications including 49 cases of ischemic colitis, a potentially fatal condition, and 21 cases of severe constipation with a total of 34 hospital admissions and 5 deaths.(3) As of December 31, 2001, there had been 13 deaths (7 strongly associated with Lotronex), 85 cases of ischemic colitis, and 352 hospitalizations (mostly due to gastrointestinal problems) associated with Lotronex.(4)

Dangers of Lotronex Were Known Before Approval

In July 1999, Glaxo Wellcome filed a New Drug Application (NDA) for Lotronex; a drug designed to treat Irritable Bowel Syndrome. Lotronex was granted an accelerated review, even though IBS is a non-fatal condition.

Dr. John Senior, the FDA Medical Officer responsible for the safety review of this drug, took special note of the high percentage of women in the clinical trials who suffered serious constipation while taking Lotronex: 27% of women experienced constipation and 10% withdrew as a result of its severity. For women with IBS, constipation can lead to very serious complications, some requiring hospitalization or surgery, including "obstruction, perforation, impaction, toxic megacolon and secondary ischemia."(5) Despite the clear risk, Glaxo Wellcome knowingly submitted a labeling proposal citing constipation as an infrequent side effect. Senior responded, "This is inappropriate. Constipation was NOT infrequent, but occurred in more than a quarter of the patients; it was COMMON, and almost to be expected."(6) The FDA prevailed in the final labeling. However, this was last time Glaxo Wellcome would show a lack of concern for the public's health.

More worrisome to FDA reviewer Senior than the cases of constipation were the four instances of ischemic colitis (lack of blood flow to the colon leading to death of bowel tissue(7)) that occurred during the clinical trials. The women who developed ischemic colitis during the trial eventually recovered, but that four cases had occurred was reason for concern. There were no cases in the control group. Ischemic colitis is so uncommon in a patient with IBS that a gastrointestinal specialist can practice for "decades" without ever encountering one case, according to Senior.(8) Moreover, drug-induced ischemic colitis is a very serious condition. It can result in "gangrene, perforation, peritonitis, and death."(9) Senior criticized Glaxo Wellcome for attempting to bury these cases "in the fine print" as well as mislabeling this side effect as "rare."(10)

Although he did not state an opinion regarding the approval of Lotronex, Senior called for additional testing with particular attention to be paid to the instances of constipation and ischemic colitis. He wrote in his review: "this finding represents a signal of a potentially serious problem that should be anticipated, perhaps even more severely expressed, if the drug is approved for clinical use in hundreds of thousands of women with IBS."(11)

Too Small a Benefit for Such a Large Risk

Lotronex was not only unsafe it was barely effective. In the clinical trials, patient improvement directly attributable to Lotronex occurred in only 10% to 20% of overall cases.(12) It had a higher efficacy in women suffering from "diarrhea-predominant" forms of IBS, but diarrhea is not the most common symptom of IBS. Only 20-30% of IBS sufferers experience diarrhea as their principal symptom while the other 70-80% of women have either constipation predominant or dual symptom (diarrhea and constipation) IBS (for which Lotronex is neither an effective nor an approved treatment).(13)What's more, on a scale of 0 to 4, women in one clinical trial only registered their level of relief between 0.12-0.14 above the relief registered by patients taking the placebo.(14) Overall 73% - 80% of Lotronex s apparent efficacy is due to the so-called placebo effect.(15) Even with this low level of improvement and high risk, top officials and the FDA s Gastrointestinal Drugs Advisory Committee ignored the serious message in these warnings and approved the drug on February 9, 2000.

Glaxo Wellcome & the FDA: The Black Box Warning

Reports of serious adverse events started to come in April 2000, 1? months after the drug hit the market. By June, the FDA had received word of at least eight cases of ischemic colitis and six patients were hospitalized as a result of Lotronex use.(16) In a rare move, the agency reconvened the advisory committee on June 9, 2000 to review its earlier decision. The FDA proposed a black box warning for Lotronex, the most restrictive labeling option open to the agency, to highlight serious side effects of the drug; however, Glaxo Wellcome did not want to bring attention to the potentially deadly complications that could result from Lotronex. According to Dr. Richard Kent, Vice President of Glaxo Wellcome when Lotronex was on the market, "We don t feel& that this drug is a dangerous drug and merits a black box& patients and physicians may end up making inappropriate decisions around whether to use this drug."(17) The FDA backed down and allowed Lotronex to stay on the market without a black box warning. In return, Glaxo Wellcome changed the label to include the "infrequent reports of serious complications of constipation" and the "incidence of ischemic colitis in female subjects in clinical trials as approximately 1 in 700 patients."(18)

The FDA also insisted that Glaxo Wellcome create a Medication Guide to accompany each prescription of Lotronex. But the guide, which described the symptoms of ischemic colitis and other dangerous side effects, was ineffective. The warning signs of adverse reaction due to the drug are virtually the same as symptoms of IBS.(19) The Medication Guide warned patients to stop taking the drug if they "get severely constipated" or experience "worsening or bothersome constipation with increased abdominal discomfort" signature symptoms of IBS. This was the first drug to have a Medication Guide required by the FDA. Applying this requirement to Lotronex represents a dangerous perversion of the intent of this program. The original design of the Medication Guide was to provide helpful information for the consumer, instead the FDA used it as a way to avoid Lotronex s withdrawal.(20)

Consumer groups, including Public Citizen s Health Research Group, calling for the drug s immediate withdrawal were ignored. By November 2000, at least five people were dead and dozens more had experienced serious complications from Lotronex.

FDA Medical Officers Call for Withdrawal in November

In early November 2000, the Division of Drug Risk Evaluation II (DDRE2), a division within the Office of Post Marketing Drug Risk Assessment (ODPRA) now known as the Office of Drug Safety, made a presentation to Dr. Janet Woodcock analyzing Lotronex adverse event reports. Following this meeting, and in response to a risk assessment presentation by Glaxo Wellcome, Dr. Kathleen Uhl, Acting Division Director, along with other FDA specialists in DDRE2 and ODPRA, produced a memo on November 16, 2000 addressing the overall safety and risks associated with Lotronex.

FDA Medical Officers took issue with Glaxo Wellcome s proposal to manage the risk of Lotronex by restricting its use to women under the age of 65 because ischemic colitis is more common in older women. But FDA officers found that more than 70% of those with ischemic colitis and more than 57% of those who encountered constipation were under the age of 65.(21) In fact, the Medical Officers concluded that Lotronex therapy was unsafe for women regardless of the proposed risk management strategy because "the sponsor has not identified a subset of women who will respond to Lotronex therapy safely." They went on to say that "a risk management plan cannot be successful that will eliminate deaths, colectomies, ischemic colitis, and complications of treatment that were never seen previously in the management of IBS."(22)

Even with DDRE2 s strong recommendations against continued use and marketing of Lotronex ringing in their ears, top officials at the FDA went into a meeting with Glaxo Wellcome on November 28, 2000 offering "restricted distribution" as an option for the company.(23) The FDA defied its own safety and risk specialists, who had clearly stated that there was no safe way to market Lotronex due to its unmanageable health risk, when they gave Glaxo Wellcome the option to keep the drug on the market, albeit for a more limited group of women.

Later that day, Glaxo Wellcome instead chose to withdraw Lotronex completely. In 8? months on the market, Lotronex had more than $56 million in sales.

Reintroducing a Drug that Kills: the FDA Listens to GlaxoSmithKline(24)

As of December 31, 2001, there had been 13 deaths (7 strongly associated with Lotronex), 85 cases of ischemic colitis, and 352 hospitalizations (mostly due to gastrointestinal problems) associated with Lotronex.(25) Yet, in the face of these clear examples of the unmanageable risk associated with Lotronex, the FDA and GlaxoSmithKline (formerly Glaxo Wellcome) have been making arrangements for the possible reintroduction of the drug.

In a May 2001 editorial published in the esteemed medical journal, The Lancet, Richard Horton lambastes the FDA for an inappropriate relationship with GlaxoSmithKline regarding the reintroduction of Lotronex. Despite the warnings of agency scientists those in the best position to know of the dangers, senior officials at the FDA have been advocating for the reintroduction of Lotronex. Horton shows that shortly after the withdrawal of Lotronex, officials at the FDA contacted GlaxoSmithKline about how to bring Lotronex back to market. In one of those conversations, Dr. Florence Houn, Director of the Office of Drug Evaluation III, spoke with Dr. David Wheadon, a GlaxoSmithKline executive, reassuring him the FDA will "work with them on developing the agendas and questions" for the advisory committee dealing with the drug s reintroduction.(26) In another conversation, Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research, reassured GlaxoSmithKline that the FDA "can manage" the media with regard to bringing Lotronex back hardly the actions of an impartial scientist.(27)

Still looming is the question of how the FDA will justify the reintroduction of this drug given the final conclusion of its own Division of Drug Risk Evaluation that there is no way to protect patients from dangers of Lotronex because "[n]o pattern has emerged with regard to factor or factors that can provide a meaningful prediction for those patients who developed ischemic colitis or constipation that required surgery."(28) This was true in November 2000 when the memo was written; it is even more true now that more deaths and injuries have accumulated.

What is particularly alarming about the details of the Lotronex story is not just that the FDA approved a dangerous drug and appears poised to reintroduce it but that, in the words of The Lancet s Horton, it acted more like a "servant" to the pharmaceutical industry than a protector of the public s health.(29)


1. David Willman, "How a New Policy Led to Seven Deadly Drugs," Los Angeles Times, December 20, 2000.

2. Peter Lurie, Sidney Wolfe, "FDA Medical Officers Report Lower Standards Permit Dangerous Drug Approvals," Public Citizen, Health Research Group,, December 2, 1998.

3. Richard Horton, "Lotronex and the FDA: A fatal erosion of integrity," The Lancet. Vol. 357, Issue 9268, May 19, 2001.

4. Sidney Wolfe, M.D., Director of Public Citizen s Health Research Group, in testimony before the U.S. Food & Drug Administration s Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science, April 23, 2002.

5. Ibid.

6. John R. Senior, M.D., "FDA Medical Review: Lotronex, NDA 21-107, 90-Day Safety Update" November 30, 1999, p. 22.

7. Public Citizen s Health Research Group, "Petition to the Food and Drug Administration to remove Lotronex from the market," Publication #1533; August 31, 2000.

8. David Willman, "How a New Policy Led to Seven Deadly Drugs," Los Angeles Times, December 20, 2000.

9. John Senior, "FDA Medical Review: Lotronex, NDA 21-107," October 22, 1999, p. 62.

10. John R. Senior, M.D., "FDA Medical Review: Lotronex, NDA 21-107, 90-Day Safety Update" November 30, 1999, p. 22.

11. Ibid.

12. David Willman, "FDA Minimized Issue of Lotronex s Safety," Los Angeles Times, November 2, 2000.

13. Joseph Shapiro, "A pill turned bitter: How a quest for a blockbuster drug went fatally wrong," U.S. News & World Report, Vol. 129, Issue: 23: December 11, 2000.

14. Public Citizen s Health Research Group, "Petition to the Food and Drug Administration to remove Lotronex from the market," Publication #1533; August 31, 2000.

15. Ibid.

16. Ibid.

17. David Willman, "Lotronex: Study Finds FDA Conflict of Interest," American Political Network: American Health Line, November 2, 2000: Vol. 6, No.9.

18. Richard S. Kent, MD, "Dear Healthcare Professional Letter Re: Safety-related Revisions to Labeling for Lotronex," August 24, 2000.

19. U.S. Food and Drug Administration, "FDA Creates Medication Guide for Lotronex: Health Professional Labeling Revised to Help Manage Risks," HHS News, August 24, 2000.

20. Public Citizen s Health Research Group, "Petition to the Food and Drug Administration to remove Lotronex from the market," Publication #1533; August 31, 2000.

21. Ibid. 6.

22. Ibid. 2.

23. U.S. Food and Drug Administration, "Glaxo Wellcome Decides to Withdraw Lotronex from the Market," Talk paper: T00-65; November 28, 2000.

24. Glaxo Wellcome merged with SmithKline Beecham in December 2000 to become GlaxoSmithKline.

25. Sidney Wolfe, M.D., Director of Public Citizen s Health Research Group, in testimony before the U.S. Food & Drug Administration s Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science, April 23, 2002.

26. Ibid.

27. Ibid..

28. Kathleen Uhl, et al, "NDA 21-107: Lotronex (alosetron) Safety & Risk Management Summary," November 16, 2000, p. 10.

29. Richard Horton, "Lotronex and the FDA: A fatal erosion of integrity," The Lancet. Vol. 357, Issue 9268, May 19, 2001.