BMJ  2003;327:E163-E164 (4 October), doi:10.1136/bmjusa.02110002 (published 20 February 2003)

BMJ USA: Education and debate

Commentary: The reintroduction of Lotronex for diarrhea-predominant irritable bowel syndrome

Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD (woodcockj{at}cder.fda.gov)

From BMJ USA 2002;Nov:637

The Food and Drug Administration approves program to provide patient access and manage risk

Immediately after the November 28, 2000 announcement of the safety-related withdrawal of Lotronex, distraught patients, stunned that this therapy had been taken away from them, began to contact the Food and Drug Administration (FDA). Thousands of individuals from all walks of life—businesspeople, military personnel, government employees, teachers, health care workers—wrote or emailed the agency, demanding access to a drug they characterized as "giving them their lives back." Meanwhile, the drug's manufacturer, Glaxo Wellcome, was shutting down production lines and ongoing clinical trials, having rejected the FDA's proposal to create a limited access program for severely affected people. Subsequently, under ongoing pressure from patients, the manufacturer opened discussions with the FDA on potential drug availability programs. Thus began the arduous process of crafting a proposal for the reintroduction of Lotronex.

Lotronex had been withdrawn because outcomes from ischemic colitis (a known side effect) were more serious than predicted by the results of clinical trials and because of serious complications of constipation (a pharmacologic effect of a drug intended to reduce urgency and frequency). Cases of small bowel ischemia and a number of deaths had also been reported to the FDA. Irritable bowel syndrome (IBS) is a very common disorder, but most cases are manageable and none are progressive or life threatening. Clearly, for the majority of people with IBS, the risks of Lotronex outweighed the benefits. However, for people with disabling symptoms that precluded a normal life, a greater level of risk might be acceptable. The challenge was creating a program that provided access for these people and prevented use by individuals with less severe IBS or with non-IBS gastrointestinal disorders.

To further characterize drug side effects, the manufacturer submitted to the FDA data on 8000 additional Lotronex-exposed patients from trials conducted since the initial drug approval. These data were combined with data on 3000 patients that had been submitted before approval. In the clinical trials, although the overall incidence of constipation was much higher in Lotronex-treated patients, the rate of severe complications from constipation was similar in the Lotronex and placebo arms. The trial procedures, which required withdrawing the drug for side effects, were thought to have helped prevent patients from progressing to complications. In contrast, reports received by the FDA after drug marketing included more than 80 cases of constipation requiring hospitalization, including cases of fecal impaction, and bowel obstruction, necrosis, or rupture. The occurrence of constipation was dose-related.

Over a period of approximately 3 months in the clinical trials, ischemic colitis occurred (above the placebo rate) in about 2 in 1000 patients. While cases in the clinical trials were generally self-limited, 11 cases that were reported after marketing required surgical intervention, and there were 2 deaths. No predisposing risk factors could be identified for development of ischemic colitis.

The FDA also conducted further analyses of benefits. Patients appeared less likely to respond to the drug if they reported fewer than 2 stools daily or hard stools. Subgroup analyses revealed significant treatment responses in people reporting severe and frequent urgency. Correspondingly, many testimonials of major benefit sent to the FDA came from people suffering socially disabling urgency and fecal incontinence.

Given the findings described above, the most important factors in maintaining a positive benefit:risk ratio appeared to be: 1) maximizing benefit by limiting use to properly diagnosed patients with disabling diarrhea-predominant IBS, and 2) minimizing risk by educating clinicians and patients about the need for close monitoring for side effects, as well as cautious dose adjustment. In addition, patients needed to be adequately informed of both potential risks and benefits. Finally, any reintroduction program should have elements allowing evaluation of the success or failure of the measures taken.

On April 23, 2002, the FDA convened a joint meeting of two advisory committees to discuss the new data and proposed reintroduction programs.¹ Both the manufacturer (now GlaxoSmithKline [GSK]) and the FDA proposed various elements that could be included in a risk management program (eg, lower starting dose, evaluation of treating physicians' qualifications, patient education, patient or physician registries, evaluation programs). Members of the public, including a number of IBS patients, also presented their views. Patients generally expressed the desire to make a fully informed choice, in consultation with their doctors, about whether or not to take the drug. The committee considered restricting prescribing to gastroenterologists to ensure that patients were properly diagnosed. Although a majority of committee members favored this approach, they recognized that restriction could limit access, would be difficult to implement, and was of unknown effectiveness in improving diagnostic accuracy.

After the advisory committee meeting, the FDA worked with GSK to compile a formal risk management program for Lotronex, which the agency approved on June 7, 2002. This program included 1) a prescribing program encompassing physician qualifications, physician agreements, and a prescription sticker procedure; 2) an education program for physicians, pharmacists, and patients; 3) commitments by GSK to report adverse events; and 4) an evaluation of program effectiveness. The indicated patient population was narrowed, and a lower starting dose was specified in the label. GSK also agreed to an extensive series of clinical investigations aimed at better characterizing risk and benefit.

The FDA has approved a number of programs designed to limit the risks of specific drugs. In the case of certain drugs (eg, thalidomide, clozapine) these programs are of proven benefit. In other cases, the jury is still out. These programs are generally used only when drug approval is otherwise not feasible, since they may impose burdens on the health care system, result in unintended consequences, or be of unproven utility. The FDA, with other stakeholders, is exploring ways to systematize and improve these interventions.² The effectiveness of the Lotronex risk management program is not yet known, but it will be evaluated and modified if necessary.

For those who wish to argue that the FDA is overly influenced by the pharmaceutical industry, Lotronex is not a good case. The drug's manufacturer was not pushing for reintroduction. Without the advocacy of individual patients, the drug would likely have been abandoned. The FDA can be accused of listening to, and being influenced by, the needs of patients and practitioners. This, in fact, is true. Many thoughtful people would not have it any other way.

References

1. Transcript of Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science. Available at: www.fda.gov/ohrms/dockets/ac/cder02.htm#gastrointestinal (accessed October 15, 2002).
2. Risk Management of Prescription Drugs; Public Hearing Transcript. Available at: www.fda.gov/ohrms/dockets/dockets/02n0115/02n0115-tr.htm (accessed October 15, 2002).

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