Editorials

Alosetron for irritable bowel syndrome

Some patients may pay a high price for the FDA's decision to put the drug back on the market

News p 561 Education and debate p 592

On 9 February 2000 alosetron (marketed as Lotronex by GlaxoSmithKline), a type 3 serotonin (5-HT₃) receptor antagonist, was approved by the US Food and Drug Administration (FDA) for the treatment of patients with irritable bowel syndrome, a benign though unpleasant disorder that affects one in five adults in the industrialised world.¹ By November 2000, the FDA had received 49 reports of ischaemic colitis and 21 of severe constipation related to the drug, resulting in 44 admissions to hospital, 10 surgical interventions, and 3 deaths.² The drug was withdrawn from the market by its sponsor. Severe adverse events continued to be reported for some time, with a final total of 84 instances of ischaemic colitis, 113 of severe constipation, 143 admissions to hospital, and 7 deaths.³

On 7 June 2002, however, the FDA issued a supplemental new drug application that permits marketing of alosetron through a prescribing programme for treating women with irritable bowel syndrome whose main symptom is severe diarrhoea (5% of patients). Doctors will have to sign an attestation of qualification and acceptance of responsibilities. Patients will have to sign a patient-physician agreement attesting that they have been adequately informed of the risks and that they have the form of irritable bowel syndrome that may be treated with alosetron.⁴

This prescription programme is unlikely to prevent severe adverse reactions due to alosetron. In November 2000, the FDA's office of post-marketing drug risk assessment underlined that ischaemic colitis could not be predicted, some patients were not able to recognise the signs and symptoms of constipation, the reversibility of ischaemic colitis had not been established, and the signs and symptoms of these severe adverse effects were too similar to those of the disease being treated.² The increasing number of severe adverse experiences reported after the "Dear Doctor" and "Dear Pharmacist" letters issued in June 2000 at the request of the FDA also suggests that a real and effective risk management policy is not possible. The FDA's decision to put alosetron back on the market was made despite strong opposition of an insider (read Paul Stolley's story, p 592), and dissent is now being voiced by members of the advisory committee (see p 561).

According to the information given in the patient-physician agreement, severe constipation occurred in about 1 in 1000 patients treated for six months, and ischaemic colitis in 1 in 350. The present prescription plan would theoretically allow up to two million people in the United States to receive alosetron, which might result in 2000 cases of severe constipation, 5714 cases of ischaemic colitis, 1109 surgical interventions, and 329 deaths; 240 000 women would experience some relief of symptoms.⁵ The price to pay for this benefit looks very high.

What can have driven the FDA to reinstate alosetron on the market, while stating in the same letter that the drug "poses a serious and significant public health concern?" Lobbying by the Lotronex Action Group may be one reason. This group has been formed on the initiative of people belonging to the IBS Self Help Group.⁶ The IBS Self Help Group does accept sponsorship from companies, and GlaxoSmithKline's banner is displayed on its website.⁷ The group claimed that alosetron conferred life changing benefits on a large number of users on the grounds of a survey conducted by Drug Voice, a profit making "consumer research and marketing company specialising in taking the consumer's voice to pharmaceutical and healthcare leaders."⁸

A second reason for reinstating alosetron may be lobbying from the pharmaceutical industry. With 40 million potential patients in the United States, irritable bowel syndrome is a gold mine of the size of hypertension or type 2 diabetes. GlaxoSmithKline is obviously not the only one to crave this new market: the IBS Self Help Group's website also displays banners of Novartis and Solvay Pharmaceuticals, two laboratories that seek to enter the United States market for irritable bowel syndrome with tegaserod (a 5-HT₄ antagonist) and cilansetron (a 5-HT₃ antagonist) respectively. With massive direct industry funding of the FDA through the Prescription Drug User Fee Act, some doubts can be expressed about the ability of the agency to resist pressure from industrials.⁹

A third reason may be a shift in the FDAfrom being traditional and paternalistic to holding a more republican view of public health. The agency would now rather provide the best information for patients and doctors to make their own decisions than to make the decisions in their name.

The main mission of the FDA's Center for Drug Evaluation and Research is to "protect the public health by ensuring that human drugs are safe and effective."¹⁰ By allowing the marketing of alosetron, a drug that poses a serious and significant public health concern according to its own terms, the FDA failed in its mission. Moreover, in waiving its responsibility, the agency transferred it to the patients, asking them to attest that they belong to the target population and can manage the risks. Most patients obviously lack the background and training necessary to assess correctly the balance between risk and benefit, and they may be misled by self help groups that have financial ties with the pharmaceutical industry. If the decision regarding alosetron is the harbinger of future FDA policy, the entire population of the United States will need full medical training, with access to genuinely independent therapeutic information.

Michel Lièvre, associate professor. 

Clinical Pharmacology Unit, Faculté de Médecine Laënnec, BP 8071, 69376 Lyons Cedex 08, France (ml{at}upcl.univ-lyon1.fr)

Footnotes

Competing interests: ML has been reimbursed by Novartis Laboratories for attending a symposium and has received funds from Novartis for performing the data management of a clinical trial.