Alosetron Use Drops Dramatically With Risk Management
About 10,000 patients obtained supplies of alosetron hydrochloride, or Lotronex, during the first 14 months after the product was reintroduced to the market—a volume that manufacturer GlaxoSmithKline (GSK) describes as too low to support studies of the product's safety and efficacy.
Members of FDA's Drug Safety and Risk Management Advisory Committee, joined on May 5 by two experts from the agency's Gastrointestinal Drugs Advisory Committee, were asked to consider easing restrictions on the prescribing of Lotronex to encourage more people to use the drug.
"At the current rate of prescribing," lamented Craig Metz, GSK's vice president of U.S. regulatory affairs, it "could take 15 years" to complete ongoing studies of the drug.
FDA initially approved Lotronex in February 2000 for the treatment of diarrhea-predominant irritable bowel syndrome (IBS) in women. GSK withdrew the drug from the market nine months later, after reports linked alosetron use to serious gastrointestinal adverse events, including fatal cases of ischemic colitis.
FDA advisers met in April 2002 to consider returning alosetron to the market, and the product was reintroduced six months later through a risk management program designed to limit the drug's use to women with severe IBS in whom the benefits clearly outweigh the risks.
Collectively, the 10,000 patients who used alosetron in the 14 months since the product's reintroduction obtained about 30,000 prescriptions for Lotronex, generating sales of about $5.9 million at today's Red Book price. In contrast, GSK reported $54 million in sales from Lotronex during the eight months that the product was marketed in 2002.
Metz told the advisory panel that the number of appropriate candidates for the drug "could be as high as 2.9 million."
"It is not 10,000" patients, he said.
Pharmacists Are Messengers for Risk Management Program
At a May 5 meeting, members of FDA's Drug Safety and Risk Management and Gastrointestinal Drugs advisory committees heard about the role alosetron manufacturer GlaxoSmithKline (GSK) hopes pharmacists will play in the drug's risk management program.
Craig Metz, GSK's vice president of U.S. regulatory affairs, said that physicians are expected to enroll in a prescribing program for alosetron before writing prescriptions for the drug. After enrolling, physicians receive special stickers to affix to each prescription for alosetron. Pharmacists should fill an alosetron prescription only if it is written by an enrolled physician and bears the sticker.
But Metz acknowledged that no mechanism exists to prevent physicians who are not enrolled in the program from writing prescriptions for alosetron.
"It would be akin to a physician writing an off-label prescription for a product, which they have the right to do," Metz said.
He added that when a pharmacist receives a prescription written by a nonparticipating physician, "there is a little bit of tension created, because for the pharmacists that are aware of the program, they're faced with filling a prescription that doesn't have a sticker on it and what they're going to do about that."
Metz said GSK hopes that the pharmacist will "contact the prescriber and say, 'Are you enrolled? I've got a letter from GSK or from the prescribing program for Lotronex, and it says there has to be a sticker on each prescription.'"
But, he said, "we can't force that conversation to occur."
ASHP Executive Vice President Henri R. Manasse Jr., who is a member of the Drug Safety and Risk Management Advisory Committee, asked Metz what GSK is doing to address "the intense time" element for pharmacists who adhere to the risk management program.
Metz described the issue as "a balancing act" and said GSK is working with FDA "to look for ways to make this [process] less onerous without undermining the integrity of the system."
Creating barriers. Metz identified aspects of the risk management program that GSK believes have created barriers to use of the drug by women who could benefit from it. Physicians, Metz said, are balking at signing the attestation form required of prescribers who enroll in the risk management program for Lotronex.
"Physicians are unaccustomed to signing a document like this and feel that somehow there has been a unique transfer of liability from GSK to the prescriber," Metz said. "In addition, physicians feel that having to sign an attestation form is an affront to their professional training and somehow constitutes an unnecessary duplication of the licensing process."
The attestation form describes the elements of the risk management program and the conditions under which alosetron should be prescribed. In addition, the form requires physicians to affirm that they can diagnose and treat IBS and diagnose and manage ischemic colitis and other known complications of alosetron therapy. The form also outlines patient-education issues and adverse-event reporting.
Physicians who sign the attestation form are enrolled in the Lotronex prescribing program and receive special stickers to affix to all prescriptions written for the drug.
"Only 5053 [physicians] have even enrolled to prescribe Lotronex through the prescribing program," Metz said. He added that GSK was disappointed to find that "approximately half of the prescribers who have enrolled have not written a single prescription" for the drug.
Of note, about 13-20% of the prescriptions written for Lotronex since 2002 have originated with physicians not enrolled in the program. Metz said that periodic outreach efforts eventually lead 75% of these physicians to comply with the program, either by enrolling or by ceasing to prescribe the drug.
Metz said that another factor that contributes to the low prescribing rate for alosetron is that "language in the product labeling tends to frighten the patient rather than inform them."
He explained that 20% of patients who were screened to participate in current clinical trials of alosetron "refused to participate, because, after reading the study information that's similar to the product labeling, they stated that they were afraid to take Lotronex."
Outside of the clinical trial setting, Metz said, patients are put off by the patient–physician agreement that must be signed before the drug is prescribed.
Metz said that having to sign such an agreement is "something unusual" for patients. "They don't typically have to do it, and it gives them pause," he said.
"Our ultimate goal," Metz said, "is to modify the [risk management program] to improve product access to appropriate physicians and patients while continuing to effectively manage risk."
The expert panel responds. Although some advisers spoke in favor of modifying the risk management documents to improve their clarity, the general sense of the panel—which did not vote during this meeting—was that the prescribing program is performing as it should.
"I am not convinced that the low numbers of prescriptions or patients is due mainly to unreasonable barriers," said Stephanie Crawford, associate professor of pharmacy administration at the College of Pharmacy, University of Illinois at Chicago. "It could be that it's being prescribed more appropriately, and patients are making good, informed decisions."
Crawford said that "many aspects of the program seem to be working," and that the program has greatly cut "what appeared to be a very large amount of inappropriate prescribing" during the product's initial marketing period.
Arthur A. Levin, director of the Center for Medical Consumers, had little sympathy for GSK's goal of easing the restrictions on prescribing alosetron.
"In the context of risk management programs," Levin said, "this is 'risk management lite.' "
"Having barriers is what risk management is about," he added. "We have to recognize that this was an extraordinary case, the first time in history where a drug which had been withdrawn came back on the market, and about which there was little known about how to predict risk. And that everybody, including all of the patients that testified [at the April 2002 hearing], seemed willing to endure this special program in order to have access to the drug."
Some panel members compared the risk management program for alosetron to that for isotretinoin, which F. Hoffmann-La Roche Ltd. markets in this country as Accutane. Jacqueline Gardner, associate professor of pharmacy at the University of Washington School of Pharmacy, described the isotretinoin program as "really restrictive."
Gardner said that there does not seem to be pushback against the risk management program from physicians who prescribe isotretinoin, even though physicians and patients must complete forms similar to those for alosetron. In addition, women who take isotretinoin, a teratogen, must undergo frequent pregnancy testing and agree to use two effective forms of contraception simultaneously to avoid pregnancy.
Ironically, the risk management program for isotretinoin does not seem to be reducing pregnancy rates among women who use the drug, and an advisory panel recently recommended that additional restrictions be placed on the product's use.
The risk-benefit equation. Metz said that 37 serious adverse events have been reported since alosetron was reintroduced to the market. These include 6 medically confirmed cases of ischemic colitis, all of which, Metz said, "resolved without sequelae."
"No deaths attributable to Lotronex have been reported" since the November 2002 relaunch, Metz said. "The adverse events of special interest that we've observed are few, and the outcomes being observed are generally less severe" than during the initial marketing period.
At the time Lotronex was withdrawn from the market, FDA had received reports of 70 serious adverse events, including 3 deaths, among patients who used the drug.
Brian Strom, professor of biostatistics and epidemiology at the University of Pennsylvania School of Medicine in Philadelphia, said that a problem that led to the creation of the risk management program still exists today:
"You can't predict who's going to benefit and you can't predict who's going to be hurt" by taking alosetron, Strom said. He advised against making major changes to the risk management program "until we have data on predictors of efficacy and for risks of adverse events."
Strom noted that "only a small subset of people who get the drug" seem to benefit from it, adding that only 10% of patients who used alosetron in 2000 continued taking the product long-term before it was pulled from the market.
GSK's data from patient surveys indicate that 26% of those who received a prescription for alosetron have stopped taking the drug and 72% are still using it. According to GSK, 55% of the patients who received a prescription for alosetron under the risk management program also took the drug during 2000.
The 36% question. Some advisers were troubled by GSK's revelation that only 36% of the patients who received an alosetron prescription have participated in the company's voluntary postmarketing survey about the product. Patients who participate in the survey are asked to complete a baseline questionnaire and to submit additional assessments periodically thereafter.
Strom said that, although the 36% response rate is high for a marketing survey, the rate is "shockingly low" from an epidemiologic point of view and points to "vast underreporting" of adverse events.
Curt Furberg, professor of public health sciences at Wake Forest University Health Sciences in Winston-Salem, North Carolina, likewise said that the 36% response rate was "very, very troubling."
Furberg was also perplexed at the number of serious adverse-event reports that were culled from the patient survey and not reported by physicians.
Of the 127 serious alosetron-related adverse events reported to GSK from November 2002 through December 2003, 60% were communicated by patients instead of physicians. Furberg said that this phenomenon is unusual, and he admonished Metz to improve physician reporting of adverse events.
Metz acknowledged that GSK may not have done a good job of "communicating to the practitioner community what it is we want them to report."