NEWS

Consumer Groups Look To Improve Adverse Event Reporting Systems

Brian Vastag

Few multiple myeloma patients, let alone anyone else, had heard of osteonecrosis in 2001. The rare affliction, in which bone marrow dies and bones collapse, is found most often in the hip. But starting in 2002, patients with multiple myeloma began turning up with bone deformities in their jaws.

Robert Kyle, M.D., a noted myeloma specialist at the Mayo Clinic, Rochester, Minn., remarked that in his 40 years of practice, he had never seen osteonecrosis of the jaw. And yet, in 2003 and 2004, oral surgeons published reports of dozens of myeloma and other cancer patients with the potentially disfiguring disorder.

Michael Katz, of the International Myeloma Foundation, a patient advocacy organization, said online discussion groups soon made a link: the jaw problems appeared only after patients began taking the drug Zometa (zoledronic acid), a new bisphosphonate. The drug's maker, Novartis Pharmaceuticals, was heavily promoting Zometa to replace its older bisphosphonate, Aredia (pamidronate), which had gone off patent in 2001.



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Michael Katz

 
"The push to migrate patients to this new drug was very strong," Katz said at a November Institute of Medicine workshop on improving adverse event reporting. "My oncology nurse wanted me to switch (from Aredia) without even talking to my doctor." Katz said no and stayed on Aredia.

To sort out the issue, Katz helped organize an online survey that drew responses from 904 myeloma patients and 299 breast cancer patients taking bisphosphonates. The responses implicated Zometa, as detailed by Brian Durie, M.D., a hematologist–oncologist at the Cedars-Sinai Outpatient Cancer Center in Los Angeles, during a December 2004 American Society of Hematology meeting. Durie reported that at 36 months of use, 10% of patients taking Zometa had been diagnosed with osteonecrosis of the jaw or had symptoms indicative of it. Four percent of patients taking Aredia had developed the condition.

So in the absence of data showing that Zometa led to longer survival than Aredia, Katz and other leaders of the International Myeloma Foundation "started telling everyone to go back to Aredia."

The survey was not "conventional science, it's not bulletproof," said Katz. And yet, "the scientific community embraced it." In addition to Durie's presentation at the American Society of Hematology meeting, Katz presented the survey at a special meeting of the FDA's oncology drugs advisory committee meeting in March, and the New England Journal of Medicine published the results in July.

As the case against Zometa and, to a lesser extent, Aredia, built, skeptics maintained that the evidence of a link was weak. That reaction echoed what Salvatore Ruggerio, M.D., chief oral and maxillofacial surgeon at Long Island Jewish Medical Center, heard when he approached Novartis in 2001. Ruggerio repeatedly called Novartis and the U.S. Food and Drug Administration to report osteonecrosis of the jaw in patients taking bisphosphonates, and representatives from the company finally met with him in December 2003. By 2004, the company had amassed more than 500 case reports, but a spokesperson maintained that no causal link had been shown. The company plans to finish its own study of the issue in about a year.

However, at the direction of the FDA, Novartis did revise the package labeling for Zometa in September 2004 to encourage dental exams before and during bisphosphonate therapy.

The episode highlights the underappreciated role that patient organizations can play in ferreting out adverse events, said Alex Ommaya, Sc.D., of the IOM panel that organized the November meeting in Washington. "Consumers are a large untapped resource," he said.

Many Reports

Other speakers made similar points, saying that consumers should be encouraged to report possible adverse reactions. Marvin Lipman, M.D., from Consumers Union, publisher of Consumer Reports, encouraged the FDA to provide leaflets with every prescription sold that direct consumers to the FDA's Medwatch phone number and Web page. He also suggested FDA-sponsored public service announcements encouraging patients to report adverse events. The ads could help "restore confidence in the FDA process that failed consumers" via high profile adverse-event cases such as that of Vioxx. Drug maker Merck pulled the nonsteroidal anti-inflammatory drug from the market last year at the urging of the FDA after adverse event reports suggested increased rates of heart attacks and stroke among users.

In the storm of criticism that followed, the FDA asked the IOM to review its drug safety procedures, one action that led to the November meeting.

Alison Rein, from the National Consumers Union, presented the United Kingdom's "Yellowcard" program as a model for the FDA to consider. The cards accompany every prescription in the United Kingdom and can be returned via mail or keyed into a Web page. They explicitly tell consumers to report adverse events and are available in several languages.

Although several speakers pointed to the need for more consumer involvement, others warned against it. "You have to be careful what you wish for," said Sidney Kahn, M.D., Ph.D., president of Pharmacovigilance and Risk Management Inc., a consulting firm that advises industry on safety issues. "We don't need thousands of reports" of minor known adverse events, such as coughing in people taking angiotensin-converting enzyme inhibitors. "The question is, how do you separate the signal from the noise?"

The deputy director of the FDA's Office of Drug Safety, Anne Trontell, M.D., said that the agency could easily be overwhelmed by a consumer campaign. In fiscal year 2004, her office handled 24,553 reports from the Medwatch program's Web site and toll-free number. About 15% came from consumers directly, she said; the rest were from physicians.

But overall, in fiscal year 2004 the FDA dealt with 426,109 adverse event reports. Most were submitted by drug makers, who are obligated to track adverse events. The Office of Drug Safety ultimately concluded that 263,352 of the reports were from individuals experiencing potentially serious adverse events caused by a prescription or over-the-counter drug.

The volume of reports brings into focus the need for efficient monitoring and data mining, said Richard Platt, M.D., chair of the department of ambulatory care and prevention at Harvard Medical School in Boston. He pointed to the FDA's Vaccine Adverse Event Reporting System as a model with "real time" tracking capabilities. Physicians who immunize children report events as they occur. The system worked as conceived, said Platt, when the rotavirus vaccine, approved in August 1998, was shelved 11 months later after 15 reports of the same serious adverse event, a type of bowel obstruction.

Platt said that Medicare's new prescription drug plan for seniors presents the perfect opportunity to begin such monitoring for drugs. "We're going to have 40 million seniors [in the plan] who can serve as sentinels," he said. However, the Centers for Medicaid and Medicare Services has not organized such a database. This theme—a lack of a cohesive strategy—wound through the 2-day meeting. "We need a unified adverse event system, and we don't have one," said committee chair Jeffrey Drazen, M.D., editor in chief of the New England Journal of Medicine.

Patient groups will continue to fill that vacuum the best they can, said committee member Musa Mayer, a patient advocate and author of the Web site AdvancedBC.org. "Consumers and advocates are the most motivated to discover and report adverse events," she said.

Katz, whose myeloma group inspired Mayer's remarks, said that adverse events take too long to identify in the current environment. It took 5 years for the serious cardiac risks of Vioxx to surface, he pointed out, which he called "prima facie evidence" of the validity of patient-centric adverse event reporting. "It may mean that we never prove that these events were caused by the drug," he said. "But fewer people will be harmed."



             
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