GAITHERSBURG, Md. - Biogen Idec Inc. unveiled details of its risk-management strategy for Tysabri (natalizumab), a proposed plan that generally received support from the FDA and multiple sclerosis patients, during the first day of a two-day public hearing on the once-heralded MS drug.
At issue is Tysabri’s link to an often-fatal disorder called progressive multifocal leukoencephalopathy (PML), currently considered a 1-in-1,000 risk, and whether that probability is outweighed by the drug’s benefit in reducing relapses among MS patients. Its ability to do so - demonstrated at 68 percent at the end of a two-year study - is more than double that of the other primary drugs for MS.
"The plan seeks to minimize the risk of PML," said Carmen Bozic, Biogen Idec’s vice president of drug safety and risk management. Notably, the risk-management plan, also being called a risk-minimization plan, would allow access to Tysabri for certain patients. Cambridge, Mass.-based Biogen Idec and its partner, Dublin, Ireland-based Elan Corp. plc, have been working in concert with the FDA to develop it as part of their application to get Tysabri back on the market.
Noting that if Tysabri is cleared to return, Robert Temple, director of the FDA’s Center for Office of Drug Evaluation I, said there would be "no question" about an accompanying risk-management plan. "What we’re talking about here is a drug that unequivocally works," he said, adding that because "there isn’t any alternative that’s perceived as being as good," it has to be considered. Only once in the past has the FDA allowed a drug to return to the market after its removal.
Bozic detailed a revised label with language specific to the drug’s risk of PML and warnings against combination use with immunosuppressants. In fact, both companies said the drug should be used as monotherapy, and proposed that its use should be restricted to relapsing-remitting MS patients, notably those intolerant to other therapies or exhibiting disease activity despite other treatment, and contraindicated in immuno-compromised patients. A checklist would be used to eliminate certain patients, given their individual profile or drug history.
The proposed risk-management plan calls for mandatory enrollment in a Tysabri registry and limits the drug’s distribution from Biogen Idec to registered infusion sites. It also mandates the use of a monthly patient questionnaire before dosing to detect the possibility of PML. Should symptoms surface, dosing would be suspended. Also, patients who abandon Tysabri treatment would nevertheless remain in the registry for six months after their final dose.
All elements of the plan are designed "to reinforce the importance of clinical vigilance," Bozic said, conceding that although "PML is a rare but very serious side effect of Tysabri treatment," the risk-management plan "justifies its reintroduction on the U.S. market."
To further define Tysabri’s overall risk-benefit profile, she outlined plans for an observational cohort study to include 5,000 MS patients worldwide, and follow them for five years. In addition to watching for PML, the study also would track serious opportunistic infections.
FDA officials largely were supportive of the proposed risk-management plan. In particular, Diane Wysowski, a reviewer in the agency’s Office of Drug Safety, praised the companies’ proposal to distribute Tysabri solely through registered infusion centers that she estimated would number about 2,000 in the U.S. But she suggested that assigning specific vials of the drug to particular patients would lessen chances of off-label use, and said a broader checklist of exclusion criteria could provide a better safety check.
Three hours of public testimony took up half of Tuesday’s hearing, which drew a standing-room-only crowd and spilled into the hallways.
Most speakers were MS patients or their relatives, and nearly every one of them spoke of Tysabri-induced improvements in their conditions and pleaded for a chance to take it again.
"[Patients would] like an opportunity to think" about taking the drug, said Temple, noting that "many of the very issues" raised Tuesday are to be contemplated by the advisory committee today.
"We understand the risks of using experimental drugs," said MS patient Pamela Clark, who traveled from Salt Lake City at her own expense to speak at the meeting. "But we also understand the risks of doing nothing." Her comments were echoed by MS patient Heather Smith, who traveled to the meeting from Indiana. "Each MS patient has the right to make an informed choice," she said, "and create their own risk-benefit analysis."
However, not all the public hearing speakers were as enamored, including Greg Shoukimas, a doctor for one of the two Tysabri patients who died from PML. Noting that her MS diagnosis "was never clearly established," he called her enrollment into a Tysabri study "incomprehensible." He charged Biogen Idec and Elan with being "incapable" of correctly conducting further studies, calling into question their previous results.
The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee will meet again today to consider whether Tysabri is suitable for market re-entry, and if so, whether the risk-management plan is appropriate or needs tweaking. Temple declined to speculate on the future of other drugs in the same class.