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Clancy, Frank

Ms Experts Weigh in

How much risk is worth taking in the hope of staving off an often-debilitating but not fatal disease? Who should decide whether the risk is acceptable? Should individuals decide for themselves? What role should the federal government play? What is a physician's responsibility?

Those and other decidedly non-scientific questions have suffused public discussion of the innovative MS drug natalizumab (Tysabri), a monoclonal antibody, which returned to the news almost exactly one year after all use was suspended because several patients developed progressive multifocal leukoencephalopathy, or PML. A rare disease, PML is caused by the JC virus and affects almost exclusively people who are immunodeficient.



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The Food and Drug Administration (FDA) first announced in late February that it was partially lifting the ban on natalizumab, allowing the drug's makers, Biogen Idec and Elan Pharmaceuticals, to supply it to patients with relapsing-remitting MS who had previously received the agent in clinical trials. Weeks later, after two often-emotional days of public testimony, an FDA advisory committee voted unanimously to recommend that the companies be allowed to resume commercial sales of natalizumab, albeit with stringent restrictions. The agent could be used only for adult patients with relapsing MS; as monotherapy, and it could not be used with any interferon or chronic steroid treatment.

The panel was divided on one issue: whether it should be limited to patients who had tried and experienced a relapse with standard and presumably safer medications. The panel voted 7-5 in favor of allowing natalizumab to be used as a first-line treatment.

The agency's final decision on these recommendations, originally scheduled for late March, has been delayed for up to 90 days to work out details of a risk management plan (RMP). A major goal of that plan, said Russell Katz, MD, the FDA Director of the Division of Neurology Products, will be to monitor patient data and constantly update the risk of PML. Agency officials have said openly they expect more cases of PML in patients taking natalizumab.

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This discussion of natalizumab came on the heels of three articles and an editorial about natalizumab in the March 2 issue of the New England Journal of Medicine. Two of the articles reported that the benefits of natalizumab last for at least two years:

  • The Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis study, dubbed AFFIRM, found that, used alone and compared to placebo, the agent reduced the risk of “sustained progression of disability” in patients with relapsing MS by 42 percent over two years (N Engl J Med 2006;354:899–910). An earlier report said it reduced the relapse rate by 68 percent in one year. Treated patients also had significantly fewer brain lesions than those in the placebo group. Adverse events included fatigue, allergic reactions, and hypersensitivity. There were no cases of PML in this trial, which involved 3,417 patients.
  • The so-called SENTINEL trial (The Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis) compared natalizumab in combination with interferon beta-1a to interferon to placebo (N Engl J Med 2006;354:911–923). Working with a somewhat different population than the AFFIRM trial – MS patients who had experienced at least one relapse in the previous year while being treated with interferon – this study reported a 24 percent reduction in the relative risk of sustained progression of disability. The authors had previously reported a 54 percent reduction in the one-year relapse rate. SENTINEL, a 120-week trial, was halted about a month early because of two reports of PML in patients who had received both natalizumab and interferon.

In light of these cases of PML, and a third involving a patient with Crohn disease, an effort to find undiscovered cases of PML linked to natalizumab was given high priority. This independent review gave regulators and physicians a rough – some say crude – estimate of the risk of developing PML: 1 in 1,000, for patients taking it for a mean of 18 months.

In an accompanying editorial (N Engl J Med 2006;354:965–967), Allan H. Ropper, MD, Chair of the Department of Neurology at Caritas St. Elizabeth's Medical Center and Tufts University School of Medicine, said the three studies together “provide reassurance that the risk of PML is small with relatively brief use.”



“Within the limits of the retrospective method, the safety review did a good job,” Dr. Ropper said. “If there were other PML cases, there were few… With the incredible publicity in the neurology community about PML, I would have thought that if there were any other cases, they would have come to light. On the safety side, we've got the numbers within reason: The risk is 1 in 1,000.”

Dr. Ropper, who treats few MS patients, declined to say whether he thinks the FDA should approve natalizumab for commercial use. “The data are the data,” he said. “Approval is a sociopolitical process.”



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The National Multiple Sclerosis Society (NMSS), on the other hand, has praised the advisory committee's careful evaluation of the data on natalizumab. John Richert, MD, a neurologist and NMSS Vice President for Research and Clinical programs, said the challenge is to strike a balance between what is known about efficacy and risk. And that will be done largely through the risk management plan, the details of which are yet to be worked out. (See the sidebar, “An Independent Advisory Panel: Looking for PML,” page 10.)

“I'd be disappointed if the restrictions are so onerous that in practicality, it does not get used,” Dr. Richert said. “That could happen if, for example, the paperwork required of physicians is so extensive that they cannot afford the time to do it. Or the population for whom it is earmarked is so restricted that few people would be eligible to use it. I would be surprised if either of those things happened.”

What's most important, Dr. Richert suggests, is for “people with MS to have a choice in the process. The onus is really on physicians, patients, the FDA, and the companies to be sure that everyone involved in the process is well-educated about the risks and benefits. Then it will come down to an individual decision for a well-informed patient in consultation with a well-informed neurologist.”

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Eugene O. Major, PhD, a neurovirologist at the NIH who chaired the independent adjudication committee that looked for additional cases of PML, said he hopes the risk management plan – if natalizumab is approved – will require monitoring of the JC virus. “It would be disappointing if there were no recognition of our ability to monitor patients on this drug for reactivation of the JC virus,” he said.

The monitoring methods using PCR for the viral DNA in the blood, Dr. Major concedes, do not distinguish between a healthy or a sick individual who may be at risk. Some healthy people, for example, have high blood levels of virus. But there is a difference, he contends, between someone with a normal immune system and one taking a powerful drug that alters the immune system and may not be able to clear the JC infection. It might make sense, Dr. Major said, to carefully consider whether such individuals with virus in the bloodstream are good candidates for natalizumab.

Monitoring CSF is another option. “We have said, and firmly believe, that this virus is not present in the CSF of non-PML patients,” Dr. Major said. “…Presence of viral DNA in the CSF is a diagnostic criterion.” But everyone with PML does not have detectable levels of virus in CSF depending on when the CSF sample is taken and tested. Dr. Katz, of the FDA, said the agency is unlikely to require lumbar puncture because there is too much uncertainty about what CSF results mean.

David Clifford, MD, a neurologist at the Washington University School of Medicine who also sat on the independent adjudication committee, watched much of the public testimony at the FDA hearing. “The people who testified were extraordinarily moving, with many MS patients supporting it,” he said.

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The decision to prescribe or use natalizumab involves a complicated risk-benefit analysis, Dr. Clifford said. “It's not as though they have a fatal cancer, when they have MS. It's a terrible disease, but it's not rapidly fatal. It's a tough choice. There will be legal battles and ethical battles, and people weighing risks and benefits in different ways.”

Dr. Clifford supports the panel's recommendation to approve the commercial reintroduction of natalizumab. “I think people should be allowed to make a risk-benefit analysis on their own, to assess how much risk they're willing to take to deal with a disease,” he said. “We all worry that communication with patients will be incomplete, and they'll make decisions based on a flawed understanding. …I'm philosophically supportive of allowing people to take even a fatal risk, while wishing not to fuel unrealistic expectations by encouraging patients to think we have a wonder drug.”

As Director of the University of Colorado Multiple Sclerosis Center, John Corboy, MD, sees patients who are generally sicker than those treated by a typical neurologist. Among that self-selected population, he said, “I can't tell you how many people have asked, ‘When is this stuff coming back? Sign me up.’ My patients are eagerly awaiting this – some virtually demanding it.”



“I think patients and doctors perceive risk differently,” Dr. Corboy explained. “Patients perceive risk in the context of how they function every day, all day long.” Physicians, he suggested, tend to be more philosophical and abstract; they also think about what a given risk means in medical-legal terms. “Patients think in terms of what it means for them: ‘Am I going to be in a wheelchair or not?’”

The overriding issue, Dr. Corboy suggested, is “How do patients measure risk? It's going to be very individual. And patients will have a perspective that differs from the ideas of physicians, or scientists, or the FDA. Ultimately, they're the ones who have to take the risk. We have to guide them. We have to listen to them, because they're the ones taking the risk, not us.”

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Still, many questions remain unanswered. Among the most basic: Will the benefits of natalizumab continue over the long term? Will the risks increase? Will more opportunistic infections appear with time? What was it about the three patients with PML that put them at risk?

“We need more basic and clinical research to understand why this therapy allows the immune system to permit reactivation of this virus,” said Dr. Major.

Some experts think discussion about the future of natalizumab is the harbinger of debates to come. Dr. Richert, of the NMSS, for example, pointed out that several drugs used regularly to treat autoimmune disorders such as rheumatoid arthritis and lupus are potentially dangerous – even deadly. “We've been extremely fortunate so far with the treatments for MS that have been approved by the FDA,” he said. “They have been reasonably safe but that has not been true for agents used to treat other autoimmune disorders.”

In treating MS, Dr. Richert said, neurologists will have to “reformulate our view so that we think of the risk-benefit ratio with MS like rheumatologists view rheumatoid arthritis, for example. Rheumatologists have learned over the last decade or so to educate themselves about risk and deal with the risks and benefits on an individual basis. I think we will need to follow suit in our treatment of MS.”

Those greater risks, Dr. Richert told the FDA panel in early March, “need to be weighed against the risk of doing nothing.”

Dr. Clifford calls natalizumab “a brilliant job of biological engineering.” “It was a tremendous translational achievement to recognize the importance of inflammatory cells entering the brain and to develop a monoclonal antibody to block it,” he added. “There's an elegance to this new science that I find pleasing. But at the same time, the normal process we interrupt is there for a reason. When we interrupt normal processes, it has consequences. PML is one of those unintended consequences.”

As researchers continue to develop highly targeted therapies, Dr. Clifford said, “We're going to uncover tough problems. My hope is that the FDA and the public do not throw the baby out with the bathwater” – that is, they don't preclude development of effective treatments of MS for fear of risk.

“In the process of drug development,” Dr. Clifford added, “we have to go through this process. We cannot make computer models of disease to the extent that we can completely avoid these tragic problems.”

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At the public hearing of the FDA's Peripheral and Central Nervous System Advisory Committee in early March, natalizumab's makers, Biogen Idec and Elan Pharmaceutical, outlined a proposed risk management plan. Although details of that program are yet to be worked out – the FDA announced in late March that it was delaying its final decision on natalizumab for that purpose – the plan will likely include:

  • A mandatory registry of all patients taking natalizumab.
  • Both physicians and patients will have to sign information/consent forms.
  • Checklists designed to be sure that patients at greatest risk of PML do not received natalizumab. It will be a Web-based system linked to Biogen/Elan's drug distribution centers, with questions for both doctors and infusion centers.
  • Patients, physicians, and distribution centers that do not fill out checklists will not be allowed to take, prescribe, or distribute natalizumab.
  • Physicians must evaluate patients for signs of PML at stipulated intervals (three months, six months, and every six months afterwards).
  • Ongoing monitoring to track the risk of developing PML.
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Soon after use of natalizumab was halted in February 2005, the FDA and natalizumab's makers, U.S.-based Biogen Idec and Dublin-based Elan Pharmaceuticals, together formed a committee to conduct a systematic search for unidentified cases of progressive multifocal leukoencephalopathy (PML). The Independent Adjudication Committee (IAC) consisted of Eugene O. Major, PhD, a neurovirologist at the NIH with expertise in PML and the JC virus; David Clifford, MD, a neurologist with a special interest in HIV and other viral infections at the School of Medicine of Washington University in St. Louis; and Tarek Yousry, Dr.Med.Habil., a neuroradiologist at the Institute of Neurology in London.

Although Biogen and Elan funded this research and helped collect data, the committee functioned independently. Physicians employed by the companies, for example, participated in discussions but could not vote and were excluded from closed sessions of the IAC.

All 3,417 patients who had received natalizumab in a clinical trial – whether for multiple sclerosis, Crohn disease, or rheumatoid arthritis – were invited to participate in this follow-up study; 3,116 (91 percent) agreed to do so. Letters were also sent to physicians who had prescribed natalizumab outside of clinical trails, advising them to evaluate patients for signs of PML and inviting them to refer potential cases to the IAC.

The committee asked all physicians to conduct a structured evaluation, including a neurological exam, of every patient who had been given natalizumab. Doctors were also asked to arrange for an MRI scan of the brain, and, when possible, to collect samples of CSF.

All MRIs were sent to a reading center for review by an experienced neuroradiologist. Two NIH labs independently tested each CSF sample for the JC virus.

All cases in which there was possible evidence of PML were sent for review to the IAC, which reviewed a total of 44 cases.

The committee concluded that there were no undiscovered cases of PML among patients who had received natalizumab.

Based on existing figures – three confirmed cases of PML among 3,116 individuals – the committee estimated the risk of developing PML at roughly 1 in 1,000 for patients taking natalizumab for a mean of 17.9 months. “The risk associated with longer treatment,” the authors wrote, “is not known.”

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  • ✓ An FDA advisory committee voted unanimously to recommend that the pharmaceutical companies be allowed to resume commercial sales of natalizumab, albeit with stringent restrictions. But the FDA delayed a final decision until a risk management plan is in play. Experts provide a window into the thinking behind the advisory panel decision.
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• Polman CH, O'Connor PW, Sandrock AW, et al, for the AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899–910.
    • Rudick RA, Stuart WH, Sandrock AW, et al, for the SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911–923.
      • Yousry TA, Major EO, Clifford DB, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;924–933.
        • Ropper AH, Selective treatment of multiple sclerosis. N Engl J Med 2006;354:965–967.
          ©2006 American Academy of Neurology