The FDA’s decision on alemtuzumab stimulate neurologist activism! #MSBlog #MSResearch
“If you have been following the alemtuzumab rejection by the FDA story you will find this letter in the Lancet of interest.”
…. Has the US Food and Drug Administration asked for an impossible trial, or protected patients with multiple sclerosis from a drug with unknown benefits and clear risks?…
….. “I think it was a very disappointing decision”, says Richard Rudick, director of the Cleveland Clinic Mellen Center for Multiple Sclerosis. Rudick advocated for alemtuzumab on behalf of Genzyme at an advisory committee meeting in November, but says he donated his consulting fee to a charity…..
…. 70 clinicians, both with and without ties to the drug, have also signed an open letter to the FDA calling on the agency to reverse their decision. They argue that the CD52-targeting antibody—which depletes the lymphocytes that may drive the autoimmune disease—offers compelling efficacy and manageable toxicity for patients with few therapeutic options…..
…… But not everyone is convinced, and longstanding clinical trial design issues lie at the heart of the FDA’s rejection. FDA reviewers argue that the pivotal trials were vulnerable to bias because Genzyme ran open-label trials in which patients knew which drug they were on while neurologist raters were blinded. The setup, said FDA officials at the advisory meeting, could have skewed the baseline characteristics of the control and active groups (dropout in one trial was 12·6% in the control group and 2·3% in the active group). Clinical outcomes in multiple sclerosis are “highly subjective”, they added, and are susceptible to inadvertent or deliberate distortion from unblinded patients. If 6% of the interferon-treated control patients over-reported their symptoms (inadvertently, or because they had previously failed on interferon and wanted to be switched to a new drug) and 10% of alemtuzumab-treated patients under-reported their symptoms (perhaps because they had high hopes for alemtuzumab and didn’t want to be taken off the drug), the treatment-experienced pivotal trial can be written off as a false-positive result, showed one FDA analysis…..
….. “I personally support the FDA’s decision”, Dennis Bourdette, director of the Multiple Sclerosis and Neuroimmunology Center at Oregon Health & Science University, tells The Lancet. “The considerable toxicity of alemtuzumab renders it inappropropriate for treating most patients with MS.” The drug’s risks include the potentially fatal immune thrombocytopenia, Graves disease, and opportunistic infections…..
….. Nathan Fountain, a neurologist at the University of Virginia School of Medicine who was chair of the November independent advisory panel, hopes that there is room for compromise. “It would have been wrong to approve the drug as a first-line treatment for MS”, says Fountain. “But for more aggressive disease, or for second line therapy, an approval would have been reasonable.” …..
….. Without some resolution, however, the community remains stuck in a bind. “The single-blinded design has its downsides, there is no question about it”, says neurologist Olaf Stüve of VA North Texas Health Care Systems. “But while you can design a double-blind study on paper, it’s not feasible to run it.” Alemtuzumab and interferon have different dosing schedules and different adverse event profiles, he explains, which would effectively unmask blinded patients…..
…. Even if trials were run only against a placebo comparator, or against an active comparator with placebo injections to make up the differences in dosing regimens, injection-site reactions could unmask participants. So what do you do when the FDA’s need for reliable data conflicts with the practicalities of running trials? With the MS specialty moving towards embracing active-comparator trials, the difficult question is particularly pressing. “It was a very complex decision”, says Stüve. “It’s hard to say whether they made the right or the wrong choice.”…….
“What do you think?”