Sunday, 9 March 2014

FDA's rejection of alemtuzumab divides neurologists

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?"

CoI: multiple


  1. FDA has probably forgotten its past evaluations of products approving products with obvious unmasking.
    A recent example with Tecfidera : patients not experiencing a flushing have only a -30% decrease in relapse rate instead of 50%
    This information is available in the FDA evaluation,.why not in the SPC ?

  2. How many of the signatories of the letter to the FDA have conflicts of interest? I bet most of them have links to Genzyme.

  3. So, if the trial was run with alemtuzumab and placebo instead of interferon it would have been approved. Those that wanted to be in the trial would have failed interferon already, so using a placebo would be just as bad as interferon. But the msers were taking the chance to get on alemtuzumab. If I were in this position I would take the chance on a placebo controlled trial since it might help me know and I would be instrumental in getting it approved at paying it forward. If the trial could not have been blinded it should have never been initiated.

  4. The question is how do you truely blind studies. So many of the drugs have characteristic side effects that can reveal themselves. They unlike their competitors went head to head with an active comparitor in their pivotal trials. Now this has to be the norm as their is no excuse to have people on placeboo, yet pharma still find ways to do this by moving eastwards where curent therapies are unavailable, It is now not going to be which drug is better as they will all be much or a muchness and the drug with the better side effect profile will be better recieved. However this situation means that it keeps certain drugs in the likelight. Who wants to inject themselves daily with a useless placebo just because you have to do a head to head with say glaterimer acetate.

    Furthermore this problem means that trials cost so much extra you have to make plastic injectors doing nothing this costs massive amounts of money, You have an induction therapy of 5 intravenous injections plus a course of steroids verses the injectables throughout the year. Now that aubagio is licenced this is a lower hanging fruit agaist which future trials will be based as eating useless capsules for three years is easier to do than have ateo to three years of self injections. The FDA were fully awareof the phase II data the question has to be how did they allow fingolimod and tecfidera and aubagio to go against placebo when you had the beta interferons and glaterimer acetate available which was know to works where is the ethics in that. However putting your drugs against or worse on top of an active drug means it will be harder to find an effect. So here is the problem we will keep relatively ineffective drugs in the pharmacopia because they are difficult to knock of their perch.

    1. If you have to compare this drug to an existing therapy I don't think interferon is it. It seems like Tysabri would be more appropriate, though I don't know who makes both drugs. If I had highly active disease I would rather go on Lemtrada than Tysabri, but since I am doing good on GA, I would choose neither at this point. This drug should be targeted for the right ms patient, but with the available drugs for Ms this could be difficult. You cannot continue developing new drugs indefinitely for MS and expect them to be all approved. And you won't be able to tell which is the best drug based on a two year study.

    2. If you are a company you would not put your David against a Goliath unless you think it can win putting say tecfidera against tysabri and the efficacy of tysabri would probably look better. So not a got marketing ploy for tecfidera.

  5. How many signatories?. There is transparency just look.


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