What did the FDAand EMA have to say about Alemtuzumab

What did the FDA have to say  (Click here) read the report for yourself, it is 370 pages

They saw something that the EMA (Click here) Didn’t, 
it is 116 pages

                         One aspect appears to be more tumors 
                                      and extra thyroid tumour 

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  • "There were 6 (0.4%) cases of thyroid cancer in 1485 alemtuzumab-treated subjects (Pool C). In
    Pool E there were no cases in IFNB-1a subjects."

    This is pretty high incidence, isn't it?

  • With inadequate evidence to suggest that alemtuzumab prevents progression of
    disability and with potentially biased evidence for a reduction in relapse rates, there is
    doubt that the risks of alemtuzumab outweigh any benefits. So what does this tell us ?

    Regards as always

    • I think there's doubt that alemtuzumab provides any benefits whatsoever, nevermind the risks. If the FDA believes none of the three studies can be relied upon, then what statistically valid proof do we have? Certainly not enough to prescribe it.

    • There is no doubt that alemtuzumab provides some benefit….there are enough MSers here to testify to that. However, the trials were unblinded because you either got beta interferon or alemtuzumab so the perceived quality of the trials reduced and bias is introduced.

      However, surely it is no longer ethical to do placebo trials in RR MS, so the control group needs to be an active drug. At the time that meant the injectables or natiluzimab. Natalizumab adds to cost and also you drug would not look as good,so you pick the low hanging fruit the injectables as they are not that efficient. Therefore you score by showing your drug is better which is good marketing. However, existing MS companies making injectables have a factory making plastic injectors that can be filled with placebo. A new kid to the block does not have that manufacturing capability so it will add to costs to do this and who wants to jab themselves in the leg needlessly for two or three years.

      I guess in future companies with target aubagio as the low hanging fruit as it is cheaper to make a dummy pill than a plastic injector.

      You seem to come from the Dr. Dre school with regards to MS drugs.

    • "There is no doubt that alemtuzumab provides some benefit….there are enough MSers here to testify to that"

      Interesting how anecdotal evidence all of a sudden can be used to support unproven claims.

  • Incidence and incidence rate of treatment-emergent malignancy in female and U.S. demographic subgroups. All alemtuzumab subjects (Pool C)

    All subjects
    22/1485 (1.5%)

    All female subjects
    21/972 (2.2%)

    U.S. subjects
    15/555 (2.7%)

    U.S. female subjects
    15/397 (3.8%)

  • Is occurrence of secondary autoimmune diseases common to most immune reconstituting drugs? Is this the reason that immuno-suppresors are used?

  • Not to my knowledge it is unusually high in MSers.
    This does not appear to be a problem with cladribine that similarly depletes white blood cells but it does not appear to cause an overshoot of b cells when cells repopulate after treatment

  • I received alemtuzumab in a trial 8 years ago and have done very well ie no relapses since first infusion. I did get Graves disease, had my thyroid destroyed and now on thyroxine (no big deal). What's worrying about the FDA assessment – they question whether the drug has any effect and highlight cancer concerns cases. Both Prof G and Dr Coles have received consulting fees from Genzyme in relation to Alemtuzumab. However, both have remained silent. As ever Prof G is on a foreign trip (no wonder NHS waiting lists are long to see a neuro). Why have both remained silent? As someone who took the risk of taking the drug on a trial ( my choice), surely I'm entitled to hear their views on the efficacy and safety of the drug. Why do they think the FDA has taken a different stance to the EMA? I've always been a supporter of the hit hard and early approach. But I need someone to tell me who is right and wrong here.

    • I am sure they will speak in due course. Any drug that removes large parts of your immune system carries a risk of tumours because the immune system deals with them.

      In virtually all trials there are cancers that are seen, because they do occur naturally. The question is what is the increased risk.

      As you have the drug 8 years ago it is probable that your immune function has returned by now and it should be able to fight cancers The unusual cancers in the trial were the thyroid cancers and as it was destroyed I suspect the risk of these cancers gets destroyed too, although I do not know precise details. Someone more qualified than me needs to answer this.

      P.S.Just because you get consulting fees from company X, Y or Z does not mean that you know everything that the company knows. In trials it is companies who have control of the data and collating the monitoring

    • Mouse, thanks for your response. My issue isn't with you. But as a trial recipient and having followed the subsequent trial results, I thought there was very good evidence of the effectiveness of this drug (I'm in contact with two others who received campath and have seen the same results as me). Dr Coles was a Principal Investigator and Prof G was heavily involved in the trial (I know both and trust both). I'm therefore surprised that the FDA can question whether the drug has any effect and raise concerns that it is seriously dangerous / sometime fatal. If these claims are false then surely the Cs in Cambridge and Prof G should be issuing a response. As i read it cold, the FDA sre insinuating that the efficacy figures were made up, trial design was biased and the investigators were charlatans ( if the first two claims are right). Surely this is an attack on their academic standing? In any other business those being attacked would get their press office working hard on a rebuttal. I also worry that the EMA will reopen their assessment given the FDA claims. Lots of people with MShad high hopes for this drug – as ever those with the disease are the losers.

    • The FDA can question anything and the fact that the trial was not blinded adequately has been a real cause for concern and the issue for bias is there.

      I do not know if it was the EMA or FDA who agreed to this design before it was done, maybe it was the EMA?

      You have to remember the trial was done by Sanofi/Genzymne and not Coles/Giovannoni, yes they may have had some influence on design, likewise they may not the Company is King, but the data collection and handling is done by the company. Likewise the C's from Cambridge are at the mercy of the participating sites about the quality of data they collect and report for the phase II they would have more control than phase III and the phase II data was much better. I know that our site has been audited by the FDA as part of their preparations for the meeting, I believe there was nothing untoward in anything.

      If the C's did not believe in the efficacy they would not have pursued the drug over the 30 years they have spent on the programme and it is not without issues (a) Worsening of symptoms on infusion that occurred (b) ITP deaths (c) Autoimmunities, is this Gung-Ho or belief. The issues with Cladribine are a lot less and that got rejected.

      As to issuing a response, it is really the job of the company to do this.

    • It was obviously the EMA that approved the trial design the FDA wanted a double blind trial, their view on this is now clear to me the reviewers were calling for more trials.

    • Mouse Doctor has asked me to reply to the posts about the FDA's postings about alemtuzumab. I can understand the concerns people are raising.

      The FDA's preliminary assessment of alemtuzumab was more critical and more negative than any other independent review of the drug. You might want to compare it, for instance, with the detailed reports examined by NICE (http://guidance.nice.org.uk/index.jsp?action=byID&o=14060) or the European regulatory authorities (http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003718/human_med_001678.jsp&mid=WC0b01ac058001d124).

      All of these independent bodies have looked at the same evidence and come to very different conclusions. So, there must be a degree of subjectivity about their assessments. There are two main differences. Firstly, in their different attitudes to the design of the trials. The first FDA assessor is not happy with the way we compared alemtuzumab with interferon beta 1a. Secondly, the FDA's safety reviewer has taken a different approach to examining alemtuzumab's safety data from previous reviewers. It is not appropriate for me to go through the details of the arguments, just at the moment, because these are "sub judice" but I want to just make these points:

      1. Several years ago, we discussed the design of the alemtuzumab trials with the FDA at a face-to-face meeting. The FDA approved the trial design then.

      2. So far, we have not heard the "last word" from the FDA. We await the response of the main FDA committee to the reports that have been written and the advice they have received from experts. It is only fair to wait until the FDA have come to a conclusion.

      You can read the trial results yourself, and other papers written on alemtuzumab, at our website here:

      It is perfectly true that I have received honoraria from Genzyme (and some other companies). That is in the public domain. I choose to pass these on to my favourite charities.

      Alasdair Coles

    • So there you go. I thank Dr Coles for a swift response, There is no blood money trail, but a clear desire to help people with MS.

  • It seems the FDA is reluctant to approve alemtuzumab but they seem obligated due to the lack of highly effective therapies. They state that it should only be an option for highly active disease. What does this mean exactly? If a patient is "highly active" meaning they are deteriorating or have many exacerbations wouldn't immune suppression with short term steroids be prescribed? It seems they are saying "We will approve it because unfortunately there are no other options and we don't want the backlash from frustrated patients."

    • Don't see why they are obliged to do anything. I would say Cladribine had similar side effect issues. perhapsless so and they did not approve that

  • Do you have pdf links for similar committees reports for Gilenya, BG-12 and cladribine, natiluizimab? i
    It will save some hunting?

  • Gilenya's briefing package is below. You'll note that very much unlike Lemtrada, the FDA reviewers don't draw conclusions, just questions for the committee. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM214670.pdf

    Cladribine was rejected without a committee meeting, so there's nothing on it that I can find.

    BG-12 didn't have a committee review (it wasn't "on the fence"), so you've just got the final approval documents. Locate them by going to the FDA's drug search page: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Type in Tecfidera and click on the "Approval History" link.

    Aubagio was also approved without a meeting, so follow the Tecfidera instructions.

    I'm not sure if Tysabri had a review back in 2004, so use the Tecfidera instructions to see the approval package. Same goes for the platform therapies, and I think that covers all the MS drug options.

  • I thought I'd add to the debate about this drug that has been waging on various posts over the last couple of months.

    I have very recently had my first year's dose of Alemtuzumab. I am relatively newly diagnosed (1.5 years since my first symptoms and abnormal MRI). I have a low lesion load and no permanent symptoms. Such symptoms I do have are 'grumbling' – and any relapses, if you could call them that, non-disabling, more just irritating and pyschologically stressful as a reminder of all not being well internally, so to speak. My MS is however active – in that I have had new lesions in the 1.5 years since my initial MRI. Despite being entirely 'normal' in terms of functioning, I took the decision, along with a neuro who thankfully adopts an 'informed' patient choice apporoach, to use Alemtuzumab as a first line treatment. Why have I done this? In my mind, life is a numbers game. Despite my current relatively 'well' state, the odds of staying that way for 10, 20, 30 years are not great (although it is more of a possibility than some of the MS dooom-mongerers of this forum would like newly diagnosed people to believe). Taking Alemtuzumab adds some other negative factors into that equation at varying degrees of severity/likelihood but, equally, it moves the MS-disability odds further in my favour. Does it guarantee anything? No. Might my MS have been fine without this or might it still end up severe even though I've taken it? Yes. But it's about playing the odds. Examining the data for yourself with professional help to interpret if you need it and deciding what is right for you and your family. Personally, for me, the risks are worth it for the benefits the data shows. For others, they won't be. But that should be your informed decision, not the FDAs. I don't buy the issue with the non-blinded nature of the trials – you can't placebo MRI outcomes (well, maybe, on some level, you can but that's a whole other debate). Based on what I've read, studies and anecdotally, if every newly diagnosed MS patient with actiive disease to Alemtuzumab as the first opportunity, the impact of MS on a macro scale could be hugely reduced. I would venture so far as to guess (and it can only be a guess) that wheelchair use from MS (as an important 'marker' for people in quality of life) would be virtually reduced to only the most very serious/long-term cases.

    I believe Alemtuzumab offers me the best chance of remaining well far into the future and having a stable, 'benign course', of MS and, properly monitored, believe the serious side-effects can be caught and treated. If it doesn't work as well as hoped, I'll see what else is around when that point comes and, again, make an informed choice on the basis of available evidence. There are no guarantees either way and anyone looking for them from any drug, let alone drugs for a condition as poorly understood as MS, is foolish. That's life – you roll the dice and you take your chances, but you should be the one doing the rolling, not a patronisingly paternalistic neuro and not the FDA.

  • Perhaps the FDA should approve Lemtrada with a label that lists the side effects and says:

    "Sanofi has done a tremendous job of creating hype among MS patients and doctors based on faulty clinical trials. It is impossible to tell how well it works, and thus impossible for patients or doctors to make any type of informed risk/reward decision. While the entire purpose of our agency is to keep pharma companies from deluding patients and profiting from them (and believe us when we tell you this is happening ALL the time), we are sick of being labeled as stodgy paternalistic morons. So go ahead, take Lemtrada. It might work for you, it might kill you, it will very likely give you serious side effects. We'd also like to send a message to all the other pharmaceutical companies out there – feel free to completely ignore our advice on structuring your clinical trials for 10 years. It's a lot more profitable to engineer the data as you like, pay doctors to promote it, and convince patients that you are the angels and we are the devils. Good luck everyone, we're going on holiday."

    • Anon 7:00- you are far too emotional in your arguments in support of the FDA.
      1.'faulty clinical trials'- please look at Dr. Coles answer above of 19th Nov- the FDA approved the trial some years back. There is also the question of the ethics of giving someone a placebo for a couple of years when there is a treatment out there.
      2. 'it might kill you'- a possibility with many licensed drugs for various reasons under various circumstances- even paracetemol
      3. 'it will very likely give you serious side effects'- upto 20% may get an autoimmune disease- not pleasant and it may be serious, or it may be very treatable. To me 'very likely' means over 50%.

      You claim to work for the FDA- come out from behind your anon. It sounds like you need a holiday

    • What warped, bitter, anti-pharma garbage. The trials provide a lot of information, regardless of perceived flaws, as does the clinical experience of neuros who have used Alemtuzumb – often to good effect. Fatalaties from Alemtuzumab under properly monitored patients are zero. Serious side effects are not 'very likely' – 1.5% for ITP and c. 25% for thyroid complications of varying severity. Without pharma there would be no treatment for MS – is that what you want? There are many valid arguments over their pricing strategies etc but there are real possibilities of major advancements in MS, even a cure, over the next decade but perhaps you'd prefer the next generation not to benefit from these because you haven't been able to? Who knows what agenda you have but it strikes me as distinctly unpleasant.

    • There are a few drugs that put your rate of brain shrink down into the ball park of the normal aging process, guess the name of one of them….this is rhetorical.

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