Friday, 7 April 2017

#NeuroSpeak: is Prof G losing his marbles?

Why is the neurology community so sceptical about NEDA? #NEDA #NeuroSpeak #MSBlog

I am currently on a lecture tour of several academic German neurology centres and was told by one of my hosts that ‘NEDA’ was a marketing gimmick and term invented by the Pharmaceutical industry to sell DMTs. I was informed that this was widely held perception amongst German neurologists. I was taken aback and had to inform my host that this information was incorrect and that in fact I had been partially responsible for coining the term NEDA and helping promote the concept as a treatment target for MS. The observation that Pharma had adopted the concept, and is actively promoting it, is not necessarily a bad thing; that is if you accept the data that pwMS with NEDA do better than pwMS who have ongoing evident disease activity (EDA). It is clear that Pharma have much more reach in terms of disseminating information than academics. Your response to the latter depends on your worldview; if you think Pharma is all-bad, and what they have to say is all-evil, then nothing I am going to say will make a difference.


A brief history of NEDA

In short NEDA replaced the term DAF.

The germ of the idea of replacing DAF (disease activity free) with NEDA (no evident disease activity) came to me at the first DAF meeting held at the Cleveland Clinic in September 2012. At this meeting Ted Phillips gave a talk that was entitled ‘Disease free status, complete disease control, and disease remission. What can we learn from other medical fields (e.g. oncology, gastroenterology, or rheumatology?)’. In this talk Ted spoke about the oncology terms NEDD (no evidence of detectable disease) and MEDD (minimal evidence of detectable disease). Ted explained that oncologists had replaced using the term ‘cure’ with NEDD simply because too many of their patients had come back with recurrent disease despite being told they had been cured. NEDD was a term that referred to the here and now and did not really make unrealistic predictions about the future. MEDD was used to describe disease that was only detectable with molecular techniques (DNA sequencing via PCR), when disease was not evident using conventional methods (imaging and histology). It was clear that NEDD was not set in stone and could evolve as new technologies emerged. 

After the Cleveland Clinic DAF meeting I realised that DAF was clearly an unsuitable term and implied that we knew everything we needed to know about MS disease activity, which clearly we do not. Therefore we needed a better term.



The first opportunity that I got to pen my thoughts on these issues was in late 2012 when it was my turn to draft the Editors’ welcome for MSARDS. The following is the exact paragraph I wrote:

Banwell B, Giovannoni G, Hawkes C, Lublin F. Editors' welcome and a working definition for a multiple sclerosis cure. Mult Scler Relat Disord. 2013 Apr;2(2):65-7. 

‘Defining a cure in MS is a difficult task. How long should we wait before declaring a victory; 15, 20 or 25 years? Oncologists have back-tracked on this issue and instead of a cure they now prefer to use the term NEDD, or no evidence of detectable disease, at a specific time-point knowing full well that a limited number of subjects will relapse and present with recurrent disease after this point. We propose using the term NEDA, or no evident disease-activity, at 15 years as a starting point for defining a cure. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a usual end point. In addition, the median time to the onset of secondary progressive MS is 10.4 years (Kremenchutzky, Rice et al. 2006) and is well within the 15 year time window of our proposed definition of a cure. At present NEDA is defined using a composite of a) no relapses, or b) no EDSS progression, or c) no MRI activity (new or enlarging T2 lesions or no Gd-enhancing lesions) (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). This description is currently based on data that is routinely collected in contemporary clinical trials (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). The definition of NEDA will evolve with technological innovations and clinical practice, and in the future it will almost certainly include patient-related outcomes (PROs or PROMS), grey matter disease activity and an index of brain atrophy.’

Shortly after the publication of the MSARDs Editors’ Welcome, and my ECTRIMS 2012 highlights paper in the same issue, Rick Rudick emailed me to say he liked both pieces and agreed with our reasoning to use the term NEDA rather than DAF. When Rick and Robert Bermel arranged the second Cleveland clinic meeting, this time in Las Vegas, they adopted NEDA and called the meeting ‘No Evidence of Disease Activity as a treatment target in MS’. I was given another platform at this meeting and used my talk to explain to the audience why we had changed the terminology from DAF to NEDA.

I don’t recall any dissenting voices at the meeting and I would say that this meeting was when the wider community adopted and started using the term NEDA. Although there were a few Pharma representatives at the meeting they didn’t comment on the issue, and at no time did they play a role in the formulation of the term NEDA. In reality the term NEDA is plagiarised from NEDD, which came from oncology.



A similar argument can be made for treat-2-target; this term was coined and popularised by rheumatologists and subsequently adopted by several other disciplines before embedding itself in the modern MS lexicon.

In comparison, the term DAF was first used in the post-hoc analysis of the natalizumab vs. placebo phase 3 trial (AFFIRM Study) and again in the post-hoc analysis of the oral cladribine vs. placebo trial (CLARITY Study). As both these studies, and analyses, were industry-led it could be argued that DAF as a concept was Pharma driven.

Havrdova et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol. 2009 Mar;8(3):254-60.

Giovannoni et al.  Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurol. 2011 Apr;10(4):329-37. 



I suspect is because of these two trials that the misconception has arisen about the source of NEDA. 

I think this episode illustrates how resistant neurologists are to adopting tried and tested treatment principles from other disease areas. The real question that we should all be asking ourselves is why wouldn’t we want to adopt NEDA as a treatment target in MS? Does it take too much effort and time to monitor our patients? If you had MS would you want ongoing inflammation in your brain? 

I have had a very hard time coming up with a list of diseases where we have effective disease-modifying therapies that you wouldn’t want to suppress all evidence of disease activity. The only diseases I have come up with is prostate cancer in older men, where the treatment of the disease may be more severe than the disease itself, and in end-stage malignancies, which have become resistant to currently available treatments. Even in the field of psychiatry the treat-2-target NEDA paradigm makes sense; would you be satisfied with a little residual psychosis or depression? 

Why would we want MS to be one of the exceptions to the rule? Or may be I am losing my marbles?

CoI: multiple

14 comments:

  1. Prof G this is not only a German phenomenon. I think the same attitudes exists in the UK. Don't let them get you down, keeping doing what you are doing, we appreciate your efforts.

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  2. Slow to treat and what seemed to be the automatic application of the escalation approach means, you know what ProfG, that I was actually pleased to have a second relapse within 6 months and then 3 months later an MRI showing a new lesion because it gave me access to Alemtuzumab. Even then the neurologist local to me was saying that their view was that I'd be OK on a category one drug. And yes I get disturbed when I read your posts about the damage caused in just my kind of circumstances and yes I'm that bit more disabled in my walking capacity due to the second relapse, but I've actually found myself saying to people 'Thank god I had it!' Crazy that,isn't it?! But the idea of TTT and NEDA, which to me are so startling obvious, as is treat someone ASAP is so far removed from the reality on the ground! I was pleased to read your post this morning, putting all this in a helpful summary and normally I'm the positive person, grateful to have the NHS and access to Alemtuzumab and the drive and determination to help myself as much as possible. But, if we can make so much progress in oncology and other areas why aren't we with MS?? Is it because society doesn't get just how evil it is and the medical world reflects this? New movie 'The monster calls' about a mother dying of cancer. The irony isn't lost on some of us that the actor playing her son, being heaped with praise for his role, lost his own mum to MS three years ago, when he was 11 and she was 53. Please keep up the good work and please keep trying to get across the key message in this post to your colleagues out there.

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    1. The licence for alemtuzumab is very liberal and there only has to be evidence of activity so not need for relapses had lesions should do it.

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  3. Maybe we should make a word LBN lazy blumming neurologists. People who can't be bothered to read and assimilate and are quite happy to prescribe and stick with drugs just becuase they are easy and require no monitoring by the LBN

    They are probably rolled out to ectrims by sponsors as a reward for supplying a the low efficacy treatments.
    Maybe cladribine could be the new answer for the LBN. A few treatments a year and few monitoring requirements.

    It will be a shame if Merck have not gone for and get a first line licence.

    I'm not convinced this is the space they are aiming at.

    The LBN won't know the history and with the right marketing they could become number one. I can see slogan now. Cladribine for the lazy assed laggard.
    Actually LAL may be a better description:-) only an idiot can think having brain lesions is a good thing.

    Maybe the only thing they read was about neuroprotective autoimmunity....

    I find posts like this so depressing and frankly embarrassing that this is the state of the medical profession.

    Yes some will say it is embarrassing that I speak this way. I can live with the embarrassment, i don't people paid to abuse people seems that some neurologists do.:-(

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    1. Righteous comment there MD. I too was dumbstruck reading the above post.

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    2. Lol. It almost seems like the MS neurologists are waking up from a lifetime academia to a world populated by patients.

      As for only an idiot can think having brain lesions is a good thing...

      'it’s only a small enhancing lesion'
      'my neuro said I’ve only got 5 new lesions from when I started xyz 2 years ago'

      and finally, according to the mayo clinic, "Some people have such mild symptoms that no treatment is necessary."

      http://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/diagnosis-treatment/treatment/txc-20131903

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    3. Yes, some pwMS do end up having benign MS. It is probably in the order of 5% in hospital-based populations.

      The debate is whether or not you under-treat everyone so as not to over-treat the group of patients destined to have benign disease, or do you over-treat the patients with benign MS so as not to under-treat the majority of patients with non-benign MS.

      If you treat someone with benign MS with a DMT and they become NEDA then you have to assume it is the DMT that is doing it and not the natural history of the disease.

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    4. It is not a debate.

      It is a hole in the medical knowledge.

      If you don't know, spell out the pros and cons and allow patients to make a decision.

      "Some people have such mild symptoms that no treatment is necessary." is advice. Given that no neuro can predict in any given individual how long any symptoms will remain mild or not for their life, the advice given to patients cannot be "Some people have such mild symptoms that no treatment is necessary."

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  4. I don't know what my prognosis is (this post indicates it's not great) or what treatment is suitable for me. I only know that GA made life painful and difficult and that reporting symptoms was not to be encouraged and patient education not on the agenda. I am standing on the outside, looking in, and wondering what to do and whether there is anyone that actually delivers any of the content in this post or can be bothered with anything more than 'shut up and take the drugs'. If there is I would appreciate a consultation, but how do you find them?

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  5. Yes we are bad pharmas, some more than others.
    Yes for marketing (or greed) reasons we do try to evaluate our drug in a "cure" perspective and use acronyms helping to quantify "how close to a cure we are". This is done in all therapeutic domains.
    NEDA is very important in MS, guiding patients and neurologists for appropriate follow up and in treatment decision. Wether or not it is invented by pharma is a worthless debate, it helps the MS patient population to fight their disease best. Lazy neurologists can complain, to achieve NEDA is more work and more expectations from patient. Yes is it hard to achieve, time-consuming and stressful as more high risk DMT are to be used. Lazy neurologist or the one fighting NEDA probably just do not want to take this challenge... Don't waste your time and continue to promote NEDA !

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  6. I've taken copies of your posts in to my neurologist, asking them to read. I don't have access to a MS specialist, so I feel his lapses are due to not enough time to get smart on MS when he's dealing with General Neuro problems as well. What does drive me crazy is that he's doesn't read the posts!

    I honestly feel I know more what I should be doing for my disease then he does.:(

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  7. This post brought a whole new meaning to TED talk!

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  8. Great text!

    In consultations unintentionally sometimes I use the term NEDA and has the residents in neurologist that makes the expression that doesn't know what I'm talking about. And this is here in Brazil, just as it is in Germany.

    The problem is in the dissemination of knowledge and how it is interpreted and becomes a tool within the academic routine itself.

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