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?
Labels: #NeuroSpeak, Cleveland Clinic, Germany, NEDA, treat-2-target