Sunday, 25 June 2017

The Burden of Multiple Sclerosis

This study examines the cost of MS in different European Countries if you go East the amount spent on people with MS is lower. However you can see that the costs are not harmonised across Europe. 

In the UK the cost is low. Is this because of efficiency or are we near the bottom of the pile (yes you could add about 10-20%  to get a fairer view, because I used todays exchange rates).

Switzerland is out in front on the amount it spends

Multiple et al. New insights into the burden and costs of multiple sclerosis in Europe Mult Scler. 2017 Aug;23(2_suppl):4-216

BACKGROUND:To assess the value of management strategies in multiple sclerosis (MS), outcome data have to be combined with cost data. This requires that cost data be regularly updated.

OBJECTIVE AND METHODS: This study is a cross-sectional retrospective study in 16 countries collecting current data on resource consumption, work capacity and health-related quality of life (HRQoL). Descriptive analyses are presented by level of severity; costs are estimated in the societal perspective, in 2015

A total of 208 patients (mean age: 38.5 years) participated in the Russian study; 97% were below retirement age, and of these, 49% were employed. MS was reported to affect productivity at work in 63% of patients. Overall, 87% and 41% of patients felt that fatigue and cognition were a problem. The mean utility and costs were 0.769 and 578,000 RUB at Expanded Disability Status Scale (EDSS) 0-3, 0.509 and 826,000 RUB (€12,407) at EDSS 4-6.5, and 0.071 and 1,013,000 RUB (€15,214) at EDSS 7-9. The average cost of a relapse was 33,000 RUB (€496) 

A total of 747 patients (mean age 47 years) participated in the Czech Republic; 86% were below retirement age and of these, 49% were employed. Employment was related to disease severity, and MS affected productivity at work for 82% of those working. Overall, 92% and 66% of patients experienced fatigue and cognitive difficulties as a problem. Mean utility and annual costs were 0.832 and 257,000CZK (€9,776) at Expanded Disability Status Scale (EDSS) 0-3, 0.530 and 425,500CZK (€16,183) at EDSS 4-6.5 and 0.141 and 489,000CZK (€18,606) at EDSS 7-9. The average cost of a relapse was estimated at 12,600CZK (€480)
A total of 521 patients (mean age 47 years) participated in Hungary; 85% were below retirement age, and of these, 47% were employed. Employment was related to disability and MS affected productivity at work for 82% of those working. Overall, 94% and 66% of patients experienced fatigue and cognitive difficulties as a problem, respectively. The mean utility and annual costs were 0.691 and 3,432,000HUF (€11,0680) at Expanded Disability Status Scale (EDSS) 0-3, 0.491 and 5,262,000HUF (€16,970) at EDSS 4-6.5 and 0.076 and 6,235,000HUF (€20,108) at EDSS 7-9, respectively. The average cost of a relapse was estimated at 240,500HUF (€776).


A total of 779 patients (mean age = 57 years) participated; 72% were below retirement age and of these, 36% were employed. Employment was related to disease severity, and MS affected productivity at work for 84% of patients. Overall, 96% and 72% of the patients experienced fatigue and cognition as a problem. Mean utility and annual costs were 0.735 and 11,400GBP (€12,949) at Expanded Disability Status Scale (EDSS) = 0-3, 0.534 and 22,700GBP (€25,785)at EDSS = 4-6.5, and 0.135 and 36,500GBP  (€41,460) at EDSS = 7-9. The mean cost of a relapse was estimated at 790GBP (€870).

A total of 411 MS patients (mean age = 40 years) participated in Poland; 94% were below retirement age, and of these, 59% were employed. Employment was related to disability, and MS affected productivity for 85% of those working. Overall, 97% and 71% of patients experienced fatigue and cognition as important problems, respectively. Mean utility and total annual costs were 0.686 and 48,700 PLN (€11,523) at Expanded Disability Status Scale (EDSS) 0-3, 0.521 and 59,200 PLN (€14,008) at EDSS 4-6.5 and 0.208 and 81,600 PLN (€19,308) at EDSS 7-9, respectively. The average cost of a relapse was 3,900 PLN.(€924)


A total of 462 patients (mean age 43 years) participated in Spain; 96% were below retirement age and of these, 45% were employed. Employment was related to disability, and MS affected productivity at work for 72% of those working. Overall, 92% and 64% of patients experienced fatigue and cognitive difficulties as a problem, respectively. Mean utility and total annual costs were estimated at 0.772 and €20,600 at Expanded Disability Status Scale (EDSS) 0-3, 0.486 and €48,500 at EDSS 4-6.5 and 0.182 and €68,700 at EDSS 7-9, respectively. The mean cost of a relapse was €2050.
A total of 491 patients (mean age 47 years) participated in France; 82% were below retirement age, and of these 56% were employed. Employment was related to disease severity, and MS affected productivity at work for 90% of patients. Overall, 95% and 67% of patients experienced fatigue and cognition as a problem, respectively. The mean utility and annual costs were 0.735 and €22,600 at Expanded Disability Status Scale (EDSS) 0-3, 0.500 and €38,100 at EDSS 4-6.5, and 0.337 and €48,100 at EDSS 7-9, respectively. The average cost of a relapse was estimated at €2300.

A total of 5475 patients (mean age 52 years) participated in Germany. In all, 84% were below retirement age, and of these, 51% were employed. Employment was related to disease severity, and MS affected productivity at work for 80% of patients. Overall, 96% and 78% of patients experienced fatigue and cognitive difficulties as a problem, respectively. The mean utility and total annual costs were 0.786 and 28,200€ at Expanded Disability Status Scale (EDSS) 0-3, 0.586 and €44,000 at EDSS 4-6.5 and 0.273 and €62,700 at EDSS 7-9, respectively. The mean cost of a relapse was estimated at €2500.
A total of 516 patients (mean age, 53 years) participated in Austria; 72% were below retirement age, and of these, 46% were employed. Employment was related to disability, and MS affected productivity at work for 77% of those working. Overall, 94% and 67% of patients experienced fatigue and cognition as a problem. Mean utility and total annual costs were 0.778 and 25,100€ at Expanded Disability Status Scale (EDSS) 0-3, 0.579 and 44,100€ at EDSS 4-6.5, and 0.244 and 73,800€ at EDSS 7-9. The mean cost of a relapse was estimated at 2563€

A total of 1010 patients (mean age = 45 years) participated in Italy. In total, 94% were below retirement age, and of these, 56% were employed. Employment was related to disability, and MS affected productivity at work in 77% of the patients. Overall, 96% and 65% of the patients experienced fatigue and cognitive difficulties as a problem, respectively. Mean utility and total annual costs were 0.735 and €22,900 at Expanded Disability Status Scale (EDSS) of 0-3, 0.534 and €40,100 at EDSS of 4-6.5, and 0.135 and €53,300 at EDSS of 7-9. The mean cost of a relapse was estimated to be €2600.
A total of 535 patients (mean age 48.5 years) participated in Portugal ; 92% were below retirement age and of these, 43% were employed. Employment was related to disease severity, and MS was felt to affect productivity at work by 72% of patients, most often through fatigue. Overall, 98% and 74% of patients felt that fatigue and cognition were a problem. Mean utility and costs were 0.756 and €16,500 at the Expanded Disability Status Scale (EDSS) 0-3, 0.572 and €28,700 at EDSS 4-6.5 and 0.206 and €34,400 at EDSS 7-9. The average cost of a relapse was estimated at €2930.
A total of 1856 patients (mean age: 54 years) participated in Belgium; 66% were below retirement age, and of these, 44% were employed. Employment was related to disease severity, and MS affected productivity at work in 85% of the patients. Overall, 95% and 72% of the patients experienced fatigue and cognitive difficulties, respectively, as a problem. Mean utility and annual costs were 0.703 and €26,400 at Expanded Disability Status Scale (EDSS) 0-3, 0.478 and €45,300 at EDSS 4-6.5, and 0.193 and €62,000 at EDSS 7-9. The mean cost of a relapse was estimated to be €3000.
A total of 382 patients (mean age: 54 years) participated in the Netherlands; 81% were below retirement age and of these, 31% were employed. Employment was inversely related to disease severity, and MS affected productivity at work for 82% of patients. Overall, 96% and 73% of patients experienced fatigue and cognitive difficulties, respectively, as a problem. Mean utility and annual costs were 0.744 and €23,100 at Expanded Disability Status Scale (EDSS) 0-3, 0.595 and €32,300 at EDSS 4-6.5, and 0.297 and €50,500 at EDSS 7-9. The mean cost of a relapse was estimated at €3000.
A total of 1864 patients (mean age 56 years) participated in Sweden; 74% were below retirement age, and of these, 55% were employed. MS was reported to affect productivity at work in 78% of patients. Overall, 94% and 72% of patients felt that fatigue and cognition were a problem, respectively. The mean utility and costs were 0.757 and 244,000SEK (€24953) at Expanded Disability Status Scale (EDSS) 0-3, 0.563 and 384,000SEK (€39,271) at EDSS 4-6.5 and 0.202 and 888,000SEK (€90,814) at EDSS 7-9, respectively. The average cost of a relapse was 36,900SEK (€3774).
A total of 721 patients (mean age 48 years) participated in Switzerland; 90% were below retirement age, and of these, 65% were employed. Employment was related to disease severity, and MS affected productivity at work for 69% of patients. Overall, 93% and 64% of patients experienced fatigue and cognition as a problem, respectively. The mean utility and annual costs were 0.799 and 29,600CHF (€27,272) at Expanded Disability Status Scale (EDSS) 0-3, 0.614 and 66,800CHF (€61,547) at EDSS 4-6.5 and 0.348 and 110,800CHF (€102,087) at EDSS 7-9, respectively. The mean cost of a relapse was estimated at 7,600CHF. (€7,002)

Saturday, 24 June 2017

The ProfG's need a kick up the backside. Publish trials

Stefaniak JD, Lam TCH, Sim NE, Al-Shahi Salman R, Breen DP. Discontinuation and non-publication of neurodegenerative disease trials: a cross-sectional analysis. Eur J Neurol. 2017. doi: 10.1111/ene.13336. [Epub ahead of print]

BACKGROUND AND PURPOSE:Trial discontinuation and non-publication represent major sources of research waste in clinical medicine. No previous studies have investigated non-dissemination bias in clinical trials of neurodegenerative diseases.
METHODS: ClinicalTrials.gov was searched for all randomized, interventional, phase II-IV trials that were registered between 1 January 2000 and 31 December 2009 and included adults with Alzheimer's disease, motor neurone disease, multiple sclerosis or Parkinson's disease. Publications from these trials were identified by extensive online searching and contact with authors, and multiple logistic regression analysis was performed to identify characteristics associated with trial discontinuation and non-publication.
RESULTS: In all, 362 eligible trials were identified, of which 12% (42/362) were discontinued. 28% (91/320) of completed trials remained unpublished after 5 years. 


Trial discontinuation was independently associated with number of patients (P = 0.015; more likely in trials with ≤100 patients; odds ratio 2.65, 95% confidence interval 1.21-5.78) and phase of trial (P = 0.009; more likely in phase IV than phase III trials; odds ratio 3.90, 95% confidence interval 1.41-10.83). 

Trial non-publication was independently associated with blinding status (P = 0.005; more likely in single-blind than double-blind trials; odds ratio 5.63, 95% confidence interval 1.70-18.71), number of centres (P = 0.010; more likely in single-centre than multi-centre trials; odds ratio 2.49, 95% confidence interval 1.25-4.99), phase of trial (P = 0.041; more likely in phase II than phase IV trials; odds ratio 2.88, 95% confidence interval 1.04-7.93) and sponsor category (P = 0.001; more likely in industry-sponsored than university-sponsored trials; odds ratio 5.05, 95% confidence interval 1.87-13.63).
CONCLUSIONS: There is evidence of non-dissemination bias in randomized trials of interventions for neurodegenerative diseases. Associations with trial discontinuation and non-publication were similar to findings in other diseases. These biases may distort the therapeutic information available to inform clinical practice

Last week we reported a discontinued Cambridge trial, where the results have not been reported yet (Only at least 15 months from termination), we have mentioned the Ely Lilly Trial that has yet to be reported..

This paper has spotted that loads of  trials don't get finished and loads don't reported. I can see that recruiting for trials is a problem, the PROXIMUS is eighteen months late but now fully recruited, the Canbex trail is very late too but almost there

However before having a rant, you've said "kettle and black"...

You are right we have to hold our hands up and say yes we need to give ourselves a bit of a kick or should I say I need to give the Profs a good kicking 

We (you and I ) know, but the rest of the World don't... that the INSPIRE trial has expired, but a failure is no reason not to publish. 

I heard a "a negative trial can tell us as much as a positive trial"...rubbish....negative trials always leave us with two questions.

It may not always tell us about biology but it may tell us that we do some poorly designed or executed trials. If we aspire to negative trials we have lost before we start. 

I have said that many of our good ideas have been killed off because of bad trials. Not popular with the Neuros and Funders of the trials, but I will stick to my guns on this one. 

I have been saying until I am blue in the face, if you don't have a trial that can work, it doesn't matter which drug you try, it won't work. 

Until beta interferon came along we didn't know how to do relapsing trials not it is easy to work out if an agent is active of not. For progressive trials we are not sure if we are using good outcomes or maybe the trials aren't long enough. 

Our idea of cannabinoids controlling nerve loss is supported by more biology that you can shake a stick at, but the trial failed. 

Speaking to one of the investigators this week. 
They said, the placebo arm just did not progress as expected
(if you are in a trial you do better even if you are on placebo) , so if tyou don't get worse in the placebo arm how can you ever find a positive result of stopping people getting worse. 
It took 6 years to learn this lesson. 

Maybe if the trial was loaded with people who could respond and in people who may get worse if they don't get treated, then we would see something

If you have evidence that your disease is worsening in may be easier to get on to trials or to get access to drugs.

So are you monitoring? 

Do you have a 9 hole peg test, do you know your time for a 25m walk. Because to get into trials or to get access to drugs you may have to show that you have documented worsening

Anyway, we need to come clean, the ProfGs needs to put pen to paper, because until they do that we can't give anyone a roasting,

Oh I forgot ProfG the CLARITY extension is also only about 3 years late so still time:-)....Yeah I know the third reviewer;-)

We collect so many metrics, maybe the number of trials reported has to be a good one when deciding who is funded to do more trials. 

People are risking a lot to participate in the studies, they have a right to know what happened. 

Friday, 23 June 2017

July comes Early

I came across this clock many months ago ticking away in French and English after I stumbled on a Norwegian Website

I nearly made a post for April the first..... so July comes early



Maybe the name will be a grower, but cladding does not have a good reputation in the UK at the moment :-) Don't understand Click

Well done, Prof G, DrK & Merck.

The Tortoise gets there in the end. Will it beat the Hare?



#NewsSpeak: another eagle has landed only this time it is a maven

Oral cladribine finally gets licensed for the treatment of relapsing MS #NewsSpeak #MavenClad

I was invited to a meeting to advice Serono in 2002 whether, or not, they should in-license an oral formulation of cladribine. We advised yes and today the CHMP have recommended that the EU give Merck a marketing authorisation for oral cladribine. The process took 15 years. Who said MS drug development was fast? 

The oral formulation of cladribine, Mavenclad, is the first oral selective immune reconstitution therapy (SIRT)* for treating patients with active relapsing MS. 

*Please note SIRT is a new term to describe the class of drugs that work via immune depletion, which can be non-selective or selective, followed by immune reconstitution. 


CoI: multiple  

#NeuroSpeak: reclaiming MS as one disease

Redefining what is a relapse and making MS one disease? #1-disease-not-2-or-3-diseases #NeuroSpeak

I was reminded at a meeting last night why it is important to publish consensus statements. Barts-MS hosted a UK NEDA meeting in 2014. As a group of UK MSologists we reached a consensus that we would stop referring to new MRI activity as 'MRI activity' and start to refer to it as a 'subclinical relapse'. In other words we all agreed to change our working definition of a what constitutes a relapse. This is not new. I was involved in another consensus meeting in 2010, held by the CMSC, during which we came to the same conclusion and published our recommendations in 2013. The problem is we didn't publish our meetings conclusions. I will now harass the chair of the meeting to get typing. 

We also did a survey on this topic in 2014 and you the community who read this blog agreed with us. 



Changing the definition of what constitutes a relapse has implications for how we use DMTs in clinical practice and challenges the older NICE guidance on not being able to escalate DMTs on MRI criteria alone. To escalate from a platform, or a 1st-line, DMT you need to have clinical attacks. However, the newer NICE guidance allows alemtuzumab to be prescribed to pwMS with active MS defined either clinically or on MRI and to retreat on MRI activity . The latest guidelines therefore recognise that clinical attacks and MRI activity mean the same thing biologically; i.e. that MS is active. This position statement is also in keeping with the new 2013 Lublin criteria of classifying MS disease activity. 

One of the consequences of this change is that pwPPMS who have active scans will be reclassified as having relapsing MS. This is not a bad thing because it starts to bring MS back under one umbrella. This also become less relevant with the emergence of effective DMTs for PPMS. Ocrelizumab now has a US label for relapsing forms of MS and PPMS. Is there a population of people with MS that is not covered by this label? Yes, patients with inactive MS defined clinically and on MRI. The latter is disease course agnostic. 

All this supports our campaign that MS #1-disease-not-2-or-3-diseases.

Cook et al. Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course: A Report from an International CMSC Consensus Conference, March 5-7, 2010. Int J MS Care. 2012 Fall;14(3):105-14.

It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5 to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS.

Lublin et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014 Jul 15;83(3):278-86.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.