Saturday, 28 May 2016

CongressSpeak & BrainHealh: European Neurological Association Meeting 2016 - Copenhagen

I am trying not to neglect my own brain health, but it is difficult. #CongressSpeak #ENA2016 #BrainHealth #MSBlog

"I am not a happy bunny; I am about to spend another weekend working, including bank holiday Monday. Monday is a holiday in the UK; it is called a bank holiday because the banks are closed. I had to get-up at 6am this morning to pack and travel to Copenhagen (still in transit) to attend the 2nd congress of the European Neurological Association (ENA). I am a bit frustrated that I didn't have to time for a run. On balance my brain health is suffering (sleep deprivation and too little exercise) and my personal wellness (not enough downtime). Saying that the ENA is an important meeting that can't be missed. Although it is not one of the 'big MS meetings', it is a meeting that a large number of general neurologists attend and is therefore an excellent forum to get across our 'Brain Heath: Time Matters' message. I will get at least three opportunities to discuss the policy document."

"I have uploaded the ENA programme for you to browse; if you search the document you will find the term 'multiple sclerosis is used 166 times, in other words there is a lot of activity in relation to MS at this meeting."

"I am involved with 8 abstracts; I will personally be presenting two. I will also be talking on one of the satellite symposia  on 'The time to act: optimising patient care'.  My talk is essentially a call to action and is underpinned by all the important issues presented in our 'Brain Health: time matters' policy document. I will upload my slides after the symposium."

"When I get back to London next week I will summarise the meeting for you and give you my highlights (post and pod-cast)."

"If you haven't done so already I would recommend reading our policy document and if you agree with it please pledge your support and sign-up for updates; we have a large programme of activities planned for this year all aimed at getting the policies front of mind and acted upon. The latter however needs support from the MS community, which includes readers of this blog. Thank you."

CoI: multiple 

Friday, 27 May 2016

SurveySpeak: routine cognitive testing

Wow MSers want routine annual cognitive testing. #SurveySpeak #MSBlog #MSResearch

"The following are the results of yesterday's survey. It is clear that the majority of you want to be offered cognitive testing. Professor Dawn Langdon will be happy. Regular cognitive testing may bring one of the hidden problems of MS out into the open and reinforce the observation that MS is a preventable dementia. Ignoring the impact of MS on cognition could be referred to as the 'ostrich syndrome'."

Saving Animals is the name of the game, but is the Masterchef approach to Science going to be Counterproductive

Prof B presented at this weeks nights "Pint of Science " 
offering in London in the Beautiful Mind section

It was nothing to do with potatoes as shown in the advert above.
but a Journey of Discovery that started with an unlikely observation
in a Beetle (Cow pea weevil) and ended in MS.
ProfB presented the group's lastest findings in MS to a public audience. He asked for no tweets, as he revealed our way to potentially control spasticity (So what happened in Clerkenwell, stays in Clerkenwell (area in central London). There was no filming). Maybe you will get this at the research day or you will have to wait until it is published).

The UK government has been pressing for open-ness about animal research and QMUL have signed up to this.

Therefore, they want us to talk about our Animal work and the pint for Science was an opportunity to do this. The Blog is also another conduit, so sad to say we not going to be a completely animal-free zone.

However, if you want such papers discussed then pop them into comments as a suggestion of "What do you think of this?  We may then have a look and post

However, few people will go in public to talk about animal studies, in case there is a militant animal rights protester in the audience.

This harks back to the bad-old days of harassment and life-threatening actions by a few sad individuals (In the USA exchange "abortion" for "animal-rights" activists to get the gist). The UK Government have been clamping down on the activities of the militants, but it is still easier not to put your head above the parapet, as we are being watched;-)

However, as basic research is an important part of the drug discovery process for MS, it is important that people understand some of the issues relating to animals work as it relates to MS and how animals are part of the drug development process. It also  indicates why such research can be very expensive.

The National Centre for the 3Rs of Animals in Research sponsored the session and specifically asked to talk about the beasties.

 As you can see. The talk was given by an electrically powered (see the cable:-) ProfB robot look alike, just in case there were any nutters there. There weren't and the audience was lovely. 

Adoption of the principle of refining experiments to maximise knowledge creation and reduce animal suffering such that you reduce the numbers of animals used and where possible you should strive to replace the use of animals with non-sentient or in silico alternatives is at the heart of the 3Rs. 

This is part of European Legislation on Animal use. However this seems at odds in the way that Animal Science has been moving, notably from our chums in the US.
Masterchef (UK) is a cooking contest, where the people strive for Michelin-starred delivery of food. Time and time again, we see the contestants take the same ingredient and cook it “3-ways”.  e.g cook the breast, make the leg meat into a meatball, and a jus from the liver , etc. etc, This approach can create wonderful looking and tasting puds and dishes, but it appears this is the way that experimental work is going.

So to get “Nature/Science-starred” research papers there is an increasing tendency to do the experiment “3-ways”.  So you do the experiment in three/multiple different MS models or go after the same target and select multiple ways to hit the same thing. So much work that you can't argue against it. 

So costly that most people can't repeat it:-(.  

However, doing this is, is surely blowing the concept of 3Rs out of the water? 

I guess people will say that by getting the "right" answer then the extra animal use can be justified, but is it the right answer?
What happens in human is probably the critical point.  

However, such an experimental approach, leading to experimental design by numbers :-(, is becoming prescriptive and grant and paper referees are asking for the same experiment to be done using different models.  

Do you have to go with the flow or simply sink? 

Thursday, 26 May 2016

ResearchSpeak: reflections on the ABN

My pod-casting experiment from the ABN #ResearchSpeak #ABN2016 #MSBlog 

I spent most of last week at the annual Association of British Neurologists (ABN) meeting in Brighton. I chaired two debates, presented 4 posters and was co-presenter on another 2 posters. I also networked and met many young neurologists and saw some old friends.

The debates:

Debate 1: ‘Was the NICE mandate that pwMS should have annual cognitive assessments appropriate or not?’

Professor Dawn Langdon made the case for annual cognitive assessments arguing that knowing if someone with MS had cognitive impairment would affect how you manage them. Cognitive impairment is associated with poor drug adherence and difficulties with following self-management strategies. For example, pwMS who have cognitive impairment are more likely to get recurrent urinary tract infections. I suspect that this may not be causal, but simply an association; i.e. people with cognitive impairment may simply have a greater chance of associated bladder problems. She was implying that they were less likely to follow medical advice on how to manage their bladders and adhere to their treatments. She also stressed that annual cognitive assessments does not mean full neuropsychometric testing, but could simply be done using a rapid screening battery such as BICAMS (Brief Cognitive Assessment in MS). She slipped in that BICAMS takes 15 minutes to do and needs to be done by a healthcare professional. At our centre with 1200+ MSers on our books that is 400 hours of testing per year. Dr Brenner, a good friend of mine, argued against the motion. He focused on the NHS resources it would require, and consume, implement annual cognitive assessments across the UK; resources he felt would be better used on more pressing problems. He made the point that as we have no treatment for MS-related cognitive impairment it was unethical to do the tests. Do pwMS want to know they are cognitively impaired? He assumed that pwMS wouldn’t want to know about an MS complication they could do littke about. I am not sure we can make any assumptions, this is a question that needs to be answered by you people with MS.

There were too few voters to really assess which way this debate went, but the debate generated lively discussions. I concluded that this debate needs a larger audience and should include people with the disease. I wonder if NICE asked MSers their opinion before recommending annual cognitive assessments?

Debate 2: ‘To manage MS properly we need a new MS disease activity score or DAS’

As chairman I set the scene drawing on the experience of rheumatolgists who have been using the RA DAS (disease activity scale) for decades. In RA a DAS score is used as a metric to treat-2-target. The RA-DAS semi-objectively measures how active RA is and allows rheumatologists to assess how effective their DMARDs (disease-modifying antirheumatic drugs) are at controlling RA. The RA-DAS has been instrumental the paradigm of treating-2-target that underpins what we are trying to copy and promote in MS.

Dr Leonora Fisniku, from Haywards Heath, argued for a new MS-DAS. She opened the debate by reviewing the treatment landscape and made the argument that because most of the inflammatory disease activity in MS occurs below the surface, i.e. the iceberg analogy, we need to use biomarkers (MRI) to quantify MS disease activity. She made a strong theoretical argument for a MS-DAS without actually defining what components should would include in her score. Dr Waqar Rashid, from Brighton, countered her argument with a pragmatic approach telling us to shy away from perfectionism and to use what we have already and what we have been trained to do in the clinic. He argued that there is no reason to reinvent the wheel and that we should simply use what we collect routinely in clinic to make an assessment of whether the patient is active or not. In other words the clinician's acumen. He stressed the difficulties we would face with having to validate a new MS-DAS and that it is unlikely to capture all aspects of the disease. Both debaters covered the EDSS and mentioned its failings, but neither were brave enough to confine it to history. I was surprised that the vote went against the MS-DAS. I suspect what won the day was that Dr Rashid managed to exploit neurologists fears of a new unvalidated MS-DAS consuming valuable clinic time and forcing neurologists to change the way they practice clinical neurology. Neurologists don’t like change; they have been examining the nervous system the same way for over 100 years, why change the way we do things with better tools? This debate generated a lot of discussion from the floor, a lot of which focused on a prognostic scoring systems rather than the issue at hand.

I am of the opinion that a new MS-DAS is essential; we need it to get wide adoption of the treat-2-target approach of NEDA. Its development would clearly need careful consideration and multi-stakeholder input if it had any chance of being adopted. I personally would argue for it to include a PROM (patient-related outcome measure). A PROM will at least get the individual with MS engaged with the process of monitoring their own disease activity. The latter aspect may be why the RA-DAS has been so successful as a change agent in the management of RA. As I have said before patient-engagement is a no-brainer and one of the most underused therapeutic interventions we have. A MS-DAS could also be used as a driver of quality. If your neurologist refused to use the MS-DAS you may be tempted to find another neurologist who did. Now wouldn’t that be something worth talking about? I am aware from comments on this blog that some of you have done this already and moved neurologists simply to get annual MRI scans.

The posters:

Although the posters were up for most of the meeting we had just over an hour to stand by the posters to field questions from the attendees. This caused me problems although I had three posters in a row the fourth poster was in another location so I had to split my time between the two locations. It was a pity because the data in all my posters was worth talking about. The isolated poster showed that disability improvement on alemtuzumab occurs across most functional systems of the EDSS and is not simply limited to one functional system. On reflections isn’t amazing that with the more effective DMTs we can now expect disability improvement? Interestingly, we are seeing disability improvement occurring in years 3 and 4 and not just in year 1 and 2 post-alemtuzumab. This challenges the dogma about recovery mechanisms in the central nervous system and finally buries the dogma that the EDSS progression is a one-way street. Disability improvement, or the promise of disability improvement, is in itself proof of how far we have come with the treatment of MS. For the cynics and nihilists out there ‘eat your hat’.

Another ground-shifting poster was the ORATORIO study results (ocrelizumab in PPMS). This study is the first study to show a DMT slowing the rate of disability progression in PPMS. This is has to be one of the most significant things to happen in the field of MS in the last 10 years. Despite this I am concerned that NICE may not view ocrelizumab as a treatment for PPMS very favourably. NICE always assesses cost-effectiveness using an incremental cost model. For PPMS the cost-effectiveness of ocrelizumab will be compared to what is out there already, i.e. best supportive care. The latter will cause problems because ocrelizumab will presumably be licensed for RRMS where the comparison will be with existing DMTs that are high-cost. So the cost per QALY for treating RRMS will command a higher price than that for PPMS. Will this be the opportunity for NICE to demand differential pricing? Will the NHS pay less for ocrelizumab in PPMS compared to RRMS? Differential pricing of this nature is called value-based pricing whereby healthcare payers pay for what they get. In reality this is the system that airlines use for booking flights and what Uber use in the APP with surge pricing. Why shouldn't we bring value-based, or surge, pricing to the field of MS? Comments; I am particularly interested to hear Pharma’s perspective on this.

I also presented two posters on daclizumab. One was on NEDA rates in the phase 3 study and the other the effectiveness of daclizumab in study subjects in the extension study of the phase 2b, SELECT-SELECTION, study, appropriately called the SELECTED study. Please note that although I sat on the steering committee of the SELECT and SELECTION studies I had nothing to do with their names. There is a whole field dedicated to the naming of clinical trials; if you get the acronym right the study develops a life of its own. Not unexpectedly in the phase 3 ??? study the chances of NEDA were higher on daclizumab than interferon-beta. In the extension, or SELECTED, study the relapse rate appeared to continue to go down, hinting that the efficacy of daclizumab may increase with time. We actually saw the evidence for the ramping up of efficacy in the original SELECT study on MRI. Despite the daclizumab efficacy data, I spent most of my time at the daclizumab posters enthusing over daclizumab’s mode of action or MOA. Dac’s MOA challenges the core immunological dogma around the pathogenesis of MS. As I have said many times before daclizumab is not an immunosuppressive drug and it works by subtly changing the IL2 (interleukin 2) signaling pathways diverting IL2 away from activated T cells and T-reg cells towards the CD56-bright NK cell population. The expansion of this latter cell population seems to be closely linked to Dac’s efficacy. What is more the number of T-reg cells go down; this contrary to what we have been told by immunologists that MS is a immune mediated disease that is linked to abnormally regulated T-cells. An interesting discussion will be where Dac fits into the current treatment paradigm; I have thoughts on this but this will be a discussion for another time. 

My ABN highlight:

The real highlight of the meeting was Prof. Compston’s ABN gold medal acceptance speech. It was about his medical life from the time he entered medical school up until the present and his current retirement plans writing historical books. He summarised his career as a neurologist covering his research into the genetics and treatment of MS, his time as an editor of Brain (one of the premier neurology journals, or argubly the premier neurology journal) and his legacy - a large number of his trainees now head-up neurology departments across the UK. He voice broke a few times during his talk as it was clearly very emotional speech. Getting to an end of such a glittering career and reflecting on it must be very nostalgic. I personally find nostalgia one of the most powerful of emotions; it is not necessarily a sad, or happy, emotion, but it somehow brings tears to my eyes. At the end of the talk he was given a standing ovation; the first time I have experienced this at an ABN gold medal ceremony.

Some reflections after the meeting:

Many times we the community are criticised for not making progress in MS research. The problem is we tend to look at what happens from year to year. When you look at it from Professor Compston’s perspective and take a 40-year view of the field you realise that so much has changed. It is simply quite incredible what has happened to MS in the last 40 years. We now have treatments that render MSers with NEDA, i.e. putting some of them into long-term remission with the promise of a cure in a proportion of them. With ocrelizumab we now have a DMT that has been shown to be effective in PPMS. We have refined our diagnostic criteria and are better at excluding MS mimics from being inappropriately diagnosed as having MS. We know so much more about the causal pathway of MS and are beginning to use this knowledge to discuss and design MS prevention studies. Are there really some humbugs out there who still think we have made so little progress in MS research? If there are I suggest they take a 40 year helicopter view of the field rather than a very short-sighted one, or two, year view of the field. Another option who be to spend an afternoon discussing MS research with Professor Compston.

CoI: multiple

Wednesday, 25 May 2016

Clinical trials from three different perspectives

This post coincides with International Clinical Trials Day which is celebrated each year around the world, on or around the 20 May to commemorate the day that James Lind started his famous trial. This week, across the Barts Health NHS Trust site a number of activities are taking place to educate, raising awareness and celebrate some of the brilliant research going on in our area. Our contribution to this shares the experience of taking part in a clinical trial either as a person with MS, an MS researcher and a MSologist.


The patient perspective:

"Like many people when first diagnosed with MS there is the inevitable "why me" but also a realisation of helplessness due to a lack of drugs to fight, slow down or even just simply delay PPMS. The only thing I could do was to lose some weight and keep myself fit and with that in mind I started immediately and continue now weekly physiotherapy sessions, but I was keen to do more. This lead me to look at drug trials to fight back - take the war to the enemy!

Since then I have been involved in 3 drugs trials over a number of years and given that I have few if any allergies, no needle fears (important believe me, given the number of times that you need to give blood!) and time on my hands I guess I am a reasonably good trials patient. In addition to this there is also an altruistic motive, I am keen to help develop drugs for all pwMS and also ensure that that those clever people developing drugs get the opportunity to trial them. In return I get regular health check ups and access to the medical staff at the Royal London, which I consider to be a plus factor and I also am now on very good terms with most of Prof G's team! Additionally you also have the opportunity to maybe get a drug ahead of the general population and test its efficacy.

There are of course occasions when you really do not want to spend time in a hospital and some trials have been a little more demanding than I would necessarily wish, but overall I would suggest to all pwMS to sign up for a trial if it convenient for them to do so - you never know what might come of it.”


The researchers perspective:

"I am Lucia and I work in the Lab to test the trial samples - this helps to determine if the trial drug is effective. I also take care of all associated paperwork, as everything in a trial needs to be documented: this is important for the participants’ safety as well as for the reliability of the results.

The vast majority of trials nowadays are testing a new drug against the best current one and not against a placebo: this eliminates the risk of going without treatment for the duration of the trial. To enrol in a trial the clinician must give you full knowledge of the possible risks and benefits; your agreement is given by signing an ‘Informed Consent’ form. Moreover, you can withdraw from a trial at any time without the need to give a reason.

To run a trial we have to adhere to national and international regulation and must have the approval of an independent ethical committee; Lab and documentation are also regularly inspected by regulatory bodies. As much as it is sometimes exhausting and frustrating for me to keep on top of all these piles of paperwork I feel all of this is essential to ensure the trial participants’ wellbeing is the first priority. It is also important to safeguard the scientific value of the trial - in other words, there must be strong scientific data to prove the drug is indeed effective.

What from outside might look like a lot of unnecessary red tape it is in my opinion a guarantee only really improved and beneficial treatments will reach the clinic. I enjoying working in clinical trials as the results of the analysis I perform on samples could lead to better therapies being available to people with MS."


The clinicians perspective:

"As a clinician, doing a neurological diagnosis is usually challenging but always rewarding. Unfortunately the lack of effective treatments for neurological patients could be a huge problem. Therefore, it is important to seek for innovative and more effective therapies to allow patients affected with neurological disorders to improve their lives on a day-to-day basis.

Clinical research, especially clinical trials, has taught me the importance of searching for new and more effective therapies for people suffering from devastating neurological disorders such as MS. Being part of clinical research projects is one of the most rewarding activities I have experienced in my medical career. As a clinical research fellow, I am involved in developing research objectives, projects and proposals, helping in the conduction of internal and collaborative research projects, and disseminating research findings through scientific publications and conferences. The objective of our clinical research is to find more effective therapies for people with multiple sclerosis.

Apart from the technical work we have to do, I always try to have some time to chat with people with MS and hear their necessities, this is priceless as patients have little time during the normal NHS appointments to talk about more general problems that are important during the time of designing research projects. Besides, some patients are opened to share some personal gifts they have, like Sam who shared with me poetry he writes in his blog:

“I try daily to always be happy, I know life is hard but it's best to go throw it with sum1 so lively…” Sam*

This is very gratifying!


You can find out more information about the different events taking part across Barts Health here. We are also working to update our trials tab on this blog.