Sunday, 8 May 2016

Failures help to work to success

Pfeuffer S, Ruck T, Kleinschnitz C, Wiendl H, Meuth SG. Failed, interrupted and inconclusive trials on relapsing multiple sclerosis treatment: update 2010-2015. Expert Rev Neurother. 2016 Apr 8. [Epub ahead of print]

The treatment of multiple sclerosis (MS) remains challenging despite the great efforts made in the development of novel therapies. Driven by the growing knowledge of the immunopathogenesis of the disease, a plethora of new pharmacological agents have been developed and tested in clinical trials. However, the therapeutic advantages and positive clinical trials of some of these agents are outweighed by studies of promising agents that either failed due to negative or inconclusive results or had to be withdrawn because of serious unexpected adverse events. Most failed clinical trials did not lack a well-considered pathophysiological rationale, but concepts from experimental models were proven wrong in humans. Lessons learned from these discrepancies help to optimize future study design and, potentially more importantly, provide further insight into the immunopathogenesis of MS. Here, we summarize trials on MS treatments since 2010 that failed or were interrupted, identifying potential underlying reasons for failure or inconclusiveness.

Kleinschnitz C, Meuth SG, Wiendl H.The trials and errors in MS therapy. Int MS J. 2008;15(3):79-90.

This paper explores trials that did not meet expectations and provides a nice list of human failings as it relates to MS. Whilst it is nothing to shout about, it is important that we learn from the lessons.

Such lessons developed a successful trial for PPMS. Had that trial been designed based on no knowledge of failures, I would bet that the Ocreluzimab in PPMS study would not have shown a signficant effect. This is because rituximab failed in the same type of experiement but that informed the ocrelizumab study in how to load it for success.

Many neuros will be bleating that it just goes to show that animal models are rubbish and this delivers a fair amount of material for EAE beating, but in contruary it may show that it is them who are the rubbish ones. 


So we also need a bit of self-reflection so the neuros can beat themselves up for designing or executing a failed trial. I realise that human activity has much to bear in the failure and success of many of these studies. There are failings from the animal studies, there are failing by the neuros and failings of pharma.

Baker D, Amor S.Experimental autoimmune encephalomyelitis is a good model of multiple sclerosis if used wisely. Mult Scler Relat Disord. 2014;3(5):555-64

I get chastised about saying such things in public as it is is not news through rose-tinted glasses. 
It is an admission that we make mistakes. 

We should be seen to be invincible and united and simply be always positive....like most Charity Sites

Should we be seen as human, but the endless teriade of neuro abuse needs some comment and perspective.

Sure there is indeed a load of rubbish EAE experiments (some done by the people viewed as being the best and published in the best journals)
 out there and this should not be defended.... but stamped out!.....some people may say this is harsh. Some experiments will never repeat in another lab let alone a human.

The lamotrigine trial is a viewed as a failure of 2010...tested in progressive MS...failed ...the idea is wrong. 

Only it probably isn't a wrong idea, but if only 50% of people in the trial are taking their medicine properly then the trial fails not because of the idea but because of the execution.

If there is a side-effect issue we can move on and design ways to avoid side-effects and get the same outcome, this is what we are trying to do. But, if the idea gets chucked away because of a perceived failed trial then the research avenue is dead and an oppertunity to do something is wasted..

One of the many problems of failure...is running before we can walk.....we run because you are telling us to run, but if the tools are not to hand to make a success you have to expect failures on the road to success.

11 comments:

  1. it's not the failures that trouble me, they're part of life. it's the attitude and lack of engagement that i have a problem with, especially in the context of a chronic disease without a lot of unknowns. saw 5 different neuros with 5 different sets of advice. it would have been fine if each opinion was presented with 'look, there is so much unknown this is my opinion but i have no doubt my colleague next door might have a different one'. instead, each opinion was presented as facts and the neuros called each other names like 'less rational' and 'more rational'. of course, we were the least rational of all in daring seek so many opinions.

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    1. By delivering information with confidence it creates the aura of knowledge.

      Neuros call each other names "like less rational"....at least it wasn't ludites and laggrads as we Mousers sometimes say and god forbid "fairy light with a dimmer switch" :-)

      http://multiple-sclerosis-research.blogspot.com/2015/10/a-fairy-with-dimmer-or-beacon-of-light.html

      However, it is clear that the attitude of the neuro may speak volumes to the type of treatment options offered and ranges from we'll see how things go and there , there I'll get you a nice wheel chair" to the Neuros that say "I am not going to tolerate any disease activity!"

      We should all be reading Brain health

      http://www.msbrainhealth.org/

      For some neuros this feels like a lost cause but it forms the basis of a teaching approach...by the times the young doctors qualify and encounter MS the drugs may have changed but the goal of no disease activity should remain.

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    2. lol thank you for the reply and the reminder of the beacon of light entry.

      I have read brain health (I'm an eager beaver0.

      It will please you that 4 out of 5 neuros all recommended the same treatment (tysabri/lemtrada). It will please you less that the rationality name calling was in response to different advice on (a) jcv conversion risk (the more rational neuros said it was 2-3% annually. the less rational neuro said it's been estimated at 10% and it was discussed at their conferences - he didn't know why the others didn't hear about it. i think it was a few weeks/months ago that the 10% jcv conversion study came out). (b) how to come off tysabri. the less rational neuro was unambiguously in favour of using gilenya to come off it, with the first dose to be taken 4 weeks (i think) after last tysabri infusion. the more rational neuros wanted to use steroids. the name calling began when my partner decided to go with the less rational neuro's gilenya advice. rituximab is not available for ms in australia. and we had travelled from melbourne to canberra for the 'less rational' neuro's opinion. he was the exception to my whining - he actually backed up all his statements by digging in his messy piles of papers in his office for an article on the topic which his secretary would photocopy for us. try as i might, i couldn't get him to move to melbourne though. this experience was dated mid 2015.

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  2. Mice are not men.

    Sensible research is sensible research. If every trial were done against human there would be no research as many people would be damaged. That would be reported. That is the end of research.

    Specific to EAE? Not at all.

    Here's the thing MouseDoc, sure there will be contention between researchers in how to's, why for's, this and that's. Its always a good feeling when no matter our work we are respected by our peers and often words hurt.

    But really, its about all of us. Those that are hammered by multiple sclerosis and as one of those people myself I can tell you that people who endure MS very much appreciate the work researchers engage.

    From me personally, I communicate with many researchers, neuro's, clinicians as we move towards our goals. I cannot think of a singular group of people that I respect more than all of you at Barts.

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    In as far as clinical research trials themselves go and/or much research there is so much out there that is published it is daunting... truly. I read this stuff. I dont necessarily understand it all. While I have 3.8 years of nursing knowledge, microbiology and then some I try and learn. 3.8? Yes, MS took that career hope away from me when I was doing the clinical finals in the hospital. I just went blank under pressure. Even though the college wanted me continue and even pay my way due to my grades I had to make a decision. The responsible decision for sake of prospect patients was for me to bow out. It hurt. Bad.

    People in general as patients do not realize what it takes academically and the commitment people such as yourself engage in. I do. Medical practitioners are at times caught up in credentials, politics not to mention the care systems they work within. Its immense as is the responsibility.

    I've read for example Brain Health Matters. I've read alot as you might imagine doing what "we" do. I am not sure you are aware of our goals, regardless... Brain Health Matters is one of the most foundational multiple sclerosis documents I have encountered and most certainly the most foundational one in recent times.

    You all part of that. You have changed the world. All of you.

    How was that learned? Mice and patients, dialog, experience, academics, reading others research and much more to be sure.

    Mice are not men. But men can learn much from the mouse.

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    1. "People in general as patients do not realize what it takes academically and the commitment people such as yourself engage in. I do. Medical practitioners are at times caught up in credentials, politics not to mention the care systems they work within. Its immense as is the responsibility."

      Huh? Us commoners don't understand the academic and professional demands of a research or a medical career? A career in medicine is difficult because there are political components? I don't mind brown nosing but this just made me roll my eyes. Prof G doesn't understand the realities of living with MS (how else could he be so surprised about the size of MS closet) - but no one is going on about how misunderstood the MS patients are.

      By the way, this comment isn't out of any lack of respect for the authors of this blog (nor do I expect any doctor to know in intimate details the realities of coping with any disease). But let's put this into perspective and not build a pedestal surrounded by patients 'who just don't understand' the medico's greatness. Anyway, I'm off now to organise a national hold a candle for lawyers day as most of my clients just don't understand the academic aspects or commitment I engage in....

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    2. We do not truley understand what it is like to have MS, you are the experts when it comes to this and this is why we have a group of Expert MSers who help us in our teaching activities and they give us their real life experiences.

      Indeed ProfG may have posted the closet post because this week we were hearing from one of experts about the difficulties in forming new relationships

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    3. i know. i used it as an example because i didn't like the tone of the suggestion that patients don't understand their doctors' professional realities. still, i was surprised at extent of surprise expressed regarding disclosure of ms by people with ms. i don't have ms myself, but the first thought i have when i think of disclosure is what i would do in my work (and social life) with something like ms? the fact that i have to think about it for 20 minutes before formulating any kind of a guesswork response means it's a tough issue and it doesn't surprise me that many people with ms choose to keep ms out of pieces of their life :)

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    4. Brown nosing? Pullease. I actually communicate with many clinicians and there are many patterns that have emerged globally. Among these are:

      1. Patients have little in the way of regard (and trust) in care systems, pharma, care providers and research. Those that do are well informed about MS. That from our statistics is less than 1% of the patient population.

      2. These folks here at Barts (and some other's) are changing MS from the top down and bottom up. That's extraordinarily difficult for a handful of people to accomplish that do not have literally millions of dollars at their disposal annually.

      3. If you take the time to actually engage physicians (of all genre's) at places such as Twitter in live discussions you will gain a whole new perspective.

      4. Whether its MS, cardio, arthritis, cancer etc. many, perhaps most clinicians / resealers do not understand what it is like to have the condition. Many do. My physician's assistant as my neuro knows MS quite well and personally to his family. My fiance's doctor put his practice on hold for two years while he tried save his wife's life from cancer.

      Just because medical professionals dont disclose their personal life does not mean they are not experiencing disease.

      5. As patients we dont tend to understand the demands, politics and more that take place. Perhaps you do. But the lions share of people I speak with and we are talking thousands, they do not. Nor does that mean they should. I had absolutely no clue until about 6 months back. Long story.

      7. When you open and operate a place that is getting 7,000+ people daily visiting and interacting with them in varied ways from email, social media and even phone again... patterns arise.

      While I appreciate your statements and understand how or where you may be coming from you are presuming or making assumption towards my statements.

      My ways of saying, "Thank you" from myself or those 7,000+ people daily you clearly are misinterpreting as "brown nosing" when in fact they are genuine.

      In respect to politics, oh yes, the entire lay of the MS global landscape is chock full of this. Not politicians, but politics indeed.

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    5. I brown nose to my colleagues all the time. Sometimes I roll myself at the things that come out of my mouth on the phone.
      I’m not sure what “actually communicate” with many clinicians is supposed to denote (that you’re the expert and I just don’t understand?).
      In response to the research:
      1. I have very little trust in the Australian health care systems, pharma care and providers. I am very well informed about MS, if I do say so myself. The reason for my lack of trust is the capitalist system we live in and all the pressures that puts on a medical system. I would even go so far as to say that if you don’t have some cynism towards these issues you are putting too much trust in one man or one woman with a white coat. I’m not necessarily disagreeing with the research you are referring to but I don’t know enough about the research to comment one way (I would, however, object to the statistic that suggests only 1% of people with MS are well informed about MS. I’m interested in reading more – can you provide a link?

      2. Love what the Barts are doing and I have communicated that to them on many occasions. None of my love respect or admiration for their work is communicated in a way that suggests that patients don’t understand their work pressures. Yes I know I took a step you didn’t and suggested more than your comment was intended to convey (ie. I suggested you were insinuating MS patients should be more thankful to their doctors because they don’t realise how hard their doctors work, but that’s the risk you take when on a blog read by patients.

      3. I have been engaging with all sorts of doctors for a very long time (my partner is greedy and collects illnesses). Some of this communication has taken place in face to face consultations, some over email, some over phone and some over social media such as this. I have met with MS Research Australia on a number of occasions and as a result of my meetings with them they have improved a previously incorrect statement on their website on a treatment for MS. Does that improve my credentials?

      4. I don’t have MS, my partner does. I have been with her every step of the way. I still don’t know what it is like to have MS. Therefore doctors who have had family with someone with a disease still don’t know what it’s like to live with the disease – nor are they expected to. I’m equally not asking medical professionals to disclose their life – I was saying that in the same way some patients may not understand the professional demands of a career in medicine, doctors don’t know intimately the private demands of living with a disease such as MS. It had nothing to do with disclosing any kind of private life or information.

      5. I do appreciate the demands of a career in medicine. My partner with MS certainly appreciates them (she is a social researcher). My partner’s neuro is a female stuck in a male world. I have had discussions with some of the people she works with. The Australian media reports about the bullying in the medical industry are rife. I imagine my partner’s neuro has had a bit of frustration throughout her career. But absolutely none of that mattered when she lied to my partner about the availability of some tests, then attacked my partner for going behind her back (I called Biogen directly to check). I know the doctor is not a bad person and didn’t set out to set the embarrassing set of events into motion – she was prolly just busy and wanted to get something off her desk without too much to and fro. But when this all happened our task wasn’t to understand her frustrations, it was to ensure if she remains my partner’s doctor she won’t lie to my partner again.

      Thank you for your response. While I understand what you are doing I still remain of the view it’s a prejudiced thank you, which is why I’ve taken the time to respond.

      Bojana

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    6. 1. "Actually communicate" means I reach out or they do (clinicians/researchers/pharma and others) to communicate. I cannot begin to tell you how much I have learned. There is a great deal of accurate information and of misinformation out there.

      Its actually pretty amazing some of the people I meet not just within the clinical community but completely external. I've met assistant attorney generals, politicians, CEO's and more who have a link to MS be it spousal, family, friends, etc.

      While I am by no means expert I am learning more and more all the time. Its sorta required, MS Unites has a long laundry list of long term goals.

      I am not in Australia but am in the USA. I've communicated with some researchers in australia most notably about how they deal with PML as well as the folks at Innate Immunotherapeutics.

      Business surrounds all health care and that is not going to be changing in my lifetime. It should be a fundamental type human rights global sorta thing but money is always at the roots. As with anything, can be used for good or evil. So many equate money to happiness and never seem to understand until its too late that the two in many ways are not inclusive.

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      2. I also love what Barts does and think that the same should occur in other chronic disorders. I of course do not know the specific work pressures that they endure at Barts. I do know of others both local and that I have corresponded with and it can be really taxing.

      The folks at Barts are clearly very dedicated and motivated and that always requires time. There is a great deal to respect in what they both do, have accomplished and have learned.
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      3. I hear this. I've ran up against similar. I've been prescribed things that dont work well together. Thank goodness my pharmacist is MS knowledgeable.
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      4. I am so sorry. I hate to hear of anyone having MS. It really wrecked me for a time. She is a lucky lady to have you by her side. I am fortunate as well that my fiance' Rick stays engaged (no pun!) in my MS.

      Some of my care team do know MS, what it is like to have it as they do. Everyone's MS is as different as every persons life is as that is part of the equation. True of other diseases as well.
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      5. Wow! I had no idea. Here in the USA everything is now really multiple gender and for the most part there is mutual respect albeit it not 100%. Cultural evolution takes time and is often pretty ugly especially in granular lives seldom displayed to masses.

      I wonder how much in the way of lying happens at clinics. I've fired two general practitioners for reasons that boil down to lies. I think they meant well but hey, this is my life, ya know? If they do not know an answer dont just manufacture one. Its how I was prescribed a med that'd for sure put me in the hospital as noted above.

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    7. In respect to what we are trying to do, goals msunites has its a long list. When we began our work we just were looking to set up a little local resource as alot of folks in Western NY and Ontario Canada have MS. 17,000 in Western NY alone. Where I live is one of the known hotspots going back near 50 years now in Rochester NY.

      When the website deployed had no clue it would get the attention it has. We asked visitors what they'd like, built a laundry list from that and work towards it as time allows.

      Entry into MS is one goal but there are many more. Global solidarity we'd like see happen. Awareness in respect to patients and families knowing more about MS. Surprisingly it appears most online do not which brings into question how many offline do not.

      We want in time provide a rich environment where-by people can make real gains from each other in many ways such as finances, ways to unwind such as hobbies, creative writing, art for example. The ability for people to learn, courseware if you will with interactive elements and social networking.

      We'd like to see more in person support groups exist and independently fund them and have global scope. In doing this provide the ability for researchers, news, education, patient advocacy to "connect" via video feeds and such.

      An ability to print resources freely onsite at the support groups or in clinicians offices.

      We'd like the ability to fund research that does not get funded as research often is based on returns. We are not interested in return investment but instead forward motion.

      We do not ever want to ask a patient or families for a plug nickel towards our work directly they give and give and give many with limited means.

      These are just a few in the laundry list. We welcome anyone who wishes to help out, we are very much out of the box in our mechanisms of thought yet we do need work within the larger box if that makes sense?

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