Wednesday, 28 September 2016

#GuestPost #ThinkHand, #ECTRIMS2016: Professor Coyle's motion at the "Burning Debate"

Last week I posted my slides in favour of the motion that pwMS in wheelchairs should be included in DMT trials. You were asking to learn more about the motion against, and my opponent during the 'burning debate' at ECTRIMS 2016, Patricia Coyle, kindly agreed to share her slides and some key points of her argument for this Guestpost.

Patricia K. Coyle, MD, FAAN, FANA, is Professor and Vice Chair (Clinical Affairs) of Neurology, and Director of the Multiple Sclerosis Comprehensive Care Center at Stony Brook University Medical Center, Stony Brook, New York.  She received a BS degree with highest honors from Fordham University, Bronx, New York, and an MD degree from the Johns Hopkins School of Medicine, where she was elected to Alpha Omega Alpha.  While at the Johns Hopkins School of Medicine, she completed a residency and chief residency in neurology, followed by a two-year fellowship in neuroimmunology and neurovirology.  She then went on to establish a successful research laboratory in addition to building a busy clinical practice at the Stony Brook University Medical Center.  Dr. Coyle is the author of numerous articles on clinical and basic research aspects of multiple sclerosis (MS) and neurologic infections and she is recognized as a leading expert on MS and neurologic infections.  Her areas of expertise include Lyme disease and neurologic infections, cerebrospinal fluid, therapeutics, and neuroimmunology.  Her research has been supported by the National Institutes of Health and other organizations.  She is currently involved in a number of therapeutic trials testing new immunotherapies for MS, as well as studies addressing neurologic aspects of Lyme disease.  In addition to her busy clinical and research careers, she has held active leadership positions in a number of national and international organizations and academic societies, including the American Academy of Neurology, American Neurological Association, National MS Society, and the American Board of Psychiatry and Neurology, and has been a member of the FDA CNS and PNS Drugs Advisory Panel. She lectures widely on MS and neurologic infections to national and international audiences.

Professor Coyle's key points:
  • People with MS in wheelchairs can and should participate in many types of clinical trials (testing CNS repair strategies, symptom management, rehabilitation techniques, national history studies) 
  • People with MS in wheelchairs have been and are currently routinely excluded from pivotal trials testing progressive MS DMTs
  • This exclusion is not based on discrimination; it is done to give the pivotal trial the best chance to be successful
  • In such pivotal trials you typically enter much more restricted “idealized” populations to avoid bias of failing to see a treatment effect
  • The primary outcome in such trials remains a clinical one, which documents that a drug can slow progression over a short (typically two year) period
  • People with MS in wheelchairs are not ideal to show such a time-related change for multiple reasons:
  • They typically have had bad MS for a long time, have accumulated a lot of CNS damage, and have the least CNS reserve
  • They do not have EDSS in the walking part of the scale, which is where changes are most commonly seen quickly; they are in the EDSS ≥7 range, where EDSS changes slowly if at all
  • They have more confounding comorbidities, more symptoms that are not as well managed, less physical exercise tolerance, all of which can interfere with their evaluation
  • The two current successful phase III PPMS and SPMS progressive trials both excluded people with MS in wheelchairs
  • Once approved, progressive MS DMTs should and in fact must be made available to people with MS in wheelchairs
  • Bottom line: for the ultimate higher good, to provide the best chance for critical pivotal progressive treatment trials to be positive, people with MS in wheelchairs must continue to be excluded (but not from the right to be treated)
What do you think?

CoI: PKC has served in a consultancy capacity for Accordant, Bayer, Biogen, Genentech/Roche, Mallinckrodt, Novartis, Sanofi Genzyme, Merck Serono and Teva, and has received research support  from Actelion, Genentech/Roche, Novartis and Opexa.


  1. First, I think that there is still much confusion about the natural history of progressive MS and that this should be a priority - particularly in an age of effective DMTs which we are now understanding may have an impact on progression even in people with progressive disease.

    Why, for instance, was there a recorded decline in people with PPMS in one study? ( - is this because people who would have previously been seen as PPMS are now being seen as RRMS as they respond to treatment? Why, also, is progressive MS reportedly worse in some groups of PwMS in Australia than in Novia Scotia? Equally, some reports put 25% of people with PPMS still ambulant at 25 years. Others say that time to EDSS 6 is about 9 years.

    In short, we need to understand if 'non-resonders' are really not responding or if they are responding, just at a slower rate.

    We have seen trials where people's progression has been slower than expected. Is this because of an anomaly in the cohort or was it because those placebo progressive MSers might have been on effective DMTs before they went on the trial and this has slowed down their progression -- albeit one that occurred 2/3 years after the administration of the non-trial drug?

    Finally, I think there is a value in the Lazarus experience - the bed-ridden MS patient, infused with stem cells and hope - rising from the bed. If the end game in all MS research is a 'cure' then surely that cure should be to get the most heavily disabled walking again.

    Dareky Fidyka managed to walk again after stem cells were taken from his nose and injected into his spine. Could this not be something that is trialled in people with late stage MS?

    And if we are to begin to exclude the most heavily disabled people in trials - then should we do the same to people with ALS?

    Professor Coyle makes some very valid points. But her data on progressive disease natural history is selective (possibly due to time constraints, not lack of rigour), and her conclusions on exclusion, while logical, fail to embrace the necessity of hope that must drive all noble science.

  2. Thank you for the summary.

    I think it’s not impossible to have separate trials for people in wheelchairs and for people with lower EDSS. I don’t think the problem is if there is money to run such trials, I think the problem is distribution of money.

    Registries are supposed to track post marketing data in a non gold standard trial setting, but still it is only now that I’m hearing about some data about from Biogen and Roche about the effect of t and b cell DMTs on functions other than legs and walking. Tysabri was released in 2004 and Ritixumab used off label in some countries for a long time.

    Who is going to lobby for money (and interest) to be spent on any such trials? Apparently not me, because according to John Oliver’s humorous report,$24 billion was spent one year on marketing to health care providers and $4 billion to consumers (somewhere);

    If neuros should have some social responsibility in antagonising for much needed data, how is change going to come from them? By debating whether potent DMTs should be given to people in wheelchairs without having important data to enable them to make those decisions? I’ve heard about reliance on clinical experience in the absence of meaningful data, but the problem with it is that when I visited 6 different neuros I got 6 different clinical experiences which were often contradictory.

    If the neruos are discussing whether people with MS in wheelchairs should be included in clinical trials, instead of discussing how to obtain the much needed data to enable meaningful patient shared decision making and patent centred care even for people with MS in wheelchairs then I fear if in her lifetime my partner does end up in wheelchair, despite her best efforts to prevent that, the MS industry will still be debating immunosuppressant DMTS’ effects on progressive MS, instead of presenting her with meaningful information. I feel much of this is old news and I’m impatient.

    I recognise the efforts of this blog in addressing these issues by advocating inclusion. Perhaps I’m pessimistic (and if I am it’s all happened since August 2014 and visiting a remarkable number of neuros). But my perspective is as follows: this blog has been advocating some of these ideas for a number of years now. Theorising and collecting bits and pieces of data that comes out here and there that supports or negates aspects of theories such as the therapeutic lag. We have had Tysabri on the market since 2004 for RRMS and Rituximab used off label for about the same amount of time. 12 years later, failed trials and phrases such as “this doesn’t work in progressive MS”, we are still evaluating exactly what progressive MS is, how to get around the shortcomings associated with EDSS as a measuring tool, if progressive MS is concurrent or a separate entity and if it’s associated with relapses. The more progressive neuros are recognising slowly that progressive/relapsing label is perhaps less important in the context of DMTs, and that perhaps DMTs have a place where there is inflammation: but how much inflammation do we pick up on MRIs, how much do we miss and how reliant are we on MRIs and that subjective clinical experience in decision making are matters for personal and professional reflection.

    Can that reflection take place if we are debating whether people in wheelchairs with MS should be included in clinical trials rather than discussing how to obtain the desperately needed data?

  3. So Patricia Coyle says
    "People with MS in wheelchairs are not ideal to show such a time-related change for multiple reasons:
    1) They typically have had bad MS for a long time, have accumulated a lot of CNS damage, and have the least CNS reserve
    2) They do not have EDSS in the walking part of the scale, which is where changes are most commonly seen quickly; they are in the EDSS ≥7 range, where EDSS changes slowly if at all
    3) They have more confounding comorbidities, more symptoms that are not as well managed, less physical exercise tolerance, all of which can interfere with their evaluation
    But these are not reasons to exclude people in wheelchairs from trials.
    Point 1 is a reason to exclude people who have had MS for a long time from trials, whether they are in a wheelchair or not.
    Point 2 is a reason to use other things as well as the EDSS in the evaluation of how well a drug works (9 hole peg test for example).
    Point 3 is a reason to exclude people with comorbidities and less physical tolerance for exercise, again whether they are in wheelchairs or not - it is not a reason to exclude people in wheelchairs. Presumably all the people in the trial (and everyone else with MS) should have their symptoms managed as well as possible, again whether they are in a wheelchair or not.
    I haven't watched the debate but I should think Dr K made mincemeat of this doctor because her arguments are poor.

    1. DrK went on first and Prof Coyle would have given Hillary Clinton a good run for her money. She was quite formidable. The wagging finger and the "can't do it" sticks in my memory.

      "Current and past practice has been to routinely exclude Wheelchair people from pivotal trials, nothing has changed to rethink this.
      This is because this small MS population has significant prior CNS damage, loss of CNS reserve, confounding co-morbid issues and less function to assess and to loose, if fact you can make a very strong case to continue this practice for pivotal trials which are so critical, you don’t want to mess up, have a treatment that really worked but because you entered a poor (…study group), you didn’t use your inclusion exclusion criteria properly, you screwed it up and you lost, you lost the potential treatment. Can’t do it!, Can’t to it!, Can’t do it!"

    2. Patricia Coyle seems to be using wheelchair use as a proxy for a lot of other things. But it doesn't seem to me to be a good proxy, for the length of time a person has had MS, or how it has affected their hand function, or whether they have comorbidities, or whether their thinking capacity is affected. That is at least as likely to mess up trial results as including people in wheelchairs. For example, if the trial includes people who have had MS for a long time and have lots of neurological damage but are still walking, they may not react to the drugs as quickly as you would want. Whereas some wheelchair users have not have MS very long but have an aggressive form of the disease and you might want them in the trial. I don't think she made a good case for excluding wheelchair users.

  4. I have great respect for Pat Coyle, she's a remarkable person.

    I completely understand what she has said and its valid.

    However, exclusion of hand and upper limb function is a mistake from word go not only in PPMS trials but all MS trials.

    The EDSS scale first is a rather subjective based upon mainly visual assessment. The 25 foot walk is a timed walk. As an MS patient not in trials and having not even taken a DMT for the first 7+ years of my MS I can say both of these forms of measurement strike at the term "anecdotal" as well.

    I've had good weeks, bad weeks, good months and bad months and that includes ambulation and my abilities in walking speed and/or distance.

    This has NOT made sense to me in trials. MRI data, makes sense. CSF measurement, makes sense. Atrophy, makes sense.

    Subjective data such as EDSS which is NOT granular enough, timed walks, peg tests all are pretty well... Jurassic given what could be applied via technology.

    Upper limb function on the other hand has quite a bit of assessment that is more granular. Range of motion, strength. Why is not leg strength measured in trials? Is not that just as foundational?

    I understand waypoints and endpoints and what Pat C. is saying is essentially the levels of disability in pwPPMS would set data askee and she's potentially right, probably in fact.

    But, that is not enough to justify exclusion. Quite the opposite in fact. It points to a MUCH more significant problem of data gathering and extraction and a need for new thinking towards clinical trials as a whole.

    It simply makes sense to gather as much data as is possible and create/define new mechanisms by which more granular data can be interpolated and interpreted.

    What we have now is this sort of wayback trials paradigm. Given especially neurodegenerative diseases that mindset just does not equate as the range of disability can be enormous. Here is person "A", cognitively they are 60% of their former self yet they ambulate just peachy. That skews a trial if EDSS comes as a marker just as much as person "B" who cant ambulate at all.

    A more quantifiable and quantitative mechanism is really necessary towards functional musculature and associated capabilities *IF* that is to be considered as waypoints/endpoint measurements of disability.

    It is more easily measured than cognition, emotional disturbances, pain etc.

    If motor function is to be utilized in trials then it should really be done proper and preferably in a less broadband subjective form. Measure range of motion. Measure musculature strength. Why is evoked potentials not in the mix? Again, there sits measurable data.

    What we have now is what happens when potential to market, science and doing what is right collide.

  5. The question of advanced MSers, i.e. high EDSS, participating in DMT trials is dependent on the natural history of MS. Do PPMS and SPMS have active inflammation that is the target of clinical trials? If so than pwMS in wheelchairs should be able to participate. Since the EDSS is a less than perfect more objective tests such as OCT, MRI and CSF biomarkers would be a better choice for efficacy. If we don't understand what is driving MS progression than arguing for or against is frivolous.

  6. If a person has a lot of spinal damage, they will end up in a wheelchair relatively early. But they may have less overall CNS damage than someone with better mobility. A lot of what Coyle says seems to me to be based on patchy, blinkered logic and rather arbitrary theoretical foundations. And generally it is uninspiring. Although I don't doubt that she has the "ultimate higher good" in her mind, that she is well meaning. Perhaps she has just become stuck in her ways, as we all tend to do as we get older.

  7. I think all readers have to step back and realise that a debate is what it is a debate. The speakers are asked to take sides and debate the issue and raise points to support their argument. A debate is competitive and a good way of raising issues about a certain topic. Please note that if one of the opponents takes a certain position it doesn't mean he/she really supports the position they take in the debate.

    1. I think the problem is the debate, not the readers.

    2. Healthy debate is a good thing.

      What becomes apparent however is what many already know. The trial process itself is exclusionary based on the nature of the trial(s) .vs. the value of all data that might be gathered and/or extracted.

      When commercial interests are involved those interests are a market.

      Ampyra is a good example. In the USA prescribing of the medication is based on 25 foot walk ambulation. That is how FDA approval was tackled and probably the fastest way to get the drug approved for MS usage.

      Ampyra however can impact many many symptoms as it essentially helps nerve conduction (basically). But, in order for it to be properly prescribed, 25 ft walk parameters are used.

      All odd, Low Dose Naltrexone helps some people, some not. It gets prescribed off label.

      Evidence based science is important yet at the sametime so is real-world in the field results. The two dont tend meet well and when market becomes involved things can go more askew.

      There should be better mechanisms but defining them to suit all prospect interests be very complex indeed.

      That said, EDSS, peg tests, 25 foot walks are measurement mechanisms but they should really be expanded upon if for no other reason knowledge. Just as trials continue in drugs to display additional data perhaps towards marketing so should that of base data gathering.

      I dont expect change in these regards. Evoked potentials is often used as a marker to help diagnose MS but apparently does not get used in trials. Odd.

      Lower limb function statistically appears more prevailing than upper limb function but this should not reduce significance since everyone army of lesions differs.

  8. "pristine pure" and "more baggage". Terrible terminology at use here.


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