In some cases it can take more than 6 months to get approved with a DMT. Would running a short (3 - 6 months) study against placebo with the safeguards you suggest jeopardise patient health and outcomes that much?
Sure for phase 3 and longer term studies it's a different matter but for short term studies? As you say, a blanket ban on placebo studies will force drug development to grind to a halt.
I like this. Maybe it's unethical in a pure world where everyone gets the treatment they need in a timely fashion, but a short delay _that might happen anyway, for much worse reasons_ seems fine.
As a PWMS who is currently assessing my options for restarting a DMT after a recent relapse, I am seriously considering joining the Vidofludimus phase 3 trial despite having to travel from Wales to Sheffield. I think that, in this case, the drug sounds so interesting and promising that it may be worth taking the risk on the placebo phase. (I haven't been on a DMT for the last 5 years anyway.) After the placebo period I presume I would be entitled to the actual drug for the 8 year open label extension period, and before it is available generally.
However, I am still waiting to hear back whether this will actually be possible, and the details of the agreement I'd be entering into. I'd have thought it would be ethical to give me the choice of doing this? (Although the idea of switching straight to the actual drug in the case of a relapse would clearly be preferable.)
I agree! I believe this should be the patient’s decision. In the grand scheme of MS things, I’d say 6 months is minimal, particularly with interventions of a drug or treatment if things should go sideways. We need new DMTs and we certainly need answers for smouldering MS. I don’t believe this is unethical providing the patient is makes his or her own informed decision.
Personally, I think this is exciting, and no, I don’t think it is unethical. If a patient enters a trial (and I do not believe a limited 6 month trial is breathtakingly dangerous) with full knowledge, understanding and consent, this could benefit myriad pwMS. If it benefits the smouldering, that would be amazing. With protections built in should critical issues arise, I just do not see such trials as unethical. The potential benefits outweigh the risks, particularly if, again, the study is structured to monitor any crises that should arise in placebo arm. Just my two cents.
1st point is that drugs on trial are usually pitted against older low efficacy drugs. Is that non more unethical than using a placebo arm.
2ndly, using placebos is arguably not even generally a cross the board unhelpful/ineffective given. A not-insignificant number defy the odds and do well off dmts altogether (even if this is a minority it's still worth considering.
3rdly, concerning the use of steroids in infusions is a possible confounder in that it is a performance enhancer which I think would be banned in pro sports due to equanimity...
Lastly I am not sure asking us pwMS is east to argue as either the right or wrong choice. Perspectives vary and vary for various reasons! Also, I believe it is NOT
Unethical to change our ethics OVER TIME and as years of research advance.
Children learn quicker for many biogical reasons, but also because they far less afraid of being wrong!
and statistics are like clay and are often shaped in various directions. I'm not negative or skeptic but realism is my goal, so I always follow the money
It Richard Burt's 1st clinical , on ethical terms he offered HSCT (which far outperformed Tysabri) HSCT even though it would jeopardize long term study potential trial he offered. But again each situation is different (plus as I like to say 'god (or Darwin only knows' - so we gotta try try and try again maybe..... though I can't really say I know of what I speak... :)
"How should help decide on whether or not a placebo-controlled phase 2 MS trial is unethical?" I think the "How" in this survey question should say "Who"?
That nitpicking apart, I feel the PwMS should decide whether or not they want to participate in a trial. 3-6 months of possibly not being on a DMT doesn't seem like a big deal to me. I live in Canada and have access to all the things, however time being the variable that slows that down. I've waited up to a year to get a neuro appt, MRI, start/switch to a new DMT, so 3-6 months seems like nothing to me. I would participate in trial, but I'm too old now (57) to be considered for one, even if I wanted to participate.
Is there an age limit? I would have thought the progressive/smouldering form of this shitty disease is more attributable to older folk than younger, generally speaking.
I agree with you. I don't really I know I am just going on most other trials that seem to have a cut off age of 50. I'm speculating that researchers may find that older people have too many other comorbidities that would mess up the data? Or society at large just don't care about people once you hit a certain age. But what the hell do I know?
Yes, ME, me too. But I would do this in a heartbeat. As an older smoulderer, I would welcome any drug that would address this and were I younger, I would not hesitate to participate in such a trial.
The best trials are head to head. You either get a dominant treatment, an ICER or really good evidence that the new treatment is not as good as the existing treatment. The difficulty is convincing pharma to allow you to potentially prove that a new treatment dominates the drug that they have spent money on developing. This is why older off patent (less effective) meds are usually used in head to head research.
Yes, we have lost equipoise. All of your suggestions would be acceptable alternatives in the event placebo-control was necessary in a trial.
There are plenty of pwMS like me who aren't on DMTs anyway; in my case there isn't an ethical concern utilizing a placebo. I'm sure there are other pwMS who for other reasons don't see placebo-controlled trials as unethical either. It comes down to personal agency.
Theoretically, I understand the ethical concern regarding placebo-controlled trials, and appreciate the questioning and exploration into this subject. In the end, pwMS want/need viable therapies, and if placebo-controlled trials are the way to get it, fine: DO IT. No one is forcing pwMS to participate in a trial, and they have to sign that they understand risks associated with participation anyway.
I would think that if the mitigating measures you've listed were considered and utilized if/when appropriate in the design of a trial, I'd be satisfied. If placebo-control isn't necessary, then don't use it. If it is imperative to the advancement of science, use it. But we ask the powers that be to quit making all these decisions without input from pwMS. We aren't children, we are competent observers in matters involving MS, and can provide expert witness and testimony from a perspective that stakeholders w/out MS frankly don't have, but need. Tap into this valuable resource of patient experience; include pwMS at the table.
You are doing what most researchers and the US FDA fail to do which is involve the pwMS! I am part of Solving MS and we are very much oriented to giving pwMS a voice in research and trial design. So your question and survey are 🎯. My plea to researchers: ASK pwMS. Stop making these decisions without input from the MS community. Full stop.
Rebecca, thank you. Can this survey be sent out to members of Solving MS? The bigger the response we get to the survey, the more powerful the results will be.
Someone had already posted about your blog post in our Solving MS Research Study Group on fb, but I created a separate post asking that pwMS fill out the questionnaire in hopes of garnering more direct attention to the link ;)
Typically how many people take part in a phase 2 trial?
Of these how many will be on placebo?
You said people who partake in trials do better longer term. Does this apply to phase 2 trials or only to phase 3? ( if phase 2, wow! Really makes the point time in brain and even 6 months of intensive monitoring can make a difference. This then raises so many other ethical questions about standards of treatment in MS)
Is this drug available for other diseases already or is it a novel drug?
I think this is an incredibly difficult question. At least for me, really. For the old timers perhaps dealing with smoldering, it is much different than a newly diagnosed. The latter, most of them, are incapable of making significantly fine distinctions in their decisions at first. Too soon and not enough experience, you can’t really expect otherwise. Part of the disease is uncertainty and confusion, unlike most other illnesses. It is a major component.
In my humble opinion, at the Selfie, we are in the top 25% of rational informed decision makers about our own illness. The next 50% can be seen, for example, on Reddit, who follow peer pressure, gossip, miracle cures, unsubstantiated rumor and the like, although it seems a majority are being treated there. The lower 25% can’t effectively deal with MS themselves and wait until too late and never really know what to make of it. Those are the people who need to be protected. The available pool of subjects for the study of this disease is skewed by the misinformed and un-motivated. I don’t think we are aware of just how much this is true and what kind of difference this can make. My opinion.
As a PwMS and currently awaiting an update on the start of a trial, I fully accept that I may be on a placebo and I do not think this is unethical as is supporting future developments of essential and likely life improving treatments. If monitored whilst on a trial and an individuals condition worsens then it would be hoped / expected that an approved alternative would be made available. I would far rather ‘risk’ being on a placebo than no treatment at all.
So you were diagnosed "multiple" with evidence of only one sclerosis? Clinically Isolated Syndrome? But that's not MS; even so there are treatments for that too, according to NHS (mstrust.org.uk I'm in US). I'd contact the sponsors of the (a) trial myself and ask questions.
Sorry, I don't know what your expertise is but I was diagnosed with multiple sclerosis. I don't know why you've decided to argue with me. You clearly do not understand how the healthcare system works in the UK. The question was for Gavin not you.
In some cases it can take more than 6 months to get approved with a DMT. Would running a short (3 - 6 months) study against placebo with the safeguards you suggest jeopardise patient health and outcomes that much?
Sure for phase 3 and longer term studies it's a different matter but for short term studies? As you say, a blanket ban on placebo studies will force drug development to grind to a halt.
I like this. Maybe it's unethical in a pure world where everyone gets the treatment they need in a timely fashion, but a short delay _that might happen anyway, for much worse reasons_ seems fine.
Agree.
Good point, yes!
As a PWMS who is currently assessing my options for restarting a DMT after a recent relapse, I am seriously considering joining the Vidofludimus phase 3 trial despite having to travel from Wales to Sheffield. I think that, in this case, the drug sounds so interesting and promising that it may be worth taking the risk on the placebo phase. (I haven't been on a DMT for the last 5 years anyway.) After the placebo period I presume I would be entitled to the actual drug for the 8 year open label extension period, and before it is available generally.
However, I am still waiting to hear back whether this will actually be possible, and the details of the agreement I'd be entering into. I'd have thought it would be ethical to give me the choice of doing this? (Although the idea of switching straight to the actual drug in the case of a relapse would clearly be preferable.)
As with all things MS, information and education is absolutely critical to enable pwms to make their own informed decisions.
The ethicality should be determined by pwms as much if not more so than HCP's.
I'm a tad tired of governments, and by association areas of public services, telling us what is good for us without ever asking.
HCP's in general do a fantastic job but give me the information and I'll tell you what's best for me, not the other way around!!
I agree! I believe this should be the patient’s decision. In the grand scheme of MS things, I’d say 6 months is minimal, particularly with interventions of a drug or treatment if things should go sideways. We need new DMTs and we certainly need answers for smouldering MS. I don’t believe this is unethical providing the patient is makes his or her own informed decision.
Personally, I think this is exciting, and no, I don’t think it is unethical. If a patient enters a trial (and I do not believe a limited 6 month trial is breathtakingly dangerous) with full knowledge, understanding and consent, this could benefit myriad pwMS. If it benefits the smouldering, that would be amazing. With protections built in should critical issues arise, I just do not see such trials as unethical. The potential benefits outweigh the risks, particularly if, again, the study is structured to monitor any crises that should arise in placebo arm. Just my two cents.
1st point is that drugs on trial are usually pitted against older low efficacy drugs. Is that non more unethical than using a placebo arm.
2ndly, using placebos is arguably not even generally a cross the board unhelpful/ineffective given. A not-insignificant number defy the odds and do well off dmts altogether (even if this is a minority it's still worth considering.
3rdly, concerning the use of steroids in infusions is a possible confounder in that it is a performance enhancer which I think would be banned in pro sports due to equanimity...
Lastly I am not sure asking us pwMS is east to argue as either the right or wrong choice. Perspectives vary and vary for various reasons! Also, I believe it is NOT
Unethical to change our ethics OVER TIME and as years of research advance.
Children learn quicker for many biogical reasons, but also because they far less afraid of being wrong!
You are absolutely right 👍🏼. Proving the new drugs against the old and ineffective drugs could also be considered as "unethical".
and statistics are like clay and are often shaped in various directions. I'm not negative or skeptic but realism is my goal, so I always follow the money
It Richard Burt's 1st clinical , on ethical terms he offered HSCT (which far outperformed Tysabri) HSCT even though it would jeopardize long term study potential trial he offered. But again each situation is different (plus as I like to say 'god (or Darwin only knows' - so we gotta try try and try again maybe..... though I can't really say I know of what I speak... :)
"How should help decide on whether or not a placebo-controlled phase 2 MS trial is unethical?" I think the "How" in this survey question should say "Who"?
That nitpicking apart, I feel the PwMS should decide whether or not they want to participate in a trial. 3-6 months of possibly not being on a DMT doesn't seem like a big deal to me. I live in Canada and have access to all the things, however time being the variable that slows that down. I've waited up to a year to get a neuro appt, MRI, start/switch to a new DMT, so 3-6 months seems like nothing to me. I would participate in trial, but I'm too old now (57) to be considered for one, even if I wanted to participate.
Is there an age limit? I would have thought the progressive/smouldering form of this shitty disease is more attributable to older folk than younger, generally speaking.
I agree with you. I don't really I know I am just going on most other trials that seem to have a cut off age of 50. I'm speculating that researchers may find that older people have too many other comorbidities that would mess up the data? Or society at large just don't care about people once you hit a certain age. But what the hell do I know?
Yes, ME, me too. But I would do this in a heartbeat. As an older smoulderer, I would welcome any drug that would address this and were I younger, I would not hesitate to participate in such a trial.
The best trials are head to head. You either get a dominant treatment, an ICER or really good evidence that the new treatment is not as good as the existing treatment. The difficulty is convincing pharma to allow you to potentially prove that a new treatment dominates the drug that they have spent money on developing. This is why older off patent (less effective) meds are usually used in head to head research.
You are referring to phase 3 and not phase 2 or proof of concept studies. The placebo control period is needed for the latter and not the former.
Yes, we have lost equipoise. All of your suggestions would be acceptable alternatives in the event placebo-control was necessary in a trial.
There are plenty of pwMS like me who aren't on DMTs anyway; in my case there isn't an ethical concern utilizing a placebo. I'm sure there are other pwMS who for other reasons don't see placebo-controlled trials as unethical either. It comes down to personal agency.
Theoretically, I understand the ethical concern regarding placebo-controlled trials, and appreciate the questioning and exploration into this subject. In the end, pwMS want/need viable therapies, and if placebo-controlled trials are the way to get it, fine: DO IT. No one is forcing pwMS to participate in a trial, and they have to sign that they understand risks associated with participation anyway.
I would think that if the mitigating measures you've listed were considered and utilized if/when appropriate in the design of a trial, I'd be satisfied. If placebo-control isn't necessary, then don't use it. If it is imperative to the advancement of science, use it. But we ask the powers that be to quit making all these decisions without input from pwMS. We aren't children, we are competent observers in matters involving MS, and can provide expert witness and testimony from a perspective that stakeholders w/out MS frankly don't have, but need. Tap into this valuable resource of patient experience; include pwMS at the table.
You are doing what most researchers and the US FDA fail to do which is involve the pwMS! I am part of Solving MS and we are very much oriented to giving pwMS a voice in research and trial design. So your question and survey are 🎯. My plea to researchers: ASK pwMS. Stop making these decisions without input from the MS community. Full stop.
And thank you for asking us, Prof G.😉
Rebecca, thank you. Can this survey be sent out to members of Solving MS? The bigger the response we get to the survey, the more powerful the results will be.
✅
Someone had already posted about your blog post in our Solving MS Research Study Group on fb, but I created a separate post asking that pwMS fill out the questionnaire in hopes of garnering more direct attention to the link ;)
Typically how many people take part in a phase 2 trial?
Of these how many will be on placebo?
You said people who partake in trials do better longer term. Does this apply to phase 2 trials or only to phase 3? ( if phase 2, wow! Really makes the point time in brain and even 6 months of intensive monitoring can make a difference. This then raises so many other ethical questions about standards of treatment in MS)
Is this drug available for other diseases already or is it a novel drug?
The ethics of placebo-controlled trials aside, I wonder if this would be useful for people who have done IRT, but then have a relapse.
Somewhat related: does vidofludimus or teriflunomide have any effect on the TLR4/MyD88 pathway? Have TLR4 inhibitors ever been considered in MS?
I think this is an incredibly difficult question. At least for me, really. For the old timers perhaps dealing with smoldering, it is much different than a newly diagnosed. The latter, most of them, are incapable of making significantly fine distinctions in their decisions at first. Too soon and not enough experience, you can’t really expect otherwise. Part of the disease is uncertainty and confusion, unlike most other illnesses. It is a major component.
In my humble opinion, at the Selfie, we are in the top 25% of rational informed decision makers about our own illness. The next 50% can be seen, for example, on Reddit, who follow peer pressure, gossip, miracle cures, unsubstantiated rumor and the like, although it seems a majority are being treated there. The lower 25% can’t effectively deal with MS themselves and wait until too late and never really know what to make of it. Those are the people who need to be protected. The available pool of subjects for the study of this disease is skewed by the misinformed and un-motivated. I don’t think we are aware of just how much this is true and what kind of difference this can make. My opinion.
As a PwMS and currently awaiting an update on the start of a trial, I fully accept that I may be on a placebo and I do not think this is unethical as is supporting future developments of essential and likely life improving treatments. If monitored whilst on a trial and an individuals condition worsens then it would be hoped / expected that an approved alternative would be made available. I would far rather ‘risk’ being on a placebo than no treatment at all.
What about people who on diagnosis do not meet the criteria for a DMT? Could they not be given a chance to participate in trails?
How could you not meet the criteria for a DMT if you were diagnosed?
To recieve a DMT on the NHS you need to have had 2 relapses within the last 2 years, or one relapse and have active disease showing on an MRI
So you were diagnosed "multiple" with evidence of only one sclerosis? Clinically Isolated Syndrome? But that's not MS; even so there are treatments for that too, according to NHS (mstrust.org.uk I'm in US). I'd contact the sponsors of the (a) trial myself and ask questions.
Sorry, I don't know what your expertise is but I was diagnosed with multiple sclerosis. I don't know why you've decided to argue with me. You clearly do not understand how the healthcare system works in the UK. The question was for Gavin not you.
Very sorry, I apologize.