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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #451
    Quote Originally Posted by Wise Young View Post
    Pelican,

    I ask your opinion because I would like to know what you would consider to be a reasonably de-risked therapy that should go to trial. I respect your opinion as an investor. By the way, most spinal cord injury scientific advisors have never designed, organized, or participated in clinical trials, so I am not sure that their opinions are necessarily any more valid than yours. You (and others) have expressed the view here that any therapy that has not yet been tested in appropriate chronic spinal cord injury models should not be taken to clinical trial. There have been several groups that have been trying to say that clinical trials should be done only when specified criteria are met.

    I disagree that a therapy should meet some specified efficacy criteria before going to trial. It is already difficult enough to get therapies into clinical trials without some committee (usually a self-appointed committee with little or no experience with clinical trials) stopping therapies from going into clinical trial because somebody on the committee believes that a therapy does not work, that certain spinal cord injury models are not good, or other scientific politics. Yes, as I hope you and others here should have gathered, there is substantial scientific politics going on in spinal cord injury. There are many scientists pushing their own agenda, their theory, their treatment, and their model. They are competing with each other and they often have a lot at stake, including their reputation and funding.

    To get a therapy into trial, particularly in a non-profit network, one must convince literally hundreds of scientists, clinicians, investors, and patients that the therapy is worthwhile testing in preclinical studies, pursuade companies to donate the therapies, raise millions from skeptical organizations and donors, get regulatory approval from the FDA in the U.S. and regulatory authorities in other countries, get ethical and clinical approval from institutional review boards, and apply to dozens of funding agencies. Believe me, these are not trivial tasks and I don't think adding scientific politics to that burden is a good idea.

    Regarding clinical trials and risk, you are probably referring to risk of therapy proving to be not beneficial. I think of failure as a clinical trial that fails to provide credible data. For example, if ChinaSCINet shows definitively that umbilical cord blood mononuclear cells and lithium are not beneficial in chronic spinal cord injury, I would consider the trial a success. It means that we can close the door on umbilical cord blood mononuclear cell transplantation, which is already being practiced by clinics catering to medical tourists around the world. If the trial shows that umbilical cord blood mononuclear cells are beneficial, the trial would be even more successful. The only failure is if the trial were so poorly designed and conducted that we don't get a reliable answer one way or another.

    A review of how ChinaSCINet chose its trials illustrates that the situation is not as simple as you have suggested. In 2006, when we started the current series of trials for ChinaSCINet, the investigators of ChinaSCINet considered all the therapies that were available. We had several objectives:
    1. We wanted to prove to the world that we have a network that can carry out rigorous clinical trials rapidly and efficiently.
    2. We wanted to gain experience with testing of combination therapies in clinical trials.
    3. We wanted to test a cell therapy that is safe, readily available to the world if the treatment is effective, and that is already being used.
    4. We wanted a therapy that was safe. A trial that has to be stopped because of a safety issue means that we would have to start all over again.
    5. Of course, we wanted to have a therapy that would cure spinal cord injury.


    After reviewing all available therapies in 2006, we chose umbilical cord blood mononuclear cells and lithium because we thought these were the most promising, safe, and feasible therapies. Please note that neither of these therapies were discovered in my laboratory or "my" therapies in any sense of the word. My laboratory did not do the preclinical studies. As it is turning out, the choice of umbilical cord blood and lithium was a good one because phase II trials showed that the therapies are safe and have yielded interesting results that the group has decided to pursue. First, lithium seems to reduce severe neuropathic pain in people with chronic spinal cord injury and we are doing a phase III trial to confirm this unexpected finding. Second, umbilical cord blood mononuclear cells appear to stimulate growth of fiber bundles across the injury site of people with chronic spinal cord injury. Third, a surprising number of people are recovering locomotor function, albeit without early motor and sensory score changes. A phase III trial will confirm and convince the world that the treatment does or not does not have these effects. We could have also decided that the data that we have collected so far is not worthwhile following up and that we should start testing other therapies. Because it takes time to prepare therapies for trials, we are now seriously considering what therapy to test next after the planned Phase III trial is done. Believe me, there is no perfect therapy out there that is ready to go to trial. Should we wait? If so, how long?

    Wise.
    Dr Young, this is an absolutely tremendous post. Thank you very much for your explanation in your rationale for bringing your current trial to fruition. I agree 100% with your logic - the key to figuring out what will work is eliminating what will not work. We know air exists not because we see it, but we see the leaves move in the tree tops. As long as any trial lets us see the leaves move, it has value. Obviously some will be more valuable than others, but it seems we know so little, if we should be testing as much as we can.

    Pelican made an interesting point about limited resources etc and public vs. private funding. I do not believe that makes a difference. Everyone involved is motivated to prove their therapy works the best or is the best solution - less available money would logically mean that their evidential burden is high before it can be tested. Let it be so. I do not think anyone involved wants to go willy-nilly throwing money around - those that waste money will be proven out as poor scientists or managers.

    As long as we do not throw good money after treatments which we eliminate as not being useful to cure SCI, then I believe the system is essentially working properly. Certainly standing idly by is not an option and I think everyone agrees the time for that is over.

  2. #452
    Quote Originally Posted by paolocipolla View Post
    Wise,

    if I understand you correctly here above you agree that the "lesion environment" in chronic SCI is still a major problem.

    If there is one thing that disturbs me deeply in SCI research is the fact that the "lesion environment" (the scar) in chronic SCI hasn't been studied deeply by more labs yet. We could be much closer to a cure if we knew precisely what molecules, cells etc. are present in the "lesion environment" in chronic SCI.

    Paolo
    Paolo,

    Of course I believe that the lesion environment is a major problem. I have never said that it is not. I said that I disagree with the use of the word "scar" to refer to the lesion environment. This does not mean that I think the lesion environment is not a major problem. I have spent almost my entire career studying the contusion model. It is the most difficult model to regenerate. I just think that trying to oversimplify the lesion environment as "glial scar" is wrong.

    There are many aspects in the contusion site that we haven't discussed, including the possibility that the astrocytic environment of the contusion site is too attractive (compared to the surrounding regions) for axons to leave. Jerry Silver did a great experiment many years ago that shows that axons that start out growing an inhibitory environment can grow in an inhibitory environment but it stops being able to do so when it comes into contact with an environment that facilitates growth.

    It is not true that the injury site has not been studied deeply by any laboratory. Many laboratories have studied the environment of the contused spinal cord, including some laboratories that have characterize the expression and time course of every gene and every protein at the lesion site. There is a lot of data but difficult to interpret. It is hard to know what every protein does in the context of the lesion. To prove cause and effect you need to remove the various proteins one by one, to see their effects. There are laboratories that are beginning to do this is genetic model systems, such as transgenic mice, transgenic zebrafish, and also lamprey.

    Wise.

  3. #453
    Quote Originally Posted by paolocipolla View Post
    Wise,

    all these tasks above should become much easier if you have at least one animal study (in chronic SCI) that show efficacy of the therapy you want to bring to clinical trial, so I believe that to have a positive animal study is essential (but maybe not enough) to raise the money needed for a clinical trial.

    BTW I am an investor too since, as you know, I am putting time and money to help finding a cure for chronic SCI.

    Paolo
    No, Paolo. Most of these tasks have been already accomplished for testing umbilical cord blood cells and lithium. You haven't helped.

    Instead of being so negative, perhaps you can answer the question that I asked Pelican. What therapy would you suggest?

    Wise.

  4. #454
    Quote Originally Posted by cripwalk View Post
    Dr Young, this is an absolutely tremendous post. Thank you very much for your explanation in your rationale for bringing your current trial to fruition. I agree 100% with your logic - the key to figuring out what will work is eliminating what will not work. We know air exists not because we see it, but we see the leaves move in the tree tops. As long as any trial lets us see the leaves move, it has value. Obviously some will be more valuable than others, but it seems we know so little, if we should be testing as much as we can.

    Pelican made an interesting point about limited resources etc and public vs. private funding. I do not believe that makes a difference. Everyone involved is motivated to prove their therapy works the best or is the best solution - less available money would logically mean that their evidential burden is high before it can be tested. Let it be so. I do not think anyone involved wants to go willy-nilly throwing money around - those that waste money will be proven out as poor scientists or managers.

    As long as we do not throw good money after treatments which we eliminate as not being useful to cure SCI, then I believe the system is essentially working properly. Certainly standing idly by is not an option and I think everyone agrees the time for that is over.
    cripwalk,

    Thank you for your comments. I agree very much with what you say.

    Wise.

  5. #455
    Senior Member lynnifer's Avatar
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    Quote Originally Posted by crabbyshark View Post
    You've flippantly blown off the idea that ibuprofen could somehow help you despite scientific evidence suggesting that ibuprofen inhibits RhoA and your own admission that you've had return over the years while taking hundreds of bottles of Motrin. Correlation does not equal causation (which is why there are clinical trials) but I would think you'd be more considerate than that.
    You read but did not comprehend. The Motrin was taken LONG AFTER I had a patch of sensation come back.
    Roses are red. Tacos are enjoyable. Don't blame immigrants, because you're unemployable.

    T-11 Flaccid Paraplegic due to TM July 1985 @ age 12

  6. #456
    Quote Originally Posted by Wise Young View Post
    Pelican,

    I ask your opinion because I would like to know what you would consider to be a reasonably de-risked therapy that should go to trial. I respect your opinion as an investor. By the way, most spinal cord injury scientific advisors have never designed, organized, or participated in clinical trials, so I am not sure that their opinions are necessarily any more valid than yours. You (and others) have expressed the view here that any therapy that has not yet been tested in appropriate chronic spinal cord injury models should not be taken to clinical trial. There have been several groups that have been trying to say that clinical trials should be done only when specified criteria are met.

    I disagree that a therapy should meet some specified efficacy criteria before going to trial. It is already difficult enough to get therapies into clinical trials without some committee (usually a self-appointed committee with little or no experience with clinical trials) stopping therapies from going into clinical trial because somebody on the committee believes that a therapy does not work, that certain spinal cord injury models are not good, or other scientific politics. Yes, as I hope you and others here should have gathered, there is substantial scientific politics going on in spinal cord injury. There are many scientists pushing their own agenda, their theory, their treatment, and their model. They are competing with each other and they often have a lot at stake, including their reputation and funding.

    To get a therapy into trial, particularly in a non-profit network, one must convince literally hundreds of scientists, clinicians, investors, and patients that the therapy is worthwhile testing in preclinical studies, pursuade companies to donate the therapies, raise millions from skeptical organizations and donors, get regulatory approval from the FDA in the U.S. and regulatory authorities in other countries, get ethical and clinical approval from institutional review boards, and apply to dozens of funding agencies. Believe me, these are not trivial tasks and I don't think adding scientific politics to that burden is a good idea.

    Regarding clinical trials and risk, you are probably referring to risk of therapy proving to be not beneficial. I think of failure as a clinical trial that fails to provide credible data. For example, if ChinaSCINet shows definitively that umbilical cord blood mononuclear cells and lithium are not beneficial in chronic spinal cord injury, I would consider the trial a success. It means that we can close the door on umbilical cord blood mononuclear cell transplantation, which is already being practiced by clinics catering to medical tourists around the world. If the trial shows that umbilical cord blood mononuclear cells are beneficial, the trial would be even more successful. The only failure is if the trial were so poorly designed and conducted that we don't get a reliable answer one way or another.

    A review of how ChinaSCINet chose its trials illustrates that the situation is not as simple as you have suggested. In 2006, when we started the current series of trials for ChinaSCINet, the investigators of ChinaSCINet considered all the therapies that were available. We had several objectives:
    1. We wanted to prove to the world that we have a network that can carry out rigorous clinical trials rapidly and efficiently.
    2. We wanted to gain experience with testing of combination therapies in clinical trials.
    3. We wanted to test a cell therapy that is safe, readily available to the world if the treatment is effective, and that is already being used.
    4. We wanted a therapy that was safe. A trial that has to be stopped because of a safety issue means that we would have to start all over again.
    5. Of course, we wanted to have a therapy that would cure spinal cord injury.


    After reviewing all available therapies in 2006, we chose umbilical cord blood mononuclear cells and lithium because we thought these were the most promising, safe, and feasible therapies. Please note that neither of these therapies were discovered in my laboratory or "my" therapies in any sense of the word. My laboratory did not do the preclinical studies. As it is turning out, the choice of umbilical cord blood and lithium was a good one because phase II trials showed that the therapies are safe and have yielded interesting results that the group has decided to pursue. First, lithium seems to reduce severe neuropathic pain in people with chronic spinal cord injury and we are doing a phase III trial to confirm this unexpected finding. Second, umbilical cord blood mononuclear cells appear to stimulate growth of fiber bundles across the injury site of people with chronic spinal cord injury. Third, a surprising number of people are recovering locomotor function, albeit without early motor and sensory score changes. A phase III trial will confirm and convince the world that the treatment does or not does not have these effects. We could have also decided that the data that we have collected so far is not worthwhile following up and that we should start testing other therapies. Because it takes time to prepare therapies for trials, we are now seriously considering what therapy to test next after the planned Phase III trial is done. Believe me, there is no perfect therapy out there that is ready to go to trial. Should we wait? If so, how long?

    Wise.
    Thanks for your comprehensive reply Wise.

    I agree that the advisory boards are often so political that they end up choosing "nothing" by default. This is definitely an issue that needs to be resolved.

    I agree that advisory boards must be suitably skilled members with academic, pre-clinical, clinical and commercial backgrounds. A balance is vital. Patient representation would also be useful if possible. Perhaps members of advisory boards should be asked to "reapply" for their membership on an 24-month basis? It is after all an honour to serve on a scientific advisory board.

    I agree that clinical trials are incredibly tough to execute. I think everyone appreciates the incredible amount of hard work that has been put in to make this a reality.

    I agree that the success of a trial should be measured by robustness of the data produced ie reliable answers either way. I understand your theory of 'elimination'. There's nothing wrong with it 'in theory'. However, in reality, to sustain a non-commercial trial network that relies on funding from supporters affected by chronic SCI you may only have a finite number of chances before the faith and support is lost. We are a fickle bunch unfortunately At the same time, although China has a large population of SCIs - the number willing to take part in trials is still finite. Will participants continue to sign up in sufficient number when the network has a track record of multiple trials without 'success in their eyes'? Something to consider.

    We know that combination therapies are incredibly complex to plan clinical trials for. And I, like everyone here, want to see therapies racing through the pipeline. But, as an 'investor' who has to tirelessly interface neutrally with dozens of hungry scientists all competing, politicking, bamboozling and sniping, I'd personally like to see an additional step in the pre-clinical work for combination strategies. This way we may see at least one or two more of the dozens of scientists agreeing that the therapy is sound for clinical trial. And that would make me more confident in my 'investment' ie de-risked. Of course, it could still fail - but that's risk management.

    In terms of therapies to take to trial - well, there is one therapy that everyone seems to be sitting on their hands about. And everyone in the field seems to be OK that one commercial entity can hold it's potential in the pipeline when there is enough data to show that breathing in chronic injuries could be restored. And yes, there is a human-grade version of the agent available elsewhere. That's a crying shame - actually, that's a travesty for those on ventilators!

  7. #457
    Senior Member lynnifer's Avatar
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    Quote Originally Posted by Fly_Pelican_Fly View Post

    In terms of therapies to take to trial - well, there is one therapy that everyone seems to be sitting on their hands about. And everyone in the field seems to be OK that one commercial entity can hold it's potential in the pipeline when there is enough data to show that breathing in chronic injuries could be restored. And yes, there is a human-grade version of the agent available elsewhere. That's a crying shame - actually, that's a travesty!
    Well said. And it is a travesty if not a human rights issue.
    Roses are red. Tacos are enjoyable. Don't blame immigrants, because you're unemployable.

    T-11 Flaccid Paraplegic due to TM July 1985 @ age 12

  8. #458
    Wise, what is holding back the use of chondroitinase in your future plans? Do you think the hundreds of positive pre-clinical results at acute stages as well as positive results now in several long chronic models aren't sufficient?

  9. #459
    Quote Originally Posted by Fly_Pelican_Fly View Post
    Thanks for your comprehensive reply Wise.

    I agree that the advisory boards are often so political that they end up choosing "nothing" by default. This is definitely an issue that needs to be resolved.

    I agree that advisory boards must be suitably skilled members with academic, pre-clinical, clinical and commercial backgrounds. A balance is vital. Patient representation would also be useful if possible. Perhaps members of advisory boards should be asked to "reapply" for their membership on an 24-month basis? It is after all an honour to serve on a scientific advisory board.

    I agree that clinical trials are incredibly tough to execute. I think everyone appreciates the incredible amount of hard work that has been put in to make this a reality.

    I agree that the success of a trial should be measured by robustness of the data produced ie reliable answers either way. I understand your theory of 'elimination'. There's nothing wrong with it 'in theory'. However, in reality, to sustain a non-commercial trial network that relies on funding from supporters affected by chronic SCI you may only have a finite number of chances before the faith and support is lost. We are a fickle bunch unfortunately At the same time, although China has a large population of SCIs - the number willing to take part in trials is still finite. Will participants continue to sign up in sufficient number when the network has a track record of multiple trials without 'success in their eyes'? Something to consider.

    We know that combination therapies are incredibly complex to plan clinical trials for. And I, like everyone here, want to see therapies racing through the pipeline. But, as an 'investor' who has to tirelessly interface neutrally with dozens of hungry scientists all competing, politicking, bamboozling and sniping, I'd personally like to see an additional step in the pre-clinical work for combination strategies. This way we may see at least one or two more of the dozens of scientists agreeing that the therapy is sound for clinical trial. And that would make me more confident in my 'investment' ie de-risked. Of course, it could still fail - but that's risk management.

    In terms of therapies to take to trial - well, there is one therapy that everyone seems to be sitting on their hands about. And everyone in the field seems to be OK that one commercial entity can hold it's potential in the pipeline when there is enough data to show that breathing in chronic injuries could be restored. And yes, there is a human-grade version of the agent available elsewhere. That's a crying shame - actually, that's a travesty for those on ventilators!
    Yep, let's get ch'ase into clinical trials as soon as possible while combinations with pTen knock out and nerve grafts etc etc are worked on in animal trials at the same time.

  10. #460
    It may be a dead end but I'd also like to know how Raisman's OEG trials in Poland are progressing

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