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    Tuesday, April 18, 2006

    Spinal Cord Cures in China
    A new network of clinical trial centers in China could provide a safe and rapid way to test new therapies.

    By Emily Singer

    A growing number of patients are heading to China for experimental therapies, such as cell transplants to treat spinal cord injuries and other diseases. But scientists in the field harshly criticize the trend, saying these therapies are costly, unproven, and potentially unsafe (see "The Problematical Dr. Huang Hongyun," January 2005).

    Now Wise Young, an internationally recognized expert in spinal cord injury, aims to address some of the problems associated with humans tests involving experimental therapies. He is spearheading a new project to conduct rigorous clinical trials in China and has set up a network of Chinese hospitals to test new treatments for spinal cord injury.

    Young, a neuroscientist and director of Rutgers University's W.M. Keck Center for Collaborative Neuroscience at in Piscataway, NJ, says the availability of the enormous Chinese population will drastically speed up the clinical trial process, allowing new therapies to be tested more quickly and cheaply. He hopes the network will ultimately provide a go-to testing site for large pharmaceutical companies with new spinal cord injury treatments.

    The number of potential new therapies for spinal cord injury has blossomed in the last few years -- dozens of treatments have been shown to regenerate the spinal cord in animal models. But safely testing those therapies is a challenge. For one thing, spinal cord injury is a complex problem; patients often retain partial motor or sensory ability and may spontaneously recover some mobility after the injury.

    "Something like blood pressure is easy to assess in a clinical trial -- a pill either brings it down or it doesn't," says John Ditunno, a spinal cord injury expert at Thomas Jefferson University in Philadelphia. "But the challenge in spinal cord injury is that you're looking at a person's ability to function in real life. That's very complicated."

    Clinical testing also requires many patients. With only about 10,000 spinal cord injuries in the United States each year, recruiting for a study is painfully slow. Trials for spinal cord injury treatments in the United States have been held up for years due to slow enrollment. As a result, frustrated patients, buoyed by success stories of experimental therapies not approved in the United States, have begun to travel overseas to gain access to these treatments.

    One of best-known practitioners performing such treatments is Hongyun Huang, a controversial Chinese neurosurgeon who has transplanted in about 600 patients what he says are olfactory ensheathing cells, a type of cell that can help regenerate neurons.

    Many experts argue that these therapies, which can cost tens of thousands of dollars, have not been adequately tested. "There are no controls, no well-defined protocol for post-procedure follow-up," says James Guest, a neurosurgeon and spinal cord researcher with The Miami Project to Cure Paralysis. Guest previously visited Huang's hospital and last month co-authored a critique of the treatment for a scientific journal. "There is relatively little data on what the implants are, what the complications are, or what the outcomes are," he says.

    According to Young, who trained Huang when he was a post-doctoral student at Rutgers University, beginning in the late 1990s, this lack of follow-up is symptomatic of the medical culture in China. "Part of the problem in China is there is no system for follow-up," says Young. "When a patient leaves the hospital, [the hospital] doesn't have the resources to get the patient to come back."

    Young aims to change this practice with his clinical trial network, which now has 17 participating centers in the Chinese mainland and Hong Kong, and plans to begin its first clinical trial in June.

    The network has sponsored training sessions for the Chinese doctors involved in the trials, in which U.S. experts taught standardized procedures for assessment of spinal cord injury. "Outcome measure is always the most important thing," says Johan Karlberg, director of the Clinical Trials Centre at the University of Hong Kong, which has extensive experience conducting clinical trials and will oversee the network's projects.

    In September researchers plan to start a placebo-controlled trial of lithium, which has been shown to boost cell growth and survival in animal models. The next step, if they get permission, will be a trial of stem cells derived from umbilical cord blood transplanted into 300 patients with chronic spinal cord injury. Young says the goal is to register the trials in both China and the United States.

    "With this first trial, we want to establish proof of concept that we can take a therapy from the preclinical phase to [late-stage clinical trials] in two years -- which is very fast -- and do it cheaper, faster, and better than anyone else," says Young. "My hope is that once we establish this concept, a company with a promising therapy can come in and get a definitive answer in two years...for $20 million or less." (Young estimates that the network can run trials for about $20,000 per patient for surgery and hospitalization, compared with around $100,000 for a similar U.S. trial.)

    "This network has more capacity than any other network in the world," says Young. "We could test 6,000 patients a year if we wanted to." However, capacity will also depend on funding, he says. The network so far relies largely on fundraising and still must raise a significant amount of money to pay for its first round of trials.

    "There is probably no one better qualified than [Young] is to think about doing this," says Guest. But it may be difficult to get the different participating centers, which have very different levels of expertise, to operate at the same level, he says. "This will be an alliance between some strong, well-funded centers and other centers who are struggling and under funded, so whether it will work remains to be seen," Guest says.

    In addition, the network may not be able to enroll as many patients as predicted, says John Steeves, a spinal cord injury expert at the University of British Columbia. "People think a clinical trial network in China would have tremendous capacity given the population of China," he says. "However, the capacity of the health care system in China does not necessarily match the population, so the ability of a trial to attract appropriate numbers of candidates is limited by the health care system in place."

    Young's network is part of broader shift in China, which over the last few years has garnered attention from the pharmaceutical industry. "The clinical trial culture is rapidly changing," says Karlberg of the University of Hong Kong. "China is moving fast into global drug development, and pharma is looking at the growing market in China."

    This new interest could bring its own hurdles. The Chinese drug regulation system has evolved in response to the international attention -- the country now has strict regulations governing clinical trials and a permission process that's lengthier than in the United States.

    Back in the United States, patients are already clamoring to participate in the Chinese trials. Young moderates a website for spinal cord injury patients and their families, and says the number-one question lately has been about how to participate in these trials. (The website also has a section where people who've gone overseas for experimental treatments chronicle their experiences, both good and bad.)

    Young says that U.S. patients will be eligible for the trials. However, they will need to travel to China for the surgery and be available for follow-up exams at six weeks, six months, and a year after the treatment. While they will not have to pay for the procedure, they would need to pay for any care beyond that given to Chinese patients, says Young. As he explains, hospital care is different in China than in the United States, with Chinese families rather than nurses often caring for patients in the wards.

    And what about patients eager to find out if Hongyun Huang's controversial treatment really works? Young says the network does not yet have plans to test the cell transplant therapy used by his former student.


    WTG Dr. Young. It's also good to see that it has the support of US researchers.


      Get your roll on!


        Keep up the great work. Even though I am pessimistic, I am willing to try anything once. We'll need to get back on our feet.


          Blame it on us

          Clinical testing also requires many patients. With only about 10,000 spinal cord injuries in the United States each year, recruiting for a study is painfully slow. Trials for spinal cord injury treatments in the United States have been held up for years due to slow enrollment. As a result, frustrated patients, buoyed by success stories of experimental therapies not approved in the United States, have begun to travel overseas to gain access to these treatments.
          NOT enough SCI to enroll? blame it on us (SCI) holding things up. DONT blame the slow FDA.
          but at the same time thoudands are going over seas for experimental treatments?....What a bunch of BS on this article. only one more sales pitch?

          This new interest could bring its own hurdles. The Chinese drug regulation system has evolved in response to the international attention -- the country now has strict regulations governing clinical trials and a permission process that's lengthier than in the United States.
          Why not do trials in a country where permission is NOT lengthier??? India ? ...Argentina?.....Brazil?...Russia?
          Last edited by glider; 2 Sep 2006, 2:41 AM.


            Originally posted by glider
            NOT enough SCI to enroll? blame it on us (SCI) holding things up. DONT blame the slow FDA.
            but at the same time thoudands are going over seas for experimental treatments?....What a bunch of BS on this article. only one more sales pitch?

            Why not do trials in a country where permission is NOT lengthier??? India ? ...Argentina?.....Brazil?...Russia?

            I don't think that the article is "blaming" people with SCI for holding things up in the U.S. It is pointing out the advantages and disadvantages of doing spinal cord injury clinical trials in China. The advantage of having relatively few centers that take care of very large number of patients is offset by the lack of systematic followup of patients and a newly imposed regulatory structure that is still relatively inefficient.

            Many people do not know that China has recently imposed clinical trial regulations that are as rigorous or more so than the United States. All clinical trial centers are now required to meet the international Good Clinical Practice (GCP) standards. There is a mistakened assumption by many people that "anything goes" in China. Even in 2004, when I first proposed the idea of a ChinaSCINet to the Ministry of Health in Beijing, their main response was that the trials must follow the highest ethical, scientific, and clinical standards.

            In my opinion, China has been very responsible in passing laws and regulations to protect its people. Many of the rules are clearly intended to prevent exploitation of its people by unscrupulous companies. Their new regulation require all clinical trial centers to have well-organized institutional review boards (IRB's) and structures that protect clinical trial subjects. They are moving to stop a variety of abuses. It is true that the increased regulation has slowed things down somewhat for us at the ChinaSCINet. It has also increased the expense of doing trials in China. On the other hand, the moves by the government have helped us tremendously by forcing all the major medical institutions to adopt higher standards. For example, all the centers have not only voluntarily accepted international CGP standards but have invested a great deal of time and effort to do so. Most of our centers are now GCP qualified and the rest will soon be qualified. It is no longer an uphill battle to convince clinicians to do things the right way. The quality of trials that we conduct will be very high.

            In India, they are just beginning to face the problems of unregulated clinical trials, even as it is emerging as the preferred destination of companies seeking to outsource their clinical trials. As this article in 2004 suggests, abuses have been present in India for a while:
            India's clinical trials and tribulations
            By Indrajit Basu

            KOLKATA - The potential is huge, multinationals are willing and Indian companies are eager. Moreover, it is a type of outsourcing that is not likely to draw the protests of the anti-outsourcing brigade in rich economies. Yet even as India increasingly emerges as a preferred destination for outsourcing clinical trials - testing of new drugs on humans - the country may also be heading toward providing the greatest source of human guinea pigs for the global drug industry.

            A spate of unfortunate events over the past few years has brought to the fore the rampant practice of conducting unethical and even illegal clinical trials in India, which is fueling immense concerns culminating into a huge public outcry over the regulatory authorities' failure to check such practices, and even lawsuits.

            For instance, in early March, the Supreme Court of India hauled up two top biotech companies in India, the Hyderabad-based Shanta Biotech and Bangalore-based Biocon India, for "openly conducting illegal clinical trials of new drugs on unsuspecting patients" after a litigation filed by the Aadar Destitute and Old People's Home, a Delhi-based social organization. This non-governmental organization (NGO) alleged that the two companies had conducted improper clinical trials of Streptokinnese - a new clot-busting drug used in heart attacks - last November without requisite permissions (of the Genetic Engineering Approval Committee), as a consequence of which eight people lost their lives.

            Although the Streptokinnese case was a shocking revelation, it wasn't an isolated one. According to Monthly Index of Medical Specialities in India, an independent pharmaceuticals journal, more than 400 women who had been trying in vain to conceive were enrolled in 2003 without their knowledge or consent to take part in clinical trials across India to see if a drug called Letrozole induced ovulation. Letrozole used in India was copied (with permission) by Sun Pharmaceuticals, a large Indian generic drug company, from a patented product of the same name of Novartis, which the multinational drug maker introduced globally for solely treating breast cancer and not for any other use in any country, including India. A complaint on the Letrozole case, too, was filed in the Supreme Court by yet another Delhi-based NGO.
            In the past year, India has become *the* place to conduct clinical trials, and have taken a lion's share of world-wide clinical trial research contracts. The government of India is actively helping with legislation. As the following 2005 article in the New England Journal of Medicine indicates, India recently revised its laws to allow more clinical trials in the country by foreign companies:
            A New Colonialism? — Conducting Clinical Trials in India
            Samiran Nundy, M.Chir., and Chandra M. Gulhati, M.D., D.T.M.&H.

            In January 2005, the government of India enacted a new rule that allows foreign pharmaceutical companies and other interested parties to conduct trials of new drugs in India at the same time that trials of the same phase are being conducted in other countries. This new rule supersedes a directive of India's Drugs and Cosmetics Rules that required a "phase lag" between India and the rest of the world. According to the old rule, if a phase 3 study had been completed elsewhere, only a phase 2 study was permitted in India. Even under the new rule, phase 1 trials . . .
            Not only are many pharmaceutical companies rushing into India to start clinical trials, but Indian firms are mushrooming to help them establish clinical trial hubs and providing translation and other trial services, advertising that "the trials can get done fast and at a cheaper cost than in the West. In the U.S., trials for a single drug can cost about $150 million. Early estimates are that drugs could be tested in India at 60% of that price." (Source). The temptation is difficult to resist and pharmaceutical companies are zeroing in (Source):
            A vast, unwieldy population, a plethora of diseases, and rampant poverty: this was the picture India presented to the outside world till a while ago.

            But these days the fact that India has the largest pool of patients suffering from cancer, diabetes and other maladies is leading the country to an altogether different destination: the global hub of outsourcing of clinical trials.

            Almost all the top names in the pharmaceutical world have zeroed-in on India, setting up clinical trail facilities in major cities, especially Hydearbad and Ahmedabad.

            Global consultancy McKinsey & Co estimates that by 2010, global pharma majors would spend around $1-1.5 billion just for drug trials in the country.
            Over the past decade, most pharmaceutical companies have shifted their clinical trials overseas to reduce costs. In the last two years, however, many pharmaceutical companies have set up clinical trial operations in Asia. A recent article from Ireland revealed that Irish hospitals applied for only 58 new clinical trials in the first seven months of 2006 compared to over 200 trials the previous year (Source). Three days ago, this article reported:
            India top of the world for contract research business

            By Kirsty Barnes

            29/08/2006 - India is holding the lion’s share of the world’s contract research business as activity in the pharma market continues to explode in this region.

            In 2005 contract research in India was valued at $100-120m (€78-94m) and growing at a rate of 20-25 per cent each year, according to a report by the Chemical Pharmaceutical Generic Association.

            India holds nearly double the business of its nearest rival, Italy, with a market value of $60-70m, and nearly four times as much as the next competitor, Spain, with $25-33m, said the report, titled “Competition in the world APIs market.”

            The activity in India is being fuelled by the direct presence in the country of over 15 prominent contract research organisations (CROs), who are now operating in the country, attracted by India's ability to offer efficient R&D on a low-cost basis.


            In the contract research arena, India is streets ahead of its nearest Asian competitor, China, which currently only reaps in $23-28m in business.
            India has several major advantages over China. First, their doctors are English-speaking. Second, they have probably the most efficient chemical synthesis industry the world, stemming from their long history of making their own drugs. This has attracted ten multinational companies to establish their manufacturing hub in the country. Third, they have a very strong computer programming and database industry which is tremendously helpful for clinical trials. Fourth, the government has geared their regulatory system to accomodate overseas companies, something that the Chinese have not yet done. Together with a huge population of treatment-naive patients with many diseases, India has become totally dominant in competition for clinical trial contracts.

            China, however, is climbing up the clinical trial ladder rapidly and may soon challenge India with a different strategy. First, in the past two years, China forced their top clinical centers to adhere to the highest international GCP standards. The shift has been remarkably rapid and will assure the quality of clinical care and data collected. Second, they have a strong biotechnology industry that is getting stronger. China has invested hundreds of millions into cutting edge molecular biology and cell production facilities as opposed to drug manufacturing facilities. Third, they offer a huge clinical market that may soon be the biggest in the world. Their population of patients who can pay for therapies now is beginning to rival those of the United States and Europe. Over a quarter of their population is now covered by medical health insurance from less than 10% just 2 years ago. Fourth, they have invested in biomedical edcuation, producing more scientists and engineers than any other country at the rate that eclipse the output of the United States. Twenty multinational pharmaceutical companies have now established R/D centers in China.

            China, however, has to solve several major problems before they can compete successfully with India. First, the average Chinese doctor cannot communicate well in English. Every English scientific word has to be assigned a Chinese word and Chinese have to learn two words for every one that an English-speaking person has to in order to master a subject. In fact, some of the Chinese that I have trained in the United States cannot communicate about latest scientific or technical issues with their colleagues in China because they don't know the latest Chinese words. Second, the government has to streamline their bureacratic procedures. It now takes 8 months just to get an answer from the China sFDA, whether yes or no. In the U.S., the fDA must answer an application for clinical trial (IND) with "yes" or "no" in 3 months or less. Third, their latest regulations incomprehensibly have no provisions for universities and non-profit institutions applying for clinical trials. Ostensibly, this approach forces doctors, universities, and non-proft organizations who want to start clinical trials to form a for-profit Chinese company to run clinical trials.

            These are some of the issues that we have had to deal with in the last six months trying to get ChinaSCINet clinical trials going. It has been frustrating but we have found and are continuing to find solutions. Nobody said that it would be easy. In fact, everybody said that we would not be able to get all the major spinal cord injury centers in China to work together, that we will not be able to get Chinese patients to accept being in clinical trials, and the system is too corrupt. None of these turned out to be true. Although we have fallen behind our self-imposed schedule, we are continuing to push as hard as we can. I had originally hoped to initiate our phase 1 lithium trials in August but now must wait until October. The phase 2 lithium trial may be delayed until the beginning of 2007. In the meantime, we are ahead of schedule in getting all the centers GCP trained and qualified, have begun setting up GMP (Good Manufacturing Practice) facilities for processing cells for the trial, and have made good progress in our observational trial of 600 patients with spinal cord injury.

            Last edited by Wise Young; 2 Sep 2006, 7:14 AM.


              Dr. Wise Young: "have made good progress in our observational trial of 600 patients with spinal cord injury."
              Dr Young,

              Would you please expand on the parameters and progress of the observational trial?

              Thank you.

              "We have met the enemy and he is us."-POGO.

              "I have great faith in fools; self-confidence my friends call it."~Edgar Allan Poe

              "Dream big, you might never wake up!"- Snoop Dogg


                Originally posted by Foolish Old
                Dr Young,

                Would you please expand on the parameters and progress of the observational trial?

                Thank you.
                About 6 months ago, we started a one-year observational trial with the goal of collecting 600 subjects with spinal cord injury in the Network Centers. Not all the center were ready for this and we have been working hard with all of them to achieve IRB approvals of the trial, GCP status, and completion of formal research agreements. To date, 17 of the 18 centers have gotten their IRB approvals, 16 of 18 centers have completed the research agreement. In terms of GCP approvals, 14 of the 18 centers have achieved GCP certification for their hospital, although only 4 have gotten GCP approvals of their specific departments participating in the study. About 273 subjects have been recruited so far.

                We applied for permission to carry out a phase 1 lithium trial in July and hopefully will get approval this week to carry out the trial at Hong Kong University. We are applying for the phase 2 lithium trial but I am uncertain how long it will take to approve the trial. In the meantime, we are working on the phase 3 cord blood mononuclear cell transplant and lithium trial. In order to get that approved, we need to have GMP cell processing facilities in China. We are obtaining the funding for and establishing these facilities. There are many irons in the fire.

                In summary, I was hoping to start the lithium phase 1 this summer but it has been delayed by 2 months. The phase 2 trial may not start until January, depending on the regulatory approval process. I am aiming for a phase 3 start in May 2007. Please note that these are my goals and not prediction of when the trials will begin.



                  Why was it necessary to involve 18 centers? Seems if fewer were involved, only 5 or 6 perhaps, you'd have approval by now and the entire process would have been more expeditious. Just curious.
                  Last edited by antiquity; 6 Sep 2006, 3:43 AM.


                    Originally posted by antiquity
                    Why was it necessary to involve 18 centers? Seems if fewer were involved, only 5 or 6 perhaps, you'd have approval by now and the entire process would been more expeditious. Just curious.

                    Very good question. A number of people have asked this question. Let me give the practical reasons first and then the principles that required the decision. From a practical point of view:

                    1. Unknown quality of centers. Few of the centers had any clinical trial experience or record. It was very difficult to know from the outset which centers are the best and can deliver. In fact, we have found out that we were wrong concerning the productivity of the various centers. Our three most productive centers have turned out not to be our biggest or high-powered academic centers. These three non-academic centers are contributing over half of the patients to the observational trial. In the coming year, several centers will probably drop out and other centers will join, stabilizing probably at about 20 centers. By the end of this month, we will have 20 centers, including two in Taiwan. I think that more would become too unwieldy and impersonal. We have 4-5 doctors from each center participating in the Network activity.

                    2. Cost of having more centers is not much greater. We pay the centers on a per patient basis. Our only extra cost for having 18 centers as opposed to 12 centers is the cost of our training meetings and travel to the centers. In the past two years, our budget per year has been about $500,000 per year. I estimate that the difference in cost for us to have 12 versus 18 centers is probably $200,000 over the past two years. In exchange, we have probably 70% of the major spinal cord injury centers in China and cover most of the major population centers in China. The HKU Clinical Trial Centre has just completed development and have begun deploying a state-of-the-art web-based clinical data entry system. This will provide a very efficient monitored data collection system and reduce our visits to the centers to perhaps once a year.

                    3. The Power of Numbers. Many of our centers have a clinical volume that would allow them to randomize 50 or more acute spinal cord injury patients per year and probably 300 or more chronic patients per year. But, this is only if they really organize and we can provide them with the funding and resources to do so. However, despite our shoestring budget for the observational trial, about 12 of our centers have now recruited nearly 300 patients in about 6 months. Several of the centers are just now coming on line, having gotten all the approvals in. Our goal was to recruit 600 patients in one year and it seems that we will make it. This is actually pretty impressive considering that the National Spinal Cord Injury Study (NASCIS 2) took four years to recruit 480 patients and we had 15 of the best spinal cord injury centers in the U.S. participating in NASCIS. By 2008, I think that most of the centers should be randomizing over 100 patients per year. I initially estimated more because the costs were lower. The issue is not availability of patients but funding. For example, one of our centers is the major spinal cord injury center for a population of over 100 million people. But, even at 2000 cases per year, there is no other place that can do clinical trials so fast (except India). It is enough to do two chronic and one acute spinal cord injury treatment 600-patient phase 3 trials per year and perhaps a couple of phase 1/2 trials, at the cost of about $50 million per year.

                    Now, let me discuss the reason why I believe ChinaSCINet may not be big enough for its ultimate mission: delivering the best care and cure for spinal cord injury in China.

                    When I first went to China in 1999, everybody had a different way of examining patients. It took us two years to get everybody to examine all the patients using the International SCI Classification standard. We are now beginning to go through all the care standards, for acute spinal cord injury, for surgery on chronic spinal cord injury, and for transplantation. You can imagine what a monstrous task this is and what an an unprecedented opportunity this is. It may take a number of years to complete but we have made incredible strides. Just having four meetings a year of the heads of departments, the mid-level surgeons, and the young surgeons forged a group of spinal cord injury doctors who know and trust each other. Last year, they formed committees to work on standardizing acute, surgical, and rehabilitation care in the Network. I believe that whatever this group decides will set the national standards for China.

                    China is a huge country. It is not possible to imagine 1.2 billion people but try imagine taking care of over a million people with chronic spinal cord injury and handling 50,000 new spinal cord injuries per year. Our little group of perhaps 100 doctors in the Network has the daunting task of setting the standards for care and delivering the cure to this vast population. At our upcoming meeting in Guangzhou where we have merged our ISCITT meeting with the main spinal surgery and rehabilitation group in China, we are anticipating perhaps 700 spinal surgeons and rehabilitation doctors attending. In 2002, China had about 1.7 doctors per 1000 people, which adds up to over 2 million doctors (graduates of medical schools) in the country. These numbers are absolutely staggering. One must think BIG in China.

                    Suppose we find a therapy that works. Delivery of the therapy will be huge task. Even if each of 100 of our doctors were to treat 100 patients a year each, we are talking about just 10,000 people per year, less than 1% of the spinal cord injury population. This group has to be the training nucleus for a much larger group of doctors. What use is a therapy if it cannot be delivered? Of course, the group must continue to test therapies, always randomizing people to the best accepted therapy against the most promising experimental therapies. We must achieve critical mass.

                    By the way, we have now trained about 40 surgeons from the centers to do animal spinal cord injury experiments using the standardized impactor contusion model. We will be testing the therapies in rats before taking them to clinical trial, providing true one-stop shopping for any pharmaceutical company who has a promising therapy and would like to take the work from preclinical to phase 3 clinical trials. So, the ChinaSCINet will not only be a largest clinical trial group but also the only major multicenter preclinical consortium in the world for evaluating promising therapies. We have focussed our training efforts on producer "trainers" and "leaders" who can impart the knowledge to others and lead ChinaSCINet to the next stage.

                    Last edited by Wise Young; 3 Sep 2006, 3:53 AM.


                      Sabbaticals do not seem very restful!
                      Thank you, Dr. Young!!


                        Dr. Young,

                        I am curious about the Lithium/cord blood mononuclear cell transplant (CBMCT) procedure. Based on lab results, what type of recovery do you anticipate in humans when the trial begins?

                        Will you treat all levels of SCI, i.e., cervical, thoracic, lumbar, and sacral regions?

                        Since there are 18 centers, I would assume other promising combination treatments will be performed in parrallel, or will all the centers use the Lithium CBMCT therapy?

                        Lastly, I see nothing in this Lithium CBMCT combo that would potentially address the "scar" as a barrier to regeneration.


                          Originally posted by Schmeky
                          Dr. Young,

                          I am curious about the Lithium/cord blood mononuclear cell transplant (CBMCT) procedure. Based on lab results, what type of recovery do you anticipate in humans when the trial begins?

                          Will you treat all levels of SCI, i.e., cervical, thoracic, lumbar, and sacral regions?

                          Since there are 18 centers, I would assume other promising combination treatments will be performed in parrallel, or will all the centers use the Lithium CBMCT therapy?

                          Lastly, I see nothing in this Lithium CBMCT combo that would potentially address the "scar" as a barrier to regeneration.

                          I don't know what umbilical cord blood mononuclear cell transplants will do for people with chronic spinal cord injury. Several animal studies have suggested that transplantation or transfusion of umbilical cord blood mononuclear cells are beneficial in spinal cord injury. Many clinics around the world have been transplanting or transfusing umbilical cord blood cells into people with spinal cord injury. Our studies of lithium and umbilical cord blood mononuclear cell transplants indicate clearly that lithium stimulates umbilical cord blood mononuclear cells to produce neurotrophins, NGF, GDNF, NT-3, and the stem-cell stimulating factor LIF. We have not yet seen significant motor improvements in the rats because we have had to treat the animals with cyclosporin (immunosuppressant) to ensure the survival of the cells; we do not have a source of immune-compatible cells that can be transplanted long-term in rats without immunosuppression. Some recent data from our lab suggest that immunosuppression with cyclosporin prevents lithium stimulation of growth factors secretion by the umbilical cord blood umbilical cord blood and possibly by the spinal cord as well. In the clinical trial, we will be using HLA-matched cells and will not be using any immunosuppression in patients and thus this will not be a problem in the clinical trial. However, in rats, we don't have a good source of immune-compatible neonatal blood cells for transplantation. In culture, we find that human umbilical cord blood cells, even optimum growth conditions, will continue to grow only in a minority of cases (i.e. 1/4). We find that lithium improves survival and proliferation of human umbilical cord blood cells both in culture and in the spinal cord, as well as stimulate neurotrophin production by the cells. Some of the results are still preliminary and need to be confirmed but the current data continues to confirm my original decision, that umbilical cord blood mononuclear cells are safe for transplantation and lithium is strongly stimulates them to produce neurotrophins that many scientists believe to stimulate regeneration in the spinal cord. We are currently trying to do experiments that do not involve immunosuppression by using isogenic inbred rat strains.

                          We currently have two choices. First, we wait until there is definitive animal data indicating that umbilical cord blood mononuclear cells plus lithium will improve function in non-immunosuppressed rats. We have some data suggesting that this must be done without immunosuppression and that cyclosporin inhibits the effects of lithium. Because these experiments are very time-consuming and I do not have the people-power to do thes large-scale studies , I have gone ahead to train many of the Chinese center to do standardized animal spinal cord injury experiments and plan to have them do the confirmatory studies. Second, we go ahead and implant HLA-matched umbilical cord mononuclear blood cells into the spinal cord and randomize patients to lithium or no lithium. If this trial shows that umbilical cord blood mononuclear cells are ineffective, this will stop all the scams that are going on around the world based on claims that this is a miraculous cure for spinal cord injury. There is also the possibility that the treatment will improve function and that lithium may enhance this recovery. If so, this trial would be worthwhile.

                          There are other reasons why it is important that we do the cord blood mononuclear cells plus/minus lithium trial soon. In addition to showing that the ChinaSCINet can carry out a combination cell transplant and drug therapy trial efficiently and rigorously, it will provide a clear example of how rigorous spinal cord injury clinical trials should be done. The problem with all the non-controlled trials that are going on around the world (Lima, Huang, Beike, and others) is that they are not able to or willing to undertake the rigorous trials necessary demonstrate that a treatment is effective or ineffective (perhaps because they have a conflict of interest in depending on patient revenues). We have very limited resources for clinical trials at the present and it makes no sense for people to be spending their funds on trials that will not test the hypothesis whether the treatment is effective. While many people think that it is worthwhile the gamble to just try therapies willy nilly, I disagree. If people invest their bodies and money for therapies, it should be for clinical trials that will show that the therapy works or does not work. Otherwise, we will continually go on this merry-go-round based on desperation of people to recover.

                          I am trying to be as brutally honest about the prospects of umbilical cord blood mononuclear cell transplants and lithium therapy as I can. We will hopefully start a phase 1 clinical trial of lithium alone this month. I believe that the therapy is safe but it is important for us to know that lithium does not have any adverse effects on people with chronic spinal cord injury. This goal of the first trial is to establish the feasibility and safety of the lithium treatment of spinal cord injury. Although several experts have assured us that the treatment can be safely given to people with chronic spinal cord injury and I am grateful for their advice, I think that we need to make sure that this is the case. We are now applying for permission to do a phase 2 trials randomizing patients with chronic spinal cord injury to lithium or no lithium, to see if lithium alone improves or has deleterious effects on neurological function in people with chronic spinal cord injury. It is entirely possible that the clinical trial will show that umbilical cord blood mononuclear cells, especially with lithium treatment, will stimulate regeneration and improve function.

                          In the meantime, I am working hard to establish GMP-certified stem cell processing centers in China so that we can be assured of high quality HLA-antigen matched umbilical cord blood mononuclear cells for the trials. This turns out to be a non-trivial exercise and one that I am willing to accept because such facilities are absolutely essential if ChinaSCINet is planning to be a clinical trial that will test cell transplants in people. We not only have to know what cells we are transplanting but ensure that the quality of the cells are as high as possible. These facilities will be important not only for umbilical cord blood but for any kind of cell transplants, including embryonic stem cells, fetal stem cells, fetal olfactory ensheathing glia, umbilical cord blood and other neonatal stem cells, and adult stem cells including bone marrow cells. The regulations for clinical trials in China strongly favor cells that come from and are processed in China.

                          By the way, over the past three months, I have taken up a new hobby: computer poker. As a scientist, I am not a gambler. I have always avoided games of chance because I will not gamble with people's lives or their chances of recovery. However the past two years of organizing the ChinaSCINet has convinced me that decisions are often predicated on many unknowns and we must gamble some times if the probability favor success. We lose too many opportunities if we are conservative and play it safe all the time. On the other hand, we have to make sure that the treatments are what we believe them to be and the outcome measures are reliable. Once these are established, I think that I am willing to take chances. When we have achieved these two goals, we shall know whether a treatment works or does not work. We must be able to tell whether a treatment works or does not work. The continued waffling on the efficacy of therapies is not only wrong but deterimental to progress in the field. I am trying to convince myself that I don't mind taking a chance as long as the outcome is real and the probabilities are known. I think that we are all willing to accept a failure of a treatment as long we can trust that the information that it does not work.

                          Science is about taking calculated risks. We must accept proof that a therapy does not work as well as proof that a therapy works. What is unacceptable is when we cannot say one way or another after a lot of hard work. The main difference between clinical trials and a casino is the fact that a successful result benefits everybody, not just the person who gets the jackpot. A jackpot in a clinical trial will help everybody. That is why it is so important that we do it right or not at all in the ChinaSCINet. I make my decisions based on this philosophy. To this end, we have devoted the past two years to ensuring that the centers can actually run clinical trials and collect reliable data from clinical trials. I just came back from a visit of four of our ChinaSCINet centers. They are currently carrying out an one-year observational trial on 600 patient. These patients that are being observed for one year will be eligible for the UBCMC and lithium trial. I told the investigators that it is essential that they choose patients that can and will come back for followup. If we invest US$30,000 into the treatment of the patient and then lose the patient to followup, that would be unacceptable.

                          One question that I am asked a lot is why not try all these other therapies that are promising? The problem is that that they are not available, at least not in the quality that would assure a successful clinical trial. By success, I mean a clinical trial that provides a definitive answer whether the therapy works or does not work. It will cost $12 million to do the first umbilical cord blood mononuclear cell transplant with and without lithium. I am unwilling to initiate such a trial without strong assurances that we know what we are transplanting and that the therapy is what we believe it to be. Whether it will be successful is unknown. That is why we have clinical trials, to gain new knowledge that is reliable and definitive. If we fail at this task, we have failed.

                          What immune compatible cells are available for transplantation now? There are only two sources. One is bone marrow cells from the same person and the other are HLA-matched umbilical cord blood cells. Fetal sources of cells from aborted fetuses are too unreliable and are not available in sufficient quantity. We currently do not have the resources to establish a GMP-qualified laboratory in every clinical trial center to process bone marrow cells from the same patients. Cloned embryonic stem cells are not available. We don't have enough embryonic stem cell lines to do HLA-matching to assure non-rejection. Although there are theories that embryonic or fetal cells are not as susceptible to immune rejection, I am not yet convinced that these theories are true, at least not enough to justify the first ChinaSCINet trial on such theories. So, that is why I have chosen umbilical cord blood cells. I continue to hope that the U.S. government will see the light and fund an effort to create enough embryonic stem cell lines that can be HLA-matched to recipients of the cells. In the meantime, we work with what we have. Umbilical cord blood cells is the only source of HLA-compatible cells that we can transplant.

                          Why lithium? It is because this drug stimulates umbilical cord blood (as well as the central nervous system) to release the combination neurotrophins that so many investigators have reported to stimulate regeneration in the spinal cord. I am also attracted by lithium because it has been used for over a hundred years to treat people with manic depression, often for a life-time. Therefore, the safety record of this drug is substantial.

                          Why umbilical cord blood mononuclear cells? After 2 years of working with umbilical cord blood cells, I believe that these cells are safe for transplantation into the spinal cord. They do not grow out of control after transplantation. They respect the gray and white matter boundaries of the spinal cord. They are well behaved cells that eventually disappear from the spinal cord. If they are matched immunologically (HLA), they will survive to have beneficial effects, especially if lithium is used.

                          These are very difficult decisions but that is the way that it is in all clinical trial designs. The decisions that one makes in a clinical trial may affect history for a long time to come. For example, I have always regretted giving in to the arguments of neurosurgeons in NASCIS 2 that we should exclude all patients with gunshot wounds from the trial. A number of neurosurgeons who were strongly influenced by the Vietnam experience believed that there was no treatment that would improve recovery of function after a gunshot wound. Therefore, we excluded gunshot wounds from the trial. Now, over 10 years later, we don't know whether to give methylprednisolone to people with gunshot-induced spinal cord injury. I hope not to make that mistake again. We must separate clinical trial design from the hype and the pessimism of the field. The decisions must be dispasionate and based on the best available data.

                          These are just some of my thoughts.

                          Last edited by Wise Young; 7 Sep 2006, 1:03 AM.


                            Dr. Young,

                            Thanx for your detailed and informative response. I have read it over a couple of times since there is so much to absorb.

                            It is clear that the emerging ChinaSCINET is not to implement a "cure" but to instead establish strict clinical trial protocols using the most effacious methods according to what is presetnly available on a sufficient scale, i.e., HLA matched umbilical cord blood mononuclear stem cells and lithium.

                            By establishing a rigid consistent clinical trial infrastructure, this will be the vehicle by which emerging SCI regenerative therapies can be tested in the future. Additionally, demonstrating to business and industry that SCI based clinical trials can be carried out in a consistent, methodical, cost effective manner, the ChinaSCINET will be where new emerging therapies can be conducted.

                            In summation, the ChinaSCINET is the horse, the cart, or "cure", will be down the road sometime in the future.

                            Thanx for all your hard work.


                              Dr. Young;

                              Thank you for the thorough explanation of China SCINet's status and plans.

                              "Hope is like a road in the country; there was never a road, but when many people walk on it, the road comes into existence." Lin Yutang