Another Christmas has come and gone, surprisingly fast, as always. I had thought that it might make a good “last of 2014″ post—well, last of 2014 for me, anyway; Harriet and Steve, at least, will be posting before 2014 ends—to do an end of year list of the best and worst of the year. Unfortunately, there remains a pressing issue that doesn’t permit that, some unfinished business, if you will. I’m referring to a story I commented on last week, specifically the credulously reported story of how 86-year-old hockey legend Gordie Howe is doing a lot better after having undergone an experimental stem cell therapy for his recent stroke. As you might recall at the time, I saw a lot of holes in the story. It turns out that over the last week there have been developments that allow me to fill in some of those holes. Unfortunately, other holes still remain.
First, a brief recap is in order. (You can click here for a more detailed timeline). Gordie Howe suffered a massive stroke on October 26, leaving him hemiplegic and with serious speech impairment. Since then, judging from various media reports, he has been slowly improving, although not without significant setback. We also know that Howe suffers from significant dementia. Out of the blue, press release issued on December 19 by the the Howe family announced that on December 8 and 9, Gordie Howe “underwent a two-day, non-surgical treatment at Novastem’s medical facility. The treatment included neural stem cells injected into the spinal canal on Day 1 and mesenchymal stem cells by intravenous infusion on Day 2.” His response was described as “truly miraculous,” although, as I pointed out in my post, it’s not clear exactly what “miraculous” meant, given conflicting contemporaneous news accounts before the Howe family press release, particularly his hospitalization from December 1 to 3 for a suspected stroke that turned out to be dehydration.
I noted a number of problems with the story, the first of which is that Howe was clearly not eligible for the clinical trial offered by Stemedica, a company in San Diego that manufactured the stem cells used. Another glaring issue was my inability to locate any description of an actual clinical trial for stroke offered by Novastem. I could find no such trial listed in ClinicalTrials.gov, and you, our intrepid readers, searched the registry maintained by the Federal Commission for the Protection Against Sanitary Risk (COFEPRIS) and were not able to find any registered clinical trials for stroke being carried out by Clínica Santa Clarita, the clinic Novastem operates. What you, our intrepid readers, did find were trials of stem cells for: COPD, osteoarthritis, type II diabetes, metabolic syndrome, and erectile dysfunction (of course). I did the search again over the weekend, and there were no further trials that I could find.
So it was that I concluded my post having grave doubts that there actually was a clinical trial run by Novastem using Stemedica’s allogeneic mesenchymal stem to treat stroke. To me, it all looked very fishy, as though Dr. Maynard Howe (CEO) and Dave McGuigan (VP) of Stemedica Cell Technologies, knowing that Gordie Howe was not eligible for their clinical trial for stroke, given that Howe’s stroke was less than two months prior and the trial required that the stroke be six months old and that no neurologic improvement had occurred for two months, had shunted him to Novastem to be treated. Looking at Novastem’s website, in marked contrast to that of Stemedica, I saw no evidence of clinical trial activity at all, other than following up with patients by keeping in touch with their doctors. What I did see was (to me, at least) a very dubious-appearing stem cell clinic that charged patients large amounts of money for stem cells, cash on the barrelhead. (Seriously, Novastem only accepts cash or money transfers.) With Christmas fast approaching, I did not expect to find out anything more about this story before the end of the year.
My expectation was upended on Christmas Eve.
On the afternoon of December 24, as I was preparing to head over to my aunt’s house for the traditional Gorski family Christmas Eve celebration, I received an e-mail from a woman named Kimberly Stoddard, who represents The Townsend Team, a marketing and branding firm representing Stemedica. Ms. Stoddard referred me to a press release entitled Novastem Treats First Patient Using Stemedica’s Mesenchymal and Neural Stem Cell Combination Therapy for Ischemic Stroke:
TIJUANA, Mexico, Dec. 24, 2014 /PRNewswire/ — Novastem, a leader in regenerative medicine, announces the treatment of its first patient in its study for ischemic stroke at Clinica Santa Clarita. According to the American Stroke Association, ischemic strokes account for 87 percent of all stroke cases. Novastem continues to enroll qualified patients in the study, entitled “Internal Research Protocol in Combination Therapy of Intravenous Administration of Allogeneic Mesenchymal Stem Cells and Intrathecal Administration of Neural Stem Cells in Patients with Motor Aphasia due to Ischemic Stroke.” All participants receive a unique, combination therapy using a method covered by a United States patent owned by Stemedica Cell Technologies for the therapeutic use of its allogeneic, ischemia-tolerant mesenchymal and neural stem cells.
My first reaction went along the lines of, “Well, that’s odd. Who issues a press release like this on Christmas Eve? Nobody’s paying attention now.” My second thought was a speculation, “Well, maybe that was the point.” My third question was whether this press release was a reaction to the skeptical posts about Gordie Howe’s treatment with stem cells by Paul Koepfler and myself. In checking to see of Dr. Koepfler had written anything else, I found a followup post by him dated December 23 and entitled Response from Stemedica on Questions on Stem Cell Treatment of Howe. It’s not very informative, its only new information being that Stemedica didn’t write the press release (its author was later revealed to be Gordie Howe’s son Murray) and that “Stemedica is not a sponsor of the clinical trial referenced below; that is Novastem…”
And now we have Novastem and Stemedica’s joint press release.
It was immediately obvious to me (and anyone else who had paid attention to the stories about Gordie Howe) that this first patient treated was, in fact, Gordie Howe, although the press release quite properly did not name him. One thing I wrote in my original post that this press release did confirm for me is that the principal investigator (PI) of this “trial,” if trial it is, appears grossly unqualified to be running a clinical trial on something as tricky as testing whether stem cells might help stroke victims. If you don’t believe me, take a look at Dr. Clemente Humberto Gil Zúñiga’s CV posted on the Novastem website. He’s a geriatrician who practices at Hospital Angeles Tijuana and appears to possess no relevant clinical trial experience that I can find listed. Certainly his publication record shows nothing related to stem cell biology or clinical trials.
I’m a clinical trial maven. That’s why I had hoped to learn a bit more about the trial design, but the press release, not surprisingly, reveals little. Still, there are clues here. First, off, this trial is designed to examine the effect of this stem cell treatment on aphasia. Briefly, the general term “aphasia” describes acquired speech/language difficulties due to brain injury or damage in which part or all of speech is impaired with no affect on intelligence. For example, in simple terms a patient with expressive aphasia can understand what others say and knows what he wants to say but just can’t say it. I have personally witnessed a family member with this after a stroke. It’s incredibly frustrating to the patient. There are other forms of aphasia, such as receptive aphasia, but it’s not important for purposes of this post to describe them now. All you need to know is that various forms of aphasia are very common sequelae of strokes. It struck me as odd that Gordie Howe would be on an aphasia trial, because (1) his post-stroke impairments go way beyond aphasia, judging from the news reports and (2) he suffers from significant dementia, which would make determining aphasia scores difficult. We don’t know for sure how bad Howe’s dementia is, but in some news reports I’ve seen it’s been described as “severe.”
Next, there is this part of the title of the protocol, “Internal Research Protocol.” Right away this tells us that there is no external funding; it’s an internal protocol. Next, if we look at the paragraph above, we see a curious sentence stating that the “protocol is approved by the Research Ethics Committee of Clinica Santa Clarita, , which is federally registered and licensed by the Federal Commission for the Protection against Sanitary Risk (COFEPRIS), a division of Mexico’s Ministry of Health.” What does this mean? Not being familiar with Mexican law with respect to clinical trials, as I am with US law, I am struck by how this is described. In the US, we would say that a trial is IRB approved (Institutional Review Board), that there is an IND (investigational new drug) application, and that the trial is registered with the FDA, which presumably any company would do because trials being used as a basis for drug approval have to be registered with the FDA and conform to all the rules for clinical trials, including the Common Rule. In this press release, we see from the sentence structure that it is the clinic, Clinica Santa Clarita, that is “federally registered and licensed by the Federal Commission for the Protection against Sanitary Risk (COFEPRIS), a division of Mexico’s Ministry of Health,” not the trial. I suspected that this sort of registration is not the equivalent of what goes on in the US. Boy, was I correct, far more so than I thought! I’ll explain in the last section, when I look at this trial in more detail. First, however, I want to address a news story published Friday.
On Friday, a reporter who’s interviewed me before, Bradley Fikes, published a news story about Gordie Howe in U-T San Diego entitled Did stem cells really help Gordie Howe? This is the first—and so far only—attempt by a mainstream media outlet that I’ve seen to cast a skeptical eye on the whole story as presented. In the story, Fikes reports a number of disturbing aspects of this case.
First, we learn from Dr. Murray Howe, Gordie’s son, how he’s doing:
Howe, 86, suffered the stroke in late October, leaving him unable to walk and disoriented. He began improving within hours after receiving the stem cells in early December, said Dr. Murray Howe, a radiologist and one of Howe’s sons. For example, Howe insisted on walking to the bathroom, which he previously could not do.
“If I did not witness my father’s astonishing response, I would not have believed it myself,” Murray Howe said by email Thursday. “Our father had one foot in the grave on December 1. He could not walk, and was barely able to talk or eat.”
“Our father’s progress continues,” the email continued. “Today, Christmas, I spoke with him on FaceTime. I asked him what Santa brought him. He said ‘A headache.’ I told him I was flying down to see him in a week. He said, ‘Thanks for the warning.’”
Yes, Gordie Howe did appear to have “one foot in the grave” on December 1. I even reported it in my last post that he looked bad then and everyone thought that he had had another big stroke. Fortunately, he was just dehydrated and rapidly improved with hydration, as several contemporaneous news stories reported before Howe was ever taken to Tijuana for Novastem’s stem cell treatment.
In fairness, I have to acknowledge that there’s more:
A physical therapist who works with the elder Howe, Deirdre Bailey, said Thursday he showed “marked improvement” when she saw him a few days after the stem cell therapy. Previously able to stand only with extensive help, Howe could stand and walk on his own, although unsteadily and in need of close watching.
Bob Jones, a speech language pathologist who has worked with Howe over the last several weeks, said Thursday that Howe greatly improved his understanding and response to questions after the treatment. He was further improved when seen on Thursday of last week.
“He interacts more than he had before,” Jones said. “He responds appropriately to such things as proverbs, idioms similes,” when prompted to complete them. His speech, almost unintelligible before, is less difficult to understand.
So it does sound as though Gordie Howe is doing better, which is great. However, it’s not possible to tell whether this improvement is due to his stem cell infusions. Remember, just before he went to Tijuana, he had recently been hospitalized for dehydration that had rendered him unresponsive. Before that, he had had a rough November, with setbacks but overall small improvement. Indeed, if you look at the news coverage of Howe’s condition since October 26, you’ll see reports of rapid recovery mixed with reports of setbacks. It’s clearly been a bit of a rollercoaster ride, which makes it very hard to tell if any improvement is due to anything other than nature or if it’s durable. The point is simple: Given Howe’s fluctuating, but overall slowly improving condition, it’s hard to attribute his current condition to the stem cell treatment.
As hard as it is for Dr. Murray Howe to realize, as well, human beings are very prone to observational quirks. In fact, it’s clear that he doesn’t recognize it, given that the story reprints a complete e-mail by him in which he declares himself “an expert in my dad’s medical condition” and “confident that my credentials attest to my capacity to be a reliable witness.” (He also stated emphatically that he had written the entire December 19 press release announcing Howe’s “miraculous” progress since undergoing stem cell treatment.) Unfortunately, doctors are arguably among the worst when it comes to overestimating our capacities to be reliable witnesses. Unlike our unfortunately frequent view of ourselves as being objective observers, unless we make a conscious, skeptical effort not to be, we are just as prone to confirmation bias, in which observations that agree with our beliefs or hopes are more likely to be remembered and those that do not tend to be forgotten, as anyone else. Like every other human, we confuse correlation with causation.
In fact, if there’s one thing I learned from watching my mother-in-law slowly die of breast cancer six years ago, it’s that being a doctor does not inoculate one from hanging on every observation hopefully, latching hopefully onto anything that seems like an improvement, even if ephemeral or not even real, and discounting anything that looks like a turn for the worse. And that was observing a disease that is my specialty. Dr. Howe is a radiologist; he’s not a neurologist or stroke expert. Let’s just put it this way: Emotional connection plus confirmation bias do not equal a witness any more reliable than average. There’s a reason why doctors generally do not treat loved ones. Emotional attachment affects judgment a lot more than we would like to admit. Emotional attachment also makes one prone to denial. I know this from personal experience too. Indeed, I could give you a specific example from when my mother-in-law’s cancer recurred in which denial led me to a very stupid conclusion about a finding, but I’m too embarrassed about it to admit the details to any but my closest family.
But let’s say that Howe really is as much improved as has been described, which, again, would be awesome. That still doesn’t really mean that it was the stem cells that are responsible, given that he had been recently hospitalized and had had a rocky course. It must be conceded that it might have been the stem cells. Certainly everyone seems to be assuming that it was. For instance, the physical therapist saw him “a few days after” the treatment. When did she see him last before that? When he was in bad shape at the end of November and in early December? Ditto the speech therapist. Again, correlation does not necessarily equal causation. For example, on December 3, the Detroit Free Press reported:
Son Mark Howe told the Free Press that Gordie Howe has had a hard time sleeping since being hospitalized Monday. “Anxiety from dementia does that to him,” Mark Howe wrote via text. “Change of surrounding makes his dementia worse as well.”
With this in mind, it’s hard for me not to ask: How much of Howe’s improvement was due to his having been home a few days after a hospitalization from December 1 to 3, followed by a trip to Mexico a few days later and how much was due to the stem cell treatment? It’s really not possible to say, but news accounts before Fikes’ sure gave the impression that it had to be the stem cells.
After Fikes’ story broke, I knew, in light of Stemedica and Novastem’s joint press release, that I had to update the story. Being a clinical trial guy, I was frustrated, however, that what I really wanted to know was not in either Dr. Howe’s press release, Novastem and Stemedica’s joint press release, or Mr. Fikes’ story. Here’s what I wanted to know:
Regarding the last question, I was particularly curious about this issue in light of Novastem’s policies of cash on the barrelhead for treating basically anybody, as clearly delineated on its website, the statement in Fikes’ article that patients pay for this tria, and this statement from Dr. Howe:
Did Novastem treat our father for free? You betcha. They were thrilled and honored to treat a legend. Would you charge Gordie Howe for treating him? None of his doctors ever do. I certainly am not going to criticize them for being generous.
I find it fascinating that anyone would criticize Novastem for charging, or for not charging, for their services. They appear to have developed techniques and protocols which are safe and hold promise for countless individuals. My hat is off to them for the quality service they offer.
As sympathetic as I am to the Howe family, I’m sorry. I reluctantly have to say that Murray Howe really should know better. If Gordie Howe was treated as part of a clinical trial, then Novastem should have treated him for free! That’s because if it is running a clinical trial, it should treat everyone on the trial for free. That’s the way it’s done ethically. I realize that these stem cell treatments cost something like $20,000 to $30,000 a pop, but pharmaceutical companies testing new cancer drugs, for instance, not infrequently spend way more than that per patient on clinical trials. It’s the cost of drug development. Charging patients is also one of the big issues I’ve always had with Stanislaw Burzynski, for instance, charging patients to be on his clinical trials and justifying it by saying he’s not charging them for the experimental drug (antineoplastons) but rather a “case management fee.” In fact, I would argue that it’s even more unethical if a company doing a clinical trial charges some patients for the trial but doesn’t charge others, particularly if the reason it doesn’t charge a patient like Gordie Howe is because he is a sports celebrity. What about all the rest of the peons? According to Fikes’ story, they get charged $20,000.
In trying to answer other questions, through a circuitous route I found myself in e-mail contact with Dr. Maynard Howe (no relation to Gordie Howe), the CEO of Stemedica. He was pleasant and more than eager to talk to me about Stemedica’s products, but, after some back-and-forth by e-mail, it became apparent to me that he couldn’t (or wouldn’t) provide me with any useful information about the Novastem clinical trial that I craved. Even though it had been he and Dave McGuigan, VP of Stemedica, who had reached out to the Howe family and facilitated Gordie Howe’s treatment in Tijuana, my impression was that he was basically washing his hands of the matter, referring me to Novastem for all questions because it wasn’t Stemedica’s trial. So I tried the Novastem general contact page and, ultimately, the e-mail address for the PI of this trial, Dr. Clemente Humberto Zuniga Gil, listed on his CV page on the Novastem website. I don’t know whether it was my e-mail through the general contact page, my direct e-mail to Dr. Gil, or, again in fairness, my previous communication with Maynard Howe having led him to contact Novastem that provoked a response, but on Saturday afternoon I received an e-mail response from the president of Novastem, Rafael Carrillo.
To be fair, Mr. Carrillo was pleasant and accommodating. His e-mail responses struck me as very earnest and eager to explain his company’s position, stating that he was looking into registering Novastem’s clinical trial with ClinicalTrials.gov and COFEPRIS. He even sent me a PDF file containing a rather bare bones clinical trial schema and tried to educate me about Mexican regulations governing clinical trials. Unfortunately, the information he gave me confirmed some of my misgivings about the trial and created others. For example, remember when I expressed puzzlement earlier in this post about what the clinic’s being registered with COFEPRIS meant? Well, he informed me that it meant:
As it states in our press release Clinica Santa Clarita is federally licensed to administer stem cell therapy. This means that the Mexican regulatory agency has authorized Clinica Santa Clarita and its doctors to apply stem cell therapy as the doctor sees fit. With the abundance of research across the globe and with the safety profile and high level of manufacturing Stemedica utilizes the Mexican authorities have felt it is justified to grant us a license to administer, as well as importing and banking stem cells. We treat all patients under IRB approved clinical trial protocols. We do this for two reasons, 1. We want to publish all our results. We want to share information. We believe that the more structured our data the easier it will be to publish. 2. We want to protect the patient. We have inclusion/exclusion criteria, informed consent, adverse event reporting, etc. At this point not everyone is a candidate for treatment. We want to make sure we are ethical in selecting patients for treatment.
So, in other words, the “federally licensed” part that confused me means that Clinica Santa Clarita can do pretty much anything it wants with stem cells, which is no doubt how it has been able to advertise its services and treat patients off protocol in Tijuana. Learning this actually opened my eyes greatly as to how a weak regulatory environment in Mexico allows all sorts of dubious stem cell clinics to thrive in Mexico. In fairness, it is to Mr. Carrillo’s credit that he wants to do clinical trials and ultimately publish his company’s results. However, there is a problem—several, actually. First among them, as I pointed out before, the doctors with whom he is working appear not to have the requisite background in clinical trial design or stem cell science to produce a clinical trial that will generate useful data (more on that in a moment, when I discuss the clinical trial itself). He needs experienced clinical trialists, and I just don’t see any. More problematic from an ethical standpoint is that Mr. Carrillo what was reported in Fikes’ story and tried to justify why Novastem charges patients for clinical trials:
Another issue you have brought up is payment. We are participating in patient funded research. We feel patient funded research is a viable option for both patients and doctors alike. On one hand we are not a billion dollar corporation that can fund all research, on the other hand we are following the examples of institutions such as the Mayo Clinic and MD Anderson Clinic who use this model. Patients know they have to pay. No promises are made to patients. It is very clear to all involved. We, and the IRB, feel there is enough evidence of safety and efficacy in the journals and doctor experience to proceed. Patients who choose to participate with us feel the same way. At no point do we hide this point.
In this particular trial the cost is around $30,000. Over half the cost is the cells alone, in addition to that we pay for the follow up work, the cost of patient recruitment, doctors fees, facility use fees, etc. Although $30,000 is a lot of money, to put it in perspective, it is also the cost of a knee replacement. Without being an expert in the field I believe that if this therapy proves to be effective, the cost benefit analysis will prove that getting the treatment is a good option. Also, like everything else that is new, with time and economies of scale price will go down substantially.
It was at this point that I heard disturbing echoes of Stanislaw Burzynski and his justification for charging patients tens—or even hundreds—of thousands of dollars to be on his clinical trials. It’s also a misunderstanding of how cancer centers like M.D. Anderson do things. For example, the M.D. Anderson website specifically addresses this issue, stating that “if you are participating in a clinical trial, the trial sponsor, embassy or your insurance company may cover some of the charges. Items paid by the clinical trial will be listed in your Charge Estimate Letter” and that “you or your insurance will be responsible for the charges not covered.” Generally, sponsors of the clinical trial have to cover the cost of the drug (or, in this case, biologic) and care that’s normally not part of standard of care but is related to the trial (such as additional scans or tests). Presumably, that’s how Stemedica’s trials work north of the border. Admittedly, this method leaves a big hole. Patients who don’t have health insurance will often have a huge difficulty paying for their care not related to the clinical trial and thus will have difficulties accessing cutting edge clinical trials because they can’t pay for their own regular care. Yay, USA!
But what about the trial itself?
First, according to the document supplied me, this trial underwent IRB approval on September 28. It is summarized thusly:
This is a pilot study in which a group of 30 volunteer subjects, with motor aphasia due to stroke will receive 90 x 106 of NSC intrathecally and an intravenous infusion of 90 x 106 of MSC. Leaving a window of 24 hours in between therapies. The subject follow up will continue for six months to verify safety, tolerance and to evaluate preliminary efficacy over speech, neurological function and quality of life.
This is roughly the same number of stem cells used in the Stemedica trial (one million per kg), but given intrathecal (into the cerebrospinal fluid) and intravenously. Here is a diagram of the study:
It’s a fairly basic design, with these inclusion criteria:
Regarding #4, it is known that Gordie Howe suffers from significant dementia. It is thus highly unlikely that he was able to understand and sign the informed consent, but I suppose I could be wrong about this, given that I don’t know the result of his neuropsychiatric evaluation. There’s no mention that the family can give consent for the patient; so I assume that, strictly following the protocol, they can’t. In fact, the exclusion criteria are:
This study is a not-unreasonable phase I study, although it lacks a dose escalation component, in which doses are ramped up in order to estimate the maximum safe and tolerated dose, and some important inclusion criteria (more later). Also, its endpoints aren’t well described. It’s also highly unlikely to detect any statistically significant evidence of neurologic improvement, given that there is not a strong attempt to make the group being tested more homogeneous by, for instance, setting limits on various scores. I also wonder how Novastem defines ability to understand and sign the informed consent. There’s also the issue of how cognitive deterioration is defined. Given the news reports, it could well be that Howe’s cognition was deteriorating, but, equally importantly, it could well be that he was getting a bit better. That’s where the Stemedica trial is actually better. It includes criteria requiring neurologic stability; without that, so soon after a stroke, it’s almost impossible to tell if improvement is likely due to the treatment or if it’s just improvement that was occurring as a normal part of recovery.
There’s another issue. In Fikes’ story, Dr. Murray Howe gives the following rationale for wanting to get his father on the Novastem trial ASAP, based on his having “one foot in the grave”:
However, the [Stemedica] trial requires participants to have had the stroke at least six months ago. So Howe wouldn’t qualify until late May.
Even more to the point, there was substantial doubt whether the elder Howe would survive for six months, or even until Christmas, said Murray Howe. Howe enjoys physical activity, and if unable to move he would lose his will to live.
I totally understand the Howe family’s desire to throw a “hail Mary” pass to try to save their dad (or at least make him more functional and improve his quality of life). My wife and I looked for the same thing when her mother was dying from metastatic breast cancer, which is why we had her evaluated by the phase I group at my cancer center. I’ve been on both sides. However, in designing and carrying out a clinical trial it’s critical to be very careful not to feed into the normal desires of family to do something . It’s equally important to remember that, no matter how much you repeat that “there are no guarantees” or that “this probably won’t work,” the family will latch on to the chance that it will work. That’s part of the reason why “patient-funded” clinical trials, as Mr. Carrillo describes them, are inherently prone to becoming exploitative. Just look at Stanislaw Burzynski, if you don’t believe me.
If Gordie how really was deteriorating so rapidly four weeks ago that there was substantial doubt about whether he would survive until the end of the year, then he probably should not have been a candidate for any clinical trial for stroke. Indeed, most clinical trials for chronic conditions like stroke (and even cancer) exclude patients who are deteriorating so rapidly because they are incredibly unlikely to benefit and they make it hard to detect a real benefit if there is one. Indeed, notice how the Stemedica trial has an inclusion criteria of “life expectancy greater than 12 months.” In marked contrast, there is no equivalent inclusion criterion in the Novastem trial, which is a huge gap.
Finally, the Novastem clinical trial is designed to examine the effects of stem cells on aphasia. A man who suffers from, if news reports are to be believed, significant dementia and, if Murray Howe’s account of his father’s condition in early December is accurate (and I have no reason to doubt it), and Gordie Howe truly had “one foot in the grave” to the point where his son Murray didn’t think he could wait “even 30 days for a Compassionate IND treatment in the United States,” then he was not a good candidate for a clinical trial—any clinical trial, although an expanded use IND might still have been appropriate, particularly given that reports in early December from Howe’s other son Mark described him as “doing better overall than he was several weeks ago when he had a massive stroke” and that he had “improved enough in the past 24 hours to where we expect him to be out of the hospital and in his own bed at home before the night is over.”
In clinical trials of new therapies, particularly for conditions that are either currently irreversible and result in a greatly diminished quality of life (like a stroke) or that will ultimately kill the patient (like certain cancers), it is always difficult to balance rigorous science versus hope and wanting to help as many patients as possible. After all, hope is part of why such patients enroll in clinical trials; that cannot be denied, and good clinical trialists are acutely aware of this. However, the ethical researcher tempers that hope and tries to keep it from being unrealistic. Moreover, as the example of my own experience with my mother-in-law’s stage IV breast cancer and the writings of Dr. Murray Howe about his father show, being a physician does not inoculate one from unrealistic hope and human cognitive shortcomings like confirmation bias. As physicians, we find this hard to admit to ourselves, but it’s true.
Similarly, it is potentially exploitative to require patients to pay to be on a clinical trial. That’s why legitimate trials in the US don’t require it, except in very uncommon, highly defined situations, and even then it is generally frowned upon. It is also highly unethical to treat patients on clinical trials differently based on their status. Ideally, none should pay to be on a trial, but if patients are being made to pay then it is, in my opinion, breathtakingly unethical to excuse one patient from paying just because he is a famous sports icon. It’s more unethical when that patient is used for publicity, as Gordie Howe has been. Such a special financial arrangement is inherently unfair to other subjects on the trial. Worse, it also smacks of paying a clinical trial subject for an endorsement and is thus potentially coercive. It is profoundly disappointing to me that neither Mr. Carrillo, Dr. Maynard Howe, nor Dr. Murray Howe appears to grasp this. Indeed, Murray Howe dismisses such concerns by writing that there were “no strings attached to their [Stemedica and Novastem's] offer” and that they “never have asked us to share Mr. Hockey’s amazing response.” Assuming that’s so, unfortunately the lack of explicit “strings attached” or explicit requests to publicly share Howe’s response doesn’t make the arrangement any less unethical or potentially coercive. Indeed, Howe points out that he shared his father’s response out of a sense of obligation, which is exactly what such arrangements engender and why they are unethical!
The saga of Gordie Howe’s stroke and his treatment at Novastem is a textbook example of why clinics like Clinica Santa Clarita are a major problem. Accountability is minimal to zero, and patients pay for experimental treatment. Unlike the case with Dr. Burzynski, I actually think that the leadership of Stemedica and Novastem believes in the Stemedica stem cell treatment. However, it is very difficult now, knowing what I know, not to walk away with the impression that Novastem was a tempting way for Stemedica to sidestep the regulations of the US and that Stemedica, its leadership apparently believing in a stem cell miracle, yielded to that temptation. Meanwhile, Mr. Carrillo seems to want to do the right thing but appears not to understand what the right thing is—or to have any clinical trialists working for him who can tell him what the right thing is.
Perhaps the saddest thing to me is that Dr. Murray Howe feels sorry for “anyone who finds this miracle ‘troubling.’” Presumably he means skeptics like Dr. Knoepfler and myself who have publicly questioned the news reports. I can assure Dr. Howe that I do not find Mr. Hockey’s progress and recovery “troubling.” No one, least of all myself, begrudges the Howe family hope. Indeed, I really do hope that Howe is doing better. I even hope it was the stem cells! After all, I’m not as young as I used to be. Cardiovascular disease runs in my family. I could easily find myself in Howe’s situation 20 or 30 years from now. I would love it if there was an effective treatment for brain damage due to stroke, and I do believe that stem cells have great potential to treat conditions that were previously untreatable.
Unfortunately, it’s everything else about his story that I find troubling, particularly how it was announced in the media, leading to numerous credulous reports portraying Stemedica’s stem cell treatments as some sort of miracle cure for Mr. Hockey and how Howe’s story as related by his family came across as very much of a piece with alternative medicine cancer cures and cures for other conditions. There is a right way and a wrong way to test treatments like this. Novastem looks as though it is taking the wrong way, whatever the motives of its president. I felt obligated to point that out because not every stroke patient is Gordie Howe.
Fantastic new podcast channel from Jesse Spurr, with a gem of an episode with Ross Fisher on presentation skills. If you’re planning a presentation make certain to have a listen…..first! [SL]The post LITFL Review 162 appeared first on LITFL.
Seven years ago I returned to Michigan, where I was born and spent the first quarter century of my life, after an absence of more than 20 years. In the interim, I had done my surgical residency and earned my PhD in Cleveland, a surgical oncology fellowship in Chicago, and worked in New Jersey at my first academic job for eight and a half years. Then I was lured back with a job in Detroit. One of the odd things about this return after such a long absence was the culture shock, how much I had forgotten about the Detroit area. One of those things that I had forgotten is just how crazy about hockey Michigan, in particular Detroit (meaning the Detroit metropolitan area), is. Detroiters love their Red Wings—love them. Hockey is ingrained in the suburban culture from a very young age, so much so that many Canadians would feel right at home here. Memories of trying and failing to be halfway decent at street hockey and of not being anywhere good enough a skater even to try real hockey as a teen came flooding back to me. (It didn’t help that back then I was approaching six feet tall and weighed only 135 lbs.; “beanpole” didn’t even begin to describe me back then.) In fact, the “cultural center” of the town where I live consists of—I kid you not—a hockey rink and some classrooms that are used for various community functions. No, really, it’s named the city’s Cultural Center.
So it should be no surprise, given how much Detroiters love hockey in general and their Red Wings in particular that it was big news here in late October when Red Wing legend Gordie Howe at age 86 suffered a debilitating stroke that paralyzed the right side of his body, a condition known as hemiplegia. Understandably, there was an outpouring of good wishes for recovery, coupled with retrospectives of Howe’s stellar hockey career. Indeed, I remember that Howe’s condition sounded bad enough from the tenor of the news reports at the time that it seemed likely that he would not survive. But survive he did, and is apparently recovering slowly, with occasional setbacks, such as a recent hospitalization in early December for a suspected “mini-stroke” that turned out to be dehydration and several much smaller strokes before that. The most recent press report I saw before the announcements I’m going to discuss described Howe as on the upswing again.
Then, on Friday, I saw headlines all over the place that were basically similar to this Detroit Free Press headline, “Gordie Howe underwent stem cell clinical trial in Mexico.” The story consisted largely of a press release from Howe’s family that read:
Following the press coverage of our father’s deteriorating medical condition, the Howe Family was contacted in late November by Dr. Maynard Howe (CEO) and Dave McGuigan (VP) of Stemedica Cell Technologies. McGuigan knew our family as a result of his previous employment with the Detroit Red Wings. Stemedica is a biotechnology company that manufactures allogeneic adult stem cells in its U.S. government licensed, cGMP facility in San Diego, California. Although no relation, Dr. Howe and his brothers Drs. David and Roger are hockey players and big Gordie Howe fans, having grown up in Minnesota. They wished to help our father by generously facilitating Dad’s participation in a stem cell clinical trial at Novastem, a licensed distributor of Stemedica’s products in Mexico.
Novastem (www.novastem.mx) is currently conducting federally licensed and Institutional Review Board approved clinical trials for several medical conditions, including stroke, using Stemedica’s stem cell products. At the time we were contacted, Mr. Hockey had been rapidly declining and was essentially bedridden with little ability to communicate or to eat on his own.
After reviewing the information on Stemedica and Novastem, our family decided to give our father this opportunity. On December 8, Mr. Hockey underwent a two-day, non-surgical treatment at Novastem’s medical facility. The treatment included neural stem cells injected into the spinal canal on Day 1 and mesenchymal stem cells by intravenous infusion on Day 2. His response was truly miraculous. At the end of Day 1 he was walking with minimal effort for the first time since his stroke. By Day 2 he was conversing comfortably with family and staff at the clinic.
On the third day, he walked to his seat on the plane under his own power. By Day 5 he was walking unaided and taking part in helping out with daily household chores. When tested, his ability to name items has gone from less than 25 percent before the procedure to 85 percent today. His physical therapists have been astonished. Although his short-term memory, strength, endurance and coordination have plenty of room for improvement, we are hopeful that he will continue to improve in the months to come.
As a family, we are thrilled that Dad’s quality of life has greatly improved, and his progress has exceeded our greatest expectations. Once again, we cannot emphasize how much you have fueled Mr. Hockey’s recovery and we thank everyone for their continued prayers and support.”
Local news station WDIV picked up the story without even an iota of skepticism:
This report even ends with the anchorman telling the reporter that he hopes the FDA hears about this and gets something going here too, which, as I discovered researching this, reveals an incredible depth of ignorance and shows that not one bit of fact checking went into this story. As you will see, there are FDA-approved clinical trials of Stemedica’s treatments currently under way; so the FDA already knows.
Then on Saturday there appeared this report broadcast on ESPN in which Howe’s sister is quoted as saying that he could “come tap dancing off the plane” in a month and a half after his son Murray, a radiologist in the Toledo area, announced that Howe was going to be the guest of honor at the Kinsman Celebrity Dinner along with hockey great Wayne Gretzky in Saskatoon, where Howe spent his childhood, on February 6:
One also notes that, according to the reports listed above:
Cummine said she talked to Howe’s son Murray, a doctor, a couple of days ago and he told her the longtime NHLer is progressing nicely.
“He’s up walking a few steps, and he’s trying to put words together to form a sentence,” Cummine said. “Murray’s exact words were ‘he’s kicking ass.’”
This sounds a lot different than the press release. Naturally, my skeptical antennae, which had started twitching reading the first story, started twitching even harder. You’ll see why shortly, although hearing about a Mexican stem cell clinic ought to be enough to send up a thousand red flags. What is the real story? It’s been hard to find out, and I still don’t know for sure that I have managed it.
We at Science-Based Medicine (SBM) have written about dubious stem cell treatments on many occasions. Stem cells, of course, are cutting edge science. The problem, of course, is that that cutting edge science, with very few exceptions, has not yet been translated into safe and effective treatments for the conditions that it has promise to treat. Enter the quacks, who make what I’ve referred to as magical claims for stem cells. Are Stemedica and Novastem like this? Let’s find out. After all, just because Novastem is in Mexico does not necessarily mean it’s one of these dubious stem cell hucksters, although a first glance at the Novastem website most definitely did not allay my suspicions.
There are two types of stem cells, embryonic stem cells and adult stem cells. The first (and potentially most useful for the widest variety of conditions) are pluripotent, which means that, given the right signals, they are able to differentiate into all derivatives of the three primary germ layers in the embryo: ectoderm, endoderm and mesoderm. In other words, they are able to become virtually any kind of cell. You can easily see why embryonic stem cells are attractive as a treatment: In theory, they could be used to replace or repair any tissue that requires it, if only they could be targeted to where they are needed and the correct signals could be deduced to induce them to differentiate into the needed cell type(s). These are enormous challenges. Add to that the religious objections to these cells, given that it is necessary to create pre-implantation embryos to isolate them and, in so doing, destroy these embryos, and the challenges are even greater, particularly in the US where restrictions on embryonic stem cell generation and use are more strict than in other developed countries.
The second kind of stem cells is known as adult stem cells. Adult stem cells are undifferentiated cells that remain in children and adults and can proliferate to replenish dying cells and regenerate damaged tissues. They are also known as somatic stem cells. Their defining properties include, as for embryonic stem cells, self-renewal (the ability to divide indefinitely while remaining undifferentiated) and multipotency, the ability to differentiate into several cell types. In contrast to embryonic stem cells, though, adult stem cells are limited in the types of cells into which they can regenerate. For example, there are hematopoietic stem cells, which can give rise to all the types of blood cells: red blood cells, B lymphocytes, T lymphocytes, natural killer cells, neutrophils, basophils, eosinophils, monocytes, and macrophages; mesenchymal stem cells, which can give rise to a variety of cell types: bone cells (osteoblasts and osteocytes), cartilage cells (chondrocytes), fat cells (adipocytes), and stromal cells that support blood formation; and neural stem cells, which are found in the brain and can produce the brain’s three major cell types: nerve cells (neurons) and two categories of non-neuronal cells—astrocytes and oligodendrocytes.
Finally, there is a cell type known as an induced pluripotent stem cell (iPSC), which are adult stem cells that have been genetically manipulated to express genes and factors important for maintaining the defining properties of embryonic stem cells, but it is not yet known whether these cells can be used as embryonic stem cells and their uses now, for the most part, consist of in vitro studies and show potential usefulness in transplantation medicine. One problem with iPSCs is that viral vectors are needed to introduce the genes that “dedifferentiate” the adult stem cells, making their use in humans as yet problematic.
In any event, there remain many problems to be overcome, such as how to target the cells, how to induce them to differentiate properly, and how to prevent them from becoming cancers. Thus far, in general, most attempted clinical uses of stem cells involve the isolation of these cells from either the bone marrow or blood (or sometimes from adipose tissue). My basic opinion is that, outside of hematopoietic malignancies, for which bone marrow ablation and stem cell transplantation have been a standard of care for many years, most adult stem cell applications are not ready for prime time yet. It wouldn’t surprise me if we see some treatments clearing that hurdle in the next few years, but most of these therapies are still in either preclinical or phase I testing, with few having yet shown sufficient evidence of efficacy and safety to achieve FDA approval.
In the meantime, Steve has cautioned readers to be wary of stem cell pseudoscience, emphasized the need for transparency, and decried stem cell tourism. Jann Bellamy has commented on how regulation and law have not yet caught up with stem cell science (and pseudoscience). I myself have noted how prevalent stem cell quackery is throughout the world, including China, Ukraine, Panama, Italy, and, yes, Mexico. Given the track record of various companies offering stem cell treatments with inflated claims, my viewpoint when I encountered stem cell treatments outside the confines of reputable academic institutions tends to be one of extreme skepticism, a skepticism that usually is well-justified.
Is such skepticism justified for Stemedica and Novastem? Let’s find out.
The first thing I noticed when I perused the Novastem and Stemedica websites is a distinct—shall we say?—difference in the marketing. The Novastem website declares Novastem a “world leader in regenerative medicine and stem cell therapy” and touts as its list of experts; doctors who to me appear to have no special expertise in stem cells or stem cell medicine. There are internists, a urologist, an otolaryngologist, general surgeons, a pulmonologist, a neurologist, and an orthopedic surgeon, but a perusal of their qualifications (when listed) through Google Translate (their CVs are in Spanish) reveals little that impresses me that they have the expertise to carry out legitimate clinical trials of stem cells. Seriously, their CVs are completely underwhelming. Heck, I could make a strong argument that I’m more qualified than any of them to be doing stem cell research!
Then, Novastem describes its treatment:
At Clínica Santa Clarita, we provide the highest level of personal attention to make your experience both convenient and pleasant. Our concierge service will not only help you plan your visit, we will supply luxury, personalized, private transportation locally or to/from San Diego. Our medical clinic is less than five minutes from San Diego, and the new medical line at the border expedites return access. In addition, we can provide assistance with hotel accommodations in San Diego and medical travel insurance, if desired.
Upon arrival at Clínica Santa Clarita, you will be examined by a Novastem specialist who will discuss your medical history and your expectations. Together, you will review the information packet and sign an informed consent form.
Meanwhile, the stem cells from Stemedica, maintained in a state of cryopreservation, are being prepared for therapy and undergoing a final panel of tests to ensure their quality and viability. Prior to your arrival, Novastem does the testing at its facility and verified by a third party lab.
Then, comfortably seated and overseen by our skilled staff of physicians and clinicians, you will receive intravenous delivery of these stem cells. The process is painless and takes less than four hours. Following your therapy, we will transport you back to your accommodations.
So let’s see. The stem cells are produced at Stemedica, which is strategically located in San Diego, shipped across the border from San Diego to Tijuana, then used at Clínica Santa Clarita, which is apparently run by Novastem. They’re given to patients, even though they are not yet FDA approved, with the claim that they can treat “heart attack, stroke and traumatic brain injury,” after which:
In the weeks and months following your treatment, Novastem will maintain contact with your physician to compile data regarding the efficacy of stem cell therapy as it relates to your condition. This data will be verified by a third party Contract Research Organization (CRO), to assure validity.
So, basically, Novastem appears to be providing stem cells manufactured by Stemedical to pretty much anyone with the ability to pay. The closest it appears to be coming to doing a clinical trial is to keep in touch with the primary care physicians of patients treated at its Clínica Santa Clarita. In other words, Novastem appears to have many of the attributes of a quack clinic in Tijuana.
Now let’s look at Stemedica. This company’s web page boasts to its patents about using multiple stem cell lines to treat ischemic stroke and for a cellular scaffold enhanced by stem cell factors. It also has a link to its clinical trials (more on that later) and advertises three different stem cell product lines that have obtained investigative new drug (IND) designations from the FDA, as well as its manufacturing process, which includes a cGMP (Current Good Manufacturing Practice) facility as approved by the State Department of Health and Human Services, Food and Drug Branch. In other words, unlike Novastem, which gives every impression of being a quack stem cell clinic based on its website and marketing materials (not to mention its location in Tijuana), Stemedica does not look like a stem cell quackery clinic. Rather, it gives every appearance of being a legitimate biotechnology company.
It also touts its subsidiaries, such as StemCutis, which is described as producing stem cell-based products to treat dermatological diseases and improve the appearance of patients’ skin due to compromised skin, diabetic ulcers, hair loss, burns and hypertrophic, hypotrophic and keloid scar, and CardioCell, which is described as running clinical trials using stem cells to develop highly effective, “off-the-shelf” therapeutic products for cardiovascular indication. To me, StemCutis looks to be angling to get into the beauty and antiaging market, selling products “consisting of stem cell growth factor-based compounds with a moisturizing skin toner and an elasticity-enhancing, anti-wrinkle cream. For the maximum preservation of the stem cell factors, the factors are enclosed in sugar crystal and sterilized.” Then there’s hair restoration therapy, based on factors expressed by Ischemia-Tolerant Mesenchymal Stem Cells (itMSCs). It turns out that itMSCs are a newer wrinkle in stem cell treatment, the idea being that stem cells will do better if they undergo a preconditioning procedure that sets them into a primed state before they encounter the harsh microenvironment of hypoxia/ischemia and elevated levels of injurious factors in areas like dying heart muscle or dead brain tissue.
Then, of course, there is a clinical trial using stem cells for ischemic stroke (ClinicalTrials.gov identifier NCT01297413), “A Phase I/II, Multi-Center, Open-Label Study to Assess the Safety, Tolerability, and Preliminary Efficacy of a Single Intravenous Dose of Allogeneic Mesenchymal Bone Marrow Cells to Subjects With Ischemic Stroke.” Stemedica’s collaborators include the University of California, San Diego, Mercy Gilbert Medical Center at AZ, and Chandler Regional Medical Center at Chandler AZ. Interesting. There’s no mention of Novastem, is there? In any case, it’s not unreasonable to think that this is probably the clinical trial to which the press release was referring, because there is currently no other ongoing clinical trial for ischemic stroke run by Stemedica and no trial listed by Novastem at all.
Now that we know the background, we can take a closer look at Gordie Howe’s case. The description of his recovery has been highly variable, but we know from several news reports that Howe had been improving. For example, right after his stroke, Howe appeared to be getting rapidly worse (which is not uncommon due to the inflammatory reaction that occurs around the dead brain tissue leading to edema, or swelling, of the surrounding brain tissue, with further neurologic compromise). Then, nine days after his stroke, he was reportedly getting much better. Indeed, he had even been reported to have had great improvement in his speech and had been able to walk with the assistance of a walker. Two weeks later, on November 20, Howe was reported to have had a major setback:
Hockey legend Gordie Howe has shown minor improvements, even as he remains largely quiet and immobile.
His son, Mark Howe, told the Free Press today that Gordie Howe, “isn’t in so much pain any more. No walking or speech, but at least he’s out of the bed.”
Because:
After showing some improvement, Gordie Howe’s health again appeared dire last weekend. An epidural has helped reduce the pain, and Mark Howe said the family got Gordie Howe “to a living room chair” two days in a row. “A lot of work to do, but at least we got him out of bed,” he said.
Finally:
As of Thursday afternoon, he had been off pain medication for 54 hours, and “his blood pressure is under control,” Mark Howe said. “”He’s eating again, so his quality of life has improved, for now. We take each day as it comes, and are just happy he isn’t in so much pain any more.”
Then, as mentioned above, in early December Howe was hospitalized again because he was unresponsive for 30 minutes and his family had feared he had had another stroke. It turned out not to be the case; fortunately, he was just dehydrated.
Then, last Thursday, the day before the family issued a press release describing Howe’s treatment with stem cells, there was a report in the Detroit Free Press that described his health thusly:
Howe now has enough strength to be somewhat mobile, a stark – and much welcome – late-December development after the month began with what his children feared was another serious stroke.
Son Mark Howe told the Free Press on Thursday that his father isn’t so much able to walk, rather that “it’s more of a shuffle, but he is making his way around under his own power.”
Now let’s compare this to what the family’s press release said. On December 8, apparently, Howe was given Stemedica’s stem cell treatment at Novastem, which means that he must have been taken to Tijuana. I can’t help but note at this point that Novastem is not one of the collaborating institutions listed on the ClinicalTrials.gov entry for Stemedica’s clinical trial for stroke. Specifically, there are only two sites offering the trial: UCSD’s Department of Neurological Surgery, where the principal investigator is Michael L. Levy, MD, FACS; and Mercy Gilbert and Chandler Medical Center in Gilbert, AZ, where the PI is Nabil Dib, MD, MSc, FACC. Although it makes sense that a neurosurgeon could be a PI for a trial like this, it is a little strange given that most neurosurgeons don’t take care of ischemic stroke patients who are not candidates for an operation to remove blockages of cerebral blood flow, like carotid endarterectomy, and pediatric neurosurgeons virtually never take care of your basic run-of-the-mill adult ischemic stroke. On the other hand, Dr. Levy’s expertise is listed as studying the cerebral vasculature so I have no problem with him as the PI of such a study. I do, however, find it rather odd that the PI at the other site is a cardiologist and not a neurologist or neurosurgeon.
According to the family’s press release, at the end of Day 1 he was walking with minimal effort for the first time since his stroke. That would be December 9. By Day 2 (December 10), he was conversing comfortably with family and staff at the clinic. On the third day (December 11), he walked to his seat on the plane under his own power. By Day 5 (December 13) he was reportedly walking unaided and taking part in helping out with daily household chores, and his cognitive skills had improved markedly.
Unfortunately, this press release does not jibe with contemporaneous reports about Howe’s condition. For example, on December 13 (that would be day 5 in the press release), the Detroit News reported that, after getting worse, Howe was getting better again:
“Both of my brothers have been down in Texas for a couple of weeks, now, and I’m getting some positive feedback,” said Howe, the Red Wings’ chief pro scout, who like his father played for the Wings and is a member of the Hockey Hall of Fame.
“He had his stroke, and he was showing signs of getting better for a couple of weeks. And then, he’s been going downhill for about a month.”
Howe suffered a setback recently, but it was diagnosed as dehydration, and he was released from a hospital after what turned out to be a brief stay.
“Since we got him out of the hospital and got him back home, he’s been eating better and drinking better,” his son said. “He’s been wanting to do his therapy and stuff, again
“So, I’m getting a lot of positive signs, and that’s music to my ears, and I’m excited about it.”
That sounds promising, but nowhere near as seemingly miraculous as the description in the press release.
In the aforementioned report published on December 18 in Detroit Free Press in which Howe was described as “somewhat mobile” and able to shuffle more than walk, it was prominently mentioned that Howe had improved markedly after having arrived home to be in familiar surroundings after his hospitalization. (Howe also has significant dementia, most likely due to his strokes, and it is well known that patients with dementia do worse when removed from familiar surroundings.) In any case, however you want to slice it, let’s just say that there is a serious disconnect between the Free Press report dated December 18 and the press release dated December 19 in the description of Howe’s recovery. The press release makes it sound as if he’s almost back to normal. The other reports sound more like the sort of progress that we might expect to see in an 86 year old less than two months after a major stroke.
These conflicting stories make me wonder if there’s some sort of schism in the family, given that the press release was described by the Free Press as a “statement further detailing the improvements the Detroit Red Wings legend has made over the past few weeks” in contrast to the statement by Gordie Howe’s son Mark that his father was just “shuffling,” as if it were meant to counter Mark Howe’s description of his father’s progress. Of course, that doesn’t change the contemporaneous reports that describe much less improvement.
Be that as it may, what about the clinical trial itself? As the ClinicalTrials.gov entry describes, it’s a phase I/II trial, which basically means that it’s an attempt to do more than just a phase I trial. Recall that phase I trials primarily assess toxicity in an effort to find the best dose to use in phase II and III trials. In this case, the primary measurement outcome is safety during the 12 month study period as determined by the incidence and severity of adverse events, clinically-significant changes on clinical laboratory tests, vital signs, physical and neurologic examinations. Secondary outcomes include:
The trial is not randomized; basically, everyone gets stem cells, with the treatment described as “one dose of 0.5-1.5 million cells per kg of allogeneic adult mesenchymal bone marrow stem cells” given intravenously. Note that this is different from what is described in the press release, which includes administration of stem cells into the cerebrospinal fluid on day 1 and an infusion of stem cells intravenously on day 2. In other words, either Howe was not part of this clinical trial, or there was a massive protocol violation. Moreover, given that he received his stem cell injection at Novastem, which is not one of the approved sites, either he couldn’t have been in the clinical trial or there was an exemption granted by the FDA, the latter of which seems highly unlikely.
I think Howe wasn’t on this clinical trial. Moreover, I think he was shunted to Mexico because he wasn’t eligible for this trial. Let’s look at its inclusion criteria:
Gordie Howe had his big stroke only two months ago. True, it was suggested that he had had some “mini-strokes” before, but “mini-strokes” usually mean transient ischemic attacks, in which there is a temporary compromise of blood flow to parts of the brain, from which the patient recovers completely. Other reports have him suffering a series of strokes since summer, with the big one in late October. In either case, it really appears that Gordie Howe was not eligible for this clinical trial. His major stroke occurred less than two months ago, and, even if you accept that his first stroke was during the summer sometime, by many accounts, Howe had been slowly improving ever since, except the two setbacks, one in November and one in December, that I discussed above. Either way, even if he could somehow be squeezed in as having had his first stroke six months before, he clearly does not meet the inclusion criterion that demands no sign of neurologic improvement over the last two months.
It needs to be emphasized right here that there are valid reasons for these inclusion criteria. Stroke patients, particularly patients who suffered a major stroke, often wax and wane in the first six months. More importantly, particularly with good rehabilitation, they generally tend to improve over the first several months of their post-stroke course. Eventually, they reach an equilibrium, after which no further dramatic improvement occurs because there are no further areas of neurons that were damaged but not dead to recover and no further remodeling of neural pathways that can occur to mitigate some of the damage. That’s why testing something like Stemedica’s stem cell therapy before the patient has reached that plateau of neurologic stability can falsely make it seem as though the therapy worked when in fact all that was being observed was normal improvement that just happened to correlate with the treatment. It’s also why single patient anecdotes say little and why randomized trials will be needed to determine if Stemedica’s treatment can actually improve neurologic function after major strokes.
All of this is why I conclude that Gordie Howe’s story is not a good reason to believe that Stemedica’s stem cell treatment for ischemic stroke is why Howe has had what is described as a seemingly-miraculous recovery. In fact, given the conflicting stories contemporaneous with Howe’s treatment that were published before this press release, I believe there’s good reason to question whether Howe has actually even made such a seemingly miraculous recovery right after the stem cell treatments. Given that all I can know about Howe’s progress comes from news stories and reports that heavily rely on accounts by various family members, I cannot know for sure what the real status is. Certainly, I’m not likely ever to have access to Howe’s medical records, and his physicians can’t talk to the press unless given permission by Howe himself or, if Howe’s dementia is sufficiently advanced that he is no longer competent to make such decisions, by Howe’s family.
There are many disturbing elements to this story, not the least of which is how eager Dr. Maynard Howe and Dave McGuigan of Stemedica Cell Technologies were to glom onto Gordie Howe in order to promote their treatment and their clinical trial. First of all, they must have known that Howe is currently not a candidate for Stemedica’s trial, given that his stroke happened less than six months ago and his neurologic condition has clearly not yet stabilized. So what did they do instead? By the family’s account in the press release, they facilitated Howe’s “participation in a stem cell clinical trial at Novastem, a licensed distributor of Stemedica’s products in Mexico.”
Try as I might, I couldn’t find a description of Novastem’s alleged clinical trial of Stemedica’s products for ischemic stroke. There is no entry in ClinicalTrials.gov, which is probably not surprising if Novastem’s trial is all in Mexico. Next, I Googled “Novastem” and “clinical trial,” but all I could find were mainly articles about Gordie Howe’s stroke in which his family’s press release is cited, and articles with the words “nova” and stem” in them that link to a NOVA story on stem cells. More importantly, all I could find on the Novastem website about clinical trials was this:
…however, with the right steps in place Novastem at Clínica Santa Clarita is licensed by federal authorities. We specialize in stem cell research and therapy, and the stem cells we import from Stemedica, a biopharmaceutical company based in San Diego, have been produced under a license from the California Food and Drug Branch. The stem cells are delivered to each patient via intravenous infusion with no known side effects.
And this clinic tour, along with these Mexican certifications, which, given the number of dubious clinics in Tijuana, do not impress me at all.
Then there’s this:
At Clínica Santa Clarita, Novastem and its U.S. partner, Stemedica, believe that MSC-based stem cell therapy is advanced enough to offer as a viable and ethical option for individuals seeking solutions to life-altering ailments that have not responded to traditional treatment. Licensing agents in Mexico agree. And we routinely treat patients of all ages and from all countries, including Canada, the U.S., England and Australia.
In other words, unlike the case with Stemedica, there appears to be nothing that we would consider a real clinical trial going on at Novastem. What’s depressing is that Stemedica might actually be making stem cell products with the potential to do some good, given that the FDA has approved legitimate clinical trials, such as the aforementioned phase I/II trial of stem cells for ischemic stroke, a phase IIa randomized trial for non-ischemic heart failure, a phase IIa randomized study of allogeneic mesenchymal bone marrow stem cells to treat myocardial infarction, and a phase I/II study of bone marrow-derived stem cells to treat cutaneous photoaging. This is good. This is how a company should find out whether the new treatments it’s developed work or not.
So why is Stemedica supplying its stem cell products to Novastem to treat pretty much anyone the doctors down there want to treat? I don’t know, but the likely explanations I come up with when I think about this question are not flattering to Stemedica, particularly coupled with this blatant publicity ploy in which Stemedica “facilitated” getting Gordie Howe’s family to take him to Novastem, even though he was clearly not eligible for Stemedica’s legitimate phase I/II clinical trial offered in the U.S. It’s not mentioned whether Gordie Howe’s family had to pay for the privilege, but certainly other patients treated at Novastem do—cash on the barrelhead. Or wire transfer. No checks or credit cards, apparently. Did Novastem treat Gordie Howe for free in return for the publicity? Does Stemedica “look the other way” with respect to Novastem’s dubious practices because it needs the money to keep its company going? Why is it apparently having its customer adminster stem cells to patients outside of the US and outside of anything resembling a real clinical trials? Inquiring minds want to know. Sadly, the press was not particularly inquiring when it reported this story, failing, as it did, to note that this was almost certainly not a real clinical trial and that it’s impossible to tell whether the stem cell treatment actually did anything from what we know. That’s leaving aside how unethical it looks for Stemedica executives to have contacted Howe’s family and shunted him to a Mexican clinic using its stem cells.
Even though I hope Gordie Howe does well, well enough to appear at the Kinsman Dinner in less than seven weeks, and even hope that I was wrong and the stem cell treatment he received actually did some good, right now I have no choice based on what I know to doubt very strongly that Novastem’s treatment did anything for him. As for the press’s utter credulity and lack of fact checking and investigation, I can only hope that that changes in the future. As of now, Stemedica and Novastem just got a huge shot of free and favorable publicity, thanks to credulous press reports that did no more than regurgitate the press release. If anyone does any real reporting on this story, I doubt the publicity will be as good.
ADDENDUM: In retrospect, when I wrote this post yesterday I might have given Stemedica too much of the benefit of the doubt. I’ve since learned that teaming up with dubious non-US stem cell clinics like Novastem to distribute its product outside of legitimate clinical trials appears to have been part of its MO for quite some time now:
ADDENDUM #2, December 23, 2014: Here is a stem cell researcher’s take on the Gordie Howe case. Let’s just say that he’s as skeptical as I am.
