Top journal erred with Panama clinic stem cell for autism paper

The Stem Cell Institute; stem cells for autism
Screenshot from The Stem Cell Institute; stem cells for autism and much more.
The Stem Cell Institute; stem cells for autism
Screenshot from The Stem Cell Institute; unproven stem cells sold for autism and much more, but at a big cost.

Amongst all that is bouncing around within the stem cell clinic maelstrom out there, one thing stands out for me as the most troubling. I’m talking about for-profit experimentation on children, such as injection of kids with unproven stem cells for autism or cerebral palsy by unproven clinics.

In my opinion it’s almost always going to be risky and unethical.

Doing any clinical research on children requires extra care and planning even within an FDA-approved clinical trial context. Obviously pediatric clinical trials are crucial, but they need to be well-justified and should go the extra mile on thinking through ethical issues. Even FDA compliant work, including at Duke, on umbilical cord cells for autism and cerebral palsy raises difficult questions and concerns at times.

Although unproven stem cell clinic pediatric offerings and FDA-approved clinic trials are very different in many ways, in the area of cord blood materials for autism I feel that they have a concerning resonance together at some levels.

This is all recently back more squarely on my radar screen because of a relatively new, concerning paper in a top stem cell journal. Today’s post reflects my opinion that the journal, Stem Cells Translational Medicine (SCTM)erred in publishing the new paper on stem cells for autism. I did have a bit of an interesting email discussion with the editors which I’ll get to later in the post. Also, obviously today’s post just reflects my viewpoints and I expect others will disagree.

New clinic pub on stem cells for autism

The journal SCTM publishes a steady stream of many important papers in the translational and clinical stem cell arena. I see SCTM as a great journal overall, but again I believe they shouldn’t have published this particular paper on stem cells for autism.

The publication in question is from a for-profit stem cell clinic in Panama, called The Stem Cell Institute. Hannah Furfaro over at Spectrum News has a helpful piece on it. The two of us had a good discussion about it.

For reference, here’s the Clinicaltrials.gov listing for the study, which involves injection of a total of more than 140 million allogeneic, lab-grown umbilical cord cells via 4 doses.

What are my concerns?

Weak premise

The core hypothesis behind this research is shaky. I’ve written about the idea of “stem cells for autism” many times before. I feel that there still seems to be no solid scientific or even basic common sense to this approach.

How exactly would it supposedly work?

Neil Riordan et al paper stem cells autism Figure 2 Stem Cells Translational Medicine.
Neil Riordan, et. al paper stem cells autism Figure 2 Stem Cells Translational Medicine.

It’s unclear.

Only a few of the transplanted cord cells, maybe even none, seem to get into and take up residence in the brain outside of the vasculature. Those researchers who are upbeat about this kind of umbilical cord cell experimental approach most often invoke a purported indirect, beneficial effect on the immune system by the infused cord cells. They heavily emphasize a possible major immune system role in autism. It’s all very vague in my view.

Also autism is a spectrum of disorders that probably result from a range of complex combinations of causes. It’s very unlikely that the immune system is involved in a large fraction of the cases. Even if it were, it’s not clear how systemic infusions of cord cells would specifically “fix” that immune problem. This is particularly the case since autism is a developmental disorder. And then there’s the fact that the cells in this “study” are allogeneic meaning there’s a good chance they’ll simply be rejected by the patients.

Thus, this new SCTM paper is focused on a controversial idea to begin with so the editors needed to be cautious. Being controversial doesn’t necessarily mean wrong and today’s controversial idea can become tomorrow’s big discovery. However, I am skeptical that will happen here. I hope I’m wrong, but I doubt it.

To be clear on the FDA-compliant side of things, there’s also nothing necessarily wrong with doing a rigorous, FDA-approved clinical trial on a high-risk idea for something like severe autism or cerebral palsy if you have good data to back up starting the trial, but as things proceed with the work if the data aren’t that encouraging, do you keep going anyway and vastly expand the number of children in the subsequent trials?

Do patient families continue to shoulder some of the cost of the trials?

Pay-To-Play?

Complicating matters further with the new clinic pub in STCM, the companies behind it are again, to the best of my knowledge, for-profit stem cell clinic-related firms. I do not see a disclosure in the publication acknowledging that patients/families had to pay as an inclusion criteria. What were the financial specifics of patient family payments here?

On the clinic’s website FAQ page it has this to say about costs in a general sense, although cost is not mentioned on Clinicaltrials.gov page or again in the paper: “Fees for services start at $15,825 USD for children and $23,150 for adults.” Furfaro’s piece suggests a lower cost of $7,200 for this study, but it can really add up for families.

From Furfaro’s piece (note that Riordan is the clinic leader and “Weeks” refers to the parent of an autistic child who participated):

“Riordan and his colleagues did not mention in the paper that the families had to pay for the infusions. But Riordan told Spectrum that the $7,200 the institute charged parents was “to defray costs outside of the treatment. The actual treatments were provided free of charge.” Weeks says that the trial, travel and other expenses totaled more than $20,000.”

I don’t buy the idea that the treatments were free. Do you? (Note that it appears some families must pay for pediatric neurological trial participation at Duke too, but the details remain sketchy at this point.)

The clinic paper does have disclosures about ties to the clinic businesses. Here are the authors: Neil H. Riordan, Maria Luisa Hincapié, Isabela Morales, Giselle Fernández, Nicole Allen, Cindy Leu, Marialaura Madrigal, Jorge Paz Rodríguez, Nelson Novarro.

Clinic more broadly touts stem cells as panacea?

This Panama stem cell clinic is not solely focused on injecting stem cells into autistic kids. It touts stem cells for a whole bunch of different, most often unrelated health conditions. From their website, they offer, “Stem cell therapy for autism, cerebral palsy, heart failure, multiple sclerosis, osteoarthritis, rheumatoid arthritis, and spinal cord injury.” See screenshot above.

Does that make any sense?

Not to me as a stem cell biologist. It makes me skeptical of what they are doing in general including the autism work. Maybe they view stem cells as some kind of miracle “stuff” that can treat diverse unrelated conditions? I see that over-exuberant mentality as a red flag overall.

Paper’s data aren’t convincing

Since it was an unblinded study and those running it presumably profit financially from it in certain ways, there might be some bias in the study, right? Even so, the data in the study don’t say much in my view. There’s no convincing indication of lasting benefit. If you look at the figures, there are also huge error bars such as in Figure 2 above.

The study in addition uses subjective evaluations that are questionable in an unblinded, uncontrolled setting. In addition its other readouts are generally surrogate blood markers of things hypothesized to be linked to autism. Still the authors claim a positive effect, “Forty percent of children showed notable improvements of symptoms as measured by standardized autism diagnosis tools.” In my view it’s highly questionable as to whether that 40% claim is really solid.

For another at least equally skeptical opinion on this The Stem Cell Institute autism paper see this piece over at Science-Based Medicine by Dr. David Gorski.

So why did editors & reviewers green light it?

Overall, to me the paper just does not make a meaningful biomedical contribution to the field so it’s hard to imagine why reviewers gave it a green light given its baggage.

One possibility is that the reviewers are themselves too tied to the idea of cord cells for autism.

What about the editors? Maybe I’m “backseat editing”, but I believe that they should not have sent it out for review. Perhaps others disagree.

Also, consider that there is definite potential for harm from such a publication. For instance, what if the clinic uses the paper for PR to bring in more children (via their parents) as customers? Even though this paper and others did not report a large number of adverse events, there are going to be risks here for the kids.

I contacted the journal editors to discuss my concerns and we had a productive dialogue. They pointed me to this statement on their website,

“In the spirit of global cooperation and full transparency, and the hopes of helping science advance, speeding discoveries, and ultimately benefiting patients, STEM CELLS Translational Medicine promotes the mission of sharing the results of negative clinical trials, and trials that may not have met primary outcome endpoints or completed accrual.”

And they also said by email,

“We encourage the development of guidelines and the building of institutional mechanisms to ensure that Patient-Funded Trials promote high scientific and ethical standards to protect the interests of patient payers as well as the interests of science and society.”

What now?

Now that this paper is out there, can anything else be done about it other than post-publication peer review and discussion? Do the ethical concerns warrant considering retraction? It’s hard to say, but I’m guessing that is not going to happen. Take our poll as to what you think should happen next.

20 Comments

  1. The purpose of valid research is to prove the researcher wrong not right. Ethics must be met by researchers to be 1/2 as brave as their trial subject to publish a journal of failures. Avoid duplicitous spending of public and private foundation funding at the peril of subjects and potential patient benefits in a publish or perish academic race. Those are the ethical questions and concerns on the front burner now. So much for reinventing the wheel.

  2. Admin:

    You are imagining all sorts of ethical breaches behind this study for which there is evidence in the manuscript and from the editors did not occur; and you are imagining future fathom consequences for which there is little basis in the manuscript conclusions and representations. Here you have before you what you have said that you want to see, peer-reviewed research in this area of private stem cell clinic treatments. Though not taking place in a U.S. jurisdiction, this research is abiding by the regulations within Panama, as well as general guidelines required by an international research journal of repute. I don’t know what the original manuscript contained, but the final published report indicates a quality editorial and review process. The important findings for the safety aspects of the study are well reported; the overall efficacy findings, which are not statistically significant, are appropriately represented; and even the authors’ effort to tease out some meaningful evidence of physiological treatment responses and possible efficacy, is cautiously stated. If anything, the authors have set an important precedent for this area of therapeutic investigation. This is good medical science in that respect; and it was very important for SCTM, or another comparable journal, to publish it. Don’t worry, Paul. It’s not advancing private stem cell clinics. It’s giving us for independent evaluation empirical data on what may be occurring in these treatments, with care given to minimizing harm to the participating patients. We need this information to move us past rhetoric and conjecture, on both sides of the stem cell treatment divide, to more discussion based on scientific and medical data.

    Let me disclose that I do know the Neil Riordan from our membership in the Perinatal Stem Cell Society.

    • James,
      It seems to me that you have a puzzlingly antithetical worldview when it comes to research.

      Do I have this right? You oppose research on ES cells derived from 100-cell human embryos leftover from IVF procedures, yet you encourage for-profit experimentation on actual vulnerable children using unproven, laboratory grown stem cells (with no controls, no blinding, and pay for access just to a safety study)?

      If I have that right, how do you reconcile that conflict for yourself?

  3. Admin:

    Now, I hope you recognize how obvious your defensiveness is here. What does your question have to do with my comment? Our discussion is about whether SCTM should have published the report, which we begin with the understanding was deemed ethically sound…not that similar assessments of hESC research and research with tissue from electively aborted fetuses haven’t prevented me from protesting in the past.

    But let me address your indictment nonetheless. In this study the research is being done in an attempt to help the patients, though it doesn’t guarantee it. The patients and their parents are well informed of the risks, including the financial ones, and the uncertainties involved. There is no expectation that even one of the research patients might die as result of the research, let alone intentionally. The rationale for the study is as sound as any other prevailing basis for how a heterologous tissue cell preparation might effect unexpected beneficial responses in diseases and disorders that might have an inflammatory etiology. This is a prevailing hypothesis under investigation in human studies now, including FDA-authorized clinical trials in the US, based on observations in animal studies. It may proved wrong in the future, but presently it is a legitimate for hypothesis for formal scientific investigation. So, for me, there is no conflict here. Good ethical medical science also comes with risks to research patients. Good physician scientists work to minimize those risks, with ethical informed consenting, while maximizing gaining a better understanding of the treatment process that results, supportive or non-supportive of the therapeutic hypothesis.

    By the way, this is not an appropriate study stage for randomization and double-blinding. In fact, at this stage, such an undertaking would be inappropriate and unethical by FDA standards. This is essentially a first, and appropriately designed Phase I, study that has a primary aim of evaluating safety. There is no control group in such common studies. Evidence of efficacy is always evaluated in first treatments, but is not the purpose of the studies; though always a consideration for attention when affected patients are being evaluated. The conclusions drawn from this first study are quite appropriately represented given its inherent limitations.

    You might also disclose to your readers that you edited my earlier comment, removing my characterization of your present behavior. Yet, you included your characterization of my behavior in your own response.

    • @James,
      We’re not going to agree about this study/paper.

      As to the editing of your previous comment, I decided to remove a small (in my view, inappropriate) portion that violated The Niche comment policy rather than simply not posting your comment at all even though I disagree with it.

      My comment/question to you by comparison was about an apparent conflict in your statements re: experiments on blastocyts vs. children.

    • @admin – With regard to James Sherley’s comments, I don’t see how his view on embryonic stem cell research is relevant to his critique of your article. It seems to me that you are employing logical fallacies to deflect his criticisms out of hand. Can you please respond to his specific points?

      After reading your article and Mr. Sherley’s comments, I have a few more questions:

      What exactly is “for-profit” experimentation? Are you claiming that the money paid resulted in a profit for the clinic in Panama? Do you have any evidence of that? As far as i understand things, clinical trials, even outside the US, are not cheap to run. How much to you estimate it would cost to run a trial like this? Based on what they charged each patient, how much do you estimate their profit was?

      You comment about using “unproven” stem cells in this trial. By definition, aren’t stem cells being used in a clinical trial “unproven”? Isn’t that the whole point of conducting clinical trials? Can you please give me an example of “proven” stem cells being used in a clinical trial? This makes no sense to me.

      Can you explain why safety trials should be blinded? How does giving a patient a placebo contribute to evaluating the safety of a product? Can you give me an example of how researchers compare placebo groups to groups that receive the medication for safety? For example, in this case, why go to the extra expense of treating 40 patients when you know in advance that half of them will not be used because they won’t receive the product you are trying to evaluate? Seems to me that would approximately double the cost for no reason. My (admittedly limited) understanding of the clinical trial process is that a safety study is done first and then after that, assuming it’s “safe” to that point, a double-blinded efficacy study is done on a larger cohort of patients. Am I missing something here?

      • @Bill,
        I was pointing out that to me at least there seems to be a tension between the view that generation of ES cells from ~100 cell embryos is wrong, but that doing uncontrolled experiments on actual children for profit is apparently OK based on his comment. I wasn’t claiming that my comment in that regard addressed all the specifics of his views in his comment where he was defending the study/pub, but just that the antithetical nature of these views struck me and raised some questions for me.

        My impression is that the study in question, conducted by what seems to be a for-profit clinic, likely generated revenue for the clinic. If that is accurate, then I believe that’s not ethical. Since clinics do not release their financials, I’m not sure how one could be 100% sure either way, but that’s my take on it based on all I know. I’m trying to be consistent in the sense that I don’t view payment as a condition of enrollment in a clinical study/trial to be something that we just accept as OK so I also have raised concerns about NW requiring payment for enrollment in their autoimmune trials and I’ve mentioned my concerns about Duke requiring payments too, although there with Duke the details are less clear so far. One key difference in these examples vs. the clinic is that any given clinic often is aiming to make a profit from the study itself just from the enrollment and other associated charges (even if ultimately the product in question is not proven safe and/or effective in the end), while universities may profit in the long haul should a product ultimately be proven safe and effective.

        It should also be mentioned that my impression is that the clinic in question here likely has profited for years already from “treatments” of kids with autism and cerebral palsy using the same or similar unproven stem cells outside of studies like their published one. In other words, they aren’t waiting for their study results to guide them. They are already marketing the product and likely profiting from it. That’s also not the accepted way to go with a clinical trial of a still investigational product. As I also pointed out in the post it seems they are marketing stem cells for a whole host of health conditions and charging for all of those too.

        As to the blinding issues, first of all this was a combined phase I/II and the authors in my view were focusing in some ways on potential efficacy in their figures and discussion. Also, what was on my mind more generally is that these kinds of clinic studies just don’t tend to produce rigorous data. Admittedly, I could have articulated this part in my blog post better.

  4. Dear Dr. Knoeplfer, the ethical issues you’ve raised are indeed important and though they may raise red flags, the reality is that paid clinical trials are common at the university level and commercial level. I think all readers fully understand your take on this issue and it should be laid to rest. Ethical or unethical, the patients have the right to choose how they want to spend their money. Consents are detailed in a way where patients sign up, willingly, to take part in a study that may do good or may even do harm. Even if a study is free of charge, travel expenses etc can far exceed the cost of participation. If this particular trial were free to participate and patients had to pay $20,000 for travel costs, would you also see this as being unethical?

    I have some comments related to the science part. According to their Preparation and Culture section, they are isolating umbilical cord mesenchymal stem cells. You’ve referred to these as “cord cells” but I would stress that they are not simply cord cells. Normally, the cord is associated with hematopoeitic stem cells but this paper is clearly using mesenchymal. I have no problem with the vague scientific rationale because we don’t really understand autism to begin with. Mechanistic studies using stem cells have always been challenging because of the wide array of functions that the cells possess. Without clearly understanding how a disease occurs and progresses, how could we determine how the condition is treated? All we can hypothesize is that a variety of known functions (of the cells themselves) could help the condition through various pathways – some symptomatic, some at the root cause.

    I do have an issue with this paper and perhaps my issue can be solved with a clarification by the writer. This paper’s primary focus was on SAFETY but how can safety be discussed without details surrounding the most obvious risk, donor rejection!

    I wish I had answers to the following questions:

    1. Each patient received 4 treatments. But actually, it looks like there were a total of 7 adminstrations. The first 4 infusions were 9 million and the last 3 were 36 million. Please confirm how many ADMINISTRATIONS. Were all adminstrations for each patient taken from the same lot or different lots?

    2. Are these cells isolated from each donor and processed separately, thereby creating individual lots (at pasage 5) or does each lot contain a pool of donor cells?

    3. Was HLA taken from each donor? If so, was the HLA matched prior to infusion?

    4. The conclusion of this paper is that this was safe. Depending on what the patients recieved, the patients could, and most likely did, develop antigens to the donor cells.

    5. There were 133 adverse events that occured and 46% of them were determined to be related to the product. That’s 61 adverse events that are product related. The list of adverse events in Table 2 look like mild rejection symptoms.

    In my opinion, it is not obvious that this treatment was safe. My guess is that some patients developed mild GVHD. The writers haven’t shown anything that would prove otherwise. It is not uncommon to see this in patients receving continual donor cells (regardless of HLA). One more note, in all the testing, they did not do any genetic testing. Karyotypes of orginal cells and passaged cells should have been performed in their validations to show that genetic stability was maintained. How can one say this treatment was safe when there is no discussion on the genetic stability of the manufactured cells?

    Apologies for the long post.

    • @stemcelllady,
      You raise some really good points.
      My understanding is that travel and hotel costs can really add up for participants in trials, but if those people/firms running the trial do not benefit in any way from those travel-related expenses that are separate from the trial, then the trial can indeed be ethical although such costs may represent a barrier to participation and could complicate things greatly.
      In the case of this Panama trial, the $20K mentioned was not for travel in the news article I cited, but just for all kinds of things I think. It was hard to tell how much of that went to those running the trial even if they claim the stem cells were free.
      Yes, not all “cord cells” are the same. Sometimes that term refers to the cord blood, sometimes to the hematopoietic stem cells isolated from the blood, and sometimes to the MSCs from the cord wall. We also, as I noted, have to keep on top of whether the cells are grown in the lab or not, as that has a significant potential to change the final product.
      I’m not sure, but I think the cells and recipients did not undergo any kind of matching. GVHD in some mild form could have occurred, but I’m not an expert in GVHD and it’s hard to say from the paper.
      There is some debate as to whether allogeneic cord cells may elude immune surveillance, but I don’t see that as well established. They may simply be killed by the recipient immune system with no matching (or use of close relative’s cells) and no immunosuppression. Engraftment of cord cells is also another gray area (outside of the blood cancer/chemo kind of realm I mean). While engraftment of cells could be helpful, it also likely would raise risks (even if the risks may still be relatively low).
      I agree that overall safety was not well-established in this study. I should have emphasized that in the original post.

  5. I have visited The Stemcell Institute in Panama twice for stemcells for my grandson whom has autism. He was completely non verbal, zero social skills and unable to hold a conversation with meaning at all. His 1ss treatment was in 2017 he was 8. Within the 1st 3 months he started talking. By the 6th month he was putting together sentences. His school noticed how attentive he was and that he was able to complete his assignments in the classroom.
    His 2nd treatment was this year 2019. He can understand and comprehend and talk in an actual conversation. He is much more social in terms of engaging in activities with his peers as well as family functions. He has a love for music and sings all the time. He has been taking drum lessons and loves it. He has become self sufficient as in dressing himself, brushing his teeth, he can run the appliances and washer/dryer. He loves to bake and will read a recipe and measure , mix all by himself.
    We are currently planning a 3rd trip. The Stemcell Institute in Panama has changed his life as well as our family’s lives so much. LET IT STAND!

    • @Bobbi,
      I’m glad to hear your grandson is doing so great.
      It could be a spontaneous change as he was growing up.
      In theory the stem cells could have played a role too.
      We just don’t know in this kind of situation.
      If kids are injected with stem cells and the experiment is done with no controls like placebos and no blinding (blinding is where those running the trial and in the trial don’t know who gets the stem cells and who gets the placebo so there is less potential for bias), then we can’t really know if something for sure works and is safe for kids more generally.
      For instance, it could be that your grandson benefited from the stem cells, but many other kids may not. Some kids may even be harmed for all we know.

  6. Admin,

    Again, you should concede, or at least acknowledge, that we cannot get to the kind of ideal study you are demanding (randomized, placebo-controlled, double-blinded, and multi-site) until we first have studies undertaken, peer-reviewed, and published like the one now under discussion, which, importantly, does not overstate its reported findings.

    • I’m just looking for rigorous data that is unlikely to be biased.
      Also, most sponsors do not require payment as a condition of enrollment, right?
      James do you know if this group has published preclinical trial data in animals using the same cord product and methods used in the new paper on human subjects? If not, why not do safety studies in animals first? Because they can’t charge the mice?

  7. We have been to Panama many times. I’m a parent and special education teacher. Our oldest is now recovered. He had 4 treatments over a two year period. We had the theory of going every six months and wanted to build on previous gains. This was something we came up with after seeing the results of the first treatment. At the time there was not much data. We planned the first treatment not knowing what would happen. We had to try! Traditional medications and therapies were not working. Thank God we did.

    I’m more concerned about clinics in the US that are claiming to give live cells and operating under a study and charging money. I know that with a study you can charge for costs and not profit. I also know these clinics need an IND and I have not had one of them show proof of an IND. I also know it’s illegal for them to inject “stem cell products” systemically, meaning passing through multiple organs. These clinics don’t advertise they treat Autism, but if you call them they will say they do. The prices range from a couple thousand to tens of thousands.

    I’m not sure we will ever get clear study results in the US. I’m not sure I can fully trust study information coming from Duke. The US profits from sick people and I don’t see them giving up that cash cow.
    My son no longer sees a psychiatrist for medications as he takes none, no more therapies, no more special programs. That’s a lot of money saved.

    I think the study should stand because there just isn’t a lot of information out there. It’s up to the consumer to do their homework and decide what is best for themselves and their families.

  8. The following is a link to Mesoblast Ltd. 2018 Annual report; on page 44 in the report there is a table that depicts the ongoing clinical trials, three clinical trials are in phase 3 status. The annual report is a good resource for the developing products for various medical treatment using their proprietary tissue culture. The company recently was granted fast track designation, and orphan drug status; and is currently setting up clinical trials with the FDA for their remestemcel-L for children with aGVHD refractory to steroids.

    http://www.mesoblast.com/images/1863881.pdf 2018 annual report

    Aug. 29 2019 update: https://www.globenewswire.com/news-release/2019/08/29/1908777/0/en/Mesoblast-Reports-2019-Full-Year-Results.html

    Aug. 14 2019https://finance.yahoo.com/news/remestemcel-l-evaluated-treatment-chronic-100000839.html

    http://www.mesoblast.com

    Difficult to deny the validity of this product that has had the standard clinical trial protocol in developing their product.
    Would appreciate your thoughts on this Paul, thanks for this interesting blog.

  9. Sarah here is an interesting development by a company named Mesoblast Ltd., the NASD symbol is MESO.
    2018 Annual report: page 44 has a table depicting current clinical trails, 3 products are in phase 3 trial.http://www.mesoblast.com/images/1863881.pdf

    Aug. 14, 2019 news article:https://finance.yahoo.com/news/remestemcel-l-evaluated-treatment-chronic-100000839.html

    Aug. 29, 2019 news release:https://www.globenewswire.com/news-release/2019/08/29/1908777/0/en/Mesoblast-Reports-2019-Full-Year-Results.html

    company web site: http://www.mesoblast.com

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