September 21, 2020

The Niche

Knoepfler lab stem cell blog

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; 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.

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