Update, January 2023. Duke’s autism-stem cell “pay to play” EAP has been canceled. More details in this feature in Vice, by Anna Merlan. Stem cell biologist Paul Knoepfler has also followed up, on his blog The Niche.
Duke University charged hundreds of families $15,000 each to be subjects in a clinical trial EAP (pay-to-play study) of stem cells as an autism “treatment,” even though the Duke team’s own studies consistently showed the treatments don’t work. Why was this ever allowed?
Hundreds of American parents are traveling to clinics with the hope that stem cells will treat or even “cure” their autistic children. While dozens of unregulated stem cell clinics from the Ukraine to Panama offer to infuse children with stem cells with the claim it will treat autism, there is only one university in the US that has been associated with that claim: Duke.
It is difficult to understand why Duke continues to run clinical trials on stem cells as an autism treatment, since its most recent findings from a Phase II randomized controlled trial show no convincing evidence of benefit, nor even a mechanism that would explain the use of stem cells as an autism treatment. The Duke team’s report documented a lack of evidence for primary or secondary outcomes, concluding: “Overall, a single infusion of [cord blood] was not associated with improved socialization skills or reduced autism symptoms.”
Why, then, do the trials continue–and why did Duke University offer an Expanded Access Program to parents for a fee of roughly $15,000 per infusion? (The EAP ran from 2020-late 2022.) The answer to these questions may lie within the funding model of the program, and the promise of lucrative contracts for stem cell providers if stem cells were to ever receive FDA approval for broader uses.
Funding and professional relationships
Stem cells for the Duke trials are provided in part from the Carolinas Cord Blood Bank and Duke project partner Cryo-Cell. In June, Cryo-Cell entered into a patent option agreement with Duke University, with an option to get licensing to manufacture and sell products based on Duke’s patents. The Duke team’s research lead, Dr. Joanne Kurtzberg, is Medical Director for Cryo-Cell International and Director of the Carolinas Cord Blood Bank.
In 2021, CryoCell announced it was launching a new clinic in 2022 to exclusively sell their products to families in Duke’s EAP. [Update, April 2023: the clinics have yet to launch].
Currently, the FDA has only approved stem cells for use in “disorders affecting the blood forming system.” –not autism.
Duke’s autism trials are funded by a grant from The Marcus Foundation, a philanthropy established by Home Depot co-founder Bernard Marcus. The Foundation-endowed Marcus Center for Cellular Cures at Duke University earmarked $26 million for Duke’s autism-stem cells trials. Marcus, a long-time supporter of autism-related charities, has vowed to leave the bulk of his fortune to charity, including autism-related causes. He is a proponent of stem cells for many conditions. Mr. Marcus and his wife have also been patients at The Stem Cell Institute, an unregulated clinic in Panama. The Stem Cell Institute claims to have used stem cells to treat “hundreds of children with autism.”
“Some of the most vocal proponents of stem cells as an autism treatment include the Duke autism researchers and for-profit stem cell clinics like The Stem Cell Institute in Panama,” says Paul Knoepfler, a stem cell biologist who has been studying and writing about the Duke trials. “I’ve grown concerned that the two groups may have become entangled over the years.”
Knoepfler sees “no convincing rationale” for a stem cells as an autism treatment. “But the Duke team seemed unwilling to accept their own results and said they were ‘encouraged,’” he notes. “They’ve gone on to start another autism trial. I have to wonder… if this new study also says there’s no benefit, will they start yet another trial?”
The Duke studies raise a troubling question for universities using philanthropic sources of funding: to what extent should universities host and support clinical research programs that attract donor dollars but show little promise of developing safe and efficacious therapeutics? What are the risks of such an approach?
Stem cell hype, medical tourism
Bioethicist Leigh Turner is concerned that the hype around the Duke program has led parents into medical tourism at unregulated stem cell clinics offshore. “Although the Duke research team has yet to demonstrate effectiveness,” says Turner, “the clinical research activity and publicity has helped create an environment in which many people are convinced that stem cell therapies for autism already exist and are known to be effective.”
Turner and Jeremy Snyder, also a bioethicist, have documented families who have finished the Duke study and then launch GoFundMe campaigns to travel to The Stem Cell Institute in Panama. This is risky for the children because there can be significant long-term health complications from moving from one center to another center that uses different processes or stem cell sources. “Clinics peddling unproven stem cell interventions for autism refer to the Duke studies or media coverage about them,” to promote their products, he says.
Turner, who has followed media coverage of the Duke project, believes the research team has “participated in news coverage that makes hyperbolic claims about the use of stem cells to treat autism. It’s unsurprising that other parties are happy to take advantage of such hype and put it to commercial use.”
Several parents who contacted Duke to tell them they were taking their children to the clinic in Panama received a reply from Dr. Kurtzberg that briefly outlined potential health risks but concluded: “While these may be risks you choose to take, I would only recommend taking them if you knew that the potential benefit of the therapy were considering worth the risk. – Dr K.”
Melissa Eaton, who has been documenting the spread of health misinformation on Facebook and other social media, says it is “common” for parents to post in stem cell support groups about traveling to the Panama clinic following participation in the Duke trials. “The [Duke trials] give them a sense of hope, so they don’t want to stop,” she says. Some parents in the groups are also confused about whether Kurtzberg endorses the work of The Stem Cell Institute, an idea its CEO, Neil Riordan, has reinforced by posting a photo of himself with Dr. Kurtzberg and making assertions that he attended the meeting of the Marcus Foundation where it was decided to fund the Duke study and was asked by the Marcus Foundation to review the Duke proposal.
Fees for service: the expanded access program
Through its Extended Access Program (EAP) Duke invites parents to enroll children who don’t qualify for the study to receive stem cells infusions for a fee of $12,000 per infusion in a separate program. This runs counter to the guidelines of the FDA, which specifies that expanded access only be used for life-threatening conditions where no other treatment is available. In correspondence with parents, the Duke team refer to the EAP as a “compassionate care” program. Duke researchers recruit for the studies through parent-based channels, finding parents to proxy consent for their autistic children to be patients; it is also how EAP participants are identified.
According to Turner: “The expanded access program at Duke is troubling because parents pay substantial fees for what many of them clearly believe are safe and effective stem cell treatments for autism spectrum disorder.” Turner describes one family reportedly trying to crowdfund $30,000 to pay for the cost of two infusions provided through the expanded access protocol. “Other crowdfunding campaigns also reveal the substantial costs associated with accessing stem cells through Duke’s expanded access program.”
In the case of stem cells, an expensive area of study, bioethical issues also arise when participants are asked to contribute financially. In 2016, Northwestern University drew criticism when it required trial participants to pay hundreds of thousands of dollars to participate in an autoimmune disease clinical trial testing stem cell transplants. The Patient Handbook for the program even included fundraising tips for patients. Northwestern discontinued the program last year.
Turner says parents may be enrolling their children in the program based on false hope. “Many parents appear to be paying large sums because they are convinced that they are helping their children undergo an effective treatment for autism,” he says. “They are instead paying for access to an experimental intervention that might have no benefit for children diagnosed with autism spectrum disorder.”
Seeking FDA approval: the Cryo-Cell connection
Currently, the FDA’s position on cord-blood derived stem cells allows them to be used in certain procedures for conditions like leukemias and lymphomas, but not for conditions like autism. However, the FDA allows certain clinical trials to see whether stem cells have use with other diseases or conditions. If, after study, an institution were able to convince the FDA to approve stem cells for another use, that institution could make proprietary claims. In the case of the Duke trials, its intellectual property partners, such as Cryo-Cell, could also profit.
Although much of the language in the Phase III literature focuses on safety, Duke researchers have also made it clear they seek FDA approval of stem cells as an autism treatment. Kurtzberg stated in a video for a parent-based Facebook group in July [2020]: “I would hope we get to a point where…under practice of medicine you could go to a clinic and get an infusion and have it reimbursed by insurance companies.”
In the same video, Kurtzberg summarized the team’s research findings by stating: “We heard enough compelling stories [from parents] to believe them.”
Duke is a research institution, but Cryo-Cell is a company selling stem cells. Kurtzberg is involved with both. While Duke’s official materials describe the Phase III study as being about safe use, the language in Cryo-Cell’s marketing materials is quite different – and would probably not make it past a typical university ethics review. Cryo-Cell ‘s marketing leverages parents’ emotions while imbuing their products with a promise: that infusing autistic children with cord blood may transform them into more expressive, loving children.
Stories are the scaffolding of Cryo-Cell’s marketing. Its website tells a story about autism that begins with a false notion that autistic children are unable to express love. “Love. It is something you express to your children,” reads the first line of Cryo-Cell’s main page on autism. “Displays of affection can do wonders to how you feel, but for the mother and father of an autistic child, it may seem like they can never give that gift to their child—or receive it in return.”
Cryo-Cell’s online testimonials claim parents see changes in their children following infusion with Cryo-Cell products. One story describes a dad giving a hug to his child as a result of stem cell infusion. For another family, Cryo-Cell states: “After taking part in this Phase I trial, Gracie’s parents says her autism now affects only 10% of their day.” In some ways, Cryo-Cell is selling hope, narrowly circumscribed through its own suite of products. And parents are buying it, not just through enrolling in the Duke studies, but in pursuing other stem cell procedures offshore.
The issue of risk
It might be easier to shrug off Cryo-Cell’s bluster if it were selling a different product to a different market-–but stem cells are a highly-regulated medical product with significant risks. The FDA has documented risks associated with stem cell treatments that include allergic reactions; the ability of cells to move from placement sites and change into inappropriate cell types or multiply; failure of cells to work as expected; and the growth of tumors. In Phase II of Duke’s trials, with participants aged 2-11 years, two children experienced severe allergic reactions, with one suffering anaphylaxis.
Some autistic children have had to be sedated while receiving stem cell infusions, because the process caused them trauma and meltdowns. Duke researchers described emotional reactions by the children as “aggression, agitation, anxiety, defiant behavior, depression, emotional lability, insomnia, intentional self‐injury, and stereotypies.” Researchers noted in the Phase II study that “The most frequently occurring event, agitation during the infusion procedure, was associated with the requirements of placing and maintaining an IV and being confined to a hospital room for the infusion.”
Were these responses driven by the stem cells or by trauma during the lab experience? Eaton feels it is the latter. “These children are making it clear they don’t want to be in the lab. They are saying no.” Eaton, who has been monitoring parent stem cell discussion groups on Facebook, notes: “Parents in the groups describe their kids coming back from stem cells and having meltdowns. We need to talk about trauma risk because [they] may be experiencing distress from these procedures, which could have long term psychological risks such as PTSD.”
There has been very little research into the mental health risks to autistic children who have gone through rigorous medical procedures in attempts to treat autism. But the online autistic community is filled with testimonies of autistic adults about this topic. Many take issue with what is known as the grief mindset, where parents try to “recover” the child they’d imagined they would have through various unproven treatments. “Having a grief mindset instilled into my parents was the single most devastating thing that has happened in my entire life,” wrote one blogger. “I learned at a very young age that my parents would have preferred a version of me that did not have a disability, rather than the only version of me that will ever exist—the actual me.”
Although Duke researchers do not acknowledge the possibility of long-term mental health risks, they do address immediate physical health and safety concerns with stem cell procedures on autistic people. Their assessment of anxiety in Phase II trials was that children’s anxiety remained at relatively the same level same whether children received stem cells or placebos in the clinic. What that means, though, is that children experienced anxiety in the clinical setting, regardless of whether they received the stem cells or the placebo.
Now working with adults, the team secured institutional review board approval (IRB) to test stem cells in Phase III, basing it around the goal of determining “the safety and tolerability of a single intravenous dose of Human Umbilical Cord Tissue Derived Mesenchymal Stromal Cells (hCT-MSC) in adults with autism spectrum disorder (ASD).” While the first two phases established varying risks for children age 2-11 receiving the procedure, Phase III now endeavors to assess that risk in young adults with autism.
In Phase II, Duke’s objectives had been stated as “to evaluate whether umbilical cord blood (CB) infusion is safe and associated with improved social and communication abilities in children with autism spectrum disorder (ASD).” But researchers didn’t include language about measuring “improved abilities” in the new Phase III trial materials. Risks have already been established for autistic children: how much different will the risks be for vulnerable adults?
Participant consent and the evolution of autism research
Current Phase III participants are adults, but like the minors in Phases I and II, they are being recruited through parent channels and parent-focused groups.
Eaton believes that this recruiting decision is borne of necessity. “There isn’t a pool of autistic people who want to do this. Why would they?” Her question points to a larger issue around the Duke trials and others like it: If the only way to recruit autistic people to a study is through their parents, does this research meet the needs of autistic people? And if it is not useful to autistic people, then whose needs does this autism research meet?
Then there’s the petition. In July, autistic adults launched a petition that has gained more than 15,000 signatures, demanding that Duke’s autism-related stem cell trials be shut down and calling for “full accountability by Duke University”. While the petition focuses on proxy consent issues, the comments on the petition also point to the deeper questions about the nature of autism research. “My son deserves the right to be himself,” writes one petition-signer. “So do the children being subjected to this procedure.” An autistic signer was even more direct: “Autistic people don’t need a cure. We are not your lab rats.”
I shared the petition with the office of Duke President Vincent Price, but his office did not reply. I was surprised by this, because the petition reflects a major dialogue within the autism field, one that has been impacting the course of research. As autistic people have begun to enter the research field, and formed their own self-advocacy organizations, we’re seeing more patient-centric, participatory autism research that focuses on quality of life and away from cure-based approaches focused on “symptoms”.
“I’ve been attending INSAR, the International Meeting for Autism Research, since 2011,” says Shannon Rosa, editor of The Thinking Person’s Guide to Autism and the mother of an autistic son. “In recent years, we have more autistic researchers and more autistics in general involved in directing the course of research. And with this shift has come a focus on improving quality of life, because that’s what autistic people themselves tend to want from research.”
Rosa co-hosts the AutINSAR, a series of discussions in which autistic people and/or researchers and other community members get together virtually during the INSAR conference to discuss how autism research can better serve autistic people. According to Rosa, the most common research concerns raised by autistic people are around mental health (including suicidality), followed by sleep disruption, medication issues, best practices for job interviews/workplace accessibility, and research into seizures (a co-occurring condition for some autistic people).
Autism researchers have also been looking at autistic communication in a new way: by studying and remediating communication differences between autistic and non-autistic people (sometimes called “the double empathy theory”), instead of focusing only on trying to change autistic people’s communication behaviours to mimic those of non-autistic people. This new acknowledgement promotes inclusion, access and acceptance—all goals expressed by autistic adults. The research also has clear results, for example in the development of communication technologies for non-speaking people (such as text-to-speech apps), across various disabilities.
“I’m grateful to see autism research increasingly addressing my son’s traits through the lens of understanding rather than as a laundry list of ‘deficits’,” says Rosa.
Holding systems accountable
In some ways, Duke’s stem cells-autism trials are not just about whether stem cells are safe for autistic people (like Duke’s materials suggest)–nor are they merely about selling hope to parents (per Cryo-Cell’s marketing). The trials are a touchstone for broader issues on how and why university research gets funded; the risks of the stem cell market; and the role of research in helping autistic people.
Critics remains skeptical that Duke’s stem cell trials play any useful role in autism research. “Overall, this line of research is unlikely to be in the best interest of the kids, their families, and the stem cell field,” says Knoepfler.
What are the limits of donor-university relationships in determining priorities in research? What are the ethical implications of approving research that continually shows no evidence of benefit and clear evidence of harm? How do these studies impact autistic children–and what are the implications for science, commerce and regulation? These are all questions that deserve consideration. But it remains to be seen whether Duke University will consider them.
More info: May 2021 podcast with Professors Jeremy Snyder and Leigh Turner on stem cell autism claims and medical tourism.