Pay-to-play stem cell clinical trials: Abuse of the clinical trial process

There is little doubt that stem cell therapy has considerable promise to treat a wide variety of degenerative diseases. Unfortunately, little of that promise has been realized yet, and, even more unfortunately, the promise of stem cell therapy has attracted scammers and quacks like the proverbial flies to honey. Dubious stem cell clinics try to attract customers using a combination of high pressure sales techniques akin to those used by time share salespeople, providing free products to celebrities in order to gain publicity and testimonials, and even using dubious pay-to-play clinical trials and ClinicalTrials.gov as advertising tools. It’s for that reason that I have said on multiple occasions, every for-profit stem cell clinic is a predatory quack clinic. At least, if there’s an exception to that rule of thumb, I haven’t found it yet, and I’ve been looking for years. Unfortunately, these clinics have proliferated all over the world, including the US, without any strong scientific evidence that the stem cell treatments used are effective.

With that background in mind, I came across an article in Spectrum:

Hyperbaric chambers. Dietary supplements. Special diets. Dorinda Weeks’ son Aaron had tried them all. Ever since Aaron was diagnosed with autism at age 4, Weeks had resisted medication and behavioral therapies supported by science in favor of alternative approaches. Aaron had repetitive behaviors such as hand-flapping, persistent gastrointestinal distress, hyperactivity and sensory sensitivities to food. And none of these treatments helped. In 2014, when Aaron was 9, Weeks decided to try a more invasive therapy. “I was at a point in my life where I just had to do something for [him],” Weeks recalls. She enrolled Aaron in a clinical trial led by a for-profit company called the Stem Cell Institute in Panama City, Panama. During four visits to Panama over nine months, Aaron received infusions of stem cells harvested from tissue that lined donated umbilical cords; using stem cells from donated umbilical cord tissue is illegal in the United States. The institute charged $1,800 for each of Aaron’s visits, according to his mother.

Of course, charging a patient to be part of a clinical trial is, from an ethical standpoint, highly dubious, particularly when it’s a for-profit clinic doing the trial and even more so when the trial itself isn’t particularly rigorous. We’ll get back to that. This trial, such as it was, was published last month in Stem Cells Translational Medicine. It’s a single-arm (meaning that there was no control group) trial of 20 subjects with autism spectrum disorder. The treatment was mesenchymal stem cells derived from umbilical cord tissue (UC-MSCs).

Like most stem cell treatments for most diseases hawked by clinics like the Stem Cell Institute, the biological rationale for the treatment consists of a bunch of handwaving:

Mesenchymal stem cells (MSCs) have immune‐modulatory and anti‐inflammatory properties and have been safely used in the treatment of a variety of neurological and autoimmune conditions15, 26-33. In particular, MSCs derived from the Wharton’s jelly of umbilical cord tissue (UC‐MSCs) may possess greater immune‐modulatory activity34 and proliferative capacity compared with other MSCs35, 36. The rationale for MSC therapy to treat ASD has been discussed over the past decade37, 38; our group proposed the use of stem cell therapy to treat ASD in 200739. Some studies to date have demonstrated the safety of treatment that included MSCs40: of note, the results of a study by Sharma et al. showed that the majority (96%) of children with ASD treated with bone marrow‐derived cells including MSCs showed global improvements including behavior patterns (66%), social relationships (90.6%), and speech, language, and communication (78%)41.

Translation: There are some immune abnormalities associated with autism that no one really understands, and MSCs can have immunomodulatory activity; so stem cells should help. Basically, the biological rationale is: Stem cells are magic! So they’ll magically help autistic children. Because stem cells.

The follow-up of the subjects of the trial was as follows:

During the first visit, in week 1, participants were evaluated for safety and efficacy baseline values, and received 36 million UC‐MSCs intravenously over the course of 1 week, in four intravenous infusions of 9 million viable UC‐MSCs in each infusion. Twelve weeks later, at week 13, the subjects received the same dose of UC‐MSCs and were evaluated for safety and efficacy endpoints. This procedure was repeated at week 25 and week 37 after the start of treatment. The total dose received over the course of treatment was 144 million UC‐MSCs (4 × 36 million). In the follow‐up phase, visits occurred at week 49 (12 months after the start of treatment, 3 months after the last dose) and week 89 (21 months after the start of treatment, 12 months after the last dose).

The primary endpoint was safety, which was assessed at six different time points during the study using complete psychiatric and medical evaluations, laboratory exams, and occurrence of adverse events. Now here’s where the scientific value of the study falls to near zero:

Signals of efficacy were evaluated by parent‐reported outcomes via the CARS and ATEC tools44, in collaboration with the study pediatric psychiatrist, who evaluated the appearance, behavior, mood, speech, and intellectual functioning of the subjects to supplement parental

Parent reported outcomes with no controls? Even worse, the ATEC is the Autism Treatment Evaluation Checklist. It’s a dubious “tool” to measure the severity of autistic behaviors and symptoms used by autism quacks to “evaluate” treatment efficacy. Specifically, it was invented by Bernard Rimland and Stephen M. Edelson of the Autism Research Institute, and it was favored by autism quacks like Mark and David Geier.

Another issue is that this trial had no control group. Of course, it was a phase I/II trial; so it didn’t have to have a control group. Single arm designs are acceptable in this type of study because safety, not efficacy, is the primary endpoint and biomarkers and behavioral markers are the secondary endpoints. Unfortunately, what this means is that this trial cannot demonstrate efficacy. There are exceptions in which such a trial could demonstrate efficacy, but they are rare; specifically, if the effect size is so huge that it’s clear that there is efficacy. One example was the phase I clinical trial for Gleevec, in which the drug caused cancer to disappear in the majority of patients with chronic myelogenous leukemia (CML) that were in the early, or chronic, phase of the disease. Five years later, 98% of patients from the trial were still in remission. It is true that sometimes you can find signals of efficacy in a single arm phase I/II clinical trial, hints that the treatment being tested is having a therapeutic effect, but such signals need to be validated in a randomized trial.

This is not such a trial to me. The decreases in various cytokine levels reported were not impressive, and the changes in the ATEC and CARS scores was similarly unimpressive at twelve months and returned nearly to baseline by 21 months. In other words, I am singularly underwhelmed by the results of this study. Interestingly, there was considerable dropout as time went on such that only 14 of the subjects were evaluated at the 21-month time point. Moreover, only eight subjects showed a decrease in their ATEC and CARS scores, only five showing concomitant decrease in cytokine levels. It’s all pretty thin gruel.

As for the Stem Cell Institute, a perusal of its website reveals very quickly that it’s just another for-profit stem cell clinic, and you know what I think of for-profit stem cell clinics. Stem Cell Institute claims to be able to treat autism, cerebral palsy, heart failure, multiple sclerosis, osteoarthritis, rheumatoid arthritis, spinal cord injury, and autoimmune diseases, among others. The website is full of testimonials, like this one:

And this one:

Neil Riordan, founder, chairman and chief science officer of the Stem Cell Institute, is even appeared on Joe Rogan’s podcast with Mel Gibson, which real stem cell scientist Paul Knoepfler characterized thusly:

In it Rogan is very upbeat about stem cells and doesn’t probe much as an interviewer. He also mentions his own perceived positive experiences with stem cells. To me he seems too cheery about stem cells, and I’m a big fan of stem cells. Gibson talks about how he believes stem cells from Riordan were transformative for his elderly father. When Gibson talks about his dad, it is powerful, but that doesn’t mean this stuff really works. Gibson has also himself gotten stem cells. Riordan makes a number of medical claims about what his institution can achieve with stem cells for a whole rainbow of conditions. It is mentioned that there are published papers on this specific stuff, but from what I’ve seen there isn’t much scientific rigor there in my opinion. Mostly we hear very big, unsupported claims about outsized positive outcomes for almost any medical problem. Does it sound too good to be true? I’m highly skeptical of the safe and effective use of these cells at this time in aging and especially in autism. Injecting laboratory-cultured stem cells into kids also invokes more bioethical considerations and there could be unique long-term risks that we do not understand. Overall, to me this video again feels like an informercial that has likely greatly benefited Riordan.

No doubt it has, given that it’s had over 2.6 million views in the year and a half since the podcast first hit YouTube.

But what about the science? It is, as Dr. Knoepfler described it, not particularly scientifically rigorous. There are some preclinical studies in cell culture and animals, some speculative articles discussing the rationale for the use of stem cell treatments in various diseases, biomarker studies after stem cell infusions, and this rather uninformative phase I/II study of MSCs in autism.

This study, of course, is monstrously unethical. There was no plausible biological rationale for using MSCs to treat autism, and the treatment, although safe, is not without risk. In this trial, although there were no severe or life-threatening adverse events, there were a number of mild to moderate severity ones, including weight loss, inflammation at the site of infusion, headache, fever, and an increase in tics, hyperactivity and aggression, irritability, and obsessive-compulsive behaviors. There was, of course, also the risk of infection, blood-borne diseases, and other potential complications of any infusion of human blood- or tissue-based products, all without compelling evidence that the treatment is likely to work. To make it even more unethical, the patients’ families paid to be part of the clinical trial.

Of course, subjects in clinical trials often bear costs of being in the trial, specifically travel, time off work, and the like. Patients’ health insurance usually covers all their care not directly related to the clinical trial, such as other treatments and drugs, routine laboratory values and tests that would have been ordered anyway if not for the clinical trial, and the like. However, in general, the sponsor of the clinical trial provides experimental drug or treatment for free and bears the costs of the clinical trial itself, including the costs of the offices needed for randomization, data collection, and other expenses related to the clinical trial. However, it is generally considered at best ethically problematic to charge patients to be subjects in a clinical trial, usually in the form of making them pay for the experimental intervention, in this case stem cells. Arguments for this “pay-to-play” funding mechanism generally boil down to five, such as enhancing informed consent because the patient actually pays. There’s also an argument that pay-to-play is no different than taking part in expanded access programs, in which patients are often expected to pay for the experimental drug. Then, of course, clinics like this often claim that studies like the Stem Cell Institute study would never be done otherwise. (I, of course, would counter: Good. Studies like the Stem Cell Institute’s study shouldn’t be done.) Then, of course, there’s the “because freedom” argument.

On the other hand, there are a number of arguments against pay-to-play clinical trials, which were well enumerated in this article from 2015. To me, the most powerful argument against pay-to-play clinical trials is that they are exploitative, the psychological exploitation of individuals desperate to do anything to save their own or a loved one’s life. Desperate patients (or parents of patients) often feel tremendous pressure to raise funds. We’ve seen this many times before discussed on this very blog for dubious cancer therapies. Such patients go to great lengths to raise funds. They often take out large loans, raid their retirement savings, or even sell their house. They launch GoFundMe efforts and relentlessly fundraise on social media.

Also:

Paying for research participation might actually undermine social value and scientific validity by skewing research priorities or encouraging methodologically inferior research. Whatever its limitations, one of the critical functions of peer review is the comparative assessment of the worthiness and methodological rigor of alternative research projects. Peer reviewers can evaluate the potential social benefit of research and prioritize longer-term but more beneficial projects. Pay-to-play funding would prioritize research needs of the wealthy and their ailments. These priorities are unlikely to align with research that might be worthy but afflict individuals without the means to pay, such as interventions for lead poisoning, tuberculosis, or schistosomiasis. If successful, pay-to-play research could also skew researchers and research institutions to pursue lucrative studies that are not necessarily socially valuable. This might lead to a brain and facilities drain. Last, pay-to-play funding might enable studies that ask important questions but lack the methodological rigor to survive traditional peer review. At the extreme, pay-to-play arrangements might enable charlatans to pursue—and profit from—flawed trials that offer no, or even negative, social value (4–6).

And:

Pay-to-play arrangements also create challenges for the ethical implementation of a research study. Having a participant pay could lead to the bending of inclusion criteria, pressure on investigators not to remove participants from a study, and even inappropriate influences on decisions to terminate a study. For instance, it is not hard to imagine a pay-to-play participant pressuring a researcher to grant an exception to inclusion criteria and a researcher agreeing to do so because of the additional financial support. Similarly, patients with limited therapeutic options sometimes demand access to drugs even after studies have proven them to be ineffective. Finally, the paying participants might be reluctant to fully disclose symptoms and side effects. Having invested substantial sums, participants may not want to acknowledge problems that might result in their exclusion or removal from a study.

We can see this in this pay-to-play study by the Stem Cell Institute. A far more methodologically rigorous clinical trial would have been to do a randomized, double-blind, controlled clinical trial. Who would pay to be part of that study, though, given that there would be a 50-50 chance of winding up in the placebo control group? So the Stem Cell Institute did a less rigorous phase I/II study of patients who would have paid to travel to Panama and get the stem cell treatments anyway. To the Stem Cell Institute, this wasn’t a clinical trial. It was advertising. Riordan claims that “$7,200 the institute charged parents was ‘to defray costs outside of the treatment. The actual treatments were provided free of charge.'” One of the patients’ parents claimed that her expenses totaled over $20,000. Even if Riordan did defray some of the costs of the clinical trial, I’d conclude that it was an investment in advertising, to give the appearance of scientific rigor.

Then, I came across this:

So the Stem Cell Institute was the largest recipient of money from patients who crowd-funded their stem cell treatments. Also, given that Duke came up on the list, this implies that there is a “pay-to-play” or “pay-to-participate” component to its stem cell trials, including a stem cell trial for autism:

For families interested in receiving this treatment (who are not in the trial) they can pay Duke for the treatment through Expanded Access Protocol, but Kurtzberg said some families are frustrated because there’s a long waiting list to get in.

To me, this is disturbingly similar to what the Stem Cell Institute is doing, as was the phase I clinical trial run by Duke to show safety published in 2017. It was an open label study; so huge placebo effects were, of course, possible.

Paul Knoepfler also did a disturbing series of posts about a stem cell trial run by Richard Burt of Northwestern University that required patients to pony up $100,000 to be part of the trial, while marketing “cure-like” outcomes, thus raising (to me more than him, in fairness) uncomfortable parallels to predatory trials by for-profit stem cell clinics like the Stem Cell Institute in Panama.

Stem cells definitely show enormous promise for a number of conditions, but all too often they are treated like magic, as though just infusing them, whatever type of cells, will lead to the cells magically homing in where they are needed and magically doing what they need to do. However, testing these therapies in any sort of “pay-to-play” model is an ethical minefield that universities enter at their peril.