I’ve written quite a few times about stem cell quackery. Although I had taken an interest in dubious stem cell treatments before, because I live in the Detroit area, the stories from a couple of years ago about hockey great Gordie Howe’s stem cell treatment for his stroke, how it was credulously reported in the media, and how expressing the slightest degree of skepticism about “miracle cure” testimonials like Howe’s is not appreciated by the media or patient families because it’s interpreted incorrectly as attacking the patient or the family. Basically, people want to believe and don’t like the conclusion that follows from analyses of testimonials for seemingly miraculous treatment results that families might have been conned.
After that, stories came fast and furious about the dangers of stem cell tourism, how there are plenty of quack stem cell clinics right here in the good ol’ USA, and the hard sell techniques used by stem cell clinic “entrepreneurs” to persuade their marks to lay down their money. Even Stemedica, the company that took advantage of Gordie Howe’s fame to provide him with at least $30,000 worth of free stem cell treatments for the marketing opportunity has a history of woo and is most definitely not above the stem cell hard sell.
So it was with interest that I came across a news report about a study by Leigh Turner that examined “pay-to-play” stem cell trials listed on ClinicalTrials.gov. Here’s a report in The Washington Post:
Stem cell clinics offering unapproved treatments for ailments from hip pains to autism to erectile dysfunction increasingly are using a federal clinical-trials database as a marketing tool — a strategy that confuses patients and exposes them to “unjustifiable” safety risks and high costs, according to a new study.
At least 18 purported clinical trials — all of which involve unregulated therapies and require patients to pay to enroll — are listed on ClinicalTrials.gov, the comprehensive registry for public and private clinical trials that is run by the National Institutes of Health, according to an article published Wednesday in the journal Regenerative Medicine.
Leigh Turner, who authored the study and is an associate professor at the University of Minnesota’s Center for Bioethics and School of Public Health, said NIH should use much tougher screening tools to exclude from its database unapproved treatments, especially trials that require patients to pay to participate.
My first thought coming across this story was: Crap! Quack stem cell clinics are copying the Burzynski model! Stanislaw Burzynski, remember, is the Polish expat doctor and researcher who in the 1970s became so enamored of something he thought he had discovered in the blood and urine, namely proteins that, according to him, were part of the body’s natural anti-cancer defense system that were deficient in cancer patients. Back in the 1970s, this was a novel concept, but unfortunately Burzynski became so sure that he had found the cure for cancer, or at least a much better treatment than what existed, that he gave up his research career, opened a private clinic, and started administering his peptides, which he had dubbed “antineoplastons,” to patients. He’s been doing it ever since, for over four decades now, and no one’s been able to stop him, even though he has never produced anything resembling compelling evidence that his antineoplastons had significant anticancer activity and they did have considerable toxicity.
Now’s not the time to rehash the entire 40 year history of Burzynski, particularly after just this year he managed yet again to dodge having his medical license taken away by the Texas Medical Board and is back in businessGalileo’s Lawyer. First, patients already being treated were enrolled in a wastebasket trial known as “CAN-1” a retrospective trial looking at all patients then being treated at the Burzynski Clinic. Of this trial, Jaffe wrote:
…As far as clinical trials go, it [CAN-1] was a joke. Clinical trials are supposed to be designed to test the safety or efficacy of a drug for a disease. It is almost always the case that clinical trials treat one disease.
The CAN-1 protocol had almost two hundred patients in it and there were at least a dozen different types of cancers being treated. And since all the patients were already on treatment, there could not be any possibility of meaningful data coming out of the so-called clinical trial. It was all an artifice, a vehicle we and the FDA created to legally give the patients Burzynski’s treatment. The FDA wanted all of Burzynski’s patients to be on an IND, so that’s what we did.
The FDA also permitted Burzynski to set up nearly identical phase 2 trials for every cancer that he wanted to treat. Burzynski claimed these were based on a protocol used in a trial done by the National Cancer Institute in the early 1990s when the NCI had tried to work with Burzynski. However, these trials had only one purpose, to allow Burzynski to continue treating patients with antineoplastons:
CAN-1 allowed Burzynski to treat all his existing patients. That solved the patients’ problems, but not the clinic’s. A cancer clinic cannot survive on existing patients. It needs a constant flow of new patients. So in addition to getting the CAN-1 trial approved, we had to make sure Burzynski could treat new patients. Mindful that he would likely only get one chance to get them approved, Burzynski personally put together seventy-two protocols to treat every type of cancer the clinic had treated and everything Burzynski wanted to treat in the future.
Sadly, it worked, and Burzynski’s business model for the 2000s was born. He would enroll whoever wanted to be treated on one of his clinical trials. Now, he didn’t charge them for the experimental drug (the antineoplastons) because charging patients on a clinical trial for the experimental drug being tested was (and still is) considered dodgy at best, highly unethical at worst. (I tend to view it as the worst; patients should not be charged to help a company test its product in order to bring it to market.) Burzynski got around this (and, to my knowledge, still does) by charging exorbitant “case management” fees and providing the antineoplastons “for free.” That’s what he’s been doing for 20 years, and, I fear, that’s what he’ll continue to do until he retires or dies. Certainly neither the FDA nor the Texas Medical Board has been able to stop him.
Curious after the news report, I delved into the study itself. In the introduction, Turner notes:
Numerous US businesses that engage in direct-to-consumer advertising of purported stem cell treatments recruit clients by registering clinical studies on ClinicalTrials.gov. Some studies registered by businesses selling putative ‘stem cell therapies’ disclose that study subjects are charged. The studies are explicitly described as being ‘patient-funded’, ‘patient sponsored’ or ‘self-funded’ [1,2]. However, other studies registered on ClinicalTrials.gov by businesses selling stem cell interventions do not reveal that study subjects are charged to participate in clinical research . It is only when interested individuals contact sponsors, investigators or clinic employees and inquire about enrolling in the studies that they are then informed they must pay to participate.
Listing studies on ClinicalTrials.gov is an effective way for businesses selling stem cell interventions to solicit prospective clients. One such company was recently the subject of considerable news media scrutiny after clinicians independent from the business published a study documenting that three of its patients suffered severe vision loss after paying $5000 per person for stem cell interventions that were supposed to treat their age-related macular degeneration [4–8]. At least one of the women who were blinded reportedly contacted the stem cell clinic after learning about the one of the clinical studies this business had registered on ClinicalTrials.gov .
How on earth did I miss this report, which was published in the New England Journal of Medicine in March? It’s a horrifying set of three case reports:
We report three cases of vision loss after patients with AMD received bilateral intravitreal injections of autologous adipose tissue–derived stem cells at a stem-cell clinic, which was the study site for the fourth trial described above (NCT02024269). After treatment, in June 2015, the patients were referred to two university-based ophthalmology practices.
The study is described in its ClinicalTrials.gov entry as an “open-label, non-randomized multi-center study of adipose stem cell (ASC) implantation. ASCs will be derived from the patient’s adipose or fat.” Adipose tissue was to be collected using liposuction and used to isolate stem cells, which were delivered directly into the eye by injection. So, basically what we have here is a completely unrandomized, unblinded study of a company’s “stem cell” concoction (Bioheart, Inc.) for dry macular degeneration whose primary outcomes were:
- frequency and nature of adverse events [Time Frame: 6 months]
- Visual Field analysis (10-2) [Time Frame: 6 months]. Visual field testing can be performed clinically by keeping the subject’s gaze fixed while presenting objects at various places within their visual field.
- Visual Acuity Measurements [Time Frame: 6 months] Visual acuity is a measure of the spatial resolution of the visual processing system. VA is tested by requiring the person whose vision is being tested to identify so-called optotypes – stylized letters, Landolt rings or other patterns – on a chart from a set viewing distance.
This is basically a phase I study. Really. It sounds like a first-in-human study whose purpose is not to determine efficacy, but rather to determine toxicity and side effects. From my perspective, charging patients to participate in this trial is utterly unethical. But it’s worse than that. Basically all three patients suffered significant vision loss (one was completely blind) after the stem cell injections. The authors noted at the time:
Although numerous stem-cell therapies for medical disorders are being investigated at research institutions with appropriate regulatory oversight, many stem-cell clinics are treating patients with little oversight and with no proof of efficacy. A distinction has been made between clinical studies of stem-cell therapies that are founded on solid preclinical research with strong scientific design and programs that lack preclinical research justification. These programs are often funded by patients at nonacademic centers,8 and they may not receive FDA oversight if these procedures are performed without the filing of an investigational new drug application with the FDA, which requires extensive safety data. At least one of the patients thought the procedure was performed within the context of a clinical trial (NCT02024269). However, the consent forms signed by all three patients do not mention a clinical trial. The patients paid for a procedure that had never been studied in a clinical trial, lacked sufficient safety data, and was performed in both eyes on the same day. Experimental bilateral intravitreal injections are both atypical and unsafe.
The authors go further and note that ophthalmologists do intravitreal injections all the time safely, which strongly suggests that it is what was being injected into these patient’s eyes that was the problem, not the sticking of needles into the eyes itself. Also note the “bait and switch” for at least one patient and how none of the patients signed a formal clinical trial consent form. I’ve helped sign up patients for clinical trials, and anyone who has been involved in clinical trials knows what a pain it is to do informed consent properly—which is as it should be to protect patients. Turner’s study adds to this case series in that she shows how stem cell clinics are using ClinicalTrials.gov entries to lure patients into their clutches and extract their money from them.
What Turner did was simple. He searched the ClinicalTrials.gov database looking for pay-to-play stem cell clinical trials run by private clinics. He found seven studies in which the listings on ClinicalTrials.gov acknowledged that patients are charged to take part in the trials. Five of these were being conducted by the Ageless Regenerative Institute and two by the Lung Institute. He also found an additional 11 studies in which the listings by various companies don’t mention payment but for which he was able to find other publicly available information that makes it clear patients are charged. The studies are for all sorts of conditions, too, ranging from diabetes to osteoarthritis to chronic obstructive pulmonary disease (COPD) to critical limb ischemia (insufficient blood flow threatening to cause loss of limb) to premature ovarian failure to Parkinson’s disease and more.
As I perused the list, I noticed that virtually all the studies were open-label studies, unblinded and unrandomized. In other words, they are not particularly good trials for determining whether stem cells are actually effective or not, because there is no control group and patients and investigators are unblinded. This sort of design is generally only acceptable for phase I or early phase II trials or for surveillance trials after FDA-approval looking for adverse events that might not have been picked up in the clinical trials used to get the drug approved. Charging a patient is never appropriate, in my book, for early phase clinical trials, and, because the stem cell therapies under “trial” are not FDA-approved, a post-approval surveillance trial is not appropriate either. It’s hard not to be suspicious, as Turner was, that these trials listed in ClinicalTrials.gov are marketing tools to sell stem cell treatments more than legitimate trials designed to answer an important clinical question.
As Turner notes (and it’s worth quoting him extensively, although you can access the entire article either logging in with LinkedIn or by registering for an account):
Critiques of ‘pay-to-participate’ clinical studies have identified serious scientific and ethical problems associated with charging individuals to participate in studies conducted on an apparent for-profit basis [54–56]. In such studies, research subjects are charged before the safety and efficacy of investigational agents have been established and the interventions in question have received premarketing authorization from the FDA. It is common to find no public record of peer-reviewed preclinical research by the investigators leading these studies. The absence of any record of peer-reviewed preclinical research generates concerns about whether the sponsors and investigators responsible for such studies have sufficient safety and efficacy data to justify making the transition from preclinical research to clinical studies involving human subjects.
‘Pay-to-participate’ studies often are open-label and, therefore, do not ‘blind’ investigators, study subjects or anyone else involved in clinical research to the intervention being tested, do not use placebos or sham procedures to control for placebo effects, and do not randomize subjects to different study arms.
Many businesses conducting ‘pay-to-participate’ studies in which stem cells are administered risk promoting the therapeutic misconception by describing investigational stem cell interventions as safe, efficacious and innovative treatments. Misrepresentations on the part of businesses conducting such studies and substantial misunderstandings on the part of research participants are particular concerns in such ‘pay-to-participate studies’. ‘Pay-to-participate’ studies also risk amplifying placebo effects as a result of the sizable fees companies often charge research participants and the hyperbole sometimes used to promote such studies.
It is common for ‘pay-to-participate’ studies in which stem cells are administered to use research methodologies and designs that are unlikely to generate meaningful evidence of safety and efficacy. For example, numerous ‘pay-to-participate’ studies that administer stem cells have expansive inclusion criteria and include study subjects with a wide range of disparate diagnoses rather than focusing on a well-defined study population of individuals suffering from a particular medical condition.
In other words, these are crappy clinical studies, and patients have to pay in order to be enrolled on them. I can’t say that I’m the least bit surprised. Regular readers might recall that two and a half years ago, as I was writing about Gordie Howe’s stem cell therapy for his stroke, I got in touch with Stemedica, the company that had referred Howe and his family to its partner in Mexico, Novastem, and the Clinica Santa Clarita, where Howe received his stem cell infusions. As I noted at the time, the clinical trial design was mess, not well designed. It was basically a phase I study, unblinded, with poorly defined outcome measures and nothing resembling a rigorous design, and it, too, had pretty expansive inclusion criteria, albeit not as expansive as described above. I bet that if I were to get a hold of the “clinical trial” protocol of any of the clinical trials Turner discovered I’d find the same thing or even worse.
Yes, these clinics are following in Burzynski’s footsteps.
You might ask how they can get away with it. Well, how did Burzynski get away with it? Part of the issue is that human subjects protections are a federal issue and don’t really have a lot of bite if the institution conducting a clinical trial is not receiving federal grant money. Normally, universities and other institutions doing clinical trials are overseen by the Department of Health and Human Services Office for Human Research Protections, which can’t do a lot if the researchers’ institution isn’t receiving federal grant money. Moreover, there’s no guarantee that the institutional review board (IRB) overseeing such studies is independent or competent. Another reason is that, unless a clinical trial is being done to gain FDA approval of a new drug or device, there isn’t a lot to make sure that the institution plays straight. FDA oversight of clinical trials assumes that the researchers doing them are doing them in order to produce data to use in an application for FDA approval of a new drug or device. That’s not the case for many of these stem cell studies, and often the clinics haven’t even filed an investigational new drug (IND) application. Finally, ClinicalTrials.gov more or less operates more on the “honor system,” which, as Turner notes, “has created a situation in which sponsors and investigators can register clinical studies and deposit them in the database without careful screening by NIH employees responsible for maintaining the database.” To that end, Turner suggests:
To improve the quality, integrity and public value of ClinicalTrials.gov, the failure of NIH officials to properly screen studies submitted to the registry needs to be addressed. In particular, screening needs to determine whether clinical studies submitted for registration in ClinicalTrials.gov have been reviewed and permitted to proceed by the FDA and IRBs, where both FDA review and IRB review are required by federal regulations. In the case of trials requiring Investigational New Drug (IND) or Investigational Device Exemption (IDE) applications reviewed and cleared by the FDA, screening must also establish whether sponsors or investigators are authorized by the FDA to charge individuals participating in clinical studies. This legal requirement for IND studies is addressed in federal regulations and explored in detail in FDA guidance document [15–17]. Absent evidence that the FDA has reviewed such studies, approved all charges to research subjects and permitted clinical research to proceed, such studies should not be accepted for inclusion and public listing in the ClinicalTrials.gov registry. Regrettably, these issues were not adequately addressed in Section 801 of the Food and Drug Amendments Act and in 42 CFR Part 11, the final rule for Clinical Trials Registration and Results Information Submission [18,19].
Inded, the FDA hasn’t provided adequate guidance. Here is a recent draft rule about charging for investigational drugs. It’s so vague as to be a mess. Paul Knopfler tried to find out how the FDA determines if a clinical trial investigator is allowed to charge patients to be in a clinical trial, and he was sorely disappointed.
So what we’re left with is a situation in which quack stem cell clinics can abuse ClinicalTrials.gov by using it as a marketing tool. They are not the first to use set up dubious clinical trials as as strategy to be able to continue to sell their product without FDA approval. They’re just following the trail blazed by Stanislaw Burzynski 20 years ago. The FDA and OHRP need to recognize what these clinics are doing and reevaluate and modify their regulations in order to protect patients from such abuses.