Recent action by federal authorities against stem cell clinics charged with questionable practices appear to validate concerns raised by bioethicists like Leigh Turner, PhD, who recently warned that some stem cell clinics are charging research subjects exorbitant fees for participation in experimental treatments marketed as clinical trials on ClinicalTrials.gov.

In a related development, the FDA recently cracked down on two stem cell clinics, including one charged for using smallpox vaccine for some kind of therapy. (For more information, see related story in this issue.)

“There are a number of things that have gone on to increase FDA’s enforcement activity in this area,” says Turner, a professor in the Center for Bioethics at the University of Minnesota in Minneapolis. “I think empirical studies like the one we did last summer1 and the one that just came out on ClinicalTrials.gov2 helps put pressure on the FDA and gives them some guidance in terms of where to focus.”

In the most recent study, Turner called the NIH to account for allowing questionable “pay-to-participate” trials to be listed on its ClinicialTrials.gov site, some of which appeared to be essentially marketing tools to charge research subjects to join the study.

“In general, there are a lot of problems with charging people [in a clinical trial],” Turner tells IRB Advisor. “It raises a variety of ethical and scientific issues just in terms of the kinds of studies that people are paying for. Some of the studies are not blinded and they are not randomized. It’s a particular kind of study that seems to fall into that ‘pay-to-participate’ category. When you look at a lot of these listings, and look at study design, I think it’s fair to say what we are looking at here, for the most part, is a marketing exercise — a great way to attract customers is to put up a listing on ClinicalTrials.gov and call it a study.”

Critical Points

In the paper, Turner distilled his findings to the following critical points:

  • Some companies use studies listed in ClinicalTrials.gov to sell stem cell interventions research in the context of “patient-funded,” “patient-sponsored,” or “self-funded” studies.
  • Inclusion of these studies that have not been subject to FDA oversight and screening by NIH officials may compromise the integrity of the database.
  • Listing “pay-to-participate” studies in the database also risk confusing potential research participants by making it difficult to distinguish between commercial medical treatments and clinical research evaluating interventions.
  • As a result of these issues, there is a clear need for careful screening of clinical studies before they are registered with ClinicalTrials.gov.

“I think if someone wants to come forward with a series of arguments that address all of those concerns, I would be interested in hearing that,” Turner tells IRB Advisor. “But, in general, it is better to have a framework for clinical trials where research subjects aren’t the ones paying. We already ask a lot of research subjects because they bear of risk of participating in clinical studies. The usual idea is that research subjects take the risk of receiving an investigational agent. You are not charged thousands of dollars [to do so].”

Most IRBs probably are unaware of such studies, and many are not directly involved in them, he says.

“I think a lot of IRBs are operating at a very different status,” Turner says. “They are in hospitals, at universities, and they are getting studies from legitimate researchers and evaluating them. They are not necessarily aware of what is taking place on ClinicalTrials.gov. I think there is still a fairly widespread assumption that you can refer people to ClinicalTrials.gov because it is this reliable, clinical source of information from the NIH. But that kind of referral may send people to places that advertise and administer unproven [trials]. Providing a well-intentioned referral may put a patient at risk.”

One does not need to know a lot about federal regulations to realize, at least on the surface, these look like questionable studies, but it’s conceivable that an IRB could receive a protocol and approve it and not be aware that a particular business plans to charge people to be in that study, he notes.

“That said, a little bit of diligence if you get something from an organization, and you go on the internet and realize they are selling stem cell treatments for $20,000 a pop,” Turner says. “You would hope that IRBs figure out what is going on. I’m just trying to acknowledge the possibility. I can imagine a scenario where IRBs are simply not being given relevant information. But I think what is going on is that a small number of IRBs are operating in a way that enables these stem cell clinics. They act as a kind of rubber stamp, approving studies in which participants are charged. This ought to go through the FDA. I don’t think you can go to just any IRB in the U.S. and get this outcome — I think there are a handful of IRBs that these clinics go to, and they know very well which IRBs to approach.”

NIH Mulls Changes

As a result of Turner’s findings, the National Institutes of Health (NIH) tells IRB Advisor it will be taking additional action to protect research participants by going beyond the “disclaimer” it lists on ClincalTrials.gov, which essentially reflects the old Latin warning caveat emptor, “let the buyer beware.” IRB Advisor asked if NIH is considering taking stronger steps than posting a disclaimer on the clinical trials site.

“Yes, NIH is actively evaluating a range of options for helping potential research participants understand the potential benefits and risks of participating in clinical research studies and consider individual studies,” an NIH representative responded in an email. “More information about these steps will be announced as decisions are made. … Note that in addition, [the site] now displays that disclaimer on all ClinicalTrials.gov pages, including each individual study record. This was done to ensure that the important disclaimer message is seen by all users, including those directed to a study record by a search engine.”

Hope and Skepticism

IRB Advisor further asked NIH to confirm whether it is permissible within their policies to list trials that charge participants.

“That is correct,” the NIH representative wrote. “ClinicalTrials.gov accepts information about clinical studies involving human subjects that assess biomedical and/or health outcomes as long as the study sponsors or investigators indicate that the study conforms to applicable human subject or ethics review regulations and applicable regulations of the national or regional health authority. This may include studies that charge participants. There is no blanket legal or ethical prohibition against charging individuals to participate in clinical research, per se. Our approach of listing submitted information for all clinical studies that follow prevailing laws and regulations is consistent with the mission of ClinicalTrials.gov to increase transparency into clinical research by making publicly accessible information about such studies.”

Turner expressed hope at the NIH promise of action, but remains skeptical just how far the agency will go.

“To date, their response has been to increase the visibility of that disclaimer,” he says. “It now has a more prominent position on the homepage. I didn’t really think that that was an adequate step, just because so many people rely on ClinicalTrials.gov as a crucial source of information. As far as what they do next, I guess it’s somewhat encouraging if they are suggesting that they realize there is a problem with the ease at which people can register studies on ClinicalTrials.gov, including studies that probably shouldn’t be on there.”

As a first step, the HHS could red flag, or outright remove, the more questionable studies, Turner says. There should be some kind of vetting process so studies are not just placed on the site without any review or scrutiny, he adds.

“I can imagine some very basic steps that would improve the quality of the site,” he says. “In the past when reporters have called, some of [the NIH] responses to me have seemed fairly defensive in terms of not really doing much of anything beyond the disclaimer. I am glad to hear that you got that response. Part of it is there are some pay-to-participate studies that have already been identified — that was the point of the article. A number of international clinics have also registered these pay-to-participate studies. They are not hard to find, either, so I think these are examples of where they might start just by retracting some that are on ClinicalTrials.gov. As far as additional steps, if they look for studies that say something like ‘self-paid, patient-funded, and patient-sponsored.’ The only way you can charge people is if you have permission from the FDA. Again, those seem like good examples that should just be retracted.”

REFERENCES

  1. Turner, L. ClinicalTrials.gov, stem cells and ‘pay-to-participate’ clinical studies. Regen Med 2017 Jul 19. doi: 10.2217/rme-2017-0015. [Epub ahead of print]
  2. Turner L, Knoepfler P. Selling Stem Cells in the USA: Assessing the Direct-to-Consumer Industry. Cell Stem Cell 2016;19(2)154 -157.