ClinicalTrials.gov Registration May Be Misleading, Experts Say

Ricki Lewis, PhD

July 19, 2017

Companies are registering stem cell therapies on the ClinicalTrials.gov website but asking patients to pay for unapproved care, according to an analysis published in Regenerative Medicine.  The author says the companies are using a trusted government resource as a marketing tool.

An example of this practice came to light earlier this year in a New England Journal of Medicine article that described three patients with age-related macular degeneration who lost vision after bilateral intravitreal injection of autologous adipose tissue-derived stem cells at a Florida clinic.  Two of the women came to the clinic after reading a description at ClinicalTrials.gov.

Criteria for Listing

Registering a clinical trial at the National Institutes of Health (NIH)–sponsored website is possible because criteria are not terribly rigorous, according to the author of the new perspectives article. A listing must indicate whether there is an institutional review board, a "yes" or "no" response to indicate whether the treatment is US Food and Drug Administration (FDA) regulated, and, if so, the investigational new drug (IND) or investigational device exemption (IDE) number. An observational study need not have an IND or an IDE.

For the current study, Leigh Turner, PhD, associate professor at the Center for Bioethics at the University of Minnesota, Minneapolis, searched ClinicalTrials.gov for the terms "patient-sponsored," "patient-funded," and "self-funded," finding 7 clinical trials, each enrolling more than 100 individuals. He identified 11 other registered clinical trials using a database of companies that provide direct-to-consumer stem cell–based treatments. One trial (listed by Cell Surgical Network) had an estimated enrollment of 3000.

Companies can use a ClinicalTrials.gov listing to attract non–science savvy, and often desperate, patients, Dr Turner says. He points to a news release from StemGenex, for example, that claims, "By providing access to registered clinical studies through the NIH, we are providing patients with the ability to choose a stem cell treatment center with the highest standard of care."

"I am disgusted, but not surprised, that the clinics are using the site as a marketing tool, just like newspaper ads and free seminars. There are even weekend courses to instruct doctors to set up a clinic and market it. It's more like time-share sales than medicine," Jeanne Loring, PhD, the director of the Center for Regenerative Medicine at the Scripps Research Institute, La Jolla, California, told Medscape Medical News.

Red Flags

Dr Turner lists several harms of enrolling in an unregulated stem cell clinical trial, including the absence of adequate preclinical data to support use in medicine; likely use of an open-label, uncontrolled trial design, which is unlikely to provide useful research data; and request for payment, which can amplify a placebo effect. Moreover, the FDA must approve asking participants to pay for investigational or unapproved treatments, which it generally doesn't do.

Another sign of trouble, according to Dr Turner, is the laundry list of targets. "The stem cell clinics that most concern me claim that what they offer is safe and efficacious for everything under the sun," Dr Turner told Medscape Medical News. Cell Surgical Network's clinical trial (NCT01953523), for example, deploys autologous adipose-derived stem cells to treat osteoarthritis, erectile dysfunction, autoimmune and neurodegenerative diseases, cardiomyopathies, and chronic obstructive pulmonary disease.

"You'd never design a study with an umbrella of disorders — you'd focus on one and have inclusion and exclusion criteria, and would start with a safety study. It does take some knowledge of clinical trial design for the red flags to be waving and readily visible," he added.

Stem cells seem particularly vulnerable to exploitation, perhaps because they are neither drug nor device, which means they do not easily fit into any regulatory scheme. Intended use is important in regulation too. That's the case for autologous adipose-derived stromal vascular fraction (SVF) cells, more colorfully called a "soup" or "slurry." Even for autologous use, if the application differs from the natural role in the body, FDA regulation applies. The three patients blinded by treatment in Florida had adipose-derived cells injected into their eyes.

"There's an ideology that treatment such as SVF isn't a drug or a biologic, but a same-day surgical procedure not subject to FDA oversight. The way that FDA officials interpret stem cell treatments doesn't seem to be the same as how businesses interpret federal regulations," Dr Turner said. A biologic would require a biologics license application (BLA) from the FDA.

Looking Ahead

Jan Nolta, PhD, director of the Stem Cell Program and the Institute for Regenerative Cures at the University of California Davis School of Medicine, applauded the newly published perspectives article. "The issue of so-called clinics offering unauthorized therapies that are listed on ClinicalTrials.gov is a big problem. Patients are led to believe that this listing makes the trials legitimate, but in fact it does not. The International Society for Stem Cell Research Patient Handbook on Stem Cell Therapies has issued outstanding guidelines for patients seeking clinical trials."

The current ClinicalTrials.gov's disclaimer — "listing of a study on this site does not reflect endorsement by the NIH" — isn't enough, Dr Turner argues, and Dr Loring agreed. "ClinicalTrials.gov has deeply harmed its credibility by accepting listings from clinics that are in the business of making money, not helping desperate people," she said.

ClinicalTrials.gov has deeply harmed its credibility by accepting listings from clinics that are in the business of making money, not helping desperate people. Dr Jeanne Loring

Vetting registered studies, including whether an IND, IDE, or BLA is necessary, is essential, Dr Turner said. However, he continued on to say that  in the current political climate, such oversight is not likely to happen anytime soon. "Given the Trump Administration's interest in cutting funding to the [Centers for Disease Control and Prevention], FDA, NIH, and other federal agencies, perhaps no funds will be allocated to improving screening before studies are registered on ClinicalTrials.gov. If the problem isn't addressed and more problematic 'pay-to-participate' studies are registered, we'll see more cases of avoidable harms to patients and additional allegations of fraud."

In the meantime, Dr Loring suggested a simple improvement. "NIH can split the site and place all of the FDA-approved trials on a managed site, and all of the others on a differently named site, where there is no oversight about approvals."

Until ClinicalTrials.gov curates its information, the rule of thumb, Dr Turner said, should be caveat emptor — let the buyer beware.

Dr Turner and the commentators have disclosed no relevant financial relationships.

Regen Med.  Published online July 19, 2017. Abstract

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