A Minneapolis hospital tested powerful antipsychotics and the potent anesthetic ketamine on emergency room patients without their knowledge or consent, violating regulations on human research, federal inspectors have determined.
Based on those findings, a health watchdog group on Monday urged federal regulators to suspend all clinical trials at the hospital. In a letter to the Food and Drug Administration and the Department of Health and Human Services office that protects human research subjects, Public Citizen also called for regulators to immediately launch an investigation into the conduct and oversight of the studies and “impose severe sanctions for the serious ethical and regulatory lapses that have occurred in the ketamine clinical trials and other studies” at Minneapolis’s Hennepin County Medical Center.
The hospital committee that green-lighted the studies, called an institutional review board (IRB), “appears incapable of doing its job,” said Dr. Michael Carome, director of Public Citizen’s Health Research Group, who organized the letter. It acted unethically and placed patients in danger, he said, “including by waiving the requirement for informed consent in situations where that is not allowed.”
A hospital spokesperson said the findings by inspectors from the FDA “are neither formal nor conclusory.” Hennepin “has provided formal written responses to each” of the inspectors’ findings, she said, adding that the hospital “has undertaken several reviews by independent experts to evaluate its research and emergency medical practices with the intent to improve our processes. …We understand our mission includes providing the highest standards of medical care, and also conducting studies that help to continuously improve the health and wellness of our patients.”
Among other violations identified by FDA inspectors, the IRB ruled that researchers did not need consent to make patients part of a clinical trial in which they were given antipsychotic drugs that they might not receive as part of usual care. The Public Citizen letter said the IRB, which is legally obligated to protect research participants, “appears to lack even a basic understanding of federal regulations for the protection of human subjects and is clearly incapable of fulfilling its obligation” to do so.
In July, Public Citizen and 64 bioethicists, physicians, and other scholars submitted a complaint about two of Hennepin’s ketamine studies to the FDA and HHS’s Office of Human Research Protections. In August, FDA sent inspectors to the hospital.
Their report, obtained by Public Citizen through a public records request and shared with STAT, examined additional clinical trials beyond those initially flagged. It found that in four, the hospital IRB “did not determine that informed consent would be sought from each prospective subject” as required by law, while in another five, the IRB granted fast-track review to studies that didn’t qualify for it.
At least three of the studies cited by the FDA inspectors involved people brought to the emergency room with “severe” agitation, as assessed by emergency technicians using criteria developed by the researchers. The study leaders apparently persuaded the IRB that such patients could not provide informed consent, and so could be swept into the trial unknowingly.
In fact, such patients are considered “vulnerable,” said bioethicist Leigh Turner of the University of Minnesota, who signed the Public Citizen letter. According to federal law, they are supposed to receive special safeguards, such as having a family member or other representative give or decline consent. That did not happen.
Just as concerning, Turner said, it’s not clear that the patients were in fact too agitated to be asked for their consent, as the scientists argued to the IRB. According to the evaluation form’s scoring, “it’s not like they had acute psychosis,” Turner said. “These investigators were basically drugging up individuals with a degree of agitation many of us could experience, like after being pulled over for speeding.”
In the first study cited by the FDA inspectors, researchers injected either ketamine or haloperidol into people taken to the ER, to reduce their “agitation.” Ketamine is not approved by the FDA for that use. The unwitting participants were treated not according to clinicians’ best judgment but according to the study’s protocol: Those arriving during certain months got ketamine and those arriving in other months got haloperidol.
Among the trial’s results was that some patients given ketamine suffered breathing problems; 39 percent required intubation, compared to 4 percent given haloperidol. Before the trial began, its leaders had warned in a 2013 paper that ketamine can impair breathing and so should be reserved for only the most severely agitated patients.
The identities of five of the seven studies the FDA report flagged are redacted, but one corresponds to the second ketamine clinical trial questioned in Public Citizen’s letter. It compared ketamine to midazolam, also in “agitated” ER patients given one or the other drug essentially randomly, not according to which — if any — might help them. The study was suspended by the medical center in June, for unclear reasons, but it also failed to obtain informed consent from participants, the FDA inspectors found.
A third clinical trial compared the safety and efficacy of four drugs (the antipsychotics olanzapine, haloperidol, and ziprasidone and the sedative midazolam) in agitated patients. The hospital scientists had initially requested an FDA waiver from the informed consent requirement. FDA denied the request. The scientists then requested IRB approval, calling their study observational (meaning patients would be treated according to their doctors’ best judgment rather than receiving drugs as per the trial protocol) and therefore entitled to “expedited review.” The IRB agreed, including giving the okay to forgo consent.
In fact the study was not observational: Patients received one of the four drugs based on when they arrived in the ER. They were not informed of this, and so were unwitting participants, the FDA inspectors found.
“When the investigators didn’t get FDA clearance, they did an end-run around the agency,” Turner said. “They claimed it was no longer the randomized controlled trial they’d planned, and then pushed it through the IRB as a waiver-of-consent study,” a strategy he called “dodgy.”
The FDA inspectors found that “some or all of the subjects [in four studies] were likely to be vulnerable to coercion or undue influence,” yet the IRB did not require the researchers to do anything to safeguard the participants’ safety.
In addition to asking HHS to suspend all clinical trials at Hennepin unless doing so would harm participants, Public Citizen called it “imperative” that the hospital disband its current IRB and train a new one, retrain researchers involved in human research, and inform the unwitting participants in past trials of steps “to redress these violations.”