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.”