Investigation Sought in Minneapolis Ketamine Trials

Following revelations last month about two controlled trials of ketamine for treating severe agitation — with drugs injected by first responders without the patients’ individual consent — the consumer group Public Citizen and dozens of independent physicians are calling for a federal investigation.

The Minneapolis Star Tribune newspaper published a series of stories in June detailing the trials, which were the first quasi-randomized studies comparing ketamine with traditional medications (i.e., haloperidol and midazolam) used to sedate agitated patients in emergency settings. The trials had been approved under a “waiver of consent” process, under which the investigators said risks were minimal; they also consulted beforehand with community groups, including patients in a homeless shelter under treatment for substance abuse.

Conducted by Hennepin Healthcare in Minneapolis, the trial comparing ketamine with haloperidol was completed in 2016. The rationale seemed clear: first responders elsewhere were already starting to use ketamine to sedate agitated patients, in large part because of the rapid onset of effect, but hard data on how it compared with other tranquilizers in this setting were lacking.

That first trial in Minneapolis found that ketamine indeed had a faster onset of action than haloperidol — mean 5 minutes versus 17 minutes — but with a substantially higher rate of complications (49% versus 5% overall and 39% versus 4% for intubation). Unlike previous studies of ketamine for treating agitation in the prehospital setting, this was partly randomized: all severely agitated individuals seen during one 6-month period received ketamine; during a second 6-month period they received haloperidol. In total, 146 people were treated.

Hennepin Healthcare then began another, similar trial to compare ketamine with midazolam, but a political firestorm erupted after the Star Tribune stories appeared, and that trial was suspended. Local and state politicians have demanded answers about the trials.

Public Citizen is now hoping to make a federal case out of it. Their letter, dispatched just after midnight Wednesday, called on the FDA and the Department of Health and Human Services’ Office for Human Research Protections to “immediately launch formal compliance oversight investigations.”

The letter cited the adverse-event rates from the initial trial as indicating that the risks associated with ketamine were far from minimal, and questioned the method used to determine whether patients were severely agitated (scores of 2 or 3 on the Altered Mental Status Scale). It also said the institutional review board (IRB) that approved the trials, as well as the sponsors and investigators, should be scrutinized.

There were “unacceptable regulatory and ethical lapses in the oversight and conduct of these two prospective clinical trials,” the letter charged, “reflect[ing] systemic breakdowns in the Hennepin County Medical Center’s human subjects protection program. These breakdowns extend from the investigators to the IRB to senior institutional officials.”

The letter also suggested that earlier studies conducted at Hennepin be examined.

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