“You are receiving this form because you or someone you care for was included in a research study examining patients with agitation,” states one letter from Hennepin, notifying a patient that he or she had been enrolled in one of the trials without being asked. Depending on the period of the study when they were treated, agitated patients received either ketamine or another drug, midazolam. “Experts have recommended both drugs for agitation; previous studies from our hospital suggest both drugs have similar risk,” the letter about the midazolam study states.
But Hennepin's previous research found that ketamine has risks and can cause complications. In a study that also raised ethical concerns from experts, more patients required a breathing tube after being sedated with ketamine compared with those dosed with the schizophrenia drug haloperidol. A 2013 paper by researchers at the hospital states, “We would advocate that ketamine not be the chemical solution for every unruly or belligerent subject, as this would lead to overuse with unnecessary risk.”
Strict federal rules exist to protect patients in research trials. Generally, patients must be asked whether they want to participate in a research study and be informed of the possible risks and benefits — except in specific circumstances in which a body of experts, called an institutional review board, determines that this process can be waived. Since patients who are agitated most likely won't be able to give consent, the researchers sought and received a waiver from their board.
But the bioethicists, led by the consumer advocacy group Public Citizen, argue in a letter to the Food and Drug Administration and the federal Office for Human Research Protections that Hennepin's trials did not meet the criteria for consent to be waived — which include that the research pose only a “minimal risk.”
“These are clearly prospective clinical trials that involve much greater than minimal risk. It’s not even a close call, in our view,” said Michael Carome, director of Public Citizen's Health Research Group. “It's just a complete and utter failure of the system, and our concern is that these two protocols that have caught public attention are just the tip of the iceberg — if they made these decisions so wrong, what else is going on at this institution?”
The ketamine-midazolam trial was paused June 25, after reporting by the Star Tribune raised public scrutiny of patients being enrolled in trials and given ketamine without their consent. Initial concerns had focused on whether police were directing emergency medical personnel to use ketamine, and a police oversight report is scheduled to be released Thursday. An earlier Hennepin study comparing ketamine and haloperidol has been published, and it also did not require the informed consent of its study subjects.
Christine Hill, a spokeswoman for Hennepin Healthcare, said the institution has been participating in multiple independent external reviews of its research and care protocols and would share those findings with the public.
“We are committed to transparency and retaining the public's trust and independent outside reviews help us to do that,” Hill wrote in an email. She added that the institution's oversight board is accredited by the Association for the Accreditation of Human Research Protection Programs. In a FAQ posted on Hennepin's website, the hospital states that ketamine has been “the standard of care for patients safely since 2008" and is used across the country.
A survey of more than 10,000 U.S. paramedics published this year found that only a third were authorized by their agencies to use ketamine. Of those people, most paramedics had little experience with the drug — a third of them had administered the drug fewer than five times in their career, and a third had never given the drug to patients.
“Even if there’s a case for using these drugs, there’s a case for being very judicious about when to use it,” said Leigh Turner, a bioethicist at the University of Minnesota, who noted that the study overrides the decision of emergency medical services on the scene.
“That’s going to lead to a reduction in the scope of clinical judgment, where EMS doesn’t have the full array of medications. The study is playing a role in which medication people get,” Turner said.
An FDA spokeswoman said the agency does not comment on specific trials, but is committed to the integrity of scientific research.
“With few exceptions, patients have a right to informed consent before participating in a clinical trial,” spokeswoman Theresa Eisenman said in an email. “The FDA takes seriously reports of possible violations of the laws in place to protect human participants and will take action where warranted.”
Steven Green, a professor of emergency medicine at Loma Linda University in California who has written papers with the chief of Hennepin's emergency department, said ketamine is an effective drug for severely agitated patients who pose a danger to themselves or others.
“Nothing will be as rapidly effective than ketamine when an agitated and violent patient presents an imminent danger to himself or herself, and an imminent danger to caregivers and law enforcement,” Green wrote in an email. “There are allegations that in Minneapolis ketamine was administered to patients who did not truly need it based upon their medical condition, or solely for the purposes of research or to satisfy law enforcement. If true, this is of course not acceptable.”