Hennepin Healthcare doctors failed to comply with federal safety laws in experimental drug research on members of the public comparing ketamine and other powerful sedatives, the FDA informed the hospital in two warning letters the agency made public this week.
An FDA investigator who visited the hospital in 2019 discovered "objectionable conditions" on studies led by Dr. Jon Cole and Dr. Lauren Klein, both of whom ignored FDA regulations and used practices that subjected patients to "significantly increased risk," according to the letters. The hospital has since used "factually incorrect" statements to defend its research to the FDA, the letters say.
"It's quite clear that the agency's view is that there were significant violations here," said Patti Zettler, former associate chief counsel for the FDA, who now teaches at the Ohio State University Moritz College of Law. "The facts here are quite troubling."
The letters, sent to the doctors in May, gave Hennepin Healthcare 15 business days to reply with actions it will take to prevent similar violations in the future. "Failure to adequately address this matter may lead to regulatory action," read the letters, signed by Sherry G. Bous, director of the FDA's enforcement division.
Asked for comment, a spokeswoman for Hennepin Healthcare provided an unsigned statement saying the FDA told the hospital system earlier this year that its research did "not adhere to statutory and regulatory requirements governing the conduct of clinical trials."
The sedation studies have ended, and hospital leadership has taken steps to strengthen its review process, according to the statement. "Recently, the FDA has communicated that the measures taken result in compliance with FDA regulations."
The letters come three years after Hennepin Healthcare's leadership promised to halt its sedative research in response to community protests over revelations that police were instructing paramedics to sedate vulnerable people on the streets, and that some of those patients ended up in drug trials without first giving consent.
In June 2018, the Star Tribune reported on a draft study from the Minneapolis Department of Civil Rights that detailed instances of paramedics sedating uncooperative or intoxicated people with ketamine during encounters with Minneapolis police, sometimes when the drug didn't seem necessary and appeared to lead to serious health consequences. The reporting prompted patient advocacy nonprofit Public Citizen to file an ethics complaint against the hospital with the FDA.
Hennepin Healthcare funded an outside audit of its research and found no wrongdoing. But an FDA investigator said the hospital expedited its research at the cost of ignoring safety protocols. The next year, the FDA found the hospital had continued the studies even after saying it had stopped, along with a host of other regulatory violations.
The FDA's investigation into Hennepin Healthcare has been quiet for the past two years.
In the meantime, the use of sedatives outside the hospital settings has become more controversial, especially when police are involved. Around the country, protests have erupted seeking justice for Elijah McClain, a 23-year-old Black man in Colorado who went into cardiac arrest and died after being sedated with ketamine in 2019.
This spring, a group of doctors, nurses and other staff of Hennepin Healthcare launched a petition calling on the hospital to reduce its use of sedation, isolation and physical restraints. The petition said the hospital system too often resorts to these methods for patients — especially patients of color — who are deemed uncooperative.
The FDA's warning letters address four sedation studies on which either Cole or Klein led as investigator-sponsor. It says the doctors failed in the studies to apply for an "Investigational New Drug Application," a request from a clinical study to get permission from the FDA to administer a new drug to humans. The FDA rejected arguments from the hospital that its research was exempt from this application because it only documented a normal standard of care.
One study led by Cole compared the effects of ketamine and a sedative called haloperidol. At different stages of the study, Cole or his co-investigator, Dr. Jeffrey Ho — who serves as chief medical director for Hennepin EMS — instructed paramedics to take all sedatives out of the ambulance other than the one being used for the study. In 2015, when paramedics "requested that haloperidol be returned to appropriately treat agitated patients who could not be enrolled in the study," Ho wrote a letter denying them, according to the FDA.
"The use of these drug products was not 'in the course of medical practice,' " the FDA letter says. "FDA has long held that when an investigator limits his choices, his patients' choices, and the choices of the people working for him in the treatment of those patients, then he is conducting a clinical investigation. This is different from the practice of medicine, where the primary intent is to treat the individual patient."
The FDA letter also describes how Cole did submit an Investigational New Drug Application for a study on ketamine and haloperidol one year earlier. But Cole withdrew the application after a June 10, 2014, teleconference with the agency, which pointed out "deficiencies" with Cole's application. These included inadequate safety measures such as excluding "obviously [pregnant] women" and subjects who "appear to be less than 18 years old" from the drug trial. The panel also expressed concerns about the dangers of using ketamine on intoxicated people, along with safety issues in using the drug outside of a hospital.
Instead of addressing these deficiencies and reapplying, Cole "proceeded with a substantially similar clinical investigation," according to the FDA letter.
As a result, one pregnant woman and two children under the age of 18 were enrolled in the trials, according to the letter.
"Your failure to exclude, and the lack of any precautions for, subjects under the influence of various intoxicants significantly increased the risks and/or decreased the acceptability of the risks associated with the investigational drugs," the letter states.
The FDA letter to Klein describes a similar scenario, in which Klein applied for the investigative drug permission in 2017 for a study on four sedatives: olanzapine, haloperidol, ziprasidone and midazolam. In a March 24, 2017, teleconference, the agency put the study "on Full Clinical Hold." The study posed too high of a risk to patients, including those with organ dysfunction and those taking other medications that could interact with the sedatives. "Instead of addressing these deficiencies, you proceeded with a substantially similar clinical investigation" on the same sedatives, the FDA wrote in the letter to Klein.
Michael Carome, director of Public Citizen's health research group, said the FDA's letter to Cole in effect affirms the allegations his agency made against Hennepin Healthcare in 2018, which called for the FDA and other agencies to investigate the hospital's research. Carome said the letters show both Cole and Klein deliberately circumvented the FDA's regulations.
"In doing so, they endangered human subjects enrolled in these trials and violated those subjects' rights," said Carome. "Those are just egregious violations — they're the most serious violations I've seen in a warning letter issued to researchers like this. And I think such egregious allegations warrant severe compliance action by the FDA."