FDA says HCMC doctors kept ketamine study going after pledging to stop

Medical staff at HCMC continued to sedate people with ketamine and collect data for a study for months after the hospital's leadership told elected officials they had voluntarily halted the research in response to questions over ethics and patient safety.

New inspection reports from federal regulators also say that doctors involved in the research failed to disclose incidents of patients suffering serious medical complications — such as trouble breathing or high blood pressure — to the committee in charge of keeping study subjects safe.

HCMC officials have already responded to the reports, vigorously rebutting many of the findings.

Two inspectors from the Food and Drug Administration (FDA) visited the Twin Cities hospital 17 times, collectively, in April as part of an investigation into HCMC's sedative research. The records from those inspections, obtained by the Star Tribune through a public records request, raise a fresh set of questions over the hospital's research practices.

According to the documents:

• In dozens of cases, researchers failed to inform patients of their enrollment in hospital studies, even after the subjects were sedated.

• Hospital staff did not always properly monitor patients' vital signs after they'd been sedated.

• In one case, doctors did not report that a patient enrolled in a study died, despite a requirement to do so even if the death "is not thought to be related to the study treatment."

• The researchers did not obtain permission from the FDA for a drug study deemed "investigational," and did not appear to meet exemption from this approval.

In a separate visit to the hospital last August, the same inspectors examined records related to HCMC's Institutional Review Board (IRB), which is charged with approving research and keeping patients safe. Those inspection reports found the IRB appeared to fall short of federal guidelines in several areas, including by enrolling patients without their prior consent.

The inspection reports are not final determinations, and HCMC is aggressively defending its research. In a response to the FDA, the hospital acknowledges some mistakes, such as failing to notify a small number of subjects they'd been enrolled in studies. Leadership has also suspended one doctor from serving in the prestigious role of sole principal investigator for three years, and assigned that doctor a mentor, according to HCMC's letter to the FDA. The hospital redacted the doctor's name from the letter, saying releasing the identity could threaten the doctor's safety.

In interviews and prepared statements, HCMC leadership denies the most damning claims in the reports, arguing that the FDA inspectors fundamentally overstate the added risks the study methods pose.

"These observations and the FDA visit are concerning to us," said HCMC interim CEO Dr. John Cumming. "But we quite frankly welcome the opportunity to improve our processes in any way, and we really embrace the opportunity to have the dialogue with the FDA. … We share a common goal with the FDA of making sure that we are doing all we can do to ensure the safety and welfare of our community."

In June 2018, HCMC leadership announced it would halt its ketamine study and all other research that featured a "waiver of consent," meaning doctors don't need prior consent from patients to enroll them.

The decision came in response to a series of Star Tribune stories citing a leaked report from the Minneapolis Office of Police Conduct Review on ketamine use. The draft report questioned whether the study played a significant factor in paramedics choosing to sedate people when they respond to emergency calls in tandem with police.

In one case highlighted in the draft report, a paramedic sedated a patient suffering from an asthma attack. "We're doing a study for agitation anyway so I had to give her ketamine," the unnamed paramedic told a police officer afterward.

Then-Hennepin County Commissioner Peter McLaughlin called the ketamine study "unconscionable," comparing the lack of consent to the infamous Tuskegee experiments, in which doctors studied untreated syphilis in black men without their consent from 1932 to 1972.

"The community is hurting. I see it," Dr. William Heegaard, chief medical officer for HCMC, told members of the Hennepin County Board last June. "We don't want to add to the pain and distrust."

However, according to the FDA, the hospital continued to recruit subjects for the trial until Nov. 19. Researchers ultimately enrolled a total of 874 patients — 74 more than the total approved from the IRB, the FDA reports say.

Cumming disputed that finding in an interview this week. He said the hospital continued to sedate patients when necessary, and continued to collect data after halting the research, but it was no longer for the purpose of a study.

The FDA inspection reports reference several studies examining the effects of sedatives, which hospital staff use in emergency situations, often involving extremely agitated patients.

HCMC redacted key identifying information before turning the records over to the Star Tribune, in some cases obscuring the specifics of the research.

One study compared ketamine to a similar sedative, called Versed. Another analyzed the effects of four sedatives.

In every case, HCMC officials say, the research mandate did not change the care they gave to patients. Emergency medical staff sedated patients when it was medically necessary, they say, and the studies only added the step of recording data, such as how long it takes for the drugs to take hold.

"It is a little bit interesting to me how the FDA is interpreting it otherwise, when the only study interventions we had were a stopwatch and a data sheet," said Cumming.

The new reports have also elicited a fresh round of scrutiny from medical ethics experts.

Dr. Michael Carome, a medical expert for the consumer advocacy organization Public Citizen, called the hospital's response "deeply troubling."

"From day one, they've just denied anything is wrong here," Carome said this week. "They've boxed themselves in a corner and they're sticking to that party line."

Last summer, Public Citizen submitted a complaint asking the FDA to investigate HCMC's sedation research, signed by more than 60 doctors, bioethicists and academics. After reading HCMC's response to the FDA, Carome said "they're wrong" in classifying the study as a low-risk exercise in data collection.

Carome said it's possible the FDA could next issue a formal warning letter to HCMC.

Leigh Turner, a bioethics professor at the University of Minnesota, said he also doesn't find HCMC's response convincing.

"It's dangerous what they're doing, because we're talking about pretty vulnerable individuals who are on the other end of the stick," said Turner. "They're the ones out on the street or in the ER being given medications. They're not choosing to be in this study."

Andy Mannix • 612-673-4036