In a July 25 letter, Public Citizen – with 64 doctors, bioethicists, and academics – requested that the US Food and Drug Administration (FDA) and the Office for Human Research Protections (OHRP) investigate the Hennepin County Medical Center in Minnesota.
On ClinicalTrials.gov, the recruitment status for Ketamine Versus Midazolam for Prehospital Agitation recruitment is suspended.
The study aimed to compare two tiered dosing treatment protocols, one ketamine-based and one midazolam-based.
It hypothesized that the ketamine-based protocol would achieve a faster time to adequate sedation than the midazolam-based protocol.
The study description reads: “This study will observe the natural history of an emergency medical services standard operating procedure change from a ketamine-based protocol to a midazolam-based protocol.”
An inspection occurred from August 7 to August 23 and resulted in four FDA Form 483 observations.
Now, in response to a Freedom of Information Act (FOIA) request, the FDA has released a copy of the initial report from its inspection of the Hennepin County Medical Center’s institutional review board (IRB).
Michael Carome, MD, director, Health Research Group, Public Citizen, told us the inspection revealed that the IRB approved research testing ketamine and other clinical trials “without ensuring that the FDA’s requirements for obtaining informed consent of the subjects and for providing adequate safeguards to protect the rights and welfare of vulnerable subjects were satisfied.”
“The FDA’s inspection reveals that the Hennepin County Medical Center’s IRB appears to lack even a basic understanding of key federal regulations for the protection of human subjects,” he said.
Carome explained that the IRB incorrectly determined that the experiments involved no more than minimal risk to the subjects, a determination based on which the IRB decided to waive the informed consent requirements.
“The requirement for informed consent for human research is based on the bedrock ethical principle of respect for persons.”
For research posing more than minimal risk to patients, Carmone said informed consent can only be waived under "very limited circumstances." Circumstances which he said the FDA report reveals were not met for these trials.
The trials also used “a broad definition of ‘severe agitation,’ which likely resulted in some subjects receiving these powerful drugs when they otherwise would not have,” said Carome.
“In addition, whether subjects received ketamine or the other drug being tested was based on the month in which a subject was enrolled, not by a health care professional’s judgment of what was best for the patient,” he added, noting that the use of ketamine, in particular, made these experiments high-risk.
These risks are outlined in two papers, the first of which was written by some of the researchers involved in the ketamine trials at the Hennepin County Medical Center. The first paper advises against using ketamine – due to a risk of laryngospasm – except for in the most extreme cases of agitation, including excited delirium syndrome.
As Carome explained, none of the subjects involved in the first ketamine trial had this condition and only some in the second did.
The second paper provides the results of the first ketamine trial, in which 39% of patients who received ketamine needed to be intubated for breathing difficulty compared to only 4% of the patients who received haloperidol, Carome said.
A stopwatch and observation
In response to a request for comment, a Hennepin Healthcare media representative sent a statement via email, in which it was explained that a number of FDA-approved sedatives are available for emergency medical services (EMS) use “in circumstances where patients’ high level of agitation make them a risk to themselves or others during the pre-hospital phase of care.”
“In order to improve patient care, Hennepin Healthcare conducted a study using stopwatches to measure time- to-sedation observations, while recording patient variables such as level of agitation,” the statement continued.
According to Hennepin Healthcare, the decision to administer sedatives was “at all times” at the “sole discretion of EMS professionals and in full accordance with emergency treatment protocols.”
Per the statement, “the stopwatch and observations was the research.”
However, Carome argues that the trial didn’t simply involve the use of stopwatches to make observations about time to sedation.
“It was a high-risk, prospective, interventional trial in which the treatment that the subjects received was determined by the research protocol,” he said, adding that eligibility for each trial was determined by paramedics based on the degree of a patient’s agitation.
According to Carome, the regulatory and ethical violations identified with respect to the ketamine trials extend to other research as well. He called Hennepin Healthcare’s persistent defense of the trials as another symptom of the long-standing 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 culture of the organization needs wholesale changes,” Carome added. “Until those changes occur, all human research at the medical center should be suspended.”
Public Citizen sent another letter to the FDA and ORHP this week, calling on the regulators to suspend all research at the medical center and impose “severe sanctions for the serious ethical and regulatory lapses that have occurred in the ketamine clinical trials and other studies.”
The letter also urges the agencies to require the Hennepin center to develop a plan to inform each subject involved about their participation in the research, “the nature of the regulatory and ethical lapses that occurred, and the steps that the center has or will take to redress these violations,” Carome explained.
Carome said feedback from the FDA on any potential actions has not been received.
In its statement, Hennepin Healthcare said it has provided formal written responses to each of the observations resulting from the inspection. It said it expects to fully address them and continue work with the FDA.
“Hennepin Healthcare has undertaken several reviews by independent experts to evaluate its research and emergency medical practices with the intent to improve our processes,” according to the statement.
These reviews and the FDA’s assessment are still ongoing.