FDA warns Minnesota doc for running two ketamine trials without INDs, and with children and a pregnant woman
The FDA on Tuesday released a warning letter sent to a Minnesota physician who failed to exclude vulnerable populations from two clinical trials comparing the anesthetic ketamine with haloperidol and midazolam as potential severe agitation treatments.
The letter makes clear that not only did Jon Cole, emergency doc at Minneapolis’ Hennepin County Medical Center, never file INDs for the trials with the FDA, as required by law, he also didn’t write appropriate protocols to ensure that children and pregnant women weren’t enrolled, and didn’t exclude those who were under the influence of intoxicants, in whom the use of ketamine is cautioned.
The FDA, which inspected the trial sites in 2019, makes clear that the protocols for both trials “involved factors that significantly increased the risks (or decreased the acceptability of the risks) associated with the use of the drug products.”
Both protocols also required the removal of alternative treatment options from ambulances by Cole’s co-investigator, Jeffrey Ho, chief medical director for the Hennepin EMS, which the FDA said “limited the EMT-Ps’ [Emergency Medical Technician-Paramedics] clinical judgment and limited the drug interventions that were available to the EMT-Ps for administration to each subject.”
The agency makes clear that back in 2014, the FDA’s Division of Psychiatry Products informed Cole that excluding subjects who “appear to be less than 18 years old” or “obviously gravid women” were not reliable methods to exclude patients from a trial, and that his protocol should consider excluding those under the influence of various intoxicants.
Instead, one pregnant woman was enrolled in the trial studying ketamine vs. haloperidol, and two children under the age of 18 were enrolled in the trial studying ketamine vs. midazolam. And the cause of agitation was suspected drug intoxication in 133 study subjects enrolled (38%).
“Administration of the investigational drugs to these subjects placed them at significantly increased risk of the adverse events associated with the investigational products and decreased the acceptability of those risks,” the FDA said. “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.”
A Form 483 from the FDA in 2019 makes clear that the trials were enrolling patients without their consent, and serious adverse events and at least one death were not reported to the IRB in a timely fashion.
The FDA’s DPP also cautioned that ketamine should be used by or under the direction of physicians experienced in the maintenance of an airway and in the control of respiration.
However, Cole conducted both studies in the pre-hospital setting and did not put in place any specific measures to protect study participants, the FDA said. According to the published results of the ketamine vs. haloperidol trial, the intubation rate was significantly higher in the ketamine group, with 39% of subjects (25 out of 64) who received ketamine being intubated vs. 4% of subjects (3 out of 82) who received haloperidol.
Back in May 2019, Cole told the FDA that use of these investigational drugs did not significantly increase the risk or decrease the acceptability of the risk to subjects because the drugs were used “essentially in accord with their approved labeling.”
But the FDA fired back, in its call for further answers from Cole, “Your statement is factually incorrect, because none of the three drugs used in Protocols HSR 14-3841 and HSR 17-4306 is indicated to treat severe agitation or profound agitation.”
Cole did not respond to a request for comment.