Inspection prompts FDA shutdown: Ketamine Trial Cut Off

In July a consumer rights group, Public Citizen, with 64 doctors, bioethicists and academics, called on the US Food and Drug Administration (FDA) to investigate the Hennepin County Medical Center in Minnesota because of concerns involving informed consent. What resulted was the suspension of a clinical trial, Ketamine Versus Midazolam for Prehospital Agitation.

According to www.clinicaltrials.gov, “This research study is being done to figure out the best approach to treatment of pre-hospital agitation. It will compare two tiered dosing treatment protocols, one ketamine-based and one midazolam-based. Agitation is a state of extreme emotional disturbance where patients can become physically aggressive or violent, endangering themselves and those who are caring for them. Often chemical substances or severe mental illness are involved in this level of agitation. Specifically, the investigators are interested in studying agitation that is treated in the prehospital setting by paramedics. This study's hypothesis is a ketamine-based protocol will achieve a faster time to adequate sedation than a midazolam-based protocol for treatment of agitation in the prehospital environment. 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.”

After the FDA did an inspection of the facility between August 7 and August 23, it issued four FDA Form 483 observations. According to the FDA, an FDA Form 483 is issued to firm management at the conclusion of an inspection when an investigator(s) has observed any conditions that may constitute violations of the Food Drug and Cosmetic (FD&C) Act and related Acts. FDA investigators are trained to ensure that each observation noted on the FDA Form 483 is clear, specific and significant. Observations are made when in the investigator’s judgment, conditions or practices observed would indicate that any food, drug, device or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health.

The FDA Form 483 notifies the company’s management of objectionable conditions. At the conclusion of an inspection, the FDA Form 483 is presented and discussed with the company’s senior management. Companies are encouraged to respond to the FDA Form 483 in writing with their corrective action plan and then implement that corrective action plan expeditiously.

Apparently, the inspection raised concerns about informed consent regarding the administration of a sedative. Because the institutional review board (IRB) determined that there was minimal risk to subjects in the clinical trial, it decided to waive the informed consent. The powerful drug, ketamine, that was used in the trial, was administered to patients showing “severe agitation.”

Ketamine, a sedative most often used as an anesthetic in operations, can significantly improve symptoms in disorders such as major depression and obsessive-compulsive disorder and to be effective in pain management when administered in lower doses. When given to mice with Rett Syndrome, in which the mice show imbalances in nerve cell activity in their brain, Ketamine corrects imbalances in brain activity and improves neurological function, including breathing and reactions to sensory stimuli.

However, in the human trial, some subjects encountered breathing problems. The people running the trial said the drug was given only in cases of extreme agitation. The assessment is still ongoing.