Health Letter, September 2018
By Michael Carome, M.D.
If you’re not outraged,
you’re not paying attention!
Read what Public Citizen has to say about the biggest blunders and outrageous offenses in the world of public health, published monthly in Health Letter.
On June 15, 2018, the Minneapolis Star Tribune reported that Minneapolis police officers repeatedly requested over the past three years that emergency medical system (EMS) paramedics sedate people by injecting them with the dangerous general anesthetic ketamine, sometimes over the objections of those being drugged and in some cases when no apparent crime had been committed.
A week later, the Star Tribune exposed a far more troubling aspect to this story: researchers at Hennepin County Medical Center had conducted two high-risk clinical trials that involved testing the safety and effectiveness of ketamine compared with other potent sedative drugs for management of prehospital agitation without the subjects’ consents. The drugs being tested in these trials were injected into the subjects by Hennepin County EMS paramedics.
After reviewing the Star Tribune reports and other publicly available documents describing the two trials, Public Citizen and 64 doctors, bioethicists and academics on July 25 wrote a letter to the U.S. Food and Drug Administration (FDA) and the Office for Human Research Protections (OHRP) urging them to immediately investigate the conduct and oversight of the two prospective clinical trials.
The first trial compared ketamine with the schizophrenia drug haloperidol and was conducted from October 2015 through September 2016 on 146 unwitting subjects. That trial found that ketamine was much more likely to cause serious adverse events than haloperidol. Notably, subjects receiving ketamine were 10 times more likely to have breathing problems that required placing a breathing tube in the subjects’ tracheas.
The second trial, which compared ketamine with midazolam, began in August 2017 — well after results of the first trial demonstrating ketamine’s harms were known to the researchers — and was supposed to involve up to 420 subjects.
Eligibility for each trial was determined by paramedics based on the degree of a patient’s agitation. But the trials used a research tool to quantify agitation and a broad definition of “severe agitation,” which likely resulted in some subjects receiving these powerful drugs when they otherwise would not have. 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.
Disturbingly, these clinical trials were incorrectly determined by the investigators and the Hennepin County Medical Center’s institutional review board (IRB) — a committee charged with reviewing and approving human research and ensuring that the rights and welfare of the subjects of research are adequately protected — to involve no more than minimal risk to the subjects and, based on that determination, the IRB waived the informed consent requirements, when in fact these experiments clearly involved research-stipulated interventions that far exceeded the minimal risk threshold.
The use of ketamine in particular made these experiments high-risk. Ketamine can cause severe airway obstruction, interfering with breathing. In addition, ketamine can cause hallucinations and confusion upon awakening and abnormal heart rhythms. In fact, before the first trial testing ketamine and haloperidol began, some of the trials’ researchers had published an article about the dangers of using ketamine for agitation and advised that the drug should be reserved for patients with the most profound levels of life-threatening agitation, not those with lesser degrees of agitation, as was case in both of these trials.
Following the Star Tribune’s revelations, Hennepin suspended the clinical trial testing ketamine and midazolam on June 25. The hospital has aggressively defended these trials and has mischaracterized them as “observational studies” involving minimal risk. But the trials clearly were not observational studies and involved more than minimal risk and, as a result, failed to materially comply with key requirements of FDA and U.S. Department of Health and Human Services regulations for the protection of human subjects as well as basic ethical requirements.
The regulatory and ethical lapses in the oversight and conduct of these trials reflect colossal failures of the Hennepin County Medical Center’s human subjects protection program. The failures extend from the level of the investigators to the IRB that approved the trials to senior institutional officials. The FDA and OHRP must promptly find out whether there are other ongoing trials at this medical center with similar lapses.