Outrage of Month: Researchers Conducted Unethical, High-Risk Experiments, Violated Patients’ Rights, But Only Got a Slap on the Wrist From the FDA

Health Letter, December 2021

By Michael Carome, M.D.

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In my September 2018 Outrage of the Month column, I recounted the story about researchers at Hennepin County Medical Center (HCMC) in Minneapolis, Minn., who conducted two high-risk clinical trials that involved testing the safety and effectiveness of the anesthetic drug ketamine compared with other potent sedative drugs (haloperidol in one trial and midazolam in the second) for management of prehospital agitation without the subjects’ consent. The drugs being tested in these trials were injected into the subjects by Hennepin County EMS paramedics.

The shocking revelations about these trials were first brought to light by the Minneapolis Star Tribune. After reviewing the Star Tribune reports and other publicly available documents describing the two trials, Public Citizen and 64 doctors, bioethicists and academics in July 2018 wrote a letter to the U.S. Food and Drug Administration (FDA) and the Office for Human Research Protections (OHRP) calling for immediate federal investigations into the conduct and oversight of the two ketamine clinical trials.

Disturbingly, these clinical trials were incorrectly determined by the researchers and the HCMC 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 erroneous 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, which is not approved by the FDA for management of agitation, 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 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 the case in both trials.

Prompted by Public Citizen’s July 2018 complaint letter, the FDA in August 2018 conducted an on-site inspection of the HCMC IRB’s records related to the review and approval of the two ketamine trials, which were led by Dr. Jon B. Cole, as well as two similar trials led by Dr. Lauren R. Klein that assessed the relative safety and effectiveness of four sedating injectable drugs — haloperidol, midazolam, olanzapine and ziprasidone — in patients with agitation in the hospital emergency department setting. Then, in April 2019, FDA inspectors examined Cole’s and Klein’s research records for these four trials, which had been conducted from 2014 to 2018. Serious regulatory violations observed during these inspections were detailed in FDA inspection reports and in subsequent warning letters that the agency sent to Cole and Klein in May of this year and posted on the agency’s website on Oct. 19.

The findings described in FDA inspection documents and warning letters affirmed the allegations detailed in Public Citizen’s July 2018 complaint letter to the FDA and OHRP. The FDA found that both Klein and Cole had conducted their clinical trials without having submitted an investigational new drug application (IND) to the agency. An IND is a detailed written request to the FDA to obtain authorization from the agency to administer experimental drugs to humans in a clinical trial.

The FDA’s warning letters stated that both Cole and Klein each had previously submitted INDs to the FDA to conduct clinical trials that were “substantially similar” to the trials of the same experimental drugs that they subsequently conducted. However, the submitted INDs had been withdrawn (in the case of Cole) or placed on hold (in the case of Klein) because of serious deficiencies that posed unacceptable risks of harm to patients eligible to enroll in the proposed trials. Shockingly, according to the FDA, both Cole and Klein then proceeded to repeatedly conduct substantially similar clinical trials testing the same experimental drugs without submitting an IND and without addressing the FDA-identified deficiencies that posed unacceptable risks to subjects.

Additionally, the FDA found that both researchers and the HCMC IRB failed to comply with FDA regulations requiring informed consent for clinical trials. FDA inspectors also cited that HCMC IRB for failing to ensure that additional safeguards were implemented in the four trials to protect subjects considered to be vulnerable to coercion or undue influence.

The pattern of repetitive egregious violations by the HCMC researchers and IRB over a four-year period that was thoroughly documented by the FDA demands the most serious punishment to hold the responsible parties accountable and to deter similar serious noncompliance by others.

And yet the FDA appears prepared to let Cole, Klein and the HCMC IRB off with no more than a regulatory slap on the wrist. After receiving mea culpa letters from Cole and Klein — in which they asserted that they did not intend to be out of compliance with or violate the FDA’s IND requirements and described a series of remedial actions that they had taken or planned to take, including undergoing training on regulatory requirements for clinical trials and human subjects protections and limiting the scope of their subsequent research activities — the FDA responded on Oct. 6 with brief letters (see here and here) that stated, “We trust that the actions described in your letter will provide adequate measures to bring your site into compliance with FDA regulations.”

The regulatory and ethical lapses in the oversight and conduct of these trials represent colossal failures of the HCMC’s human subjects protection program. The failures extend from the level of the researchers to the HCMC IRB that approved the trials to senior HCMC officials. A slap-on-the-wrist approach for violations that significantly endangered the health and safety of human subjects and violated their rights will not suffice.

Therefore, on Nov. 17 we petitioned the FDA to promptly initiate serious enforcement proceedings — specifically, a formal process called disqualification — against Cole and Klein for repeatedly and deliberately violating agency regulations intended to protect human subjects. We also asked the FDA to take similar harsh action against the HCMC IRB.

If disqualified, Cole and Klein would be prohibited from conducting clinical trials testing experimental drugs or devices for a specified period of time. Likewise, disqualification of the HCMC IRB would effectively make it ineligible to review such FDA-regulated clinical trials.

Finally, and perhaps most importantly, we demanded that the FDA direct HCMC to contact the more than 1,700 patients who were unwittingly enrolled in Cole’s and Klein’s unethical experiments and inform of them that their rights were violated and their health potentially endangered by the medical center’s researchers.

There is clear evidence that Cole and Klein deliberately sought to circumvent the FDA’s IND and informed-consent requirements for human experimentation, and the case for the FDA disqualifying them and the HCMC IRB is overwhelming. Such FDA action is necessary to bring some measure of justice to the 1,700 human subjects enrolled in HCMC’s inexcusable experiments.