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Federal Regulators Must Halt Unethical, Reckless Sepsis Trial Funded by NIH

Clinical Trial Exposes Subjects to Grave Dangers, Is Like ‘Experiment That Would Be Conducted on Laboratory Animals’

WASHINGTON, D.C. – An ongoing clinical trial involving seriously ill sepsis patients is deeply flawed, riddled with serious regulatory and ethical lapses, and must be stopped, Public Citizen said today in a letter (PDF) to the federal government.

In the experiment, patients are being given one of two treatments for sepsis, both of which are risky and neither of which is considered standard treatment. Because no other group of patients in the trial is receiving the usual treatment for sepsis, researchers can’t ensure that the experiment isn’t causing increased deaths and organ failure. Sepsis is a life-threatening condition in which bacteria or their toxins get into the bloodstream, causing shock and organ failure.

The goal of the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis trial (CLOVERS) is to determine whether one of the two highly unusual treatments results in more patient deaths.

“The design of this disturbing trial is more akin to an experiment that would be conducted on laboratory animals,” said Dr. Michael Carome, director of Public Citizen’s Health Research Group. “These human subjects are unwitting guinea pigs in a physiology experiment that will not advance medical care for sepsis and likely will harm many.”

Sixteen institutions (PDF) currently are running the trials, including Ronald Reagan UCLA, University of Colorado Hospital, Cleveland Clinic Foundation, Beth Israel Medical Center and Vanderbilt University Medical Center. Stanford University Hospital, Mount Sinai Hospital and 26 other institutions are listed as study sites but have not yet begun enrolling patients. CLOVERS researchers plan to enroll up to 2,320 subjects by the trial’s projected completion in March 2021. (A complete list of participating institutions is in the letter.)

Public Citizen’s letter urges the U.S. Department of Health and Human Services’ Office for Human Research Protections (OHRP) to immediately terminate CLOVERS. The trial is being funded by the National Heart, Lung, and Blood Institute (NHLBI) through its Prevention and Early Treatment of Acute Lung Injury (PETAL) Network.

In analyzing the design of CLOVERS, Public Citizen was advised by two internationally recognized experts on sepsis and septic shock at the National Institutes of Health’s Clinical Center.

During usual care for early sepsis, doctors adjust the doses of intravenous (IV) fluids and blood pressure-raising medication based on each patient’s needs. But in CLOVERS, half of the sepsis patients will receive predominantly IV fluids and the other half will receive predominantly blood pressure-raising medication. Because researchers aren’t treating a third group of patients with the usual care, they can’t adequately determine if either of the experimental treatments is too unsafe to continue using. What’s more, they will have no way to draw any usable conclusions from CLOVERS because they won’t know how the experimental treatments compare to the usual treatment.

Public Citizen’s analysis showed that because CLOVERS fails to account for how current usual care varies from patient to patient, based on the severity of sepsis, each of the experimental approaches CLOVERS uses will expose many subjects to unacceptable dangers.

“The misalignments in CLOVERS between individual patients’ needs and treatments being given as part of the experiment are far outside the norms of sepsis treatment,” Carome said. “It is obvious they carry an unacceptable increased risk of organ failure and death and should be avoided.”

Public Citizen also identified serious deficiencies in the consent form for CLOVERS, including a failure to explain to patients the true experimental nature and risks of the two approaches being tested in the trial.

Public Citizen is calling for a moratorium on all other current PETAL Network clinical trials and any other NHLBI-funded clinical trials testing interventions in critically ill subjects until the multiple systemic breakdowns that permitted CLOVERS to be approved are fully understood and corrected.

“The fact that this trial successfully passed through multiple levels of review and was approved by officials at the NHLBI and the PETAL Network’s institutional review board is yet another troubling example of the dysfunction – at multiple levels – of the U.S. system for protecting human subjects enrolled in complex clinical trials,” said Carome.