HHS Will Review Watchdog Group's Call to Halt 'Risky' Sepsis Trial

Marcia Frellick

August 31, 2018

The watchdog group Public Citizen is calling for the immediate end to a phase 3 National Institutes of Health (NIH) trial testing two treatments for sepsis, citing "serious ethical and regulatory lapses related to the design and sample consent."

In a letter written August 28 to the US Department of Health and Human Services (HHS) Office for Human Research Protections, the group charged that the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial "is deeply flawed and exposes subjects to unacceptable dangers, included increased risks of organ failure and death."

Patients in the trial get one of two treatments, "both of which are risky and neither of which is considered standard treatment," Public Citizen writes. "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."

Also, because there is no usual treatment group, the researchers will not learn whether the treatments are better than the current standard, Public Citizen writes.

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

Public Citizen also cited "serious deficiencies" in the consent process, and they say patients will not truly understand the risks of the approaches and the "experimental nature" of the trial.

HHS to Review

HHS spokesperson Diane M. Gianelli told Medscape Medical News in a statement, "The Office for Human Research Protections plans to review the allegations."

Public Citizen wrote another letter on August 29  to the institutional review board (IRB) at Vanderbilt University Medical Center in Nashville, Tennessee, that approved the trial (according to Public Citizen based on a report in the publication STAT) and asked that the IRB immediately suspend the trial.

Vanderbilt's representatives did not respond to a request for an interview, but a spokesperson referred Medscape Medical News to a CLOVERS coinvestigator, Nathan Shapiro, MD, MPH, from Beth Israel Deaconess Medical Center in Boston, Massachusetts.

Shapiro told Medscape Medical News in a statement, "This study compares two approaches for the treatment of septic shock that are both currently in widespread use. Our study will provide clinicians with authoritative data on which approach leads to better patient outcomes. The study protocol was designed by expert clinicians in emergency and critical care medicine representing nearly 50 hospitals in the United States and follows a well-accepted design.

"To ensure that the study meets the highest scientific and ethical standards, the study was thoroughly reviewed by an independent protocol review committee and a Data Safety and Monitoring Board appointed by the National Heart, Lung, and Blood Institute (the study's funder), and a central Institutional Review Board before the study began."

Recruitment began in March for the trial, which aims to enroll up to 2320 patients at 44 US hospitals and other medical sites.

Ethicist Says Trial Not Necessarily Flawed

Savitri Fedson, MD, an associate professor in the Center for Medical Ethics and Health Policy at Baylor College of Medicine in Houston, Texas, told Medscape Medical News that Public Citizen's claim that the trial can cause harm "cannot be well-validated."

She said the reason there is no control group is that there is currently no accepted gold standard for treating sepsis.

"There is no clear one way to do this," she said. "There doesn't seem to be a lack of clinical equipoise."

While having no control group is a limitation and can affect the generalizability of the results, she said, it's not necessarily a flaw.

As to what will be possible to conclude in the end — and even though this trial won't show how these treatments compare to usual care — Fedson said "arguably what it may do is prove that what is being done by 30% of the people is as good as what is being done by another 30% of the people, so it may just give weight to the consensus."

Getting consent for septic patients or any critically ill patient is always going to be a concern, she said, because investigators are explaining complex subject matter to someone severely ill and because their surrogates are under emotional distress.

She said Carome's description of the trial participants as "unwitting guinea pigs" is "rather harsh. I think that's probably an exaggeration."

However, the controversy surrounding this trial may call for the data and safety monitoring board to evaluate findings at an earlier point, she said.

"If there's any question, you stop enrollment and stop the trial," she said.

Fedson has disclosed no relevant financial relationships.

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