The National Institutes of Health, the U.S. government's premier health research agency, is refusing to allow two of its doctors to respond to government investigators looking into the quality of a continuing clinical trial of new blood-infection treatments on thousands of patients, according to NIH documents and multiple interviews.
The resulting tensions within the NIH have pitted the office of the agency's director, Francis Collins, against an internal NIH committee of 24 scientists, who are raising questions over the freedom researchers are afforded to critique the work of colleagues.
That freedom has long been a crucial form of quality control in the safe development of new medicines and therapies. Barring doctors from commenting on a safety inquiry curtails that freedom, the committee contends.
The NIH director's office maintains that the decision to keep the researchers from talking with investigators concerns choosing the right people to speak for the organization, not scientists' freedom to critique.
Behind the standoff is a multiyear clinical trial to be completed in 2021, a test of new procedures to treat the often-lethal bloodstream infection known as sepsis, which affects more than a million Americans each year. The trial, funded by the NIH, is known as the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis trial, or Clovers, and involves testing two treatment approaches on some 2,320 patients.
A clinical trial typically benchmarks a new treatment against an existing one, allowing researchers to assess whether the new approach improves outcomes, has little impact or makes things worse. But, among other issues, the Clovers trial didn't adequately compare the new treatment against accepted methods, raising red flags, according to critics of the trial.
At the center of the clash are two NIH doctors, Charles Natanson and Peter Eichacker, both of whom have published frequently on the topic of sepsis, medical research and critical- care medicine. Last year, they raised concerns about the way the sepsis study was being conducted, resulting in a critical report on the trial by the nonpartisan consumer group Public Citizen. The group said the Clovers study “predictably will expose many subjects to dangerous deviations from critical care.”
That publication caught the attention of the Office for Human Research Protections, a federal agency mandated with assuring American patients aren't harmed in clinical research. The OHRP launched a federal review of the clinical trial, and sought to interview Drs. Natanson and Eichacker.
NIH Director Collins's top assistant, Principal Deputy Director Lawrence A. Tabak, confirmed he prohibited the two doctors from answering questions from OHRP investigators.
The Council of the Assembly of Scientists, an internal NIH committee of 24 doctors and researchers representing the scientists on the NIH campus, wrote in a memo to Dr. Tabak that they were “extremely concerned” that the two doctors “have been forbidden by NIH leadership to respond to OHRP, either as an official duty activity or an outside activity.”
The NIH-funded clinical trial seeks to test two approaches to sepsis care.
Dr. Collins, the NIH director who is also a well-known geneticist, declined to comment. Dr. Tabak, who ordered the blocking of the two doctors' testimony, said: “The agency has the responsibility to choose people to respond on behalf of the NIH. This has nothing to do with freedom of speech.” He said Dr. Collins was aware of the decision.
James Kiley of the NIH's National Heart, Lung, and Blood Institute, which oversees the study, said, “This protocol was developed through a deliberative process and underwent multiple external, independent reviews.” All “found the scientific question important and the approach ethical,” he said. The two doctors said they were prevented from commenting for this article. OHRP Director Jerry Menikoff declined to comment.
The National Institutes of Health, a collection of 27 institutes and centers focusing on all aspects of human health, is the world's leading funder of medical research, with a budget of $39 billion annually. Most of that money is allocated as grants to academic institutions around the U.S. Funding a clinical trial like Clovers is a core part of the mission of the NIH to help drive progress toward new treatments of diseases like sepsis. A fundamental ethical concern is how to balance the potential long-term benefits of such clinical research against the immediate risks to the human subjects of the test.
One university, the Washington University School of Medicine, in St. Louis, declined to participate in the Clovers study for some of the same reasons cited by Drs. Natanson and Eichacker, according to a person familiar with the issue and email correspondence reviewed by The Wall Street Journal. Washington University confirmed it had declined to participate, but didn't specify why.
The Clovers trial continues, encompassing about 50 hospitals, although the protocol for the study has changed somewhat. The two doctors are still troubled by the study methodology making it more imperative they speak with OHRP officials, people familiar with the issue say.
Sepsis is an infection of the bloodstream that results from simpler infections, like pneumonia, urinary-tract infections or even skin infections. By the time sepsis worsens into the more dire septic shock, it causes death in about 40% of cases. An estimated 270,000 U.S. sepsis cases end in death each year.
The trial seeks to test two approaches to sepsis care, one that emphasizes early blood pressure medicine and the other offering extensive fluids. But the study's protocol didn't compare those methods to the standard protocols for sepsis treatment, Public Citizen said.
“The trial includes two experimental groups that each involve strategies for the early management of severe sepsis that to our knowledge have never been tested previously in any clinical trial,” said Public Citizen in its report.
In 2014 there were an estimated 1.7 million hospitalizations and 270,000 deaths from sepsis, an increase of 8.7% and 4%, respectively, from the prior year.
Change froma year earlier, estimated
BY THOMASM. BURTON