According to the Wall Street Journal, the National Institutes of Health (NIH) has reversed its initial decision to prevent two of its researchers from meeting with federal investigators to comment on continuing sepsis research being funded by the organization.

The NIH is the United States’ primary governmental agency for public health research, and the largest financier of medical research in the world – channeling some $39 billion into various research programs around the country every year. Even Canadian universities are eligible for certain funding opportunities.

CLOVERS is a clinical trial sponsored by Massachusetts General Hospital, principally investigated by PETAL (prevention and early treatment of acute lung injury) Network, and funded in part by the NIH. It’s designed to test the effectiveness of vasopressors and early fluid administration in septic patients.

About Sepsis

Sepsis is the body’s extreme reaction to systemic infection. A patient is only diagnosed as septic if they demonstrate a slight (if any) drop in blood pressure (less than or equal to 100 mm Hg – normally qualifying in the healthy range for adults), an increase in respiratory rate (over 22 breaths a minute), and a change in mental status (often confusion).

The condition is commonly misidentified as “blood poisoning” – in reality it’s your own body damaging itself in a losing battle against an infection. As a case of sepsis progresses, it can decline into the much more serious state of septic shock.

Septic shock is a severe state characterized by a dangerous drop in blood pressure (under 65 mm HG without the assistance of medication) and persisting elevated levels of lactic acid in the bloodstream. Lactic acid builds up in your blood as cells continue to respire without receiving adequate oxygen supply. Most people’s familiarity with lactic acid comes from physical exercise, but any time cells fail to receive or utilize an appropriate amount of oxygen (due to exercise, infection, or heart failure) during respiration, some lactic acid is produced.

Previously, Two Doctors Prevented from Commenting

Before the NIH’s decision to reverse its stance on the issue, two doctors at the Institutes, Charles Natanson and Peter Eichacker, were prevented from speaking to federal investigators about their concerns regarding CLOVERS’ methodology.

The Office for Human Research Protections (OHRP) is one of the many long arms of the Department of Health and Human Services (HSS). The group is a federal authority tasked with protecting human participants in biomedical and behavioral research, and advising other governmental organizations regarding such matters.

Drs. Natanson and Eichacker have frequently contributed to medical research of sepsis and critical-care medications. The two initially raised their concerns about the safety and methodology of the CLOVERS study in 2018 – resulting in a poor review of the program by the consumer rights nonprofit Public Citizen.

NIH leadership stated that Natanson and Eichacker were prevented from commenting to OHRP investigators because only officials of the National Heart, Lung and Blood Institute (NHLBI) were given the authority to publicly comment on the ongoing trials.

After Pressure Mounts, NIH Leadership Buckles

Just a week after the Wall Street Journal published a report on the situation, a spokesperson for the NIH announced that the Institutes had changed its policy on the matter, and would allow Natanson and Eichacker to speak to OHRP investigators.

Natanson and Eichacker’s concerns about the CLOVERS study were chiefly related to the lack of a control group made up of patients who would receive the current standard of care.

Sepsis is currently treated with broad-spectrum antibiotics, vasopressors (medications to raise blood pressure), and plenty of IV fluids. Early detection and aggressive treatment can be important in a patient’s prognosis, as septic shock multiplies the difficulty of achieving a successful recovery several times over.

Clinical trials are conducted to evaluate the safety and effectiveness of a given drug or treatment. This is normally done in a multi-step approach that first establishes safety, then efficacy.

From a scientific perspective, “efficacy” of a drug should account for comparisons against existing methods of treatment. Assessing the effectiveness of a treatment is similar to evaluating the overall quality of anything – you can’t just compare down. If you compare me to a dog, I’m a great basketball player. But I’m not if you compare me to 1987 Jordan. Or current Jordan. Or even 14 year old me.

The CLOVERS study involved methods of treatment that involved the early administration of blood pressure medications or the generous use of IV fluids. No control group was created that would receive the standard balanced mix of antibiotics, blood pressure meds, and fluids.

Natanson and Eichacker objected to what they perceived to be a safety concern, and overall academic party foul. The study involve almost 2,500 people, which is quite a large number to not be receiving standard of care. Though not the chief purpose of control groups, they do provide the added benefit of ensuring some members of a trial will receive a recognized method of treatment.

Public Citizen wrote that, to their findings, neither of the methods under trial in CLOVERS had been previously tested in any clinical setting. None of the nearly two-and-a-half thousand participating in the study was receiving accepted treatment for a condition that, in advanced stages, kills around 40-50% it affects.

Despite Concerns, CLOVERS Trial Continues

Not only was it bad research, Natanson and Eichacker argued, it could needlessly put lives at stake. Public Citizen and others called for suspension of the CLOVERS trial until the two doctors were allowed to speak to OHRP officials, though the situation never reached that point.

A phone call to the National Institutes of Health bore no fruit – the operator was unable to tell me more about the CLOVER study or if the NIH intended to implement a control group for the study.

Dr. Michael Carome, director of Public Citizen’s Health Research Group, however, did respond to an email inquiry. It is the nonprofit’s current understanding that the CLOVERS study continues in over 50 locations across the United States, and that the National Institutes of Health had not given any indication that it intends to enforce a control group moving forward – despite the clinical trial already having entered its third phase.

Do you think the NIH should fund clinical trials with no control groups? Do you think it’s important for doctors to be able to voice their concerns? Share your thoughts with Patient Worthy!