Several major government-sponsored experiments conducted at major academic institutions highlight increasingly inappropriate clinical trial designs that disregard the individual survival needs of critically ill patients who cannot give or refuse consent to research. Their incapacity is exploited in experiments that increase the risk of death.
1996 – 1999: The National Heart, Lung, and Blood Institute (NHLBI) sponsored two experiments (ARMA and FACTT) involving critically ill patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Patients with ARDS require mechanical ventilation to help them breathe. During this kind of support, patients are administered tidal volumes with a ventilator to inflate their lung to deliver oxygen and remove carbon dioxide from the blood. However,
“In the 1980’s emerging research strongly suggested that although necessary for survival, if tidal volumes with mechanical ventilation were too large, the high airway pressures they produced might themselves be harmful.
A consensus conference of physicians in 1993 warned of the need to reduce tidal volumes if airway pressures were high, and recommended that physicians reduce tidal volumes when necessary to ensure that airway pressures remained below a potentially harmful level.”
Therefore, the level of ventilation pressure varies in accordance with each individual patient’s needs based on that patient’s clinical condition. One of the conundrums that medicine must accept is that human beings are not equal physiologically. In numerous areas of medicine, one treatment size does not fit all patients. There is no single magic bullet.
The ARMA experiment was conducted on 861 patients at 12 ARDSNetwork research centers at a cost of $41 million. ARMA tested two experimental lung ventilation methods and two experimental drugs; the FACTT trial compared two experimental methods of managing fluid (a “fluid-conservative” and a “fluid-liberal” approach.) Both trials were conducted by the ARDS Network of the NHLBI.
Both experiments were designed to compare mortality rate in patients randomly assigned to receive one of two treatments without regard for their individual medical needs. Both experiments failed to include a comparator control group of patients who would have received treatment in accordance with current best practice.
Patients enrolled in the ARDS Network experiments were unable to give or refuse consent. None of the consent forms informed their families that their critically ill loved-one would be withdrawn from current best therapeutic treatment and randomly assigned to a fixed ventilation setting –either low tidal volume (6mg/kg) or high tidal volume (12mg/kg) –which might increase their risk of dying. Neither were they informed that an alternative to participating in the experiment was available at the same medical center.
ARMA was published in the New England Journal of Medicine in 2000. Following its publication, critical care physician-scientists at the NIH analyzed the ARDS Network report and raised concerns about the design of the experiment in the American Journal of Respiratory and Critical Care Medicine (AJRCCM). Following the critical reviews of the ARMA trial, FACTT was suspended in 2002.
OHRP’s critique focused on the failure – of both the ARMA and FACTT trials – to include a control group that should have received current best standard care. And OHRP critiqued the IRBs for their failure to request or receive sufficient information to determine the nature of the risks for the patients.
Graver still, OHRP found serious deficiencies with the informed consent and with the institutional review board (IRB) oversight of the consent process. In each trial, one of the patient cohorts was put at increased risk of death without that risk ever being disclosed to them or to their surrogates. Indeed, the informed consent documents misrepresented the experimental nature of the trial: both fluid-management strategies in the FACTT trial were described as being “considered standard of care” in the informed-consent document – despite it being described in the protocol as experimental.
Neither the ARMA nor FACCT informed-consent documents properly explained the purpose of the research; the expected duration of the subjects’ participation; a description of the procedures to be followed; or which procedures were experimental. There were no descriptions of alternatives to participating in the trial. At nearly all the participating sites, the informed-consent documents failed to list death as one of the foreseeable risks of the research.
These two experiments demonstrate a fundamental ethical and ultimately, a scientific flaw when clinical trials with human subjects disregard individual patients’ needs – especially in patients with life-threatening conditions. An experiment that fails to incorporate a standard care control group against which an experimental treatment is compared, falls into the category of a physiology experiment such as those conducted on animals.
Read AHRP letter of complaint (July 29, 2002) about the ethics of the ARDS Network experiment; Read OHRP response to the AHRP complaint. Read Mechanical ventilation in ARDS: One size does not fit all – Editorial. American Journal of Critical Care Medicine, May, 2005
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