On June 10, 2003, a panel of experts convened by the federal Office of Human Research Protections (OHRP) heard presentations by critics who had filed complaints about $37 million government sponsored, multi-site experiment conducted by major academic institutions participating in the ARDSNetwork, and by the ARDSNet investigators who defend the trial.
The experiment tested two extreme, rarely used methods of mechanical lung ventilation in 861 critically ill, vulnerable patients suffering from acute lung disease (ALD) or acute respiratory distress syndrome (ARDS). The experiment was conducted between 1996-1999, a second ARDSNet experiment was suspended. The complaints concern ethical violations and scientific flaws in the research design that increased risk of death.
See: AHRP’s original complaint (July 25, 2002) and subsequent documents and links are on our website: http://ahrp.org/Initiatives/2328/ethicsARDS.php See also: Eichacker P, et al. 2002. Meta-Analysis of Acute Lung Injury and Acute Respiratory Distress Syndrome Trials Testing Low Tidal Volumes, Am. J. Respiratory and Critical Care Medicine, 166: 1510-1514.
The controversial experiment was conducted without legally valid informed consent. There were 305 deaths. Among the unresolved issues is how many of the subjects who died might have lived had they continued to receive standard, individualized care.
The invited critics were: 3 board members of The Alliance of Human Research Protection (AHRP)– Vera Sharav, John H. Noble, Jr, Ph.D., and Meryl Nass, MD. (Written comments were submitted); and Drs. Charles Natanson and Peter Q. Eichacker, senior critical care experts of the National Institutes of Health, and NIH statistician Steven M. Banks.
The critique by Vera Sharav focused on the ethical violations with reference to the ARDSNet informed consent documents and OHRP letters of determination. These documents reveal that informed consent was largely nonexistent at premier research institutions participating in the ARDSNetwork.
Institutional review boards (IRBs) at all academic institutions and at 24 hospital sites that had approved the experiment, failed to ensure that risks to the subjects were minimized–as required under federal regulations. These subjects were fighting for their lives.
Neither the known nor foreseeable risks were disclosed to any of the patients or their surrogates in the ARDSNet consent documents.
John H. Noble, Jr., Ph.D. critiqued the science, finding the experimental design of the ARDS trial fatally flawed: it failed to control the possible confounding effects of two or more variables that might have influenced the results of the experiment. Thus, Dr. Noble shows why the ARDSNet experiment failed to answer the question the investigators posed because they failed to test across the entire spectrum of commonly used ventilation settings in current (at the time) clinical practice. Dr. Noble offered a scientifically valid, ethical research design, including the same number of patients (861) that would answer the question: what is safest ventilation method that would increase survival rate in patients with ARDS?
Meryl Nass, MD, critiqued the clinical care provided to the critically ill subjects and the unlawful enrollment of subjects whose consent was waived. Dr. Nass raised concerns about whether enrolling in a clinical trial may degrade, rather than enhance, the care that the subject receives, and thus worsen the outcome.
She questioned whether the traditional large clinical trial, which generally focuses on and controls only a single variable, is not the best way to improve clinical practice. Perhaps we should reconsider our statistical methods, and adjust our techniques, in order to definitively resolve whether other variables may be confounding our results.
AHRP is concerned that the published ARDSNet findings in The New England Journal of Medicine could potentially jeopardize the lives of future patients, if clinicians wrongly altered standard of care on the basis of this flawed study.