Is This Permissible Medical Research?

Fri, 27 Sep 2002

A federally funded experiment for the treatment of acute respiratory distress (ARDS) conducted at 12 major research centers, 1996-1999, has come under sharp criticism. The ARDS researchers sought to find a method for reducing the death rate among acutely ill patients suffering from respiratory distress by comparing two–non-standard care– methods of air ventilation. But senior scientists at the Critical Care Medicine Department of the National Institutes of Health (NIH) have published a major critique of the experiment. They criticize the study design for its failure to “use control arms that reflected the current best practice standards at the time.” They note that failure to compare the experimental (low volume) treatment to the best current standard, skewed the findings and increased risks to patients. [See: “Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome,” New England Journal of Medicine (2000, May 4), 342 (18): 1301-1308]

On July 29, 2002, the Alliance for Human Research Protection (AHRP) filed a complaint about ARDS with the Office of Human Research Protections, raising concerns about violations of informed consent and failure to suspend the study before the death toll had reached 305. [See: complaint filed with OHRP, On July 29, 2002. http://www.researchprotection.org/ethical/Koski0729.php.]

The ARDS study was suspended after data had been gathered on 861 (of a projected 1,000) patients, at which point the researchers claimed to demonstrate a 22% reduction in the death rate. But that claim is seriously disputed by critical care experts at the NIH who have published a highly critical analysis of ARDS and four other studies testing low volume ventilation. Drs. Peter Eichacker, Eric Gerstenberger, Steven Banks, Xizhong Cui, and Charles Natanson, make the case in the American Journal of Respiratory and Critical Care Medicine, that the much publicized ARDS finding has no scientific merit because it was obtained by withholding the best standard of care from patients who were exposed to less favorable treatments.

Drs. Eichacker, et al further note: “Both high and very low tidal volumes and airway pressures may be associated with increased mortality rate compared to common clinical practice.” Furthermore, “In the ARDSnet trial, the protocol not only specified ‘traditional’ high tidal volume for controls rather than current practice in the study centers, but it also restricted the physician’s ability to adjust tidal volumes unless airway pressures were very high. Overall, they suggest: "this study design may have resulted in substantial numbers of control patients receiving inferior treatment in the ARDSnet trial.” See: Eichacker, et al, “A Metaanalysis of ALI and ARDS Trials Testing Low Tidal Volumes.” http://ajrccm.atsjournals.org/cgi/search?fulltext=eichacker&volume=166&issue=11&journalcode=ajrccm

In human terms that meant that 171 patients died in the high volume treatment (Group N = 429) and 134 in the very low volume treatment (Group N = 432). It is unclear how many patients who died in the experiment would not have died, had they received standard care treatment.

An anonymous complaint in 2000, led the Office of Human Research Protections to investigate. The agency’s Feb 8, 2002, letter of findings, cited violations of federal informed consent regulations– but OHRP failed to identify or evaluate the scientific / ethical design problems that may have resulted in preventable deaths. http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/feb02l.pdf

On September 19, Newhouse News Service reported that on August 30, 2002, NIH quietly suspended another ARDS study for safety reasons. See: http://www.newhousenews.com/archive/story1b091902.html

In AHRP’s July 29 complaint to OHRP, we asked: When did the Data & Safety Monitoring Board recognize the lower mortality rate with lower tidal volumes, and why was the study allowed to continue until 861 patients were enrolled?

We also questioned whether the protocol stipulated a minimum number of deaths necessary to terminate the trial once the lower tidal volume arm had resulted in reduced mortality?

The conclusion reached by the critical care experts at NIH: “We conclude that none of these trials provides a scientific basis for the use of low tidal volumes as routine treatment or patients with ALI and ARDS.”

However, the claimed ARDS study finding was widely publicized and (probably) adopted by doctors in critical care units. How many additional patients may have died as a result of an unsubstantiated claim published in the New England Journal of Medicine?

Drs. Eichacker, et al, note: “Increased mortality rates seen with low tidal volumes may also be related to the higher doses of sedatives and narcotics necessary to maintain patient comfort, the addition of neuromuscular blockade or higher carbon dioxide levels, all of which could adversely affect hemodynamics and physiologic function.”

It is troubling that an ethically and scientifically flawed study was funded by the government, and approved by 12 institutional review boards at the most prestigious research institutions in America: Harvard University-Massachusetts General Hospital in Boston; the University of California San Francisco; the Cleveland Clinic; the University of Colorado; Duke University; the University of Maryland; Johns Hopkins University; the University of Michigan; the University of Pennsylvania; the University of Utah; Vanderbilt University; the University of Washington; Baylor College of Medicine in Houston; Baystate Medical Center, Springfield, Mass.; Louisiana State Health Sciences Center; St. Paul’s Hospital in Vancouver, British Columbia; the University of Chicago; the University of Texas Health Sciences Center, San Antonio; the University of Virginia; the University of Pittsburgh; Wake Forest University.

This case demonstrates that the absence of adequate checks and balances puts patients in clinical trials at great risks. There are no systemic safeguards to prevent those who put the interest of research above the safety of the human subjects from conducting deadly experiments.

The Alliance for Human Research Protection has been on record raising concerns about systemic failure of the current institutional review board system and its inadequacy in protecting human subjects from harmful experiments. The system fails to ensure that rigorous review precedes approval of research. Since the entire process is left to the discretion of colleagues who are almost all employees of the same institution, an inherent conflict of interest puts human subjects at increased risk of preventable harm.

For additional information about research abuses, Visit the AHRP website at: http://www.researchprotection.org