RESEARCH IN BIOLOGICAL PSYCHIATRY - Commentary by Fred A. Baughman Jr., MD (9-27-02)

VERACARE wrote:

 ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

http://www.researchprotection.org

 Contact: Vera Hassner Sharav
 212-595-8974
 e-mail: veracare@ahrp.org
 
 FYI
 
 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.html.]


 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/articlesinpress.shtml

 
 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