THE ALLIANCE FOR HUMAN RESEARCH PROTECTION
New York, NY 10023
July 29, 2002
Greg Koski, MD, Ph.D.
OHRP Investigation of experimental treatment for Acute Respiratory Distress Syndrome. ARDSNet studies: ARMA, FACCT, and ALVEOLI (Fax from OHRP to ARDSNet)
OHRP Response to AHRP re: Surrogate Consent to Research
Other ARDS links on Ethical Violations page
Re: Research Project: N01-HR46063 Prospective, Randomized Multicenter Trial of 12 ml/kg vs. 6 ml/kg Tidal Volume Positive Pressure Ventilation and Lisofylline vs. Placebo for Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome.
Dear Dr. Koski:
A letter of determination by the Office of Human Research Protection (OHRP), dated Feb. 8, 2002, indicates that this human experiment was conducted without legally valid informed consent for at least 89 of 105 human subjects at the University of California, San Francisco – one of 10 participating university research centers.
According to the OHRP determination, consent for these subjects was obtained via surrogate or proxy "from another individual (spouse, adult child, parent, adult sibling)." However, consent obtained in that manner is contrary to both federal regulations (45 CFR 46.117) and California law (California Medical Experimentation Act).
Indeed, a memorandum (dated April 16, 2002) by the Executive Vice Chancellor of the University of California addressed to all Deans, Department Chairs, Division Chiefs, Investigators, and Research Personnel announced a "
"University Counsel informed our IRB that surrogate or proxy informed consent for human subjects research is inconsistent with California law.
Thus, it is astonishing that on April 11, 2002, OHRP accepted the disingenuous and untenable claims made by UCSF in its effort to absolve its researchers from compliance with both federal and state law. [A detailed discussion of the issues raised by the ARDS study is available at:
OHRP enumerated additional violations of informed consent requirements at UCSF – including failure "to adequately describe the reasonably foreseeable risks and discomforts·" UCSF, however, was part of a multicenter consortium – the Acute Respiratory Distress Syndrome (ARDS) – comprised of 10 university research centers and 24 hospitals. Did the UCSF informed consent documents differ from those used at the other centers? If not, all involved in this trial have disregarded federal informed consent requirements.
Furthermore, OHRP failed to address a fundamental ethical violation underlying this experiment. The ARDS researchers indicated that before the study was initiated they knew that animal studies and uncontrolled case studies with patients showed that the smaller rather than larger breaths of air (lower tidal volume) was correlated with a lower death rate for patients.
"Uncontrolled studies suggested that the use of a lower tidal volume would reduce mortality in patients with acute lung injury and acute respiratory distress syndrome… " [See, "Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes·NEJM, 2000; 342: 1301-8]
But this information does not appear to have been disclosed to patients and/or families when they were recruited for enrollment in the multicenter study.
The study was suspended after data had been gathered on 861 (of a projected 1,000) patients, at which point the researchers could demonstrate a 22% reduction in the death rate. In human terms that meant that 171 patients died in the higher volume treatment (Group N = 429) vs. 134 in the lower volume treatment (Group N = 432). The additional 37 patients who died in the higher volume treatment would not have died, had they received the lower volume treatment.
Was it ethical to sacrifice the lives of these 37 human beings in order to satisfy the demands of a randomized control trial?
In face of the detected small size treatment effect (d = 0.1818) of the experiment, 861 is the exact number required to achieve the magical 0.85 power of the test needed to avoid the Type II statistical error of falsely accepting the null hypothesis that the detected treatment effects were the result of chance with a probability of 15 in 100.
It seems to us that this experiment violates the Nuremberg Code standards, The Declaration of Helsinki, and federal regulations which require that in every experiment involving human subjects: "Risks to subjects are minimized·" (45 CFR 46.111)
We are disheartened that the lessons of the Tuskegee Institute Syphilis Study and the complicit involvement of the U.S. Public Health Service in that egregious experiment have not been absorbed by some researchers, though Tuskegee has left an indelible stain on Americaâs collective conscience. This is, as they say, a moment of reckoning for OHRP. The Office can use its authority to come down hard on those who violate the federal regulations and exploit the vulnerability of incapacitated patients who cannot refuse to be research subjects. By enforcing federal regulations OHRP would demonstrate that the life safety of human subjects DO receive the highest OHRP priority. If OHRP looks the other way, it will be complicit in undermining the public trust in the biomedical research enterprise and the viability of federal oversight. Your leadership is urgently needed at this critical juncture.
Among the issues that require investigation are the following:
When did the Data & Safety Monitoring Board realize the lower mortality rate with lower tidal volumes, and why was the study allowed to continue?
Did the protocol or other research design include a minimum number of deaths necessary to terminate the trial once the lower tidal volume arm had resulted in reduced mortality?
What actions has OHRP taken or will it take to ensure that the research community does not disregard basic human rights with impunity?
As you know, the Alliance for Human Research Protection is a citizensâ watchdog organization concerned with unethical conduct in research involving human subjects. We urge you to consider our concerns an urgent matter that should be promptly addressed.
Vera Hassner Sharav
John H. Noble, Jr. Ph.D.
cc: Dr. Bernard Schwetz, Commissioner, FDA