AHRP Questions Ethics of Acute Respiratory Distress Syndrome (ARDS) Study
Contact: Vera Hassner
Sharav, 212-595-8974, 
John H. Noble, Jr. Ph.D. 703-425-2120
July 24, 2002
Re: "Ventilation with Lower Tital 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.
March 1996 - March 1999
From March 1996 to March 1999, the University of California at San Francisco (UCSF), as part of a group of 10 universities and 24 hospitals across the country (ARDSNET), conducted a clinical trial sponsored by the National Heart, Lung and Blood Institute of NIH. The trial called for 1,000 subjects with acute lung injury and acute respiratory distress who would be treated with one of two alternative methods of mechanical ventilation to provide patients with breaths of air.
The subjects were largely critical care patients who lacked capacity to consent to a medical experiment. Two UCSF research sites were: the San Francisco County General Hospital and the UCSF Medical Center. 105 patients were recruited, of whom 89 were unable to give or withhold consent to participate in the research.
What did the researchers know before they began the study?
The expected mortality rate for patients with acute lung injury and acute respiratory distress was reported as 40 to 50 percent. In their May 4, 2000 report in the NEJM, 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.
The scientific literature includes numerous findings prior to the study:
"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... " The investigators suggested "the traditional approach to mechanical ventilation may exacerbate or perpetuate lung injury in patients with acute lung injury and acute respiratory distress syndrome..."
But this information does not appear to have been disclosed to patients and/or families when they were recruited for enrollment in the study.
By the time the study was halted (in March 1999) 861 patients across the country had been enrolled. The experiment was stopped when the death rate in the lower volume treatment group compared to that in the group receiving traditional higher volume treatment had declined by 22%: "mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent)."
Restating these findings in human terms: 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. The researchers knew beforehand from the literature the results of animal studies and uncontrolled patient case studies that the lower tidal volume treatment correlated with a lower death rate.
Was it ethical to sacrifice the lives of these 37 human beings in order to satisfy the demands of a randomized control trial?
The ARDSNET Website (www.ardsnet.org) does not provide adequate documentation as to what actually took place or how soon the differential rates of death between the two treatments were detectable. 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)
Informed Consents for March 1996 to March 1999
According to their report in the NEJM "Informed consent was obtained from the patients or surrogates at all but one hospital, where this requirement was waived." (p.1302)
Although the consent forms have not yet been obtained, it appears from a letter of determination by the Office of Human Research Protection (dated Feb 8, 2002) that the consents provided misleading information about the known risks and benefits of the two alternative treatments.
Were the informed consent forms revised at all study sites during the course of the experiment to reflect the data that had been collected?
Over the three-year period of the trial, the researchers gathered new data confirming "the results of experiments in animals and observational studies in humans" that the death rate was lower among the subjects receiving the lower tidal volume. Did 37 patients have to die to confirm a point? [NEJM, May 4, 2000, p. 1301]
August, 2000 Complaint Filed with OHRP
Approximately one year after the study was cancelled, a complaint was filed and OHRP commenced an investigation by writing to UCSF seeking answers to a set of questions. (It is not known who filed the complaint with OHRP and it is not known whether any lawsuits were filed in the San Francisco Superior Court.) http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/feb02l.pdf
Not until February 8, 2002 did OHRP write UCSF a Letter of Determination
OHRP found legal deficiencies with the consent forms:
The University of California at San Francisco informed OHRP that the consents signed by surrogates or proxies for patients who did not have the capacity to consent were legally valid under state law. http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/feb02l.pdf
Feb 21, 2002: University of California sponsored a proposed bill to amend the California Medical Experimentation Act
The bill, AB 2328, was introduced by Assembly member Howard Wayne in the California State Assembly on February 21, 2002. This amendment would overturn key aspects of the current California Medical Experimentation Act by enabling researchers to obtain "proxy consent" for patients who do not have the capacity to consent or refuse to be research subjects.
http://www.leginfo.ca.gov/pub/bill/asm/ab_2301-2350/ab_2328_bill_20020617_amended_sen.html
AB 2328 was passed in the Assembly on May 2, 2002, and was withdrawn from the Senate Judiciary committee - thereby circumventing a public hearing. AB 2328 will be voted on by the full California legislature in early August 2002.
http://www.mninter.net/~lbarry/Voices/2328.html
Trace status: http://www.leginfo.ca.gov/
Informed Consent Legal Discussion
Federal regulations governing human research protections are contained in 45 CFR 46. Section 116 sets forth informed consent requirements: "no investigator may involve a human being as a subject in research unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representatives." [45 CFR 46.116]
State or local law may require "additional information to be disclosed in order for informed consent to be legally effective." (States may add but not reduce the protections spelled out in the federal regulations).
Under the California Medical Experimentation Act, research conducted at an institution with a General Assurance from DHHS must comply with federal regulations. Research that is not federally funded and does not fall under 45 CFR 46 is subject to the California Medical Experimentation Act. This experiment was funded by the National Heart, Lung, and Blood Institute (NHLBI) and was, therefore, governed by federal regulations. Thus, in our view the consents signed by proxies were legally invalid under both state and federal law. Code of Federal Regulations: http://www.copyright.gov/title37/201/37cfr201-7.pdf
April 11, 2002 Second OHRP Letter of Determination
In response to the OHRP Feb 8th letter, UCSF made contradictory claims aimed at absolving itself from compliance with ANY law:
"OHRP acknowledges that UCSF interprets applicable California statutes and case law as authorizing the above classes of individuals to consent on behalf of a prospective subject to the subject's participation in the procedures involved in the research."
http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/apr02p.pdf
OHRP appears to have ignored entirely that this experiment was conducted in similar fashion in not one but 10 major research centers involving 24 hospitals.1
April 16, 2002 UCLA announces "Moratorium on IRB Approval of Surrogate or Proxy Informed Consent for Human Subjects Research."
The University of California Executive Vice Chancellor advised UC Deans, Department Chairs, Division Chiefs, Investigators, and Research Personnel that:
"University Counsel informed our IRB that surrogate or proxy informed consent for human subjects research is inconsistent with California law. Therefore, the IRBs have placed a moratorium on new and on-going approval of research with surrogate or proxy informed consent."
University of California counsel (for ALL campuses) further advised: "The Federal regulations for the protection of human subjects [45 CFR 46 and 21 CFR 50 and 56] require the IRBs to ensure approved human subject research meets both the Federal requirements and local law."
[See, UCLA memorandum at: http://www.oprs.ucla.edu/human/NewsLetters/041602.htm]
Federal regulations require prompt reporting of "Any suspension or termination of [research] approval" to the investigator, appropriate institutional officials, and the department or Agency head." (45 CFR 46.113)
Did the University of California notify OHRP (DHHS designated Agency head) that on advice of counsel, human research by surrogate or proxy consent was not legally permitted under California law? And did UC inform OHRP that such research had been suspended throughout the university?
Who Paid for the Hospital Care of the Patient / Subjects?
Did these subjects have private insurance coverage?
Until September 19, 2000, it was not legal to bill Medicare for hospital costs related to clinical trials. http://cms.hhs.gov/coverage/8d2.asp
Was Medicare or Medi-Cal billed for the hospital cost of this trial?
Summary of AB 2328
Authored by Assembly member Howard Wayne and introduced into the California Assembly in February, 2002 this proposed amendment has circumvented a hearing by the Senate Judiciary Committee and will be voted by the California legislature in early August, 2002. The current law does not permit proxy consent. The current law requires that the health of a patient who does not have the capacity to consent must be maintained or improved if they are to be enrolled in a clinical trial by a legally apppointed conservator or advance health directive.
The proposed amendment would do away with the requirement to maintain or improve health and do away with the requirement for consent from a conservator or an advance health directive.
University of California representatives testified before the Senate Health and Human Services Committee claimed that there are now adequate protections for patients without the capacity to consent, according to the Senate Health and Human Services Committee staff.
It is our understanding, however, from the same staff that the UC spokespersons who testified did not reveal to the Senate Health and Human Services Committee what had happened in the Acute Lung Injury and Acute Respiratory Distress Syndrome experiment.
Senator Martha Escutia (Chair); Senator Ray Haynes (Vice Chair); Carol Thomas and Stephanie Reid (Staff), Judiciary Committee (916) 445-5957
For additional information contact:
Vera Hassner Sharav, 212-595-8974,
John H. Noble, Jr. Ph.D. 703-425-2120
Visit the following websites for additional information & documents: http://www.mninter.net/~lbarry/Voices
http://www.researchprotection.org
1ARDS Network participants were: The Cleveland Clinic Foundation and MetroHealth Medical Center, Cleveland; Duke University Hospital and Veterans Affairs Hospital, Durham, NC; LDS Hospital and University of Utah Hospital, Salt Lake City; McKay-Dee Hospital, Ogden, UT; University of California Medical Center, Moffitt-Long Hospital, and San Francisco General Hospital, San Francisco; University of Colorado Health Sciences Center, Denver Health and Hospitals, Veterans Affairs Hospital, and Rose Medical Center, Denver; University of Maryland Hospital, Veterans Affairs Medical Center, Johns Hopkins-Bayview Medical Center, and Johns Hopkins Hospital, Baltimore; University of Michigan Medical Center, Ann Arbor; Hospital of the University of Pennsylvania and Thomas Jefferson University Hospital, Philadelphia; University of Washington / Harborview Medical Center, Seattle; and Vanderbilt University Hospital, Nashville. The Coordinating Center is at Massachusetts General Hospital, Boston.