From: "VERACARE"
To: "Dr. Bart Campbell"
Subject: RE: AHRP Response to criticism re: fatal ARDS lung experiment
Date: Tue, 1 Jul 2003

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)
http://www.ahrp.org
Contact: Vera Hassner Sharav
Tel: 212-595-8974

Dear Dr. Campbell,

In response to your objection to AHRP's June 26 Infomail about our testimonies criticizing the ARDSNetwork experiment that tested two mechanical tidal volume ventilation settings in critically ill patients with ARDS, we note the following:

First, you wrote: The trial did not, as alleged, "test two extreme, rarely used methods of mechanical lung ventilation"...

AHRP response: The experimental method used low tidal volumes (6ml/kg) which were shown in at least one survey to only be used by no more than 3% of treating physicians--that's extremely rare.

The other arm of the trial, referred to as the control, used 12 ml/kg TV and often plateau pressures higher than 35 although the ARDS literature is fairly clear that such pressures, though they may not necessarily be associated with grossly visible barotrauma, have resulted in higher mortality rates. The 1995 Washington Manual warned that ARDS patients might need TVs lower than other ventilator patients, who would often be started on 10-12 ml/kg. (The ARDSnet trial began in 1996.) Simply put, the control value chosen (12 ml/kg TV) was not the gold standard treatment (or the standard of care) it should have been.

As we note in our testimonies, the ARDSNet experimental design failed to include tidal volumes "in the range wherein 77 percent of ARDSNetwork study center practice was occurring prior to random assignment into one or other of the two extremes."

Prior to enrollment in the ARDSNet experiment, patients had been under the care of pulmonologists at leading institutions such as yours, Dr. Campbell. Indeed, Vanderbilt University, with which you are affiliated, is the primary ARDSNetwork center.

It is significant that only 20% or less of ARDS patients received 12 ml/kg tidal volumes in clinical practice. But in the ARDSNet trial, 80% of patients randomized to the 12ml/kg control arm, had their tidal volume raised to meet the protocol requirements--in some patients TV were doubled. In accepted clinical practice TV would not be raised without medical justification.

Second, you wrote: "the subjects...were fortunate to be in a trial that clearly lessened mortality in the treatment group...."

AHRP response: On the contrary, patients who declined to participate were the fortunate ones as they had a lower mortality rate than both arms of the ARDSNet trial. Furthermore, those patients who were unlucky enough to have been randomized to receive 12ml/kg TV had a 40% mortality rate compared to 30% of those who declined.

Even the ARDSNet investigators acknowledged: "...critically ill eligible patients who participated in this trial did not fare better overall than eligible patients who declined to participate."

[See: Krishnan JA, Hayden D, Schoenfeld D, Bernard G, Bower R (for the NHLBI ARDSNetwork Investigators). Outcome of participants vs eligible nonparticipatns in a clinical trial of critically ill patients. [Abstract] American Journal of Respiratory Critical Care Medicine, 2000, 161:A210.]

Third, you justified surrogate consent to research involving critically ill patients, stating "surrogate consent was commonly accepted (just as it was in providing standard care for potentially life-saving therapies in those whose loved ones gave surrogate consent)."

AHRP response: Dr. Cambell, you are blurring the issue between surrogate consent for treatment which is to provide needed treatment for the benefit of critically ill patients with the entirely different issue of surrogate consent for research. The ARDSNET experiment put critically ill patients at increased risk of death--as the survival rates of those who refused demonstrate.

Furthermore, in the case of the ARDSNet experiment, some "surrogates" turned out to be hospital employees such as social workers, not "loved ones." At least one institution's IRB waived informed consent entirely for 16 subjects.

Fourth, you wrote, "Surrogates of these desperately ill people were informed of the risks of ARDS..."

AHRP response: The informed consent documents which AHRP examined and the OHRP letters demonstrate the contrary. In our testimonies we cite specific "sins of omission and sins of commission."

For example, "In all cases the consent documents failed to disclose to patients and surrogates the experimental nature of the ventilation procedures used. In all cases, the informed consent documents "failed to adequately describe the reasonably foreseeable risks and discomforts " of either arm of the ventilation experiment. Namely, the potential for dyspnea, agitation, need for higher doses of sedatives and paralytics, volume overload, and hypernatremia associated with the low tidal-volume; and the risk of exacerbating or perpetuating lung injury, risk of pneumothorax, and increased risk of nonpulmonary organ or system failure in the high tidal volume arm." See: http://www.ahrp.org/ARDSpages/ARDSindex.php

Indeed, OHRP's letter to AHRP (Aug. 28, 2002) states: "In reviewing the above letters, you will note that in all cases OHRP found that the informed consent documents approved by the institutional review boards (IRBs) for the research failed to describe adequately the reasonably foreseeable risks and discomforts of the research." See: http://www.ahrp.org/ethical/CaromeARDS082802.php

As we note in our testimonies, in some cases grossly inaccurate information was provided in the informed consent document, misleading subjects and surrogates with false statements such as: "...both treatment groups have been extensively tested and been associated with a four-fold increase in survival for patients with severe lung disease." See AHRP testimonies:
http://ahrp.org//testimonypresentations/ARDSNet0603/sharav.html
http://ahrp.org//testimonypresentations/ARDSNet0603/noble.html
http://ahrp.org//testimonypresentations/ARDSNet0603/nass.html

As noted by OHRP the ARDSNet consent process was coercive in nature. See: http://www.ahrp.org/ARDSpages/ARDSindex.php

Fifth, you state, "Society is greatly benefited by this study and the ARDSNet."

AHRP response: How could society benefit from a trial that increased mortality rates? How could society benefit from a human experiment that provided no useful information to guide clinicians in selecting the safest method of ventilating the lungs of ARDS patients?

The researchers, who were using human subjects, had an obligation to design the trial in such a way that the controls were assigned the best alternative treatment, and had a legal and ethical obligation to obtain proper informed consent. It was not their role to decide that the laws governing human subject research should be changed for the good of society, and thus act accordingly.

Finally, AHRP agrees with your statement, "We must take great care to serve well those who put their trust in us." AHRP believes that performing research on human subjects is a privilege and requires the highest ethical and medical standards. In this particular case, both appeared to be lacking.

Meryl Nass, MD, board member

Vera Sharav, President

John H. Noble, Jr., Ph.D, board member

-----Original Message sent to AHRP---

From: Dr. Bart Campbell
Sent: Friday, June 27, 2003
Subject: AHRP Testimonies re: Fatal ARDS lung experiment

AHRP provides a service to humankind by offering alternative viewpoints in research and bioethics. However, as a practicing cardiologist with extensive experience in caring for parients afflicted with acute respiratory distress syndrome (since it was described and named by my mentors, Tom Petty and David Ashbaugh), I must object to AHRP's vilification of the ARDSNet report in the May 4,'00 NEJM. Several AHRP allegations are totally devoid of veracity. The trial did not, as alleged, " test two extreme, rarely used methods of mechanical lung ventillation" but compared instead (and for sound reasons) the traditional (and most widely used) method of ventillation in these extremely ill people to a lower ventillatory volume method. The question; "how many o f the subjects who died might have lived had they continued to receive standard, individualized care" suggests the study resulted in adverse outcomes when in reality, mortality in the group that did not receive "standard" care had a mortality strikingly lower that any of the five trials in the Eichacker et al post hoc meta-analysis. The conclusion that "the published ARDSNet findings in The New England Journal of Medicine could potentially jeprodize the lives of future patients" could not be further from the truth. This was a necessary and landmark trial that is likely to significantly lessen mortality in a catestrophic condition that has for many years claimed an extremely high mortality. These "subjects were (indeed) fighting for their lives" and were fortunate to be in a trial that clearly lessened mortality in the treatment group.

Regarding the allegation that the trial was ethically flawed, AHRP is technically correct that some patients did not have "legally valid informed consent". As IRB chair in a State that does not provide a law validating surrogate consent, I have had great concern about patients who are too ill to give consent for trials that might provide significant benefits. Prior to OHRP's decision that there was no way to include these patients, surrogate consent was commonly accepted in such States (just as it was in providing standard care for potentially life-saving therapies in those whose loved ones gave surrogate consent). Unfortunately, until a law is in place providing access, these people cannot participate even when their caregivers (and loved ones) realize they are, in some cases, being denied access to potentially life saving therapies. Is this ethically appropiate? The allegation by AHRP that "informed consent was largely nonexistent" and "Neither the known nor foreseeable risks were disclosed to any of the patients or their surrogates is simply not true and is inflammatory. Surrogates of these desparately ill people were informed of the risks of ARDS and of the high liklihood of not surviving. They are fortunate to have the study available to them.

The ARDS investigators are to be congratulated, not castigated. Society is greatly benefitted by this study and the ARDSNet. We must support them and urge them to get on with the business of reducing mortality in this dread disease. AHRP is right to ask us to think carefully about the ethical nature and validity of research. We must take great care to serve well those who put their trust in us. In this instance however, AHRP has sadly missed the mark.

W. Barton Campbell