OHRP Found NHLBI Lung Experiments Violated Informed Consent

OHRP Found NHLBI Lung Experiments Violated Informed Consent

Mon, 7 Jul 2003

On July 3 the federal Office of Human Research Protections (OHRP) issued a stinging indictment of the research review and approval process at some of the nation’s most prestigious research institutions–including the National Heart Lung and Blood Institute (NHLBI). http://ohrp.osophs.dhhs.gov/detrm_letrs/YR03/jul03a.pdf

[The retirement of Dr. Claude Lenfant, director of NHLBI was announced the same day. See: http://www.ahrp.org/infomail/03/07/03.php]

OHRP investigated two controversial NHLBI-sponsored lung experiments conducted by the 12 ARDSNetwork research centers. The first experiment tested two experimental lung ventilation methods and two experimental drugs (ARMA, published in the New England J of Medicine, 2000). The second trial tested two experimental methods of managing fluid (FACCT suspended 2002) Critically ill, incapacitated patients suffering from acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) were the subjects.

OHRP found that the researchers and institutional review boards (IRBs) at the prestigious academic research centers violated fundamental medical ethics principles that are supposed to protect patients who are enrolled as human subjects of medical research. The lives of patients in one of the two experimental groups in each trial were put at increased risk of death. But that risk was not disclosed to subjects or the surrogates who consented on their behalf.

“OHRP finds that in order to have determined whether the risks to the subjects were minimized and reasonable in relation to the anticipated benefits, if any, to the subjects and the importance of the knowledge that may have reasonably been expected to result, the IRBs should have received information adequate to assess the risks and potential benefits of each of the interventions for each arm of the ARMA trial relative to concurrent routine clinical practice outside of the research context.”

Informed consent requirements were violated with impunity by ARDSNet investigators and the IRBs failed to perform their duty under federal regulations: IRBs failed to review and justify the research design; failed to assess the increased risk of death in one of the experimental interventions; failed to justify the lack of a control arm using routine standard of care; approved the experiments and the consent documents without regard for the subjects’ rights and safety and without regard to the documents’ veracity.

OHRP validated the criticism expressed by the Alliance for Human Research Protection (AHRP) about flagrant violations of the informed consent process. Among the numerous substantive informed consent violations noted by OHRP: the ARDSNet consent documents failed to describe the purpose of the research, the nature of the experimental design, or to disclose the risks and alternative standard treatment. OHRP’s letter states:

“at nearly all study sites the informed failed to include death as one of the risks of the research.” OHRP called the consent documents in the FACTT protocol “misleading and inaccurate.”

Indeed, the ARDSNet consent documents failed to disclose to patients enrolled in the FACTT experiment (or to their surrogates) that: “the actual risks involved with the application of the specific fluid liberal and fluid conservative management strategies possess [sic] potential risks, in that these specific strategies have not been tested in patients previously.”

OHRP validated the criticism by Drs. Peter Eichacker* and Charles Natanson, senior NIH critical care physicians / researchers, finding that a patient enrolled into the trial “could have a higher risk of death depending on which of the experimental groups he or she was assigned to, in comparison to other experimental groups and in comparison to not entering the trial and thereby receiving individualized care based upon the best clinical judgment of the subject’s physicians.”

OHRP’s findings validate AHRP’s criticism about the inability of the current research protection system to protect vulnerable human subjects from over zealous researchers. Of particular concern is the culture of arrogance and utilitarian ethics that has engulfed the academic research community. In response to OHRP’s October 7, 2002 letter questioning the statement in the consent documents that mischaracterized the experimental nature of the fluid management methods used as “standard of care” the ARDSNet replied: “we agree that this phrase is suboptimal. While the specific interventions in the management strategies are considered standard of care, the actual strategies themselves are experimental.”

The ARMA and FACTT experiments reveal that prestigious research institutions and NIH are conducting human experiments by violating the spirit and the letter of the law of informed consent. Officials from NIH and the New England Journal of Medicine (that published the ARMA trial) orchestrated a defense of the ARDSNet experiments as though the interests of science override patient safety.

OHRP’s letter notes: “almost all of the consultants engaged by OHRP opined that risks to subjects participating in the ARMA [and FACTT] trial were minimized and reasonable in relation to anticipated benefits to the subjects and the importance of the knowledge that was expected to result.” “OHRP believes, however, that the interests of future human subjects would be served best by further discussion within the scientific and bioethics communities about issues regarding appropriate research design…”

AHRP agrees, as did the Maryland Court of Appeals when it noted: "the scientific and medical communities cannot be permitted to assume sole authority to determine ultimately what is right and appropriate in respect to research projects involving children.” AHRP argues that incapacitated adults such as those in the ARDSNet trials were similarly helpless.

OHRP is to be commended for defending the human rights of research subjects. However, unless a law is passed backed up with enforcement mechanisms, incapacitated patients admitted to a hospital affiliated with a research center are currently at risk of being withdrawn from standard care and enrolled in a research protocol whose experimental interventions are not ethically or scientifically justified.

See AHRP website for ARDSNet related links and documents, including AHRP testimonies of June 10, 2003. Of note, Dr. John Noble’s testimony provides a statistically sound method for testing to find the best ventilation method while controlling for possible confounding effects of two or more variables that might have influenced the results of the experiment–such as was not done by the ARDSNet investigators.

Congress should investigate how NIH misspent $37 million of taxpayer money. The ARDSNet experiments violated medical ethics and legal standards: they also failed to yield any useful information to improve clinical care of patients with ARDS.

See: Eichacker P, et al. 2002. Meta-Analysis of Acute Lung Injury and Acute Respiratory Distress Syndrome Trials Testing Low Tidal Volumes, Am. J. Respiratory and Critical Care Medicine, 166: 1510-1514; Letters by Parshuram C. and Echacker P, Banks SM, and Natanson C in same journal, 2003, Vol 167: 798-800.

For a list of participating ARDSNet centers, see: http://www.ahrp.org/ARDSpages/ARDSNetMembers.php