Article

THE ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

April 10, 2003
Letter to the Editor
The New England Journal of Medicine

View letter as finally published in NEJ

Sir:

The April 3, 2003 New England Journal of Medicine (NEJM) issue contained an array of articles largely in support of a disputed multi-site, clinical trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI), one of the National Institutes of Health (NIH), involving critically-ill, mentally incapacitated human beings with acute respiratory distress syndrome (ARDS) – who did not give their informed consent.[i]

The accompanying editorial, "Controlling Research Trials," by Dr. J.M. Drazen,[ii] who serves on the NHLBI advisory committee that had approved the disputed trial, reveals much about the NIH attitude toward the rest of the world. As sometimes caricatured, the NIH acronym stands for "not invented here" in the sense that if the research is not endorsed by the NIH it must not be valid. Dr. Drazen suggests that, since the NHLBI – sponsored studies were invented by the NIH, no outside scientist or layperson dare question any aspect thereof on scientific or ethical grounds. This, however, is not the case. Under the Public Health Service Act,[iii] the federal Office of Human Research Protections (OHRP) has delegated oversight authority over all government-supported human research, including that undertaken by the NIH.

Dr. Drazen takes great pain to lay out the seemingly meticulous process of design, review and approval of clinical trials that would appear to validate whatever decisions the NIH reaches about the direct conduct or funding of such trials. His argument, however, fails one of the basic tests of logic, "Against the fact, there is no valid argument." The NIH history and recent record demonstrate, unfortunately, that clinical trials approved by the NIH have not always satisfied the tenets of medical ethics.[iv]

The disturbing facts that apparently caused the OHRP to question the NHLBI-sponsored ARDS study to which Dr. Drazen refers stemmed from an earlier completed ARDS Network clinical trial published by the NEJM.[v] That study measured the effects of mechanical air ventilation methods at the bracketed high and low extremes of the tidal volume range that some would argue constitutes the "best practice standard."[vi] Oddly, the study did not test either extreme against that standard. Sadly, the study’s design lacked the minimum of three measured points in the tidal volume range that are needed to establish whether the trend line is positive or negative, linear or curvilinear.

In its July 2002 complaint to the OHRP about the ARDS Network study, the Alliance for Human Research Protection (AHRP) noted that curiously the sample size of 861 was the exact value needed to satisfy the power of the test criterion of 0.85 associated with a 0.15 beta level in detecting small size effects. Dr. R. Steinbrook correctly states in "How Best to Ventilate?"[vii] that the AHRP raised "an additional issue – that the tidal volume study should have been stopped earlier, given the large difference in mortality between the two treatment groups." (p. 1398) Nothing is said, however, about the Data Safety Monitoring Board (DSMB) whose responsibility it was to monitor patient outcomes to prevent continuation of the study beyond the point that it became evident that human subjects were being placed in increased jeopardy or risk of death. Inasmuch as a disproportionate number of deaths occurred in the extreme high tidal volume arm of the study, how is it that the DSMB allowed the study to continue until the target sample size of 861 was reached? Is this not an indication that – contrary to the principles of the Declaration of Helsinki – the interests of science were allowed to supersede the life of the human subjects?

Thus far, the AHRP has not been able to obtain the answer to this question. The OHRP has requested documents that may answer this question that cuts to the ethical core of the ARDS Network enterprise. The seemingly coordinated efforts by NIH-funded investigators to undermine the legitimate oversight function of the OHRP is nothing short of astonishing. Checks and balances are at the heart of the American system of government. How can citizens participating – consciously or unconsciously – in biomedical research feel secure in knowing that the NIH seeks to put itself above the regulatory authority of the OHRP to monitor and supervise the ethics of all studies, including those sponsored by the NIH?

Sincerely,

John H. Noble, Jr., AHRP Treasurer

Vera Hassner Sharav, AHRP President

cc: Dr. Bernard Schwetz, OHRP
Dr. M. Carome, OHRP
Cong. Thomas Davis, H. Gov. Reform
Cong. Christopher Shays, H. Gov. Reform
Cong. Henry Waxman, H. Gov. Reform
Cong. Dan Burton, H. Gov. Reform
Sen. Judd Gregg, S. HELP
Sen. Edward Kennedy, S. HELP
Janet Rehnquist, HHS Inspector General
Tommy Thompson, HHS Secretary

[i] See Office of Human Research Protections, ARDS Network letters of determination following investigation: http://ohrp.osophs.dhhs.gov/detrm letrs/YR02/feb02a.pdf
http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/feb02d.pdf
http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/feb02e.pdf
http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/feb02f.pdf
http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/feb02g.pdf
http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/feb02h.pdf
http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/feb02k.pdf
http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/feb02l.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/feb02n.pdf
http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/jan02m.pdf
http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/jan02n.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/jan02o.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/jan02l.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/mar02g.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/mar02o.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/apr02j.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/apr02h.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/apr02o.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/apr02z.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/may02i.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/jun02a.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/jun02b.pdf

http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/jun02e.pdf

In a letter responding to AHRP’s complaint, Dr. M. Carome wrote: "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."

[ii] Drazen, JM. Controlling research trials. N Engl J Med 348;2003:1377-80.

[iii] See Federal Register: FR 37136, June 16, 2000 and FR 10216, March 6, 2002.

[iv] Examples of NIH research lapses in fundamental medical ethics: in 1999, the director of the National Institute of Mental Helath suspended 29 clinical trials that failed to meet ethical and/ or scientific standards. See, Marshall, E. 1999. NIMH to screen studies for science and human risks. Science. 283 (January 22): 464-465. In November, 2000, an experiment conducted on 193 children at the National Institute of Child and Human Development was suspended when it was found in violation of federal protections. See, OHRP letter of determination at: http://ohrp.osophs.dhhs.gov/detrm_letrs/nov00a.pdf .

A series of NIH sponsored genetic experiments conducted in China by Harvard researchers came under severe criticism in 2000, for failure to respect the human rights of vulnerable disadvantaged farmers. In 2002 OHRP issued several interim letters of determination. See: http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/mar02a.pdf and http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/mar02b.pdf http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/mar02c.pdf

[v] The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;166:1510-4.

[vi] Eichacker, PQ, Gerstenberger, EP, Banks, SM, Cul, XZ, Natanson, C. Meta-analysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Respir Crit Care Med 2002;166:1510-4.

[vii] Steinbrook, R How best to ventilate? Trial design and patient safety in studies of the acute respiratory distress syndrome. N Engl J Med 2003;348:1393-1401.