AHRP Letter to the editor re: editorial ARDS trial


AHRP Letter to the editor re: editorial ARDS trial
July 10, 2003. The New England Journal of Medicine. Volume 349:188-192 Number 2
http://content.nejm.org/cgi/content/extract/349/2/188

Note: The April 3, 2003 the NEJM contained an editorial in support of a controversial multi-site, clinical trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI), one of the institutes of NIH. The experiment failed to compare an experimental method against a control group using standard of care. Instead, non-consenting, critically- ill, incapacitated human beings with acute respiratory distress syndrome (ARDS) were subjected to one of two rarely used experimental methods that increased mortality risk compared to ARDS patients treated in routine practice. AHRP submitted a letter to the editor on April 10: See: http://www.ahrp.org/ahrpspeaks/ARDSletterNEJ041003.php

When asked by the NEJM to shorten it to 175 words, we did. However, contrary to assurance that 4 reference notes were acceptable, the published letter was sanitized – the reference note citing documented cases of ethical violations at NIH was deleted. *

Below are two other letters critical of the editorial and Dr. Drazen’s reply

Protection of Research Subjects

To the Editor: Drazen takes great pains to lay out the seemingly meticulous process of design, review, and approval of clinical trials that would appear to validate whatever decisions the National Institutes of Health (NIH) make about the direct conduct or funding of such trials. His strong suggestion that the OHRP should back off from questioning an ARDS study sponsored by the National Heart, Lung, and Blood Institute is nothing short of astonishing. The historical and recent records demonstrate that clinical trials approved by the NIH have not always satisfied the tenets of medical ethics and, therefore, are very much in need of independent monitoring and supervision.[1] Checks and balances are at the heart of the U.S. system of governance. If the OHRP’s independent oversight authority[2,3] were to be disregarded, how could citizens participating – consciously or unconsciously – in biomedical research feel secure about their lives and safety?

John H. Noble, Jr., Ph.D.
Vera H. Sharav, M.L.S.
Alliance for Human Research Protection
New York, NY 10023

References

1. Marshall E. NIMH to screen studies for science and human risks. Science 1999;283:464-465.[Full Text]

2. Department of Health and Human Services, Health Resources and Services Administration. Delegation of authority. Fed Regist 2000;65:37136-37136.

3. Department of Health and Human Services. Amendment of statement of organization, functions, and delegations of authority for the Office of Human Research Protections. Fed Regist 2002;67:10216-10216.

* Deleted reference note: Recent NIH research lapses in medical ethics include: (1) 29 clinical trials suspended in 1999 by the director of the National Institute of Mental Health for failure to meet ethical and/or scientific standards. (See Marshall, E. NIMH to screen studies for science and human risks. Science 283;1999:464-5); (2) An experiment involving 193 children in violation of federal protections was suspended by the National Institute of Child and Human Development in November 2002 (See OHRP letter of determination at: http://ohrp.osophs.dhhs.gov/detrm_letrs/nov00a.pdf ); (3) As determined by the OHRP, 23 ARDS Network sites failed to describe adequately the reasonably foreseeable risks and discomforts of the research (See Carome, M. Letter at: http://www.ahrp.org/ethical/CaromeARDS082802.php ). (4) NIH sponsored genetic experiments conducted by Harvard in rural China were criticized for human rights violations. (See OHRP letters:
1. http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/mar02a.pdf
2. http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/mar02b.pdf
3. http://ohrp.osophs.dhhs.gov/detrm_letrs/YR02/mar02c.pdf


To the Editor: I disagree with Drazen’s assertion in his editorial (April 3 issue)[1] that the assessment of the scientific merit of a study is outside the purview of the Office of Human Research Protections (OHRP). IRBs are empowered by the federal government to review research in accordance with the Belmont report.[2] The OHRP requires IRBs to determine whether the risks are reasonable in relation to the anticipated benefits.[3] Indeed, the risks cannot be assessed without judgment of the science, since no level of risk is justifiable if the scientific design is unsound.

Drazen also criticizes the OHRP for taking excessive time to collect data and make a decision, yet any scientist would be remiss in drawing a conclusion without seeing the data. Speed and efficiency are not virtues of either high-quality research or the protection of human research subjects.

The OHRP and IRBs should not be damned for doing precisely what they were created to do. Impatience to get on with clinical research must be tempered with cautious review to ensure the safety of research subjects. Like democracy, the process is inefficient but effective.

William J. Tremaine, M.D.
Mayo Foundation Office of Human Research Protection
Rochester, MN 55905

References

1. Drazen JM. Controlling research trials. N Engl J Med 2003;348:1377-1380.[Full Text]

2. The Belmont Report: ethical principles and guidelines for the protection of human subjects of research. Washington, D.C.: Government Printing Office, 1978. (DHEW publication no. (OS) 78-0012.)

3. Code of Federal Regulations, title 45A, part 46.111: criteria for IRB approval of research. (Accessed June 20, 2003, at http://www4.law.cornell.edu/cfr/45p46.htm.)


To the Editor: Drazen’s criticism of the OHRP (formerly the Office for Protection from Research Risks [OPRR]) for excessive meddling in clinical research contrasts with our own experience. The OPRR on two occasions failed to address complaints from IRB members about financial conflicts of interest in a clinical trial at the Fred Hutchinson Cancer Research Center, in Seattle, in which it appears that all 85 patients died, including many who were told they had a 50 percent chance of cure. Research was conducted without IRB approval, NIH rules were ignored, IRB minutes were forged, IRB requests were ignored, the IRB was lied to by top staff members of the research center, patients were deceived, and known risks were ignored. The Seattle Times published a detailed, documented, award-winning series on this abuse in March 20011 showing that the OPRR never conducted an investigation when it issued a report stating that no wrongdoing by the research center was substantiated. Even now, the OHRP refuses to investigate. The NIH has many rules for protecting patients involved in research. However, like speed limits without police, they are blatantly ignored by some researchers. Physicians do themselves no favors by continuing to pretend that all is well.

John M. Pesando, M.D., Ph.D.
Pacific Technology Associates
Seattle, WA 98102

References

1. Wilson D, Heath D. Uninformed consent: investigative series. Seattle Times. March 11-15, 2001.


Dr. Drazen replies: Pesando cites an example of a case in which the now-closed OPRR of the NIH failed, in his opinion, to intervene in a situation in which there was blatant disregard for the process of appropriate oversight of protections for human research subjects. This office has been replaced by the OHRP, which is not part of the NIH. The OHRP has established a record of enforcing strict compliance with regulations concerning the performance of trials involving human subjects.

Tremaine takes issue with both my position that the OHRP does not have the resources to review the scientific merits of a clinical trial and my concern about the timeliness of the OHRP response. Noble and Sharav argue that there needs to be oversight of clinical research. It is in everyone’s best interest to have redundant and complementary checks and balances in clinical research. However, as I stated in the last paragraph of my editorial, the process needs to be responsive and open. If the common goal is to fulfill the key tenet of the Belmont report that the risks involved in research are reasonable in relation to the anticipated benefits, then there must be a mechanism for rendering a final decision on a trial in question in an open, appropriate, and timely fashion.

In a given research trial, if there is concern that the standard of reasonable risk is not met, then it stands to reason that experts in the field of study who are not associated with the trial – that is, those who are familiar with both the risks and the benefits of the research and who are dispassionate with respect to the specific performance of the research trial – are those best qualified to make this determination. As detailed by Steinbrook, this was the procedure followed by the NIH with the advice and consent of the OHRP. Despite the unanimous opinion of the panel that the standard had been met, the OHRP has decided to ignore the view of those who are most qualified to judge the risks and benefits of the research and has continued to prevent this critical work from going forward. The tragedy is that physicians caring for many patients, such as those infected by the severe acute respiratory syndrome (SARS) – associated coronavirus, are continuing to base their care on guesses rather than facts. Who are we protecting and from what risk?

Jeffrey M. Drazen, M.D.