US transplant study may have violated federal rules

BMJ 2016; 355 doi: (Published 04 November 2016) Cite this as: BMJ 2016;355:i5956
  1. Michael McCarthy
  1. Seattle

A large study assessing whether inducing hypothermia in brain dead organ donors would affect graft function in recipients of kidney transplants may have violated federal regulations by not considering the organ recipients as human participants, an investigation has found.1 The investigation was conducted by the US Department of Veterans Affairs’ Office of Research Oversight.

In the study, published in the New England Journal of Medicine in 2015,2 organ donors, after declaration of neurologic death, were randomly assigned to being cooled to 34°C to 35°C, the “mild hypothermia” group, or to be maintained at 36.5°C to 37.5°C, the “normothermia” group, pending organ harvesting. The trial’s main outcome measure was whether hypothermia reduced the rate of delayed graft function in the organ recipients, defined as the requirement for dialysis in the first week after transplantation.

The trial was terminated early on the recommendation of an independent data and safety monitoring board, after an interim analysis showed efficacy of hypothermia. At the time the trial ended, 370 donors had been enrolled, and 572 patients had received a transplant from the donor groups. The researchers found that graft function was delayed in 79 of 285 (28%) recipients of kidneys from donors in the hypothermia group and in 112 of 287 (39%) recipients of kidneys from donors in the normothermia group (odds ratio 0.62 (95% confidence interval 0.43 to 0.92); P=0.02).

In their paper the authors of the study said that the protocol had been evaluated by the institutional review board at the trial’s lead institution, the University of California, San Francisco. The board had concluded that because the organ donors were deceased the study was not human research and that informed consent was not required from the organ recipients because the study “posed minimal risk.”

This judgment was challenged by the advocacy group Public Citizen in a 20 April letter to officials at the US Department of Health and Humans Services’ Office for Human Research Protections and the Veterans Health Administration’s Office of Research Oversight.3

In the letter, Michael A Carome, director of Public Citizen’s health research group, and Sidney M Wolfe, founder of the health research group, charged that the trialists’ failure to obtain informed consent from the organ recipients was unethical and a violation of federal regulations on protection of human trial participants. “Although the brain-dead donors involved in the trial were deceased and therefore not human subjects of the trial, the patients who received kidneys from these donors clearly were human subjects,” Carome and Wolfe wrote.

Carome and Wolfe said that the claim that the risks were deemed to be minimal was not adequate to justify waiving the informed consent requirement, because to obtain such waivers, among other requirements, the institutional review board must demonstrate that the research could not practicably be carried out without such a waiver. Moreover, Carome and Wolfe said, the claim that the risks were minimal was debatable, since one of the purposes of the trial was to determine the safety of the intervention for the organ recipients.

In addition to calling for a review of the study, Carome and Wolfe called for the agencies to review all trials funded or conducted by the Department of Health and Humans Services or Veterans Affairs that involved manipulation of donor organs and clinical assessments of the recipients and to suspend all trials that did not comply with the requirements of federal regulations on protection of human participants.

In its investigation the Office of Research Oversight concluded that the transplant recipients should have been considered human research participants under Veterans Affairs regulations, noting that the study’s primary outcome was the delay in graft function in recipients. As a result, the investigators found that the study should have been referred to the Veterans Affairs’ own institutional review board, which should have considered whether informed consent waivers were justified.

The Office of Research Oversight investigators noted, however, that in the course of its review the “ORO identified considerable uncertainty and confusion within the transplant community regarding the application of federal human research protection requirements to deceased organ donor intervention research, and specifically regarding the status as potential research subjects of the recipients of experimentally treated organs.”

Because the trial was funded by the Department of Health and Human Services, a final determination will require a review by the agency’s Office for Human Research Protection. A department spokesperson said that a review of the trial was under way but noted that the Office for Human Research Protections agreed with Veterans Affairs that there was “both ‘uncertainty and confusion’ in the transplant community about how the regulations apply to these types of studies.”

A spokesperson for the University of California at San Francisco, said that the university’s bioethics board was reviewing the Veterans Affairs report and would comment when that review was completed.


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