Informed consent documents for the SUPPORT trial -- which examined different oxygen saturation targets for very premature infants -- were not deficient in the way they disclosed the potential risks of the study treatments, according to leaders from the National Institutes of Health (NIH), which funded the trial.
In March, the Office for Human Research Protections (OHRP) in the Department of Health and Human Services (HHS) sent a letter to the University of Alabama at Birmingham -- one of the lead centers for the trial -- describing deficiencies in the informed consent forms that resulted in a lack of full disclosure to the parents of the potential risks to their infants. OHRP reiterated its position and provided more detail in another letter sent Tuesday.
Debate about whether parents were adequately informed about the risks of the two interventions in the trial did not flare up, however, until April, when Public Citizen, a Washington-based watchdog group, called on HHS secretary Kathleen Sebelius to apologize for the handling of the informed consent process for the trial and to stop similar trials involving infants.
Now, leaders from the NIH have addressed the controversy in a perspective published online in the New England Journal of Medicine.
"After a detailed review of the protocol, the relevant consent documents, and the research literature, we respectfully disagree with the conclusions of the OHRP, which we believe resulted from a fundamental difference in interpretations of how the regulations should apply to the state of scientific understanding when the SUPPORT study commenced," wrote Kathy Hudson, PhD, deputy director for science, outreach, and policy for the NIH; Alan Guttmacher, MD, director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development; and NIH director Francis Collins, MD, PhD.
"The outcome of this debate could affect how we conduct and communicate about critical research on interventions that are within the standard of care for all diseases and conditions," they wrote.
The SUPPORT trial, which was conducted at 23 sites, compared two different oxygen saturation targets among infants born at 24 to less than 28 weeks of gestation. The main outcomes were retinopathy of prematurity and death.
When the study began, Hudson and colleagues wrote, a saturation level of 85% to 95% was becoming standard practice, and that range was later included in 2007 guidelines from the American Academy of Pediatrics. At the time, there was uncertainty about which level was best.
The results of the SUPPORT trial showed that infants treated to a target of 85% to 89% had a lower risk of retinopathy of prematurity but a greater risk of mortality compared with those treated to a target of 91% to 95%.
"As a result," Hudson and colleagues wrote, "last year the AAP amended its guidelines, citing SUPPORT, and physicians treating very premature infants are starting to use higher saturation rates to reduce the risk of death, even with the potentially higher risk of retinopathy of prematurity at these levels."
They said, however, that when the trial was started there was no indication that saturations in the lower range would increase the risk of death and that the OHRP's conclusions -- that the consent forms did not adequately detail that "the level of oxygen being provided to some infants, compared to the level they would have received had they not participated, could increase the risk of brain injury or death" -- were based on outdated research.
More recent studies, Hudson and colleagues wrote, "showed no increased risk of death or neurodevelopmental impairment at saturation levels as low as 70%."
In separate correspondence in NEJM, Benjamin Wilfond, MD, of the University of Washington in Seattle, and colleagues agreed that the OHRP should rescind its finding that the informed consent process was flawed.
"We believe that this conclusion was a substantive error and will have adverse implications for future research," wrote the authors, who described themselves as "a group of scholars and leaders in bioethics and pediatrics with extensive experience in ethical and regulatory issues in pediatrics and human subjects research." Five of the authors came from centers that participated in the SUPPORT trial.
Because both treatment arms aimed for oxygen saturation targets that were within standard clinical practice, the researchers could not have expected excess risks beyond what would be seen with routine treatment, they said.
"Although we acknowledge that the permission forms could have been improved," Wilfond and colleagues wrote, "we disagree that the random assignment of infants to a high oxygen-saturation level or a low oxygen-saturation level imposed additional risks that the investigators failed to disclose."
"Allowing the decision [of the OHRP] to stand would be unfair to the investigators and institutions involved in SUPPORT," they wrote. "It would also set a precedent that would impede ongoing and future patient-centered outcomes studies."
For its part, Public Citizen is still seeking greater action from the OHRP.
In its most recent letter, the OHRP said "we have put on hold all compliance actions against [the University of Alabama at Birmingham] relating to the SUPPORT case, and plan to take no further action in studies involving similar designs until the process of producing appropriate guidance is completed."
According to Michael Carome, director of Public Citizen's Health Research Group and a former employee of the OHRP, "This is an abject and unacceptable failure to protect human subjects in clinical trials and is undoubtedly because of political pressure."
In a press release, Carome called for an immediate stop to any other trials similar to SUPPORT "for which there are reasonable doubts about the adequacy of the informed consent process."
Informed consent "must not be compromised simply to satisfy the desire of medical researchers for expediency in their quest to advance medical knowledge," he said.
Wilfond reported receiving a grant from the NIH related to the correspondence. Some of his co-authors reported working at sites that participated in SUPPORT and relationships with the National Center for Advancing Translational Sciences, NIH, Genzyme/Sanofi, Johns Hopkins University, Duke University, and BPCA.
Hudson and her co-authors reported that they had no conflicts of interest.
New England Journal of MedicineSource Reference: Wilfond B, et al "The OHRP and SUPPORT" N Engl J Med 2013; DOI: 10.1056/NEJMc1307008.
New England Journal of MedicineSource Reference: Hudson K, et al "In support of SUPPORT -- a view from the NIH" N Engl J Med 2013; DOI: 10.1056/NEJMp1306986.