US researchers failed to disclose risks of newborn study, finds government office

Researchers who enrolled more than 1300 premature newborns in a study to identify the optimum levels of blood oxygen saturation did not adequately disclose to parents the risks of eye damage, neurological impairment, and death that study participation posed, the United States Office of Human Research Protections (OHRP) has found.

The study was part of the influential Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) study that also looked at the use of continuous positive airway pressure and surfactant in these patients.

The OHRP detailed its concerns about the study’s arm relating to blood oxygen saturation in a letter on 7 March to Richard Marchase, vice president for Research and Economic Development at the University of Alabama at Birmingham, which was the lead site for that portion of the study.1

The letter was written by Lisa Buchanan, compliance oversight coordinator at OHRP.

In the part of the trial criticized in the OHRP review, premature infants of low birth weight were randomly assigned to two treatment groups: a “low” range group, whose blood oxygen saturation would be maintained at 85% to 89%; and a “high” range group, whose blood oxygen saturation would be maintained at 91% to 95%.

The purpose was to determine whether it would be possible to reduce the risk of retinopathy of prematurity (ROP)—a known complication of oxygen therapy in newborns that can lead to blindness—by maintaining blood oxygen saturation in the lower range without increasing risk of death.

In her letter, Buchanan faults the consent form for its description of the study’s high and low ranges as “ranges of oxygen saturation that are currently being used with premature infants” and for describing the goal of the study as only “to pinpoint the exact range that should be used to help prevent some of the problems that occur with premature babies such as ROP.”

Although the consent form mentioned that “using lower pulse oximeter ranges [would] result in fewer babies with severe [ROP],” which most parents would see as a potential benefit, it did not mention that there may be an increased or decreased risk of death depending on which group an infant was assigned to, or that being assigned to the higher range group might, in fact, pose an increased risk of retinopathy, Buchanan noted.

“The only risk related to the part of the study involving the two ranges of oxygen levels described in the ‘possible risks’ section is the risk of the pulse oximeter to the infant’s skin,” Buchanan wrote.

The study protocol also indicated that the levels of blood oxygen saturation could not be accurately described as the current standard of care, Buchanan said.

“According to the study design, on average, infants assigned to the upper range received more oxygen than average infants receiving standard care, and infants assigned to the lower range received less,” said Buchanan in the letter. “Thus, the anticipated risks and potential benefits of being in the study were not the same as the risks and potential benefits of receiving standard of care.

“For the infants assigned to the upper range, based on the premises of the researchers, the risk of ROP was greater, while for the infants assigned to the lower range, the risk of ROP was lower,” Buchanan wrote. Assignment to one group or the other also affected the risk of neurological development and death.

In the end, the study found a higher rate of severe retinopathy and lower risk of death among infants in the high range group.2 Death before discharge occurred more frequently in the lower range group than in the higher range group (19.9% (130/654 infants) v 16.2% (107/662); relative risk, 1.27 (95% confidence interval 1.01 to 1.60); P=0.04), while severe retinopathy among survivors occurred less often (8.6% (41/475) v 17.9% (91/509); 0.52 (0.37 to 0.73); P<0.001).

In a statement released by the University of Alabama at Birmingham in response to the OHRP letter, Marchase noted that “physicians at all 23 sites worked together to develop a common consent form that was then approved by each of their [institutional review boards], and all participants received treatments that were within the standard of clinical care.”

Marchase also pointed out that mortality rates of study participants in both groups were lower than those of an historic reference group, as well as a concurrent group of non-study participants who attended the participating study sites during the study.

“OHRP guidance is invaluable to any research institution committed, as we are, to constantly improving patient outcomes through research and patient care. Per OHRP feedback, we will ensure that any future consent form clearly delineates risks to all arms of a study as completely as possible, including studies in which all arms are operating within the accepted standard of clinical care,” he wrote.