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In the spotlight. Controversy over informed consent rules stems from a study involving premature infants, such as this baby girl.

Chris Sternal-Johnson/Wikimedia

U.S. Weighs Informed Consent Rules in Wake of Infant Study Controversy

The U.S. government is considering changing how biomedical researchers inform patients about the risks of some clinical experiments in the wake of an acrimonious debate over a study involving premature infants. The rules and the controversy—which put some neonatal research on hold for several months this year—were the subject of a daylong public hearing held earlier this week by the U.S. Department of Health and Human Services (HHS) in Washington, D.C.

The dispute has divided the bioethics community and pitted the National Institutes of Health (NIH), which funded the infant study, against the Office for Human Research Protections (OHRP), the federal watchdog for research ethics. And it has focused attention on how best to ethically conduct research that compares the effectiveness of existing medical treatments, an endeavor that has grown since Congress approved $1.1 billion for such studies under the 2010 Affordable Care Act.

The controversy began in March, when the OHRP issued a letter criticizing the directors of a $20 million, 23-hospital study known as SUPPORT (the Surfactant, Positive Pressure, and Oxygenation Randomized Trial). Among other goals, SUPPORT sought to determine whether the high or low end of blood oxygen levels commonly set for premature infants was better for preventing severe disease.

The nonprofit watchdog group Public Citizen circulated OHRP’s letter to reporters, drawing widespread media attention. OHRP charged researchers with failing to provide sufficient warning to parents of the 1300 babies in the study. It said researchers should have told parents about concerns that the high-oxygen saturation group had a potentially greater risk of eye disease, while babies in the lower group might be more likely to die or suffer developmental delays. Both concerns proved true at statistically significant levels.

Many researchers and NIH officials, however, challenged OHRP’s stance. In an editorial in The New England Journal of Medicine in June, NIH Director Francis Collins called OHRP's letter “inappropriate” given SUPPORT's excellent design and importance. Collins's surprisingly sharp editorial suggested that the 13-year-old OHRP be reined in by having experts consider its opinions before they are issued. Other researchers noted that because the trial involved treatments that were all considered “standard of care,” it wasn’t clear whether researchers needed to inform parents about risks related to care that might have been provided even without the study.

OHRP ultimately backed away from plans to sanction the researchers. Instead, it announced that it would help organize the 28 August hearing and issued a letter emphasizing that it “does not and has never questioned whether the design of the SUPPORT study was ethical."

Those at the hearing offered an array of views on both the SUPPORT study and how future studies should be conducted. Kathy Hudson, an NIH deputy director, told ScienceInsider that there was no reason for SUPPORT researchers to have mentioned the risk of death at lower oxygen levels, because there was no recent data indicating that risk. OHRP Director Jerry Menikoff, however, said the agency’s examination had found that, during preliminary discussions of SUPPORT’s design, some neonatologists had raised concerns about risks at the lower oxygen levels. OHRP concluded that these concerns met a legal standard of “reasonably foreseeable risks” that researchers are supposed to warn subjects about.

The parents of one infant enrolled in SUPPORT said they should have been told. “We would never have entered our child in this study if we'd know about the risks,” Shawn Pratt, whose daughter Dagen entered the SUPPORT trial at Duke University in 2007, told the hearing panel. The child, who was born 14 weeks prematurely and weighed less than 2 pounds, now suffers from cerebral palsy, a common result of extreme premature birth. The Pratts and four other families have sued the directors of the SUPPORT trial. None know which treatment their children received during the trial.

Researchers say that the controversy prompted some trials involving infants to halt work while organizers reviewed and revised materials used to acquire informed consent. Several sites in the Neonatal Research Network, based at the National Institute of Child Health and Human Development (NICHD), stopped recruiting new patients to six other ongoing trials while they reviewed documents. Most sites have since resumed recruitment, said NICHD Director Alan Guttmacher, often with revised consent forms.

The neonatology study centers, for example, hewed to OHRP suggestions regarding the SUPPORT trial in adding warnings to documents for the network's Transfusion of Prematurity study, which compares two types of blood transfusion strategies in extreme preemies. The study's design is similar to that of the SUPPORT trial.

“The OHRP letter created a lot of scrutiny and soul searching,” said Edward F. Bell, a neonatologist at the University of Iowa in Iowa City. His group added a paragraph to its protocol explaining the study's goals to participants, and another stating, “Because your baby was born extremely premature, he/she is at extreme risk for a number of problems including death. Any of those risks could be favorably or unfavorably affected by their placement in the trial.”

At the University of Cincinnati in Ohio, neonatologists are developing two informed consent documents—one that meets the legal requirements, the other a much shorter booklet that explains the goals and potential risks of the study in plainer language, with a multiple choice test at the end to make sure trial parents have understood it.

But several bioethicists and doctors are pushing HHS to undertake a more sweeping overhaul of the informed consent system. They criticize what they say is an imbalance between the relatively strict consent requirements for research studies and the weaker requirements for everyday medical activities, which may be riskier and more experimental than the procedures studied in clinical trials. It is misleading to tell patients that experiments expose them to greater risks, while allowing doctors to choose treatments without discussing the relative risks of alternatives, bioethicist Nancy Kass of Johns Hopkins University in Baltimore, Maryland, told the panel. David Magnus, a bioethicist at Stanford University in Palo Alto, California, said he believed informed consent requirements could be waived when the risks of an experiment did not differ from those of standard of care treatments.

But others in the bioethics community hotly attacked such proposals. SUPPORT's system for randomly assigning infants to different treatments meant that they were not getting the “standard of care” in the institutions that treated them. While it is true that the SUPPORT infants got treatments within the range of normal care, they were put into high- or low-oxygenation groups, while doctors in neonatal care units often change oxygenation levels in response to a variety of signs and symptoms, said Michael Carome, Public Citizen’s director of health research and a former OHRP official.

Others worried that the controversy will cause HHS to hesitate to protect patients. “The pressure on OHRP to pull back on enforcement sets a frightening, dangerous precedent,” said Alice Dreger, a bioethicist at Northwestern University in Evanston, Illinois. “That is what is new here, not the essential nature of the research.”

Whether the debate will ultimately lead to new rules is now up to HHS officials, who have said that they are weighing the issues.