Thanks to a public outcry that included objections from bioethics experts from across the country, the federal Office for Human Research Protections (OHRP) has decided to suspend sanctions it imposed earlier this year on a study of blood oxygen levels used to treat premature infants. The OHRP’s sanctions, issued in March, sharply criticized the study’s leaders for not providing the infants’ parents with adequate information about the risks of the trial. But many bioethics experts disagreed with the OHRP’s assessment of the situation.
Last week, a group of more than 40 of the country’s top bioethicists, including two at Stanford, sent a letter to OHRP stating that the sanctions could have a chilling effect on much-needed clinical research. In a highly unusual action, Francis Collins, MD, PhD, the director of the National Institutes of Health, worked with two colleagues to write a similarly critical letter that said, in part:
This controversy has alarmed some of the parents of infants who were in the study, confused the biomedical research community, and befuddled IRBs. Several other studies seeking new insights to improve care for these vulnerable infants have been put on hold as the field tries to understand the OHRP findings.
The two letters appear online today in the New England Journal of Medicine (NEJM), and constitute a remarkably intense criticism of the OHRP, the agency within the U.S. Department of Health and Human Services responsible for overseeing the safety and well-being of human research subjects.
I’ve been following the developing story with the help of Stanford bioethicist David Magnus, PhD, who was one of the writers of the bioethicists’ letter. Last week, before the agency revised its stance, Magnus summarized what the bioethics community found objectionable about the OHRP’s sanctions: “They believe in an absolute interpretation of risk,” he said. The agency's risk assessment was based “not [on] what kids who are actually sick would be exposed to, but what a healthy child would be exposed to.” Healthy babies born at term face much lower risks of severe eye disease, neurological damage and death than the babies in the study – but the tiny preemies in the study weren’t healthy term infants, and were not placed at additional risk, the bioethicists assert, because of their participation in the study.
The tussle has a complex back story that involves 1,300 fragile premature infants, their parents, 23 academic medical centers and an important piece of paperwork.
The infants, their parents and the medical centers (which included Stanford) were part of the SUPPORT trial, a large study conducted by the NIH-funded Neonatal Research Network that ran from 2004 to 2009 to determine the optimal blood oxygen levels for very premature babies born between 24 and 28 weeks’ gestation.
In the early 2000s, before the trial began, neonatologists at Stanford surveyed medical centers in the U.S. about their target oxygen saturation ranges for preemies and found that the standard of care varied widely, with target blood-oxygen saturations ranging from 82 to 100 percent. No one was sure if blood-oxygen saturations at the lower or higher end of that range were better, although there were some indications that the higher end of the oxygen range was linked with more severe eye disease from a disease called retinopathy of prematurity.
In practice, doctors tried to keep their patients within a target saturation oxygen range, but the target range varied from one hospital to another. In other words, the ‘standard of care’ wasn’t very standard. The situation was a prime candidate for a comparative-effectiveness study, which randomly assigns patients to different treatments within the standard of care to see which works best. In the study, after obtaining parents’ consent to enroll their infants, researchers randomized infants to have their blood-oxygen saturations levels targeted to the lower (85 to 89 percent) or higher (91 to 95 percent) end of the range most commonly used. The trial, published in the New England Journal of Medicine in 2010, found that babies at the higher oxygen saturation levels were more likely to develop severe eye disease from retinopathy of prematurity, but those in the lower-oxygen group were more likely to die. However, the rates of eye disease and death for both groups were lower than for a third group of similar infants who were not enrolled in the study but were treated for prematurity during the same time frame.
In March of this year, well after the study had concluded, the OHRP sent a letter to the study’s lead investigator at the University of Alabama at Birmingham criticizing the consent forms that parents signed to let their infants participate in the study. In the agency’s view, parents were not adequately informed about the risks their infants faced in the study. OHRP’s letter said, in part:
We determine that the conduct of this study was in violation of the regulatory requirements for informed consent, stemming from the failure to describe the reasonably forseeeable risks of blindness, neurological damage and death.
The two letters published in NEJM today disagree. As the bioethics experts put it in their letter:
The conclusion of the OHRP that the SUPPORT investigators violated federal regulations in failing to include specific information elements regarding risks of the study interventions in the parental permission documents is without substantive merit and overreaches.
… The OHRP should not sanction research institutions simply because it disagrees with their assessment of the risks of research but should do so only if it finds that an institution has failed to meet the terms of its federal-wide assurance, such as in the manner in which its institutional review board is constituted or operates.
“There is always this balancing act between the need to protect participants in research and the need to do what we can to ensure that valuable research takes place,” Magnus told me. “We worry that the OHRP is overreaching, balancing toward unnecessary sanctions that don’t serve to protect subjects and only serve to make it harder to conduct valuable research. The concern is that research in which patients are randomized within the range of standard, accepted practice – a type of research which is not done very much and is really needed – is going to be made much more difficult if this decision is allowed to stand.”
The agency’s revised decision, while still somewhat critical of the information that families received in consent forms, backs down considerably from the office’s original stance, and acknowledges the need to clarify the rules for obtaining informed consent from patients who participate in clinical-effectiveness research. In part, they say:
OHRP has become aware of widespread misunderstanding about the risks that are required to be disclosed in obtaining informed consent for certain types of clinical trials … we recognize OHRP’s obligation to provide clear guidance on what the rules are with regard to disclosure of risks in randomized studies whose treatments fall within the range of standard of care. … We will ensure that the process for producing such guidance is as open as possible, to allow input from all interested parties.
Magnus looks forward, he said, to the bioethics community’s engagement in developing a template for how to assess the risks of comparative-effectiveness trials and communicate them to prospective participants.
“We have had a much bigger impact than I could have imagined,” he said. “There’s now an acknowledgement that these are very complex issues that need to be sorted out with a lot of input from many different people, not just a small number handing down a decision by fiat at OHRP.”
