When those who participate in medical research are unable to consent, who serves as advocates for them?
This provocative—and fundamental—question was brought to the fore by a front-page article in last week’s New York Times. A key government agency, the Office for Human Research Protections (OHRP), has determined that a national study of 1,300 extremely premature infants failed to provide parents with adequate disclosure of the risks of participating in the research. That federal agency is charged with overseeing taxpayer-funded research on human subjects.
The National Institutes of Health–funded study, involving 23 academic sites across the country, including Yale, Duke and Stanford, looked at babies born at 24 to 27 weeks and already at risk for death or eye disease. The babies were divided into two groups: those who received higher amounts of oxygen and those who received lower amounts of oxygen. The researchers were trying to determine the optimal level of oxygen administration for this high-risk group. Those who administered the study say that all the infants were kept within a band of 85 to 95 percent oxygen saturation, which is considered “normal.”
Citing an OHRP letter about the study, the New York Times noted: “Babies assigned to a high-oxygen group were more likely to develop eye disease and blindness, and babies assigned to a low-oxygen group were more likely to die. Ultimately, 130 babies out of 654 in the low-oxygen group died, and 91 babies out of 509 in the high-oxygen group developed an eye ailment that in serious cases can lead to blindness.”
The OHRP did not find that the infant study itself was unethical. Rather, it determined that the consent forms were incomplete. In a letter detailing its concerns, the OHRP noted that the consent forms to parents should have explained that “there is significant evidence from past research indicating that the oxygen provided to an infant can have an important effect on many outcomes including whether the infant becomes blind, develops a serious brain injury or even possibly whether the infant dies.”
Informed consent is one of the key ethical requirements for the protection of the rights and welfare of human participants in research. When those subjects are infants or children, as in this study, parents are the ones who must decide whether to enroll their offspring.
Another layer of protection—the institutional review board (IRB) system—requires prospective review of research by institutional committees comprising biomedical researchers, ethicists and community representatives. The two main responsibilities of IRBs are to determine whether the risks of proposed research are “reasonable” in light of anticipated benefits, and to review the adequacy of informed-consent documents prepared by the researchers or sponsors.
The requirements for these forms are clear. They must be written in language understandable at roughly an eighth-grade level and they must include at least the purpose of the research, the procedures to be undertaken, the risks, the anticipated benefits and alternatives to participation.
In a 14-page letter to the University of Alabama at Birmingham, the lead site of the study, the OHRP said that the consent form failed to adequately disclose study risks:
“Based on the consent form template and UAB consent forms, 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 foreseeable risks of blindness, neurological damage and death. . . . Although the consent form did not identify a single specific risk relating to the randomization to high or low oxygen ranges, it did include a section that was quite specific in noting possible benefits to participating infants from the change in oxygen ranges. That paragraph observed that ‘[t]here may be benefits to your child directly, including . . . a decrease in the need for eye surgery as a result of exposure to oxygen.’ The . . . consent form [suggested] that this was a low risk study, noting that all of the treatments in the study were ‘standard of care,’ and that there was ‘no predictable increase in risk for your baby.’”
One would have to read the entire 14-page letter (which I did) to understand fully the charges, as well as the researchers’ claim that infants in the study received the “standard of care” and that therefore the study carried “minimal risk.”
That claim points to two controversial areas in the review of research on human subjects. The first is uncertainty about how to determine what is the “standard of care” in medical practice. The second is whether a study should be considered to carry “minimal risk” when the interventions carry significant risks but patients receiving similar interventions outside the study would undergo similar risks.
Institutional review boards at some of the nation’s premier research institutions failed to provide clarity on these questions. Why didn’t any of the IRBs involved in the study notice that the risks were not properly described?
- Is it because none of the reviewers on these committees read the consent forms carefully?
- Is it because IRBs tend to concentrate on simplifying the inordinately complex technical jargon in which forms are typically written?
- Is it that even these expert reviewers’ eyes glaze over when they plow through 18-page, single-spaced consent forms that today have become more like legal documents designed to protect the institution than clear communications to prospective research subjects?
- Or is it because in multicentric studies sponsored by the National Institutes of Health, IRBs (falsely) believe that they cannot make any changes in the consent documents?
Reasonable people may disagree on the answers to the controversies surrounding informed consent. But there is no doubt that the consent forms in this study of premature newborns failed to disclose what these parents should have been told before enrolling their infants in the research.
What do you think about the informed consent in this study? Tell us in the comments section.
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Very informative. Thank you Dr Macklin for this great summary and link to the OHRP document.
One of the major “lessons” from this incident is that just having a patient, parent or other healthcare proxy sign the consent form isn’t enough. There also has to be a way to measure their understanding of the medical or research procedures to which they consent.
The New England Journal of medicine has responded with an editorial refuting the claims of the Federal Office for Human Reseach Protections (OHRP): https://www.nejm.org/doi/full/10.1056/NEJMe1304996
The only outrage here is the bogus claims made by a government bureaucrat. The design of this study had to pass through the institutional review boards of over a dozen universities, including Stanford and Yale.
Premature babies do not come with an medical instruction book passed down by god, complete with warning labels stuck to their posteriors. The risks and proper levels of oxygen were not known before the study began. It is only because of studies such as this one that proper levels of oxygen have become known.