Health Letter, June 2016
By Michael Carome, M.D.
If you’re not outraged,
you’re not paying attention!
Read what Public Citizen has to say about the biggest blunders and outrageous offenses in the world of public health, published monthly in Health Letter.
Image: Steve Lovegrove/Shutterstock.com
“Because all of the treatments proposed in this study are standard of care, there is no predictable increase in risk for your baby.”
“Each of the study treatments is already being used by many doctors across the country.”
“The [oxygen] ranges used in this study are in common use in [neonatal intensive care units] across the country.”
These excerpts are taken from different versions of the consent form signed by the parents of premature babies who were enrolled in a controversial clinical trial. Similar statements appeared in most of the consent forms used for the research. But such statements misrepresent the true nature of the trial.
A new study — published by researchers at Public Citizen and the National Institutes of Health (NIH) on May 18 in the medical journal PLOS ONE — shows that some key procedures used in the experimental trial were inconsistent with usual or standard care for premature babies. (Note: Dr. Carome was co-author of the PLOS ONE study.)
The trial — conducted from 2005 to 2009 and known as the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT) — was funded by NIH and involved the random assignment of more than 1,300 extremely premature infants to receive different amounts of oxygen. One group of babies was to be maintained at a low-oxygen target range (85-89 percent) and one at a high-oxygen target range (91-95 percent).
The primary objective of the trial was to see whether premature babies were more likely to die or suffer retinal damage, which can lead to blindness, if their oxygen levels were targeted to the low or high range, respectively.
For the experiment, the SUPPORT researchers used oxygen monitors that were programmed to display inaccurately low or high blood oxygen values, depending on a baby’s group assignment, to prevent the babies’ medical teams from knowing which trial group the babies were assigned — a research procedure known as “blinding.” Such a research procedure obviously was a significant departure from usual care.
For the new PLOS ONE study, the authors analyzed the consent forms approved by institutional review boards at 22 U.S. hospitals that participated in SUPPORT. Twenty of these consent forms explicitly or implicitly described the two oxygen ranges used in SUPPORT as “standard of care,” “usual care” or “a desired approach.” Consent forms used at 11 hospitals had additional statements indicating that there was no predictable increase in risk to infants enrolled in the study.
To assess the accuracy of these consent form statements with respect to the two oxygen target ranges, Public Citizen and NIH researchers systematically identified all studies published in English-language medical journals from January 1990 to May 2014 that examined usual-care oxygen management for premature babies at hospitals worldwide. An analysis of these studies revealed that the high-oxygen target range (91-95 percent) tested in SUPPORT was consistent with usual care at the time the trial was designed and conducted. In sharp contrast, however, the analysis documented that the low-oxygen target range (85-89 percent) tested in the experiment had not itself been used clinically when SUPPORT was designed and conducted. During usual care, when oxygen target ranges with lower limits less than 88 percent were used at some hospitals, they were always combined with upper limits of 92 percent or higher.
Thus, the low-oxygen target range and the use of oxygen monitors intentionally programmed to display inaccurate oxygen level readings clearly represented significant deviations from usual or standard care for extremely premature babies.
To tell the parents of the babies enrolled in SUPPORT that all of the trial procedures were consistent with usual or standard care — and therefore involved no predicable or expected increase in risk — was a serious misrepresentation. As a result, the parents were misled and deprived of the opportunity to make a voluntary, informed decision about whether to allow their babies to enroll in the experiment.
Whether intentional or unintentional, these misrepresentations constituted an egregious violation of the ethical principle of respect for persons, one of the three basic ethical principles applicable to all human subjects research.
Controversy about SUPPORT erupted in 2013, shortly after the federal Office for Human Research Protections (OHRP) determined that the SUPPORT consent forms failed to disclose to the parents of the babies the risks of the trial, including the risks of blindness and death. In response to OHRP’s findings, the SUPPORT researchers; the editor of The New England Journal of Medicine, which published the SUPPORT results; many bioethicists and pediatricians; and the NIH director fiercely defended the adequacy of SUPPORT’s consent process. They argued that, among other things, all of the SUPPORT procedures were within usual or standard care, essentially echoing the same misrepresentations made to the parents of babies enrolled in SUPPORT.
The findings of the new PLOS ONE study definitively repudiate all of the assertions that SUPPORT was limited to usual- or standard-care procedures. The time has come for the SUPPORT researchers and their defenders to acknowledge the trial’s ethical violations and to commit to preventing similar lapses in the future.
Last but not least, the SUPPORT researchers need to apologize to the parents who were misled into enrolling their babies in the trial.