During the 1940s, an alarming increase in the rate of blindness in premature infants was linked to the high oxygen saturation rates, used in the management of those infants. Subsequently, oxygen levels dropped, which was followed by a 60% decrease in blindness rate . But, there were concerns regarding the use of low oxygen levels and its association with brain damage and, eventually, death. As a matter of fact, in 1973, an epidemiological analysis concluded that “it would seem that each sighted baby gained [by limiting the use of oxygen] may have cost some 16 deaths” . Today, oxygen saturation levels range from 85% to 95% but the optimal level remains undetermined. In 2010, the University of Alabama in Birmingham (UAB), along with 23 other institutions, published the SUPPORT study – a controlled trial with the aim to learn the appropriate levels of oxygen saturation in extremely low birth weight infants by comparing a lower versus a higher range of levels of oxygen saturation in such infants. The study has been criticized by the Department of Health and Human Services (HHS) along with the public opinion of exposing enrolled children to increased risks as well as duping the parents with a failed informed consent process. As a result, the parents of 5 enrolled children took SUPPORT to court and the study was terminated despite the frustrated defenses from officials at the UAB.
According to HHS, the SUPPORT study poses increased risks to the enrolled children. Premature infants cannot be randomly assigned to oxygen saturation levels. Just like standard care, these levels should constantly change according to the infants’ needs. Limiting a child to only one end of the range is a danger that may lead to the child’s death, although SUPPORT investigators claimed that mortality rate in non-enrolled children is higher. Surprisingly, the enrollment of extremely low birth weight infants in a clinical research study may not be representative, published by the study investigators of SUPPORT, compared demographic and clinical factors for the enrolled babied to the non-enrolled. The study showed significant difference between the two groups with an overall less favorable outcome for the non-enrolled babies. Hence, the fact that the non-enrolled babies had a higher mortality than the babies enrolled in the SUPPORT study was expected . Most disturbing are UAB’s dismissal of those previous studies’ results and the IRB approval of the 23 institutions involved. Nonetheless, it was officially claimed that SUPPORT included a non-randomized case-control that confirmed, through “[non] definitive findings”, that enrolled patients were not at increased risks. Furthermore, the HHS was accused of hindering medical progress, arguing that SUPPORT is a comparative effectiveness research and that “there is no additional risk to being randomly assigned to one or another equally well-supported treatment option that falls within the standard range of care in clinical practice” .
After identification of the increased risks, the HHS’ most important concern with the SUPPORT study is the failure of the informed consent process to properly transmit those risks to the parents of the enrolled children. The informed consent form was misleading and short on background information that would have led to fewer parents enrolling their babies in the study. To begin with, the informed consent form did not mention there were prior researches on the same subject that exposed the risks of oxygen-levels randomization on premature infants. The informed consent also ignored the relationship between high and low oxygen levels and retinopathy of the premature (ROP) and mortality, respectively. Nowhere was it stated that children receiving low oxygen levels were at risk of developing brain damage. In fact, the only risks mentioned in the consent form were those associated with the use of the pulse oximeter. Not only that, but the consent form indicated that study participation has the benefit of reducing the incidence of suffering from ROP. On the other hand, the study investigators, believing that there are no increased risks for the study, were arguing that the study should have been waived of informed consent.
As a result to their violations, the HHS requested from UAB, as the leading entity in SUPPORT, to submit their corrective plan as well as help identify and prevent other areas of non-compliance. Regardless of the consequences, it still remains that 23 renowned institutions and their IRBs approved of SUPPORT and of the informed consent form. Whether this wrongful approval was a common lapse or an intended act is questionable. The Public Citizen sent a letter to Katheen Sebelius, HHS Secretary, requesting the department to issue an official apology to the parents of the enrolled parents. It also called for an “independent investigation into how the HHS system for review and oversight of clinical trials failed so miserably. This should include an assessment of all entities within NIH or other HHS agencies that played a role in the review, approval and funding of the study” . Indeed, it seems that a thorough investigation and a reform are in need for the ethics policies on a national level.
- L.K. Altman. Arnall Patz, a Doctor Who Prevented Blindness, is Dead at 89. New York Times, March 15, 2010. As cited in the Department of Human Health Services’ letter Human Research Protections under Federalwide Assurance (FWA) 5960, March 7, 2013.
- K.W. Cross. Cost of Preventing Retrolental Fibroplasia. Lancet 1973; 302:954. As cited in the Department of Human Health Services’ letter Human Research Protections under Federalwide Assurance (FWA) 5960, March 7, 2013.
- Public Citizen. Letter to Dr. Richard B. Marchase, April 11, 2013.
- David Magnus, PH.D and Arthur L. Caplan, Ph.D. Risk, Consent and SUPPORT. April 18, 2013 DOI: 10.1056/NEJMp1305086.
- The Public Citizen. HHS-Funded Experiment Exposed Babies to Risk of Death and Blindness Without Informing Parents. April 10, 2013.
The debate continues
“OHRP Suspends Compliance Action Against SUPPORT Study Sites Pending Public Hearing & Guidance
Regular readers may recall that recently, OHRP sent a determination letter to one of multiple sites (the University of Alabama at Birmingham (UAB)) involved in an RCT (the SUPPORT study) of optimal oxygen levels for premature infants (prior coverage here, here, and here). OHRP’s criticism itself led to considerable criticism among many research ethicists and physician-researchers (see, e.g., here, here, and here), as well as the SUPPORT researchers themselves (here), while others defended OHRP to varying degrees (here, here, and here).
Now, in a new letter to UAB, OHRP clarified that it has no objections to the study design; its objections, instead, pertain to what parents were told in the informed consent documents. Then, in a remarkable move, it announced that it is suspending its compliance actions against UAB, and plans no further action vis-a-vis other SUPPORT sites, pending its issuance of new guidance to address the risks that must be disclosed when conducted clinical trials like SUPPORT. OHRP promises not only the usual notice and comment period following the draft guidance but also an open public meeting, presumably in advance of the draft.
As the OHRP letter itself suggests, the fight within the research ethics community over the SUPPORT study can be seen as part of a larger conversation about the future of human subjects research regulation in the learning healthcare system. OHRP’s guidance-making process in this matter will clearly be one to watch.”