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05/23/2013

A Fight Against Providing Informed Consent and The Risk of Randomization in the SUPPORT Clinical Trial

A Fight Against Providing Informed Consent and The Risk of Randomization: Informed Consent in the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) 

by Bernard W. Freedman,JD, MPH    

In their article Risk, Consent, and SUPPORT  David Magnus and Arthur Caplan chastise the Office for Human Research Protections (OHRP) for their findings of a failure to provide adequate informed consent as required by federal regulations, in a clinical trial.  The OHRP is right in their position.

The underlying clinical trial, Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT), published in 2010, sought to evaluate the effects of different levels of oxygenation provided to premature infants with extreme low birth weights (ELBW).  Two groups were randomized, one to provide oxygen saturation levels from 85% to 89% and the second group from 91% to 95%. The purpose of the study was to find a percentage of oxygen saturation that would avoid reducing oxygen levels low enough to result in retinopathy of prematurity (ROP) but not so low to increase morbidity and mortality.

What I will discuss in this article is the difference in perception between the researchers and the parents; the negligent or purposeful withholding of crucial information from the parents.  Magnus and Caplan, two stalwarts in the bioethics academic community, attempt to ride to the aid of the researchers but fail in their “we didn’t know” defense.

The controversy developed over whether or not parents were provided with adequate information before allowing their child to participate in the study. The researchers told one thing to the IRB and left out critical information in the consent form provided to the parents of infant research subjects who were being recruited.

Compare the explanation for the need for the study 1) placed in the Clinical Trial Protocol , with 2) the description provided to parents in the informed consent form.

Clinical Trial Protocol Statement:

“… there is no definite recommendation or standard teaching regarding the level of oxygenation that should be maintained in ELBW infants. Oxygen supplementation has to be used liberally as ELBW infants frequently have desaturation episodes and thus wide saturation ranges are tolerated clinically. However, oxygen toxicity can result in increased risk for CLD, [chronic lung disease] retinopathy of prematurity (ROP) and other disorders. Alternatively, oxygen restriction may impair neurodevelopment.”

Informed Consent Statement:

“…ROP is increased by the prolonged use of supplemental oxygen from observations published in the 1950s, but the benefit of higher versus lower levels of oxygenation in infants, especially for premature infants, is not known. In going back and looking at how babies in the past were managed, is being suggested that the use of lower saturation ranges may result in a lower incidence of severe ROP.

The consent form uses the word “benefit” but does not discuss risks to individual infants and fails to mention any risk that oxygen restriction might impair “neurodevelopment” or death.

Specifically, the concerns and criticisms of the OHRP stem from their review of prior research reflecting known risk factors that might lead to differences in whether an infant survived or developed blindness in comparison to what might have happened to a child had that child not been enrolled in the study, i.e., the effects of oxygenation on (ROP) on the one hand and neurologic morbidity and mortality on the other. The OHRP suggested, in part, that the parents should have been told that:

… the study involves substantial risks, and that there is significant evidence from past research indicating that the level of oxygen provided to an infant can have an important effect on many outcomes, including whether the infant becomes blind, develops serious brain injury, and even possibly whether the infant dies…”[i]

The informed consent form did not mention any difference in risk in being assigned to one group or the other. The assignment, they were told, was the same as a “flip of a coin.” Parents were told, “Participation in this study does not involve any known risks to you or your child.” Here, however, the the risk of higher oxygen levels could lead to blindness while the risk of too low oxygen levels could lead to death.

The concept of “foreseeable risk” under the federal regulations is not limited to specific, direct, exacting scientific evidence. Indeed, the determination of actual, direct scientific evidence was the endpoint of this trial. “All foreseeable risk” encompasses all adverse effects that could occur. It is clear that as the OHRP wrote, “the level of oxygen provided to an infant can have an important effect on many outcomes, including whether the infant becomes blind, develops serious brain injury, and even possibly whether the infant dies.”  

Magnus and Caplan, take issue with the OHRP. They declare that:

“…there is absolutely no evidence to support the claim that the infants enrolled in the study were exposed to greater risk than infants outside the study.”

This may be true from an epidemiologic, biostatistical standpoint as to the group of infant research subjects, but not true as to individual infants. Parents do not decide what is best for the group of the clinical trial participants, only what is best for their child. The consent they are asked to give means nothing without receiving and understanding all information.

Magnus and Caplan make the point that, “there was a variation in clinical practice…based upon random physician preference. ”  Random physician preference is the risk of randomization.  Medical treatment that is being randomly chosen is different from an individual physician’s medical decisions being made for an individual infant – a patient – not a group.

“Random physician” here means a statistical range of possible oxygen saturation levels, but not a clinical decision made by a physician for a unique patient. Not all physicians are the same. Their education and experience varies and so with it the efficacy of the decisions they make. The care of an ELBW infants nuanced and many parents make the effort to find a highly respected physician whose treatment decisions are  based on the individual merits of the infant’s physician. So, being recruited into a trial without being fully informed of the risks of randomization is a breach of medical ethics as well as the federal regulations requiring that all information be provided.

There is a long history here leading up to the SUPPORT study. Research in early trials in the 1950s and 1960s demonstrated the possibility that although lower oxygen levels reduced ROP, it also threatened significant morbidity and mortality. In 1973, a study found that: “it would seem that each sighted baby gained [by limiting the use of oxygen] may have cost some 16 deaths.” A 2006 retrospective review noted that “lower oxygen for prolonged periods of hypoxemia may result in poor growth, cardiopulmonary complications of chronic lung disease, neurodevelopmental disabilities, or increased mortalities . . . Although maintaining ranges of hemoglobin oxygen saturation in the vulnerable preterm population in the proximity of 85% to 90% is gaining increasing acceptance, marked variability in opinion exists.” (SUPPORT ranges went to 95% saturation).

“Marked variability in opinion” means that different well-respected careful and prudent physicians in the medical community specializing in neonatology do, indeed, differ. Thus, in failing to explain that there has been a long- standing controversy in the community regarding the effects of increasing or reducing oxygen levels in ELBW patients and potential complications ranging from blindness to chronic lung disease to death is: a misrepresentation, at best, and a failure to obtain legitimate consent to enter the infant into the study protocol.

Magnus and Caplan, in an attempt to justify the withholding of information, argue that the ends justified the means. They say, in retrospect, “The study made clear that higher oxygen saturations within the then-recommended range increased the risk of retinopathy but decreased the risk of death.”  Yet, it is clear that information obtained after a study has nothing whatsoever to do with the relevant and material information that must legally be provided to the parents before the study.

Magnus and Kaplan seek refuge behind the argument that the “standard of care” included the range of oxygen saturation of 85% to 95%. Yet, admittedly, the standard of care, if one can call it that, was unclear and controversial and differed among physicians. In fact, the principal investigators of the study do not say that there is a “standard of care.” Instead they explain in there protocol that:

“… there is no definite recommendation or standard teaching regarding the level of oxygenation that should be maintained in ELBW infants.”

Even if there is a range of oxygen saturation levels which some consider to be a standard it should be understood that under the law in most states a “standard of care” is not determinative of the adequacy of disclosure of information that a reasonable person would deem relevant and material to his or her decision-making process. Thus, failing to include all information will bear on any issues of liability that may arise.

The reality is that neonatologists make medical decisions as to what percent of oxygen saturation is best for an individual infant is based upon their experience, education and unique assessment of their individual patient. Individualized care was withdrawn when the infants were randomized. Before research subjects leave individualized care and enroll in randomized clinical trials, the highest amount of information and candor owed.

Accordingly, the action taken by the OHRP was proper and should be seen as a legitimate effort to protect the research subjects in this clinical trial. 



[i] The OHRP stated: It would have been appropriate for the consent form to explain (i) that the study involves substantial risks, and that there is significant evidence from past research indicating that the level of oxygen provided to an infant can have an important effect on many outcomes, including whether the infant becomes blind, develops serious brain injury, and even possibly whether the infant dies; (ii) that by participating in this study, the level of oxygen an infant receives would in many instances be changed from what they would have otherwise received, though it is not possible to predict what that change will be; (iii) that some infants would receive more oxygen than they otherwise would have, in which case, if the researchers are correct in how they suppose oxygen affects eye development, those infants have a greater risk of going blind; and (iv) that the level of oxygen being provided to some infants, compared to the level they would have received had they not participated, could increase the risk of brain injury or death.

that the study involves substantial risks, and that there is significant evidence from past research indicating that the level of oxygen provided to an infant can have an important effect on many outcomes, including whether the infant becomes blind, develops serious brain injury, and even possibly whether the infant dies; (ii) that by participating in this study, the level of oxygen an infant receives would in many in stances be changed from what they would have otherwise received, though it is not possible to predict what that change will be; (iii) that some infants would receive more oxygen than they otherwise would have, in which case, if the researchers are correct in how they suppose oxygen affects eye development, those infants have a greater risk of going blind; and (iv) that the level of oxygen being provided to some infants, compared to the level they would have received had they not participated, could increase the risk of brain injury or death.”

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