This post is a part of our Bioethics in the News series. For more information, click here.
By James L Nelson, PhD
Quite some time ago as breaking news is measured—back on April 10th—the New York Times printed a story(1) on the Office of Human Research Protection’s (OHRP) official response to a five year, multi-center study: the Surfactant, Positive Pressure, and Oxygenation Randomized Trial, aka SUPPORT. In an effort to refine guidelines for the use of oxygen for premature infants, SUPPORT enrolled 1316 infants born at between 24 and 27 weeks of gestational age and randomized them to one of two treatment protocols. Contemporary practice was only weakly guided by data, but had generally settled on maintaining blood oxygen levels at levels ranging from 85-95%; just where in that range had been determined as much by clinical intuition as anything else. The children in the study were to be maintained within either an 85-89% blood oxygen range, or within a 91-95% level; the hope was to determine whether practice might become more precise.
The results, as reported in The New England Journal of Medicine(2) were somewhat surprising to clinicians. More of the children randomized to the lower level died—19.9%, contrasted with 16.2% in the higher group. On the other hand, the group maintained at 91-95% experienced a higher incidence of severe retinopathy—17.9, contrasted with 8.6. Perhaps an even bigger surprise was the letter OHRP wrote to the study organizers. OHRP found that the informed consent documents used in the study were deficient. Parents were not properly informed that that their children’s risk of death or damage could be affected by their participation in the study.
The Editorial Board of the Times called the informed consent lapse “startling and deplorable”(3), and in an entry on the Albert Einstein College of Medicine blog dated April 18, Ruth Macklin claimed “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”(4). But at least some of the researchers involved in the study have made it clear that they’re doubtful about that, to say no more. In a reply to the Times editorial, three SUPPORT investigators claimed that there was no reason to list an increased risk of death as a risk of participation in the study, as “the best evidence showed that lower oxygen targets…resulted in less eye disease without a higher death rate.”(5)
Nor is it just among the researchers involved in the study that one finds OHPR skeptics. Several bioethicists, including David Magnus and Art Caplan in NEJM(6), and Ruth Faden and Renee Boss in a blog post from the Berman Institute of Bioethics at Johns Hopkins(7), have written to praise SUPPORT and bury OHRP—or at least its letter to the study leaders.
In what is to my mind the most authoritative of these critiques, John Lantos posts in The Hastings Center blog that criticisms of the study by OHRP and the advocacy group Public Citizen were not merely “off-target” but “dangerous” as well(8). “Off-target,” because SUPPORT’s critics tacitly assume what was only known after the study’s completion—that lower levels of blood oxygen were a greater threat to children’s lives than higher levels. “Dangerous,” because the OHRP’s careless response will discourage research, in part by making parents reluctant to participate in research. Indeed, as Lantos sees it, OHRP’s position rests on discounting completed research—which, at the time of the study, provided no basis for thinking that any position within the 85-95% band was more risky than any other.
The article’s text does indicate that a possible correlation between higher death rates and lower oxygen levels seem to have been on the researcher’s minds in designing the study. The authors note that SUPPORT results “add to the concern” that “oxygen restriction may increase the rate of death among preterm infants”(9). It’s natural to read this as suggesting that the SUPPORT study was in part motivated by pre-existing worries about greater risks of mortality at lower levels of oxygen support. Lantos’s post makes a distinction that might explain this apparent discrepancy. Determining whether a lower range was or was not safer in terms of mortality and morbidity was among the goals of the research; Lantos allows that the consent document for SUPPORT did not mention the study’s goals, and that they ought to have done so. But goals are different from risks—which were not, as he sees it, misreported. That would have been grounds for serious complain; the failure to state the goals he sees as a comparative peccadillo. For Lantos, it is OHRP whose behavior has been shocking, elevating the ongoing risk to babies inherent in neonatal practice by reducing the chances that further prospective randomized trials will help clinicians get a better grasp on what risks and benefits such children actually face.
Lantos, along with other OHRP critics, make such an effective case that one might wonder whether there was any moral (as opposed to legal or regulatory) reason for requiring consent at all. All babies enrolled in the study were treated according to the contemporary standard of care: no one had any reason to believe that any child’s assignment to either arm of the trial would have any impact on any outcome. No child therefore, was at added risk of harm. Nor was any child used as a “means to an end solely” since they were getting precisely the kind of treatment that, on the basis of medical knowledge, was most likely to help them. Further, apart perhaps from a decision that any treatment would not be in their child’s interest, it’s at least questionable whether parents have authority to prevent their children from getting oxygen support considered simply as a therapy: parents’ discretion with their children is wide ranging, but it doesn’t extend to exposing them gratuitously to grave risks. If therapy in such cases is close to mandatory anyway, and the research introduces no extra risks and is consistent with the respect due the children, why make any fuss about consent at all?
I’ll introduce another distinction by way of hazarding a reply. A parent’s decision to allow their child to be randomized to a position within the standard range doesn’t heighten their risks relative to what we know. Yet what a parent decides may well change what actually happens to her child. A given child could die if randomized to the lower range of support who might have lived if her physician had decided, based on clinical judgment or intuition or coin-flipping, to treat her at the higher range.
As it happened, this wasn’t likely—among the many useful things to be learned from Lantos is that study participants had better overall outcomes than children eligible for the study but not enrolled. Yet if my child had been one of those who were randomized to the low oxygen group and had died, I would have to live with the fact that my decision might have been one of the causal factors in my child’s death. I don’t think there’s anything idiosyncratic about such a reaction, and what it suggests is that arguably, moral responsibility, and certainly grief and guiltiness, track what we actually bring about, not only how rational we are in our choices. From that perspective, I should have wanted to know that the study was designed to answer an open question—were different positions within the customary range more or less dangerous for these tiny infants—and that my decision about participation was not routine, but could be of the highest consequence for my child.
The OHRP critics are very concerned not to discourage parents from participating in high quality research that targets pressing problem—that is, research like SUPPORT. They are right to be so. But to achieve that goal responsibly, we need to be alert to what matters to actual people, and not just to idealistic epistemic agents.
References:
- Tavernise S. Study of Babies Did Not Disclose Risks, U.S. Finds. New York Times website. http://www.nytimes.com/2013/04/11/health/parents-of-preemies-werent-told-of-risks-in-study.html?pagewanted=all&_r=0. April 10, 2013. Accessed May 3, 2013.
- SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Early CPAP versus Surfactant in Extremely Preterm Infants. NEJM. 2010; 362(21): 1970-1979.
- NYT Editorial Board. An Ethical Breakdown. New York Times website. http://www.nytimes.com/2013/04/16/opinion/an-ethical-breakdown-in-medical-research.html. April 15, 2013. Accessed May 3, 2013.
- Macklin R. Informed Consent in Infant Research: Ethical Problems Remain. Albert Einstein College of Medicine Blog. http://blogs.einstein.yu.edu/?p=4403. April 18, 2013. Accessed May 3, 2013.
- Carlo WA, Bell EF, Walsh MC, for the SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Oxygen Saturation Targets in Extremely Preterm Infants. NEJM. April 17, 2013; DOI: 10.1056/NEJMc1304827.
- Magnus D, Caplan AL. Risk, Consent, and SUPPORT. NEJM. April 18, 2013; DOI: 10.1056/NEJMp1305086.
- Boss R, Faden R. Sensationalizing SUPPORT Harms Us All. Johns Hopkins Berman Institute of Bioethics Blog. http://bioethicsbulletin.org/archive/sensationalizing-support-harms-us-all/. April 25, 2013. Accessed May 3, 2013.
- Lantos JD. OHRP and Public Citizen Are Wrong about Neonatal Research on Oxygen Therapy. Bioethics Forum, a blog of the Hastings Center. http://www.thehastingscenter.org/Bioethicsforum/Post.aspx?id=6306&blogid=140. April 18, 2013. Accessed May 3, 2013.
- SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Target Ranges of Oxygen Saturation in Extremely Preterm Infants. NEJM. 2010; 362(21): 1959-1969.
James L Nelson, PhD, is a Professor of Philosophy and the Associate Dean for Graduate Studies in the College of Arts and Letters at Michigan State University.
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MSU Bioethics 
It is helpful to read the OHRP determination letter (http://www.hhs.gov/ohrp/detrm_letrs/YR13/mar13a.pdf) to understand their position.
1) “the best evidence showed that lower oxygen targets…resulted in less eye disease without a higher death rate.”
This was the conclusion of V.E. Kinsey. Retrolental Fibroplasia: Cooperative Study of Retrolental Fibroplasia and the Use of Oxygen. Archives of Ophthalmology 1956;56:481.
OHRP Letter: “As time passed, and experience with treating premature infants grew, some experts began to question the conclusion that there were no adverse health consequences from the decreased levels of oxygen. Flaws were found in the early study, which had ignored deaths that occurred during the first day of life. In 1973, an influential epidemiologic analysis concluded that “it would seem that each sighted baby gained [by limiting the use of oxygen] may have cost some 16 deaths.”
2) OHRP Letter: “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.” (J.S. Greenspan, J.P. Goldsmith. Oxygen Therapy in Preterm Infants: Hitting the Target. Pediatrics 2006;118;1740. See also, e.g., an analysis of the literature performed for the Cochrane Collaboration. L.M. Askie, D.J. Henderson)
3) Study protocol: “Thus, it is necessary to determine if lower oxygenation levels that may prevent ROP and [chronic lung disease] are deleterious for brain development and result in impaired neurologic outcome.” (p.2 “Background,” 2004 protocol)”
4) Informed consent requires that ANY reasonably foreseeable risks or discomforts to the subject be described.
OHRP Letter:
a) The paragraph does not include any information about the prior research and analyses that had been done looking at the relationship between oxygen and ROP, and what that work indicates about how changing the oxygen range might affect whether an infant develops ROP.
b) The paragraph does not include any information about the prior research and analyses that had been done looking at the relationship between oxygen and mortality and other forms of morbidity (apart from developing ROP).
c) The paragraph does not identify any specific risk relating to randomizing infants to a high or low range of oxygen.
5) OHRP Letter:
The relationship between oxygen and development of severe retinopathy of prematurity had been examined for over 50 years. While the details of that relationship were not fully known, it was well recognized that changing a premature infant’s amount of exposure to oxygen could have an impact on a number of important health outcomes, including the development of severe eye disease (and possibly blindness); reduced neurologic development, including brain damage; chronic lung disease; and could even lead to death.
The SUPPORT study was designed as an interventional study. It specifically enrolled very premature infants and randomized them to one of two levels of oxygen. For many of those infants, the level of oxygen they received was different from what they would have received had they not participated in the study. A major purpose for doing this was to increase the likelihood that there would be a measurable difference in the outcomes of the two groups. The primary outcome of interest for the researchers was whether the infants would develop severe eye disease or would die before being discharged from the hospital.
The template for the consent form used in this study did not mention any risks relating to the randomization between the higher and lower levels of oxygen, instead suggesting 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.”
While it would have been unwarranted to predict, ahead of time, specific outcomes (i.e., which infants developed which outcomes), the researchers had sufficient available information to know, before conducting the study, that participation 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.
6) From the IRB perspective it is hard for me to conclude that listing risks as “unknown and confidentiality” fully informs the participant. To say that there is “no predictable increase in risk” may be true, but it does not seem very helpful to a parent considering if they want their child randomized to a treatment that their physician may not have chosen, except for the research. Consent is required to describe ANY reasonably foreseeable risks or discomforts. This study was done in order to be able to better predict the serious risks and therefore these risks were reasonably foreseeable.
Public Citizen (www.citizen.org/hrg2111) published an extensive critique of the SUPPORT informed consent and criticizes OHRP for being too lenient. It includes the actual informed consent documents from many of the study sites.
Harry McGee’s comment highlights a distinction that John Lantos makes in his discussion of SUPPORT, referenced in my post. Lantos allows that the goals of the study were to determine whether different positions in the “standard” range of oxygen support would provide an optimal balance of risks and benefits. This suggests that researchers had reason to believe that different locations within that range might well offer a different range of benefits and costs. However, he insists that, relative to what was known before the study, there was no basis for thinking that any position posed any different set of risks and benefits to any child eligible for the study than any other position would.
So far as I can tell, there is no clear disagreement on this issue among McGee, Lantos, and myself. Lantos is inclined to think that OHRP’s criticism of SUPPORT on the basis that study goals were not disclosed is unwarranted, in part because it is perilous to discourage participation in such a well-designed and significant study. McGee is inclined to think otherwise, in part because it is perilous not to provide parents with information about what might happen to their kids as a result of research participation. For reasons I developed in my post, I share McGee’s inclination; it seems to me that parents had respect-worthy reasons for wanting to know just what might happen as a result of enrolling their kids in the study. A fuller explanation to parents of what enrollment might mean does not strike me as overly chilling, but of course, even if it were to discourage enrollment, that wouldn’t be a good reason not to provide it; just the opposite. If the informed consent protocols used in SUPPORT can be defended by reference to this distinction, according, as it were, to the letter of the law, perhaps we need to change those letters.
“If we knew what we were doing it wouldn’t be called research” Albert Einstein
Interesting post on IRB Forum:
Subject: Re: Some thoughts about SUPPORT
Author: John H. Noble Jr. – Posted: 06/10/2013 08:16PM
Anonymous asked, “What were the pre-SUPPORT practices of the NICU re saturation levels? Were they all within the national norm? Did they review their records to examine the number of instances when they were not within that norm?
Had the SUPPORT researchers reported results for the control infants, as described on p. 16 of the SUPPORT protocol, the first of your questions would receive answer—pre-SUPPORT practices re: saturation levels were not described. The protocol states, “Control infants are to be treated using an approach considered similar (bold italics added) to current standard of care. It is anticipated that the majority of infants will be intubated and receive surfactant in the delivery room.” Control infants received prophylactic early surfactant in combination with randomized assignment of static low versus high oxygen saturation levels. Thus, I conclude that the SUPPORT similar standard of care was not as usually interpreted to mean neonatologist-titrated interventions based on continuous observations of patient, aided by accurate metrics of relevant monitoring equipment. The MCH Healthcare Neonatal Intensive Care Unit Policy and Procedure Manual ($229.99 annual subscription) provides fairly detailed policies and procedures to implement them in this regard. Google search did uncover the website of the International Association of Neonatologists with a statement of core values, including “Standards of Care, Practice, and Education,” but no actual document containing them.
The two New England Journal of Medicine reports of the results of the SUPPORT trial raise many questions about the representativeness of the study sample and its clinical generalizability. It starts by the profiling of 3546 infants (3127 pregnancies) who were assessed for eligibility. Of this number, 2230 (62.9%) were excluded for various reasons, including 235 (6.6%) who did not meet eligibility criteria, 699 who were eligible, but consent was not sought and 68 who had consent provided but did not undergo randomization (767 total (21.6%). No reason is given for why 767 (21.6% ) of the potentially consented eligible pool were excluded from the study. The principal eligibility appears as “24 0/7th to 27 6/7ths weeks at birth for which a decision has been made to provide full resuscitation as required.”
Absent documentation by the researchers of the whys and wherefores for excluding consented eligible infants–as one trained in the canons of empirical science—I cannot suspend disbelief about the representativeness and clinical generalizability of the SUPPORT study. What will lead me to suspend disbelief beyond an ugly rant against my rationality? The reviewing local IRBs in this experiment, as far as I can tell on the basis of lots of evidence about the nature of IRB functioning, do not pay much attention to the quality of the science of the research proposals that they evaluate but instead depend on the representations and reputations of the researchers. The informed consent form’s adequate protection against legal liability for researchers, sponsors, and the research organization is mostly the bottom-line consideration. Thank god for the exceptions! Most every successful lawsuit for whatever cause involves a research proposal that passed IRB muster.
How do we remove the suspension of disbelief? The OHRP oversight agency and researchers must document the whys and wherefores for excluding consented eligible infants. The burden of proof is on the researchers to show that they did not “cream” or manipulate the potential eligible infant population to optimize statistically significant findings. In the hierarchy of threats to inference, statistical significance testing is minor. It is easy enough to construct an eligible population that will optimize the likelihood of obtaining statistically significant differences between experimental and so-called control groups. Eliminating a valid control group works wonders!
Last, let me say that the IRB Forum respondents are far more civil and rational than the so-called medical professionals whom I’ve encountered on the Hastings Center blog site. While acknowledging my position that one respondent had erroneously argued the validity of SUPPORT findings on the basis of superior outcomes for non-study participants who were not randomized into that non-study status, the ranting response wildly accused critics, including the Public Citizen Health Research Group and the Alliance for Human Research Protection, as irresponsible anti-science no-nothings. One rant referred to the allegations of critics as “Bull Shit.” I wonder in whose bag this guy is?!
I also do wonder about the research competence, professionalism, and mentality of such ranters. More important, though, are the stakes for reporting of results based on unbiased data to support evidence-based medicine and treatment of the most vulnerable of infants in neonatal intensive care units (NICUs).
Last, I’m happy that I’m retired and not subject to recrimination by a university or other research organization IRB or members of my profession for asking uncomfortable questions or expressing opinions that the powers that be within and outside a research organization hustling grant and contract funding may deem threatening or heretical. I’m not “anonymous,” but myself by name. Bring it on, I’m retired and have lots of knowledge and a network of experts with whom to confer, energy, and time to dig more deeply than you can imagine.
JHN
jhnoble@verizon.net
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