Public Citizen: The SUPPORT Study was Even Worse than We Thought
Research
Michael Carome and Sidney Wolfe, 05/21/2013

Public Citizen: The SUPPORT Study was Even Worse than We Thought

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In his April 18 Bioethics Forum article, John Lantos criticized the findings of the Department of Health and Human Services Office for Human Research Protections that the conduct of the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) violated HHS regulations regarding informed consent. He also attacked Public Citizen’s position that the conduct of the study was unethical because parents of babies enrolled in the study were not informed of the purpose, nature, and risks of the research.

Lantos claimed that OHRP and Public Citizen were “deeply misinformed” about the design of the SUPPORT study. We acknowledge that as of April 10 when we first wrote to HHS Secretary Kathleen Sebelius about this study, Public Citizen only had access to limited excerpts from the study protocol and one institutional review board-approved consent form that were presented in OHRP’s March 7, 2013, letter to the University of Alabama at Birmingham (UAB).    

We subsequently obtained the complete SUPPORT study protocol and consent forms that were approved by 22 IRBs and used at approximately two dozen neonatal intensive care units . Our analysis of these documents not only affirms the appropriateness of OHRP’s determination that the UAB consent form failed to mention the reasonably foreseeable serious risks of the oxygen experiment, but it demonstrates that the consent form deficiencies were far more significant than those discussed in OHRP’s letter. Indeed, the important, material factual omissions from the consent forms, combined with mischaracterizations of the study, misled the parents of babies enrolled in the study about the true purpose, nature, and risks of the research. 

Study Overview

The study involved two simultaneous complex experiments. In one experiment, the babies were randomly divided into two groups, each receiving a different treatment to assist breathing. Babies in one group were treated with a face mask, called a continuous positive airway pressure (CPAP) mask. Babies in the other group were intubated and given the drug surfactant, which helps lungs stay open, and placed on mechanical ventilation.

For the other experiment, babies in both the CPAP and mechanical-ventilation groups were further randomly divided into a low-oxygen group and a high-oxygen group (the oxygen experiment). For the low-oxygen group, the investigators tried to maintain oxygen saturation levels in a low target range (85% to 89%), and for the high-oxygen group in a high target range (91% to 95%), rather than adjust each baby’s oxygen levels within the broader range of 85% to 95% — identified as the “normal” range by the investigators — to meet the baby’s individual needs, as would have been the case if the baby had not been in the study.

Consent Form Deficiencies

The serious deficiencies in the SUPPORT study consent forms become readily apparent when information in the protocol, as well as statements made by the investigators, is compared with information in the consent forms.

The oxygen experiment’s purpose was to test the hypothesis that “relative to infants managed with a higher Sp02 range . . . the use of a lower Po02 range (85% to 89%) will result in an increased survival without the occurrence of threshold ROP [retinopathy of prematurity, which can  cause blindness] and/or the need for surgical intervention.” Consistent with this hypothesis, the primary endpoint was a composite of death and ROP. Knowing that death was a key endpoint was critical for understanding the true purpose of the experiment.

In contrast to the protocol, while most of the consent forms noted that the purpose of the oxygen experiment was to assess the effects of the two oxygen targets on the incidence of ROP, none disclosed that another key purpose was to determine whether babies were more likely to die in the low- or high-oxygen group. The incomplete descriptions of the purpose of the oxygen experiment in the consent forms were therefore misleading.

The protocol summarized the oxygen experiment’s design as follows: “A prospective comparison of a lower SpO2 range (85% to 89%) with a higher more conventional SpO2 range (91% to 95%) until the infant is no longer requiring ventilatory support or oxygen.”

Thus, the investigators themselves considered the high oxygen saturation target range to be “more conventional” treatment for premature babies receiving routine standard of care, which implicitly meant that the low oxygen saturation target range was more unconventional.

This clear protocol characterization of the relative difference between the low- and high-oxygen targets contrasts sharply with the statements in most of the consent forms implying that both ranges were equally conventional, such as the following from the UAB consent form: “[Both target] saturations are considered normal ranges for premature infants.”

Condensed, incomplete descriptions of oxygen treatment, such as the one above, were misleading because they lacked an appropriately detailed explanation of the usual standard of care in critically ill premature infants and the segment of the broader 85% to 95% “normal” target oxygen saturation range that was most commonly targeted as part of routine NICU care at the medical centers conducting the study. Of note, one consent form suggested that an oxygen saturation range of 88% to 92% was most commonly targeted in many NICUs, whereas another stated that the saturation was usually targeted at 88% to 94%. Disclosures of the oxygen saturation ranges most commonly targeted for premature infants at a particular institution should have been included in all consent forms to allow parents to have better understood how the experimental interventions would have altered the care of their babies.

A more disturbing component of the oxygen experiment was the procedure under which the medical team caring for each study baby was according to the protocol, intentionally given inaccurate information about the baby’s oxygen saturation levels by using pulse oximeters miscalibrated across the wide range of oxygen saturations between 85% and 95%. Medical teams apparently were instructed to try to maintain the oxygen saturation for study babies between displayed readings of 88% and 92%. However, for any displayed oxygen saturation level between 88% and 92%, the actual oxygen saturation was 85% to 89% in the low oxygen group and 91% to 95% in the high-oxygen group. The 5% to 6% difference in the actual saturation levels between groups represented clinically important differences in the babies’ actual blood oxygen content, which certainly could have adversely impacted clinical decisions made by the medical teams caring for these babies.

Half of the 22 IRB-approved consent forms did not disclose that the medical teams caring for babies in this experiment would be intentionally given inaccurate information about the babies’ oxygen levels. Moreover, none of the consent forms described how this experimental procedure could have impacted important clinical decisions related to the babies’ care.

The combined experimental procedures of randomly assigning infants to interventions using narrow low or high oxygen saturation targets plus the use of miscalibrated pulse oximeters represented a clear departure from the standard of care that these critically ill infants would have received had they not been enrolled in the study. Yet, the majority of the consent forms included statements assuring subjects’ parents that all research procedures used in the study were “standard of care.”

Study risks

Surprisingly, the “Risks and Benefits” section of the study protocol listed no risks of the oxygen experiment. Nevertheless, other parts of the protocol, as well as recent statements made by the study investigators, reveal that the oxygen experiment posed significant risks to the premature infants who were enrolled.

For example, the “Background” section of the protocol indicated the following: “[O]xygen toxicity can result in increased risk for [chronic lung disease], retinopathy of prematurity (ROP) and other disorders. Alternatively, oxygen restriction may impair neurodevelopment.”

Some study investigators also recently stated: “Death was included in the primary outcome because it competes with retinopathy . . .

Thus, the investigators were aware when designing the study that manipulating oxygen therapy to target narrow low and high oxygen saturation ranges in premature infants could have had different effects on these acknowledged competing risks. Targeting the high-oxygen range could have increased the risk of ROP, whereas targeting the low-oxygen range could have increased the risk of brain injury and death. Furthermore, the study’s statistical analysis plan revealed that the death rate was an important variable to be measured for the oxygen experiment.

A small minority of the IRBs that reviewed the study actually appear to have recognized some of the risks posed by the oxygen experiment because two consent forms identified ROP as a risk of the high-oxygen group. However, all of the consent forms failed to disclose that death was a risk of the research, even though an increased risk of death was reasonably foreseeable based on the information presented in the protocol.

Finally, perhaps the most troubling aspect of the consent forms was the universal failure to disclose the additional reasonably foreseeable substantial risks of harm to the infants resulting from providing the medical teams with inaccurate information about the babies’ blood oxygen saturation levels. The blood oxygen saturation level is a critically important clinical parameter monitored in such patients. This experimental procedure had the potential to adversely impact important clinical decisions, such as whether to intubate a baby and start mechanical ventilation or whether to extubate an intubated baby and discontinue mechanical ventilation. Inappropriate decisions regarding intubation and extubation certainly could have exposed babies to foreseeable risks of harm. (For specific examples of how babies could have been harmed see: Carome M, Wolfe S, Macklin R. Report prepared for Secretary of Health and Human Services Kathleen Sebelius: http://www.citizen.org/documents/2124.pdf.)

The following protocol statement indicates that the investigators recognized the potential for inappropriate intubations and extubations in study infants: “CPAP infants who require intubation three times, for any criteria, will have all subsequent treatment including subsequent extubations and any further re-intubations performed using unit Standard of Care. This addition is to prevent such infants from being exposed to further protocol driven intubations and extubations.”

Even more disturbing, the majority of the consent forms included extraordinarily misleading statements like the following: “Because all of the treatments proposed in this study are standard of care, there is no expected increase in risk for your infant.”

Our conclusions

Lantos states that the “most important ethical issues for the future of clinical research . . . are the issues of honesty, transparency, and safety.” Public Citizen agrees. Disturbingly, the consent forms used in the SUPPORT study failed to present an honest and transparent disclosure of the purpose, nature, and risks of the oxygen experiment, thereby leading parents to believe the experiment was safer than it was.

It is neither OHRP’s determination nor Public Citizen’s critique regarding the study that poses a threat to biomedical research and the advancement of medical knowledge and innovation. Rather, the real threat to such scientific endeavors is unethical research, which undermines the public’s trust in the motives and conduct of researchers. Conformance with the fundamental ethical principles for conducting human subjects research must never be sacrificed in the quest to advance medical knowledge.

Lantos’s accusation that “criticism [of the study] . . . discredits bioethics” is completely without merit. The findings of consent-form deficiencies by OHRP and Public Citizen were well-founded and carefully explained. Indeed, as more information about the study has become available, the apparent degree of seriousness of the consent failures has only escalated. Attacking messengers who raise serious, well-reasoned concerns about the ethics of a study does not discredit bioethics. Instead, it discredits the attackers.

For a more detailed discussion of the problems with the SUPPORT study, see http://www.citizen.org/documents/2124.pdf.

Michael Carome, M.D., and Sidney Wolfe, M.D. are, respectively, Deputy Director and Director of Public Citizen’s Health Research Group.

Posted by Susan Gilbert at 05/21/2013 02:30:26 PM | 


Comments
The central question in this controversy comes down to this: At the time of the SUPPORT study’s initiation, what was a reasonably foreseeable risk?

The investigators, the IRBs, and the NICHD did not think that babies in the study were at higher risk of death than babies who were not in the study and so did not think that this needed to be disclosed. OHRP and Public Citizen do think that the babies were at higher risk and that therefore this risk needed to be disclosed. The simple fact is that that investigators, IRBs, and NICHD were right. Babies in the study had better outcomes than babies who were not in the study.

Drs. Carome and Wolfe point out all the ways that it could have turned out differently.
They write, “manipulating oxygen therapy to target narrow low and high oxygen saturation ranges in premature infants could have had different effects…” With regard to the experimental techniques, they write, “This experimental procedure had the potential to adversely impact important clinical decisions…” They write, “Inappropriate decisions regarding intubation and extubation certainly could have exposed babies to foreseeable risks of harm.” (Note: "Had the potential, could have, etc) Yes, these things could have happened. The investigators and IRBs had to decide whether or not such risks were reasonably foreseeable and thus a crucial element for a parent’s informed decision about whether or not to enroll their baby in the trial. Disclosing all possible risks, rather than reasonably foreseeable risks, is not an ethical requirement of research and does not empower patients. Foreseeing is not easy. Hindsight is much easier.

The odd thing about this controversy is that the investigators foresight is borne out by hindsight. The investigators' intuitions about reasonably foreseeable risks were borne out by the results. Maybe that is because the study was designed by leaders in the field from many different countries who were very knowledgeable about prior studies and current treatments.

Nevertheless, Drs. Carome and Wolfe think that both foresight and hindsight were flawed. They think that the consent forms were not just inadequate but egregiously inadequate. They believe that parents were denied important information that should have been part of their decision. Their call for a public apology by the Secretary of HHS suggests that the harms here were analogous to the harms of Tuskegee. They write that “the consent forms used in the SUPPORT study failed to present an honest and transparent disclosure of the purpose, nature, and risks of the oxygen experiment, thereby leading parents to believe the experiment was safer than it was.”

I disagree. I think the consent forms adequately conveyed the reasonably foreseeable risks of the study. I believe that parents were given appropriate and accurate information by which to make an informed decision about whether or not to enroll their babies in the study. I think that the information that they were given was based on the best information that was available at the time. And no information that has accrued since then suggests otherwise.

Had Drs. Carome and Wolfe been in charge, parents would have been given misleading or inaccurate information that might have led them to not enroll their babies in this safe and well-designed study. As a result, those babies and their parents would have been made worse off in the name of bioethics and patient protection. This would have been a tragedy for the babies and their parents and a huge step backwards for evidence-based neonatology.
Posted by: jlantos@cmh.edu ( Email ) at 5/22/2013 11:47 AM


Dr. Lantos continues to vigorously deny that anything was wrong with the consent forms for the SUPPORT study, yet in doing so he conveniently ignores many of the key points made in our May 21 commentary, and for the one point he does selectively address, he offers no cogent arguments in response.

With respect to the disclosure of the purpose of the study, we noted the following: "In contrast to the protocol, while most of the consent forms noted that the purpose of the oxygen experiment was to assess the effects of the two oxygen targets on the incidence of [retinopathy of prematurity (ROP)], none disclosed that another key purpose was to determine whether babies were more likely to die in the low- or high-oxygen group. The incomplete descriptions of the purpose of the oxygen experiment in the consent forms were therefore misleading."

Dr. Lantos offers no response to this criticism of the purpose statements in the study consent forms.

With respect to the nature of the research interventions, we noted the following:

"The protocol summarized the oxygen experiment’s design as follows: 'A prospective comparison of a lower SpO2 range (85% to 89%) with a higher more conventional SpO2 range (91% to 95%) until the infant is no longer requiring ventilatory support or oxygen.'

"Thus, the investigators themselves considered the high oxygen saturation target range to be 'more conventional' treatment for premature babies receiving routine standard of care, which implicitly meant that the low oxygen saturation target range was more unconventional.

"This clear protocol characterization of the relative difference between the low- and high-oxygen targets contrasts sharply with the statements in most of the consent forms implying that both ranges were equally conventional, such as the following from the UAB consent form: '[Both target] saturations are considered normal ranges for premature infants.'"

Dr. Lantos offers no response to the criticism that the consent forms failed to disclose to parents that the high-oxygen target was viewed by the investigators as the “more conventional” approach before the study was initiated.

Also with respect to the nature of the research, we noted the following:

"Half of the 22 IRB-approved consent forms did not disclose that the medical teams caring for babies in this experiment would be intentionally given inaccurate information about the babies’ oxygen levels. Moreover, none of the consent forms described how this experimental procedure could have impacted important clinical decisions related to the babies’ care.

"The combined experimental procedures of randomly assigning infants to interventions using narrow low or high oxygen saturation targets plus the use of miscalibrated pulse oximeters represented a clear departure from the standard of care that these critically ill infants would have received had they not been enrolled in the study. Yet, the majority of the consent forms included statements assuring subjects’ parents that all research procedures used in the study were 'standard of care.'"

Dr. Lantos offers no argument explaining how randomly assigning infants to interventions using narrow low- or high-oxygen saturation targets plus the use of miscalibrated pulse oximeters reasonably could have been construed as “standard of care.”

With respect to the risks of the research, we noted the following:

"For example, the 'Background' section of the protocol indicated the following: '[O]xygen toxicity can result in increased risk for [chronic lung disease], retinopathy of prematurity (ROP) and other disorders. Alternatively, oxygen restriction may impair neurodevelopment.'

"Some study investigators also recently stated: 'Death was included in the primary outcome because it competes with retinopathy . . .'

"Thus, the investigators were aware when designing the study that manipulating oxygen therapy to target narrow low and high oxygen saturation ranges in premature infants could have had different effects on these acknowledged competing risks. Targeting the high-oxygen range could have increased the risk of ROP, whereas targeting the low-oxygen range could have increased the risk of brain injury and death. Furthermore, the study’s statistical analysis plan revealed that the death rate was an important variable to be measured for the oxygen experiment."

In criticizing our (and OHRP’s) conclusion that the study consent forms failed to disclose the reasonably foreseeable risks of the research, Dr. Lantos ignores the above statements made by the investigators that establish the firm basis for concluding that ROP, brain injury, and death were reasonably foreseeable risks of the research. Instead, Dr. Lantos relies upon unsupported blanket denials that the risks simply were not foreseeable and a seriously flawed, post hoc comparison of outcomes in SUPPORT study subjects to infants not enrolled in the study. He also offers no rebuttal to our prior critiques of such post hoc comparisons.

Finally, Dr. Lantos offers no explanation for why the experimental procedure involving use of miscalibrated pulse oximeters did not pose reasonably foreseeable risks of harm to study subjects, despite the fact the investigators themselves acknowledged in the protocol that the study procedures, in contrast to “unit Standard of Care,” could have resulted in “protocol driven intubations and extubations.”

Dr. Lantos concludes his most recent defense of the SUPPORT study by stating, “Had Drs. Carome and Wolfe been in charge, parents would have been given misleading or inaccurate information that might have led them to not enroll their babies in this safe and well-designed study.” However, the following statements would not have been inaccurate or misleading:

• A key purpose of the study is to determine whether babies are more likely to die in the low- or high-oxygen group.
• The investigators conducting the study consider the high oxygen saturation target range to be “more conventional” treatment for extremely premature babies.
• Miscalibrated oxygen monitors would never be used for critically ill premature infants who are not enrolled in the study, and using such monitors may have important implications for your baby’s care.
• Babies assigned to the high-oxygen target group may have an increased risk of eye disease and blindness. Babies assigned to the low-oxygen target group may have an increased risk of brain injury and death.
• The use of miscalibrated oxygen monitors may result in some study babies undergoing unnecessary or inappropriate intubations and extubations and other study babies not undergoing these procedures when they are clinically appropriate.

We reject Dr. Lantos’s flimsy and extremely selective arguments as he seeks to defend the indefensible. The parents of study subjects were misled about the oxygen experiment by the exclusion of the above statements from the consent forms used in the SUPPORT study, as well as by the inclusion of other statements assuring the parents that all research procedures were standard of care and presented no increased risks to the babies.

We do agree with Dr. Lantos that had parents been provided with the above information — and had there been a sufficient consent procedure that ensured that the parents understood the research — many parents likely would have declined to enroll their babies in the study. One has to wonder whether the exclusion of such statements from the consent form was motivated by the desire to avoid alarming parents of prospective subjects about the true purpose, nature, and risks of the research.
Posted by: mcarome@citizen.org ( Email ) at 5/28/2013 4:25 PM


Dr. Lantos makes a specious inference in order to confront critics of the neonatal SUPPORT study, namely: "The simple fact is that that investigators, IRBs, and NICHD were right. Babies in the study had better outcomes than babies who were not in the study." In point of fact, the babies who were excluded from the eligible pool might well have been in poorer condition than those selected for inclusion and thus were excluded for that reason. However, there is no way of knowing the truth of the matter unless ALL THREE GROUPS had consisted of randomly assigned subjects--those eligible and randomly assigned to either (1) extreme higher oxygen saturation, or (2) extreme lower oxygen saturation, or (3) those declared ineligible and excluded from the study. Comparing differences between two randomly assigned groups and any non-randomized third group is statistically erroneous. Only randomization protects against selection bias. Thus, Dr. Lantos' argument against the neonatal SUPPORT study's critics should be rejected as illogical and specious--indeed, a straw on which to base an unjustifiable ad hominem attack on the neonatal SUPPORT study's critics. One wonders why the researchers had not created a proper randomized "standard of care" control group in which physicians were free to titrate oxygen and other interventions according to their sense of patient need. If the researchers postulate that the standard of care is faulty, then they should explicitly test the assertion by means of a properly constructed control group . . . and make sure to fully inform and obtain the consent of the parents whose babies will be put to the test.
Posted by: jhnoble@verizon.net ( Email ) at 5/31/2013 12:13 AM


The comments by Public Citizen (and jhnoble) reveal a complete lack of understanding of neonatology and of clinical research in general. Clinical research involves evaluating and comparing different approaches to treatment in order to figure out which is preferable. It requires uncertainty as to the best approach, and will often produce surprises. If there were no surprises then there should be no research, if we already knew the answers then it would indeed be unethical to perform the research.
Neonatology is a specialty in which a lot of clinical decisions are made by protocol. There was no valid reason why a protocol for care before the SUPPORT trial should have excluded 85 to 89% as a target range for saturations in very preterm infants, and indeed some centers were using those very target ranges, and some even lower.
We do not individualize oxygen saturation targets in the very preterm infant. There is no data on which to base a specific target for a specific baby. In the case where an individual physician believes that a specific target range is preferable for a very preterm baby, then he is ethically bound to remove the baby from the study, to use a normal pulse oximeter and prescribe the range that he believes (even lacking any evidence) to be the best treatment for the baby. In the COT trial, just published in JAMA (Schmidt B, et al.: Effects of targeting higher vs lower arterial oxygen saturations on death or disability in extremely preterm infants: A randomized clinical trial. JAMA 2013:1-10), which used very similar procedures, there were indeed 35 babies out of the 1200 randomized (supplemental information on-line) who were taken out of the study at physician request, 17 turned out to have been in the low saturation group, and 18 in the high saturation group.
So the study compared two groups of babies, both of whom received ‘standard of care’. This was not a comparison of a standard of care to something new and innovative, it was comparing two approaches which were both considered acceptable.
Public citizen are also mistaken in assuming that the study was set up to detect differences in mortality. The reason for including mortality in the primary outcome variable is that death and retinopathy are competing outcomes. In other words if you die before screening then you cannot be diagnosed with RoP. Thus a combined outcome is created for the purposes of having a dichotomous variable that can be readily analyzed. There was no prior reason for supposing that (as public citizen suggest) babies in the low saturation group would have an ‘increased risk of brain injury or death’ in fact a large number of observational studies performed before SUPPORT showed NO increase in brain injury or death. In fact, in contrast, many of the investigators thought that one possibility was that brain injury or death might be higher in the high saturation group.
There was also no good reason before the study to suppose that very severe retinopathy would be higher at 91 to 95% than at 85 to 89%. The old data showing toxicity of oxygen was from a very different era of neonatology, where prolonged 100% oxygen for babies who would nowadays be considered mildly premature, was compared to a maximum of 40%, which was only given if the baby was blue. Such old data are not applicable to 21st century neonatology, the comment that there were substantial prior data to predict these findings is just untrue.
In a similar vein Public Citizen are deeply mistaken about the effects of having a masked pulse oximeter on respiratory management. Much respiratory management is protocol driven in the NICU also. We wean and extubate, or re-intubate, infants based on NICU practice. As the target range for saturations was variable before the study, and the protocols for respiratory management were also variable, the ‘protocol-driven decisions’ to intubate an infant, or to extubate were entirely within the range of normal NICU practice. Any physician who truly thought, for example, that it was incorrect to extubate an infant when the study protocol told him to, is ethically obligated to deviate from the protocol. Such ‘protocol violations’ occur in every large study. The fact that there were very few violations is an indication that the physicians felt that the study protocol driven decisions were reasonable for their patients.
Dr Carome and Wolfe have maligned the ethics and integrity of many thousands of neonatologists, research nurses and assistants, neonatal trainees and their research ethics boards. Not only those involved in SUPPORT, but also in the very similar BOOST2 UK, BOOST2 Australia and New Zealand and COT trials.
There is a grain of truth in what jhnoble states; randomization is required to balance groups, which is why we do it. A comparison with un-enrolled infants is likely to be biased in several ways, but his suggestion that a 3rd ‘standard of care’ group should have been enrolled also shows his ignorance of neonatal care: there were already 2 ‘standard of care’ groups. Titrating oxygen and other interventions according to our ‘sense of patient need’ is not what we do. He has obviously never cared for a sick preterm infant, they cannot tell you whether a saturation of 87% or 93% is better for them, nor did we have any way of deciding, before SUPPORT and the other trials. Referring to these small differences in saturation as being ‘extreme’ is also evidence of his or her ignorance, the differences were well within usual care, even higher and even lower limits were in place in many NICUs.
The SUPPORT investigators and the investigators of the other studies that I mentioned above should be congratulated, not vilified, for answering a question that has plagued the neonatal community, and the babies that we care for, since pulse oximeters were introduced. This research will save many thousands of tiny preterm babies who will no longer be exposed to a level of oxygen saturation that many thought was safe, or indeed preferable, but which we now know increases mortality. The trust of the parents of the enrolled infants was entirely justified, attacks on that trust by Public Citizen can only have adverse effects for the future for premature babies.
Posted by: keith.barrington@umontreal.cA ( Email | Visit ) at 5/31/2013 10:00 AM


Thanks to Dr. Barrington for adding a bit of reality to what is, otherwise, a fairly surrealistic discussion.

I agree with jhnoble that the comparison group of babies who were not enrolled in the SUPPORT study is flawed. In designing a study, the best way to determine the risks is for experts in the field to review all the existing data about those risks. In this case, there was virtual unanimity among all of the most knowledgeable neonatologists in the world that the risk of targeting 02 sats in the high 80s versus 02 sats in the low 90s was negligible. That is what justified the conduct of this study. The finding of a difference in mortality was a surprise, but an important one. It is only following the baseless accusations of Drs. Wolfe and Carome that doctors should have expected this that one looks for other data that might help one interpret these otherwise unexpected findings. Since this was the only prospective randomized trial that was conducted looking at oxygen levels for premature babies in the last fifty years, there is no other trial to look at. So one must look at other possible comparison groups. This is an increasingly common approach to comparative effectiveness research. I refer jhnoble to these articles discussing the relative strengths – and weaknesses – of prospective randomized trials compared to observational data:

John Concato, Study Design and “Evidence” in Patient-oriented Research, American Journal of Respiratory and Critical Care Medicine, 2013, 187, 11, 1167onlinelibrary.wiley.com/doi/10.1002/pds.3245

D'Agostino RB Jr., D'Agostino RB Sr. Estimating treatment effects using observational data. JAMA 2007; 297: 314–316.

Rawlings M. De Testimonio: On the evidence for decisions about the use of therapeutic interventions. Lancet 2008; 372: 2152–2161.

Borgerson K. Valuing evidence. Bias and the evidence hierarchy of evidence-based medicine. Perspect Biol Med 2009; 52: 218–233.

What one finds when one looks at those comparison groups is that THERE IS NO PUBLISHED DATA FROM ANY GROUP OF 24-27 WEEK PREMATURE BABIES IN WHICH THE MORTALITY RATE IS AS LOW OR LOWER AS IT WAS IN EITHER ARM OF THE SUPPORT STUDY. NO PUBLISHED DATA! So, one can impugn the integrity of the investigators all you want and suggest that they should have known what has never, ever been shown. But, at some point, if the argument is going to be based on reality, then you have to confront the data.

Wolfe and Carome’s arguments are similarly flawed. Just because they say something over and over again does not make it true. So, they can repeat that “A key purpose of the study is to determine whether babies are more likely to die in the low- or high-oxygen group.” That is nowhere in the protocol and nowhere in the published reports, it was not a primary endpoint of the study, and was included in the combined primary endpoint for the reasons that Dr. Barrington explains.

Yes, the investigators used the phrase “more conventional.” But it is not clear what that means, exactly. A 2004 study of common practices in NICUs in the United States showed that doctors targeted oxygen saturations ranging from 82% to 100%. (Journal of Perinatology (2004) 24, 164–168. doi:10.1038/sj.jp.7211067). That would seem to be a better description of what was conventional at the time than a single phrase in a study protocol. But here, the question would be this: do you believe the hundreds (literally hundreds) of neonatologists around the world who believed that this was an important research question because they did not know the answer, or do you believe those who question the neonatologists sincerity about their uncertainty because the study yielded surprising results.

In spite of these disagreements, we do have some common ground. I agree that the consent form should have said, as Wolfe and Carome suggest, that “Babies assigned to the high-oxygen target group may have an increased risk of eye disease and blindness. Babies assigned to the low-oxygen target group may have an increased risk of brain injury and death.” But it should have continued and added, “Babies in the high-oxygen target group may not have an increased risk of eye disease or blindness. Babies in the low oxygen group may not have an increased risk of brain injury or death. Babies in the study may or may not have a higher or lower risk of any of these problems than babies who are not in the study. If we knew which treatment would lead to these problems or which would prevent them, we would not be doing the study. So whether you are in the study or out, you are taking a chance.”

More common ground: I agree, too, that the consent forms should have described the technique by which doctors and nurses would be masked regarding the actual oxygen saturations. That was done in similar studies that were conducted in Australia, New Zealand, the UK and other countries. It did not lead parents to opt out. Their consent rates were just as high as here.

There is no evidence that the use of the altered oxygen monitors led to unnecessary or inappropriate intubations or extubations. But of course, Wolfe and Carome never claim that these complications actually happened. They just say that the study design “may” have led to them. Or it may not have.

The key lesson to be learned from this study and the controversy surrounding it is that comparative effectiveness research is complicated. It challenges our traditional notion of research risks. The situation that prevailed prior to the SUPPORT study is a common one – doctors in different centers use different therapies to treat the same disease. It is difficult to study such therapies. But it is important to study them rigorously, ethically, and only when fully informed patients consent (or give permission for their babies) to become research subjects. Carefully studying it is the best way figure out how to best protect patients from the harms of non-validated treatment. And protecting patients from harm is, I hope, a goal that everybody in this discussion shares.
Posted by: jlantos@cmh.edu ( Email ) at 6/3/2013 5:34 PM


RESPONSE TO DR. BARRINGTON’S POSTING

Dr. Barrington unfortunately continues to rely on ad hominem proclamations against Public Citizen in his response to our letters rather than the facts as presented in the SUPPORT study protocol and consent forms.

For example, he stated in his most recent posting that “Public [C]itizen are [sic] also mistaken in assuming that the study was set up to detect differences in mortality.” However, this statement does not take into account the following facts, which are apparent upon reading the SUPPORT study protocol:

• Death was one of the two components of the composite primary endpoint.
• The percentage of infants with death or neurodevelopmental impairment was a pre-specified secondary outcome measure.
• Sample size calculations for the oxygen experiment were based on assumptions about the combined rate of death and retinopathy for each group.
• Death was one of four specified serious adverse events that “may be related to the study maneuver” and was to be evaluated on a monthly basis as part of continuous safety monitoring. If a difference in the incidence of death had been determined to be 5%-10% greater in any arm of the study, this information was to have been provided immediately to the study principal investigator and the data safety monitoring committee for consideration of termination of the study or treatment arm.

Given the above facts, the consent forms should have explained to parents of study babies that the purpose of the oxygen experiment was to determine whether premature infants were more likely to develop retinopathy or suffer death when blood oxygen levels were targeted at either the low or high levels to be tested in the experiment, but none of the consent forms did.

Likewise, Dr. Barrington stated that “Public Citizen are [sic] deeply mistaken about the effects of having a masked pulse oximeter on respiratory management … the ‘protocol-driven decisions’ to intubate an infant, or to extubate were entirely within the range of normal NICU practice.” However, if one examines the facts, it is not within the range of normal NICU practice to make decisions about intubation, extubation, or supplemental oxygen concentrations (FIO2) based, in whole or in part, on intentionally miscalibrated pulse oximeters. Unlike in standard NICU practice, the pulse oximeters in the SUPPORT study displayed inaccurate readings that represented one of two oxygen saturation levels that differed by as much as 6 percentage points for any given actual saturation levels between 85% and 95%, and the medical team was blinded to the actual oxygen saturation level of each infant. For example, an actual level of 89% would have been displayed as 86% on the pulse oximeters for the high-oxygen group, indicating that the infant may not be doing well and may need a higher FIO2 to breathe, intubation if not already intubated, or a delay in extubation if already intubated. In the low-oxygen arm, the same actual level of 89% would have been displayed as 92%, indicating that the infant may be doing well enough to consider lowering the FIO2 or extubating the infant if already intubated.

The SUPPORT study protocol stated that “CPAP infants who require intubation three times, for any criteria, will have all subsequent treatment including subsequent extubations and any further re-intubations performed using unit Standard of Care. This addition is to prevent such infants from being exposed to further protocol driven intubations and extubations.” Such statements were a clear acknowledgement by the investigators that the criteria specified in the research protocol for intubating and extubating babies differed from the “standard of care.” The consent forms failed to explain to parents of subjects the potential for, and risks of, protocol-driven intubations and extubations.

Finally, Dr. Barrington observed that “many of the investigators thought that one possibility was that brain injury or death might be higher in the high saturation group.” Although it seems more plausible to us that the low-oxygen group would have been more likely to have an increased risk of death or brain injury than the high-oxygen group, if the investigators felt there was a plausible basis for concluding that the high-oxygen group might have a higher risk of death or brain injury, then the consent forms should have identified these as among the reasonably foreseeable risks of being randomly assigned to the high-oxygen group.

RESPONSE TO DR. LANTOS’S JUNE 3 POSTING

We are somewhat encouraged by Dr. Lantos’s most recent comments suggesting common ground between us. He appears to finally acknowledge some of the fundamental deficiencies of the consent forms for the SUPPORT study that we and OHRP have highlighted — in particular, the failure of the forms to adequately describe important aspects of the experimental interventions
Posted by: mcarome@citizen.org ( Email ) at 6/5/2013 11:57 AM


Reposting of RESPONSE TO DR. LANTOS’S JUNE 3 POSTING (part of last sentence in original posting got cutoff)

We are somewhat encouraged by Dr. Lantos’s most recent comments suggesting common ground between us. He appears to finally acknowledge some of the fundamental deficiencies of the consent forms for the SUPPORT study that we and OHRP have highlighted — in particular, the failure of the forms to adequately describe important aspects of the experimental interventions and the risks of the research.
Posted by: mcarome@citizen.org ( Email ) at 6/5/2013 12:20 PM


Dr Carome continues to misrepresent this study, he also clearly does not understand the term 'ad hominem' which he has accused me and Dr Lantos of. I have never attacked Dr Carome's personal integrity, nor his personality. I am attacking his opinions. That is not ad hominem, that is appropriate debate. One could question 'full of shit' a term I used on my website, that colorful term is generally understood to mean that your opinion has no basis in fact.
To state that you are mistaken, misled, or lack understanding, is not to malign you as a person,it is to point out that I think you are wrong.

The use of the masked pulse oximeters which seems to be agitating you so much, was a way to mask the dose of oxygen given. But to follow your logic, no blinded studies could ever be performed. A blinded comparison of a beta-blocker to an angiotensin blocker for hypertension as one example, according to your logic would be unethical, as the doctors wouldn't know what to do if the patients hypertension was not controlled.
You again clearly show your lack of understanding (not ad hominem, appropriate debate) when you suggest that the instruction to follow 'unit standard of care', at a certain point in the protocol means that previous interventions were not standard of care.
That is another misapprehension. Unit standard of care in neonatology usually means 'arbitrary local protocols created to standardize practice despite the lack of an evidence base' and not 'Standard-Of-Care', which is a standard of practice proven to be the best course of treatment.
There are many reasons why the higher saturation target may have had worse long term developmental outcomes, which we have now proven is not the case.
Hyperoxia and the resultant oxidative injury has been though to be important in the pathogenesis of brain injury, both directly and indirectly though an increase (which we thought was a possibility) of lung injury. BPD being associated with both mortality and neurodevelopmental impairment.

The importance of SUPPORT and the poverty of the arguments of Public Citizen (which I will continue to use as a collective term [sic] as it is clearly a group of individuals)is demonstrated by the recent change in the guidelines of the European Working Group. As recently as 2010, they recommended a saturation target range of 85 to 93%. That is good evidence that no-one thought that the high 80's were risky, and indeed may well be preferable. As of 2 weeks ago, that group has changed their recommendations to 90 to 95%, largely as a result of this impeccably ethical study.

Fortunately OHRP have now seen sense, and withdrawn the sanctions against the university of Alabama.
Posted by: keith.barrington@umontreal.cA ( Email | Visit ) at 6/6/2013 3:01 PM


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Nevertheless, Drs. Carome and Wolfe think that both foresight and hindsight were flawed. They think that the consent forms were not just inadequate but egregiously inadequate. They believe that parents were denied important information that should have been part of their decision. Their call for a public apology by the Secretary of HHS suggests that the harms here were analogous to the harms of Tuskegee. They write that “the consent forms used in the SUPPORT study failed to present an honest and transparent disclosure of the purpose, nature, and risks of the oxygen experiment, thereby leading parents to believe the experiment was safer than it was.”

Read more: http://thehastingscenter.org/Bioethicsforum/Post.aspx?id=6367&blogid=140#ixzz3AjfDRFA6
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The use of the masked pulse oximeters which seems to be agitating you so much, was a way to mask the dose of oxygen given. But to follow your logic, no blinded studies could ever be performed. A blinded comparison of a beta-blocker to an angiotensin blocker for hypertension as one example, according to your logic would be unethical, as the doctors wouldn't know what to do if the patients hypertension was not controlled.
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Dr. Barrington unfortunately continues to rely on ad hominem proclamations against Public Citizen in his response to our letters rather than the facts as presented in the SUPPORT study protocol and consent forms.
Posted by: yronen4@gmail.com ( Email | Visit ) at 8/29/2014 9:37 AM


The use of the masked pulse oximeters which seems to be agitating you so much, was a way to mask the dose of oxygen given. But to follow your logic, no blinded studies could ever be performed. A blinded comparison of a beta-blocker to an angiotensin blocker for hypertension as one example, according to your logic would be unethical, as the doctors wouldn't know what to do if the patients hypertension was not controlled.
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