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04/18/2013

OHRP and Public Citizen Are Wrong about Neonatal Research on Oxygen Therapy

On March 7, 2013, the federal Office of Human Research Protections notified the
principal investigator of the Surfactant, Positive Pressure, Oxygenation Randomized
Trial (SUPPORT) that “the conduct of this study was in violation of the
regulatory requirements for informed consent, stemming from the failure to
describe the reasonably foreseeable risks of blindness, neurological damage and
death.” OHRP claimed that the consent form should have explained that the
study, a clinical trial that studied oxygen therapy for premature babies “involves
substantial risks,” and 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.”

On
April 10, 2013, the advocacy group Public Citizen reacted to OHRP’s findings
with a letter to Kathleen Sibelius, director of Health and Human Services.
Public citizen criticized HHS for being too mild in its critique and too
lenient in its proposed remedy. It claimed that the study was “highly
unethical” because it “exposed 1,316 extremely premature infants to increased
risks of either death or retinal damage.” It also claimed that egregious
omissions in the informed consent process “caused parents to enroll their
premature infants in this experiment under the false pretense that it was much
safer for their infants than was known to be the case.” Public Citizen’s
critiques go beyond informed consent. They suggest that the study should never
have been done in the first place because enough was already known about oxygen
therapy that “any study comparing the two experimental target levels of oxygen
saturation would be both unethical and not compliant with requirements of HHS
regulations.” Public Citizen demanded that the directors of both HHS and NIH
personally apologize to all of the parents who enrolled their babies in the
study.

OHRP and Public Citizen are deeply misinformed about the design of SUPPORT, about
the well-being of the infants enrolled in it, and about oxygen therapy for
neonates generally. Their criticisms of the study are not only off-target, but
dangerous.

In the study, infants were randomized to doses of oxygen that would maintain their
oxygen saturation levels at either 85-89% or 91-95%. At the time, standard care
was to keep infants somewhere in the range between 85% and 95%, without any
greater specificity. According to OHRP, the consent form accurately described
this as the normal range for oxygen saturations and accurately stated that all
infants who were in the study, as well as those who were not, would receive
oxygen at concentrations that would keep oxygen saturations between 85%-95%.

At the time the study was designed and conducted, there was wide variation in
standard practices of oxygen administration throughout the world. As one
scholarly review of such therapy noted, “NICUs in the US today have a wide
range of SpO2 [oxygen saturation] guidelines… A randomized, controlled trial is
needed to establish a safe upper limit of SpO2 in the premature infant at risk
for developing ROP [retinopathy of prematurity].”(1) Most clinicians
and investigators at the time believed that lower oxygen levels were safer than
higher ones in that they protected infants from retinopathy without increasing
mortality. Very few people would have guessed that lower oxygen levels would
lead to increased mortality, although many hoped that it would lead to lower
levels of retinopathy. The SUPPORT study was designed to determine whether
these beliefs and hopes were true. The consent form thus focused on ROP and
stated, “the benefit of higher versus lower levels of oxygenation in infants,
especially for premature infants, is not known.”

As it turned out, the study showed that the mortality rate was higher in the lower
oxygen group than in the higher oxygen group. This surprising finding has now
led OHRP to conclude retrospectively that the consent form was inadequate and
for Public Citizen to conclude that the study was unethical and that the
parents of babies who were enrolled deserve an apology. I believe that both
OHRP and Public Citizen are learning the wrong lessons and drawing the wrong
conclusions. To see why, I focus on three questions that bear on the ethics of
this study and of neonatal research more generally: 1) Was the study design
ethical and appropriate at the outset? 2) Were babies in the study harmed? and
3) Was the consent form adequate?

Was the SUPPORT study design ethical and appropriate at its outset?

Public Citizen says no. OHRP and the investigators (and their IRBs) say yes. OHRP and
the investigators are right. At the time of the study design, there was
significant uncertainty within the professional community about the optimum
level of oxygen to provide to premature babies. In 2002, Tin reviewed the
available data and concluded, “Oxygen must have been given to more infants than
any other medicinal product in the last 60 years. Despite that, we still know
very little about how much infants actually need, or how much it is wise to
give. The depth of our ignorance is really quite embarrassing.”(2) Silverman
echoed these sentiments, noting that “the optimum range of oxygenation… remains
to this day, unknown.”(3) The recognition of the need for better data
was not limited to the United States. An international consortium of
researchers in neonatology recognized the need for – and conducted – similar
trials. In fact, this is the only time in the history of neonatology when
researchers around the world acknowledged the urgent need for a prospective
randomized trial. There was clearly a state of “community equipoise” about
oxygen dosing. Studies of the effects of oxygen on survival, retinopathy, and
long-term neurological outcome were essential and ethically appropriate.

Were babies in the study at higher risk than babies who were not in the study?

Public Citizen and OHRP say yes. The investigators and IRBs say no. The investigators
and IRBs are right. Every baby in the study received treatment that could have
and perhaps would have been given to babies who were not enrolled in the trial.
At the outste, nobody knew which treatment was safer. Babies who were
randomized to one treatment or the other were thought to be at no higher risk
of a bad outcome (or likely to have a good outcome) than babies whose treatment
was decided based on clinical judgment. This was true at the beginning of the
study and, we now know, it remains true now that the data have been analyzed.

How do we know? The fact that this study was conducted within the NICHD Neonatal
Research Network actually allows the risk of the study to be quantified. That
is because the network collects data on all babies born at these gestational
ages, whether they are in a study or not. The data for babies in the study, and
for all babies treated at these same hospitals, can be found in two papers, one
in the New England Journal of Medicine and one in Pediatrics. The first,
published May 10, 2010, reported survival rates and rates of severe eye disease
for all babies in the SUPPORT study.(4) The other, published August
23, 2010, reported the same outcomes for all babies in the neonatal research
network (some of whom were in the SUPPORT trial, most of whom were not).(5)
Here is what they show. The babies in the “low oxygen” arm of the clinical
trial had a mortality rate of 19.9%. The babies in the “high oxygen” arm of the
study had a mortality rate of 16.2%. Babies in the network overall had a
mortality rate of 24%. For severe retinopathy, the numbers are 8.6% (low oxygen
group), 17.9% (high oxygen group) and 24.1% (overall group). In other words,
babies in both arms of the study had higher survival rates and lower rates of
retinopathy than babies who were not in the study. The fact that some babies in
the study were in the overall group minimizes these differences. The true
differences were probably larger. Babies enrolled in the study were protected,
not endangered, by being in the study.

How can this be? There are a few possible explanations. It may have been a
selection bias, as Rich and colleagues suggested.(6) Since consent for
the study was sought prenatally, pregnant women who were receiving prenatal
care were more likely to enroll their babies in the study than women who did
not receive prenatal care. Another possible explanation is that damage from
oxygen toxicity is not related to the absolute level but instead is associated
with fluctuations in oxygen level, so that the babies in the trial, who
received more stable levels of oxygen than babies not in the trial, may have
been better off as a result. Or it may reflect the well-known but poorly
understood phenomenon of “inclusion benefit,” by which subjects in either arm
of a randomized trial have better outcomes than patients who were eligible for
the study but not enrolled.(7) The fact is, we don’t know why babies
in the trial did better. But we know that they did. Thus, to claim that babies
were harmed by being in the study and that those harms could have been avoided
by receiving conventional therapy is not just wrong, but dangerously wrong, as
it will discourage research, discourage parents from enrolling their children
in important research studies, and, by ignoring the actual data, suggest that
even completed research ought to be ignored.

In spite of this data, OHRP suggested that the consent form should have stated
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” (OHRP letter, page 10). Given the data, it is hard to
know how to interpret OHRP’s reasoning. Their position is apparently that
informed consent forms need to inform parents not only of known risks and of
possible risks, but also of risks that the investigators did not think were
possible – even after those risks have been shown not to exist. Essentially,
there is no risk that does not fall into this category. By these criteria, consent
forms should state something like, “ANY risk that you can imagine, and ALL
risks that you cannot even imagine, and EVEN RISKS THAT HAVE BEEN SHOWN NOT TO
EXIST, are possible as a result of participation in this study.”

Should the consent form have more accurately disclosed the goals of the study?

The goals of a study are different from the risks of the study. The SUPPORT study,
according to its protocol as cited by OHRP, was designed to determine whether
“a lower target range of oxygen saturation (85% to 89%), as compared with a
higher target range (91% to 95%), would reduce the incidence of the composite
outcome of severe retinopathy of prematurity or death among infants who were
born between 24 weeks of gestation and 27 weeks 6 days of gestation.” The
consent documents did not mention the goals of the study. They should have, and
they should have explained that nobody knew if either arm of the study would do
better or worse or whether babies in the study would do better or worse than
those receiving “conventional” therapy outside the study. A model for such
disclosure can be found in the consent form for a similar trial conducted in
New Zealand, in which the consent form described the risks and benefits as
follows:

“Too high oxygen in the blood for long periods may 1) contribute to abnormal
development of the retina (a condition called retinopathy of prematurity – ROP)
and affect vision – it is even possible for some babies with ROP to become
blind; 2) contribute to changes in the lungs that mean the baby needs ongoing
help with breathing for weeks or months (a condition called bronchopulmonary
dysplasia – BPD); 3) be one cause of damage to brain cells and lead to
developmental problems.

Too low oxygen in the blood for long periods may 1) increase the risk the baby will
not survive or contribute to poor growth; 2) raise blood pressure in the lungs
and contribute to bronchopulmonary dysplasia; 3) damage the brain cells and
lead to developmental problems.” (BOOST-NZ consent, July 2005, personal
communication from Brian Darlow, principal investigator of BOOST-NZ)

The risks of reckless opinions

The most important ethical issues for the future of clinical research, both in
neonatology and in other areas of medicine, are the issues of honesty,
transparency, and safety. Trials should not be done if the risks are too high
or if the study subjects aren’t informed of those risks. Interim analyses of
data should allow studies to be stopped if one arm is clearly riskier or more
beneficial than the other.

It is difficult to convey the need for randomized trials to any patient, but
perhaps particularly to parents of critically ill children. Perhaps for this
reason, there have been very few prospective randomized trials in neonatology. As
a result, many therapies in neonatology have not been validated and may be
dangerous. Neither parents nor babies are well served by a system that is
exquisitely attentive to the risks of randomized trials but oblivious to the
risks of unvalidated therapies. But that is exactly what OHRP and Public
Citizen recommend. If their recommendations are followed, avoidable harm to
babies will occur.

Their criticism of this important trial also discredits bioethics. Bioethics, at its
best, advocates for the most vulnerable patients and criticizes doctors and
researchers who put those patients at risk. In this instance, OHRP and Public
Citizen have, in the name of bioethics and advocacy, criticized clinical
investigators who were trying to prevent the use of harmful and unvalidated
treatments and, instead, endorsed an anti-intellectual, unscientific approach
to medical innovation for the most vulnerable patients.

The SUPPORT trial should be praised for its design. It was a crucially needed,
rigorous evaluation of risks and benefits of supplemental oxygen for premature
babies. Moreover, the study demonstrably protected babies. Study subjects were
benefitted, not harmed, by being in the trial. The risks to babies in the trial
were lower, not higher, than the risks to which babies not in the study were
exposed. No apology is needed for that.

It is shocking that OHRP and Public Citizen did not see fit to understand the
study or, apparently, to analyze the results before claiming that it was risky
to babies. The real risk to babies comes from reckless and ill-informed opinion
about highly ethical scientific studies. To minimize this risk, OHRP and Public
Citizen should apologize to the investigators and to the parents of the babies
in these studies for their sensationalistic misinterpretations of the support
study. If they do not, and if fewer babies are enrolled in such studies, then
more rather than fewer babies will die, more rather than fewer babies will go
blind, and OHRP and Public Citizen will have been responsible for those harms
to innocent babies.

1. C.G. Anderson, W.E. Benitz, A. Madan, “Retinopathy of Prematurity and Pulse
Oximetry: A National Survey of Recent Practices,” Journal of Perinatology 24
(2004): 164-68.

2. W. Tin, “Oxygen Therapy: 50 Years of Uncertainty,” Pediatrics 110 (2002):
615-16.

3. W.A. Silverman, “A Cautionary Tale about Supplemental Oxygen: The Albatross of
Neonatal Medicine,” Pediatrics 113 (2004): 394-96.

4. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research
Network, “Target Ranges of Oxygen Saturation in Extremely Preterm Infants,” New
England Journal of Medicine 362 (2010): 1959-69.

5. B.J. Stoll et al., “Neonatal Outcomes of Extremely Preterm Infants from the
NICHD Neonatal Research Network,” Pediatrics 126 (2010): 443-56.

6. W. Rich et al.,“Enrollment of Extremely Low Birth Weight Infants in a Clinical
Research Study May Not Be Representative,” Pediatrics 129 (2012): 480-84.

7. J.D. Lantos, “The ‘Inclusion Benefit’ in Clinical Trials,” Journal of
Pediatrics 134 (1999): 130-31; W.A. Silverman, “Disclosing the ‘Inclusion
Benefit,” Journal of Perinatology 22 (2002): 261-62; G.E. Vist et al.,
“Outcomes of Patients Who Participate in Randomized Controlled Trials Compared to
Similar Patients Receiving Similar Interventions Who Do Not Participate,” Cochrane
Database Systematic Review July 16, no. 3 (2008):MR000009.

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