Ten years ago, the Office of Human Research Protection (OHRP) found that two federally sponsored lung experiments conducted by the ARDS Network at 12 major academic centers , had violated medical ethics standards by exposing non-consenting critically ill patients to increased risk of death, and had failed to comply with legal informed consent requirements.
Today we learn that the National Institute of Health (NIH) sponsored the so-called SUPPORT experiment conducted on 1,316 extremely prematurebabies at 23 prominent academic medical research centers. These include: Stanford University, Yale University, Brown University, Duke University, Wake Forest, and University of Alabama at Birmingham (a complete list is at the end).
Two of the medical centers–Duke and Wake Forest–were also involved in the ARDS experiments.
SUPPORT was designed to find out whether premature babies whose fragile lungs required oxygen, were more likely to die or become blind, if their oxygen levels were targeted to either a low or high range.
The subjects in both the ARDS abd SUPPORT experiments required individualized titration of oxygen levels based on the individual patient’s clinical condition, and requiried continuing monitoring and oxygen level adjustment–as is current best practice. In both cases, the treatment provided to critically ill patients in these experiments did not meet that standard of care.
Critical care physicians have long known that giving high levels of oxygen to premature infants can lead to retinal damage, blindness and lung injury; giving too little oxygen can cause brain damage and death.
The SUPPORT study design increased risks of either death or retinal damage leading to blindness, depending on which oxygen level group a baby was randomized to.
At the 23 participating medical centers, premature infants who were not subjects in the experiment were maintained at oxygen levels within a range of 85% to 95% based on a baby’s individual medical condition and needs.
Babies enrolled in the experiment were taken off the individualized level of oxygen they had received and were randomly assigned to either of the two oxygen ranges– a low range of oxygen (85-89% saturation) or a high range (91-95% saturation). .OHRP’s letter of determination (March 7, 2013) states:
“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.”
This experiment qualifies as a medical atrocity of the worst kind–yes, it does compare with the Nazi era experiments.
The physicians who conducted the experiment failed to comply with Federal informed consent requirements:
They failed to disclose the purpose of the experiment to the parents; failed to disclose the risks for the infants of being randomized to either of the two treatment arms that were used in the experiment; and failed to inform parents about the available alternative individualized treatment. They feared they would not gain parental permission for the infants’ enrollment in the experiment.
Neither the premature infant SUPPORT experiment, nor the ARDS Network experiments met that ethical / legal standard because neither had current practice controls and it is unknown if the therapies they tested had both worsened outcome and if adopted in perpetuity would worsen outcome.
The statistically significant (p-vaue) finding for harm in this neonatal study only tells the authors they hurt babies more in one arm than the other.But the authors have no idea if they hurt babies in both arms compared to what is usually done in practice.
Pediatric specialists in intensive care units use the level of oxygen titrated so that it will still be high enough to keep the child alive and low enough hopefully to prevent blindness for that baby–that requires careful attention to the individual child’s condition. In each child different factors based on their unique medical co-morbidities go into making that decision.
The physicians who conducted the experiment failed to minimize the risks because without controls they had no way to monitor the babies’ safety.
They failed to comply with Federal informed consent requirements because they knew that if they honestly explained to parents what would be done in the trial:
—that babies would be given a fixed experimental treatment independent of the individual baby’s needs;
—that these fragile premature babies would be at greater risk of more blindness in one arm, and more deaths in the other;
Realizing that no parent would agree to put their baby in such an experiment, they lied to the parents.
This was a physiology experiment usually designed for animals. Nothing was leaned: only what was already known–that low oxygen kills and high oxygen makes infants blind.
OHRP received a complaint about the SUPPORT experiment about two years ago; the agency’s response was a letter of determination to the University of Alabama at Birmingham on March 7, with copies to the other 22 research centers. But OHRP did not take any action, nor did OHRP demand that the the universities and hospitals involved take any meaningful actions to prevent repeated gross ethical / legal violations.
Furthermore, as Public Citizen informed HHS Secretary Sebelius in a letter (April 10, 2013 ):
“Consistent with what had been known for decades, the SUPPORT study results demonstrated a statistically significant greater number of cases of serious retinal damage in the high – oxygen group compared with the low – oxygen group. In addition, as suspected for many years, the study revealed a statistically significant higher death rate in the low – oxygen group compared with those in the high – oxygen group.”
Action is needed now.
1. Go to www.citizen.org/sebelius-petition-informed-consent and sign the petition.
2. Spread the word, tell family and friends or post a link to the petition via Facebook and Twitter.
The New York Times quotes Dr. Richard Marchase, V-P for Research & Economic Dev. At the University of Alabama at Birmingham (the lead center for the SUPPORT experiment) who stated:
“that a similar group of infants born around the same time who did not participate in the study actually died at higher rates than those in the low-oxygen group. Those infants were not a control group in the study, but were roughly similar in number and in age to those in the study group; they had a 24 percent mortality rate, compared with a 20 percent mortality rate for the infants in the low-oxygen group.”
But his statement is false and meant to mislead reporters and the public; In fact, his assertion is belied by the SUPPORT researchers’ own published report in the journal, PEDIATRICS ( March 2012). The authors compared key clinical factors for the 1,316 babies enrolled in the study and 3,054 premature babies not enrolled in the study, but eligible. They presented baseline data in 3 tables showing that the non-enrolled group of babies were sicker and at greater risk of death at birth—requiring significantly more life-saving interventions in the delivery room—than those in the SUPPORT study. So it was reasonable to expect that less of the infants who weere sicker at birth wold survive.
Public Citizen urged HHS Secretary, Kathleen Sebelius, to issue a formal apology to the parents of all infants in the study and to inform them about the true purpose, nature and risks of the study. That is not only a reasonable request, it is something Secretary Sebelius had done in October, 2010: Secretary Sebelius and (then) Secretary of State, Hillary Clinton, offered extensive apologies to the President of Guatemala for an unethical experiment conducted from 1946-1948, in which US doctors infected Guatemalan citizens with sexually transmitted disease. In their joint statement, Secretary Clinton and Secretary Sebelius stated:
"Although these events occurred more than 64 years ago, we are outraged that such reprehensible research could have occurred under the guise of public health. We deeply regret that it happened, and we apologize to all the individuals who were affected by such abhorrent research practices."
Don’t the parents whose premature babies were killed or blinded in the SUPPORT experiment deserve at the least a letter of apology?
Public Citizen asked the Secretary to take the following actions:
Direct OHRP to require each participating institution to submit corrective action for avoiding such serious deficiencies in the consent process for future research; Launch an independent investigation into how the HHS system for review and oversight of clinical trials failed so miserably. This should include an assessment of all entities within NIH or other HHS agencies that played a role in the review, approval and funding of the study. Determine what system-wide actions are necessary to prevent similar future failures;· Identify and suspend any similarly unethical ongoing research involving premature infants that is funded by NIH or any other HHS agency.
We at the Alliance for Human Research Protection join Public Citizen in urging the Secretary to take the actions outlined.
Sign the petition: www.citizen.org/sebelius-petition-informed-consent
Vera Sharav
U.S. Says Study of Babies Failed to Disclose Risks
The lead investigators on a large study of the effects of oxygen levels on extremely premature babies failed to inform the infants’ parents that the risks of participating could involve increased chances of blindness or death, the federal Department of Health and Human Services has warned in a letter.
The Office for Human Research Protections, which safeguards the people who participate in government-funded research, sent a letter to the University of Alabama at Birmingham last month, detailing what it said were violations of patients’ rights.
The university, which was a lead site for the study, had not detailed the risks in consent forms that were the basis of parents’ participation, the office said in the letter. Specifically, babies assigned to a high-oxygen group were more likely to go blind and babies assigned to a low-oxygen group were more likely to die than if they had not participated. Ultimately, 130 babies out of 654 in the low-oxygen group died, and 91 babies out of 509 in the high-oxygen group developed blindness.
Some of the 1,300 infants who participated in the study, which took place between 2004 and 2009, would probably have died or developed blindness even if they had not taken part. They were born at just 24 to 27 weeks gestation, a very high-risk category. But being assigned to one or the other oxygen group in the study increased their chances further, a risk that was not properly disclosed, the office said
Richard B. Marchase, vice president for research at the University of Alabama at Birmingham, said in a telephone interview that a similar group of infants born around the same time who did not participate in the study actually died at higher rates than those in the low-oxygen group. Those infants were not a control group in the study, but were roughly similar in number and in age to those in the study group; they had a 24 percent mortality rate, compared with a 20 percent mortality rate for the infants in the low-oxygen group.
He said the study kept the infants within the standard band of treatment for oxygen levels — 85 percent to 95 — and that its findings were forming the basis for a definition by the American Academy of Pediatrics about what the standard of care should be.
He said he had assured the Office for Human Research Protections that in the future, “we will to the best of our ability let the subjects or their parents know as thoroughly as possible what previous studies suggest in terms of risk.” He added, “We are going to be very sensitive to that going forward as we look at these consent forms.”
A spokesman for the university said that researchers at another university participating in the study wrote the forms, but that they were approved by all 23 academic institutions that took part.
More than 20 major academic research centers were involved in the study, which was financed by the National Institutes of Health, and researchers at the University of Alabama aggregated the data. Boards from each institution reviewed the forms, but none took issue with them.
In the letter, the office stated that the consent form should have explained that “there is significant evidence from past research indicating that the oxygen provided to an infant can have an important effect on many outcomes including whether the infant becomes blind, develops a serious brain injury or even possibly whether the infant dies.”
The risk the study did mention was of abrasion of the infants’ skin by an oxygen monitoring device. And it mentioned a possible benefit — a decrease in need for eye surgery depending on the group the child was assigned to.
The letter was dated March 7. It was brought to the attention of media outlets by a consumer advocacy group, Public Citizen, on Wednesday. http://www.citizen.org/documents/2111.pdf
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From: Angela Bradbery Public Citizen
Sent: Wednesday, April 10, 2013
Subject: press release-Government study endangered infants
HHS-Funded Experiment Exposed Babies to Risk of Death and Blindness Without Informing Parents
HHS Secretary Should Apologize to Parents of Premature Infants Enrolled in Unethical Trial at 23 U.S. Medical CentersApril 10, 2013
Contact: Angela Bradbery (202) 588-7741; Sam Jewler (202) 588-7779; for broadcast media, Barbara Holzer (202) 588-7716WASHINGTON, D.C. – Health and Human Services Secretary Kathleen Sebelius should personally apologize to the parents of 1,316 premature infants who were exposed to increased risk of blindness and death as part of a clinical trial funded by the National Institutes of Health and held throughout the U.S. several years ago because they were not informed of the risks to their babies or the true nature and purpose of the research, Public Citizen said today in a letter to the secretary.
The trial, known as the SUPPORT study, was conducted between 2005 and 2009 at 23 prominent research facilities throughout the country, including the Stanford University School of Medicine, Yale University School of Medicine, Brown University, Duke University and University of Alabama at Birmingham (a complete list is at the end of this release).
Premature babies usually require treatment with oxygen. As part of routine care, the amount of oxygen given to such babies is adjusted based on a measure of blood oxygen level called oxygen saturation, which can be continuously checked with a probe placed on the skin.
For the medical centers participating in the SUPPORT study, routine care of premature infants not in the study typically involved giving enough oxygen to maintain oxygen saturation levels between 85 and 95 percent. The exact oxygen target level for a particular infant at any particular time would be based on the baby’s individual medical needs and the wishes of the baby’s parents.
In contrast to usual clinical care, the extremely premature infants enrolled in the SUPPORT study were randomly put in two groups that each received a different experimental target range of oxygen saturation: a low range (85-89 percent) and high range (91-95 percent). The researchers primarily wanted to see whether the babies were more likely to die or suffer retinal damage, which can lead to blindness, if their oxygen levels were targeted to the low or high range. It has long been known that, in general, giving high levels of oxygen to premature infants can lead to retinal damage, blindness and lung injury, while giving too little oxygen can cause brain damage and death.
However, as documented in a March 7, 2013, letter from the Office for Human Research Protections (OHRP) in the Department of Health and Human Services (HHS) to the University of Alabama at Birmingham, one of the lead institutions for the SUPPORT study, the consent forms for the study did not disclose to the babies’ parents any of the risks of the experimental oxygen management interventions, including risks of severe retinal damage, possible blindness, neurologic injury and death. The consent forms also failed to address two other critically important pieces of information:
– That one purpose of the research was to determine whether extremely premature infants were more likely to die if treated with the higher versus lower oxygen target; and
– An explanation of how the infants would be treated if they weren’t in the study compared to how they would be treated by participating in the study.
“The word ‘unethical’ doesn’t even begin to describe the egregious and shocking deficiencies in the informed-consent process for this study,” said Dr. Michael Carome, deputy director of Public Citizen’s Health Research Group. “The failure to disclose such critically important information about the research undoubtedly directly affected parents’ decisions to enroll their extremely premature infants in this study. It is highly likely that had they been appropriately informed about the nature of the research and its risks, many, if not most, parents would not have allowed their babies to be in this study.” (Note: For 10 years prior to joining Public Citizen, Carome was on the OHRP staff, serving most recently as its associate director for regulatory affairs and previously as its director of the Division of Compliance Oversight).
Not surprisingly, the study found differences between the two groups of infants in rates of death and retinal damage. In the lower oxygen group, 41 babies (nine percent of those evaluated) developed severe retinal problems and 130 (20 percent) died. In the higher oxygen group, 91 babies (18 percent of those evaluated) developed retinal problems and 107 (16 percent) died. Because there was no control group that received the usual care with individualized oxygen management, and because the babies were so sick to begin with, it is impossible to determine how these rates of death and retinal damage compare to what otherwise would have occurred had the babies been managed according to usual clinical care based solely on their individual needs. However, a comparison of the two study groups clearly shows more deaths in the lower oxygen group and more cases of severe retinal damage in the higher oxygen group.
OHRP got a complaint about the SUPPORT study approximately two years ago. The other research centers involved were copied on the OHRP’s March 7 letter to the University of Alabama at Birmingham. But the agency did not demand adequate and meaningful corrective actions from that school or any of the other universities and hospitals involved.
“As a result of the informed-consent deficiencies, the investigators of the SUPPORT study failed to obtain the legally effective informed consent from the babies’ parents, and the conduct of the study was highly unethical,” said Carome. “Because this study was funded by NIH, HHS has a moral obligation to formally apologize to the parents of all infants in the study and tell them at last about its purpose, nature and risks.”
In addition to issuing an apology to parents, Public Citizen urges Sebelius to take the following actions:
– Direct OHRP to require each participating institution to submit corrective action for avoiding such serious deficiencies in the consent process for future research;
– Launch an independent investigation into how the HHS system for review and oversight of clinical trials failed so miserably. This should include an assessment of all entities within NIH or other HHS agencies that played a role in the review, approval and funding of the study.
– Determine what system-wide actions are necessary to prevent similar future failures; and
– Identify and suspend any similarly unethical ongoing research involving premature infants that is funded by NIH or any other HHS agency.
The letter can be found at http://www.citizen.org/hrg2111 .
The 23 research centers that conducted the SUPPORT experiment on premature babies are:
– Brown University
– Case Western Reserve University
– Duke University
– Emory University School of Medicine
– Indiana University School of Medicine
– Sharp Mary Birch Hospital for Women and Newborns
– Stanford University School of Medicine
– Tufts Medical Center
– University of Alabama at Birmingham
– University of California, San Diego
– University of Cincinnati
– University of Iowa
– University of Miami Miller School of Medicine
– University of New Mexico Health Sciences Center
– University of Rochester School of Medicine and Dentistry
– University of Tennessee
– University of Texas Health Science Center, Houston
– University of Texas Southwestern Medical Center
– University of Utah School of Medicine
– Wake Forest University School of Medicine
– Wayne State University
– Women and Infants Hospital of Rhode Island
– Yale University School of Medicine