Health Letter, November 2013
In the June 2013 issue of Health Letter, we first reported on the serious ethical breaches that occurred during a clinical trial funded by the National Institutes of Health (NIH), known as the SUPPORT study, involving 1,316 premature infants born 10 to 14 weeks early. Since then, a major controversy has continued to rage between critics and defenders of this research. This controversy erupted in April after Public Citizen publicized findings, quietly issued by the federal Office for Human Research Protections (OHRP), that parents of babies enrolled in the study — which evaluated the effects of maintaining premature infants at either a low or high blood oxygen level — were not informed of the serious foreseeable risks of the research, including blindness, brain damage and death.
After Public Citizen widely publicized the problems with the SUPPORT study — including problems with informed consent that went beyond those identified by OHRP, such as the failure to adequately describe the purpose and nature of the research — individuals representing the academic medical industrial complex launched a well-orchestrated attack against OHRP and a defense of the study. Leading this effort were the editor-in-chief of the New England Journal of Medicine (NEJM), the NIH director, and many researchers and bioethicists with close ties to the SUPPORT study researchers or NIH.
This article highlights some of the key developments in the controversy surrounding the SUPPORT study that have unfolded in the ensuing months.
OHRP reaffirms its findings, but retreats from its enforcement action
On June 5, 2013, faced with withering criticism from the SUPPORT study researchers, NIH and others, OHRP wrote a follow-up letter to the University of Alabama at Birmingham (UAB), one of the lead institutions for the SUPPORT study, strongly affirming its original findings of inadequate informed consent and providing additional evidence to bolster that finding. OHRP stated the following:
- “[C]onsistent with OHRP’s mission to protect human subjects of research, the overarching concern of our determination was the adequacy of informed consent, a bedrock principle of research involving human subjects.”
- “To make truly informed decisions about whether or not to participate in a research study, potential volunteers or their parents or guardians are entitled to certain information, including a description of reasonably foreseeable risks … More significantly, neither the ‘Risks’ section nor any other portion of the [SUPPORT study consent form used at UAB] mentioned any risks associated with lower oxygen levels.”
- “[T]he medical profession looks at many factors when assessing potential risks. At the outset of the SUPPORT study, many in the research and clinical communities remained concerned about the possible relationship between low oxygen and increased mortality and neurodevelopmental problems within the oxygen ranges that were to be evaluated in that study. Indeed, such concerns were a core reason why the study was conducted.”
- “Unless, as is extraordinarily unlikely, an institution used for clinical purposes exactly the same randomization assignment procedure that was used in the SUPPORT trial, every child in the SUPPORT trial experienced some change in the likelihood of being assigned to the various oxygen levels. And as the above discussion demonstrates, for at least some of the children participating in the SUPPORT trial, the effect of such participation was to specifically increase their likelihood of being assigned to oxygen levels close to either end of the range of standard care – and thus to oxygen levels at which, as a clinical matter, they would not have been assigned by their individual physicians, had they not been in the study.”
Despite staying on firm ground with respect to the agency’s original finding regarding the failure of the SUPPORT study consent forms to disclose the risks of the research, OHRP bowed to external political pressure and retreated from taking enforcement action against UAB and other institutions involved in the conduct of the study, saying:
In addition … we have put on hold all compliance actions against UAB relating to the SUPPORT case, and plan to take no further action in studies involving similar designs until the process of producing appropriate guidance is completed.
In addition, OHRP offered excuses for the failures that occurred in the SUPPORT study:
The facts regarding the SUPPORT study and what was known about the use of oxygen to treat premature infants also are complicated. Accordingly, we appreciate that there is justification for an incomplete understanding of how those rules might apply to this study.
On June 6, 2013, Public Citizen issued a press statement criticizing OHRP for suspending appropriate and necessary compliance action related to the SUPPORT study and for allowing similar ongoing studies involving premature babies to continue, despite concerns that the consent forms for those studies may have similar serious deficiencies. We also noted that the rules and norms regarding informed consent for research have been clearly articulated and well-known for decades but were disregarded by the SUPPORT study researchers and the institutional review boards (IRBs) — committees charged with reviewing research studies to ensure that the rights and welfare of the human subjects who will participate are adequately protected — that approved the study. There were no reasonable excuses for the ethical lapses that occurred.
A coordinated attack on OHRP by NIH and the NEJM
In a move obviously timed to coincide with the OHRP’s issuance of its June 5, 2013, letter to UAB, the NEJM that same day published online a commentary article and a letter to the editor defending the conduct of the SUPPORT study and criticizing OHRP for its findings of inadequate informed consent for the study.
The commentary article was co-authored by NIH Director Francis Collins and other senior NIH staff. Echoing the same flawed arguments that had previously been voiced by the SUPPORT study researchers, the NEJM editor-in-chief and other defenders of the study, Dr. Collins and his colleagues argued, among other things, that the interventions compared in the study were “all considered standard of care” and that there was no reason to suspect that death was a foreseeable risk of the study based on information available at the time the study was designed. Our detailed independent analysis of the SUPPORT study had previously refuted such arguments.
One of the most troubling aspects of the NIH commentary in the NEJM was an explicit reference to OHRP’s June 5 letter and the agency’s intention to put on hold all compliance actions related to the SUPPORT study. Clearly NIH and the NEJM editors were given advance notice that OHRP was going to issue a second compliance letter to UAB. These circumstances raise concern that NIH may have had input into the drafting of OHRP’s letter. Moreover, the NIH commentary called for changes to OHRP’s process for investigating complaints about research studies. Such statements are indicative of inappropriate attempts by NIH to interfere with the regulatory activities of OHRP.
Of note, NIH has a clear conflict of interest with the activities of OHRP since most of the research regulated by OHRP, like the SUPPORT study, is funded by NIH. Indeed, more than a decade ago, OHRP (then called the Office for Protection from Research Risk) was moved out of NIH into the Office of the Secretary of the Department of Health and Human Services (HHS) because of the acknowledged conflict of interest that NIH had with the office. The NIH commentary in the NEJM suggests that this move was insufficient in insulating OHRP from NIH interference.
The NEJM also published online on June 5, 2013, a letter to the editor signed by 46 bioethicists and pediatric physicians. The letter accused OHRP of overreaching with respect to the SUPPORT study and urged the agency to withdraw its findings of inadequate consent, asserting that the agency’s findings were not supported by evidence. Among those signing the letter were several bioethicists from institutions that conducted the SUPPORT study and many others with close ties to NIH or the SUPPORT study researchers.
Group of bioethicists and others defend OHRP
After publishing multiple one-sided editorials and commentaries criticizing OHRP and defending the ethics of the SUPPORT study, the NEJM on June 26, 2013, finally published online a letter to the editor with an opposing viewpoint. The letter was written by 45 bioethicists, physicians and scholars who agreed with OHRP that the consent forms for the SUPPORT study were “seriously inadequate.” One of the lead authors of this letter was Ruth Macklin, an internationally renowned bioethicist and a co-author of Public Citizen’s May 10, 2013, report to HHS Secretary Kathleen Sebelius highlighting the many serious ethical problems with the SUPPORT study.
Succinctly summarizing the problems with the SUPPORT study consent process, Macklin and her co-authors noted:
The SUPPORT study itself was complicated. However, the question of whether the consent forms were adequate is not; they failed in each of the elements described above [i.e., the explanation of the purposes of the research; the description of the procedures to be followed and identification of any procedures that are experimental; a description of the reasonably foreseeable risks to the subjects; and a disclosure of appropriate alternative procedures or courses of treatment that might be advantageous to subjects]. Although the consent forms varied in content among the institutions at which the study was conducted, none specifically mentioned death as a possible risk of the oxygen interventions in the study…The oxygen interventions in the study differed from usual clinical care, and that information should have been included in the consent forms…
Given the seriously deficient nature of the consent documents, the determination of the OHRP on March 7, 2013 was justified and did not over-reach.
We agree with the authors of the letter. In fact, not only did OHRP not overreach in its findings regarding the SUPPORT study, the agency did not go far enough in citing many significant deficiencies related to both the consent forms and the study design.
Another unethical study on premature babies exposed
Shortly after publicizing the ethical lapses in the SUPPORT study in April, Public Citizen requested from NIH under the Freedom of Information Act the protocols and consent forms for all ongoing studies being conducted by the NIH-funded Neonatal Research Network, the same collaborative group of medical centers that conducted the SUPPORT study. Through a review of the requested documents, Public Citizen learned of another clinical trial that poses known risks to premature babies without their parents being fully informed about those risks.
The new study is the NIH-funded Transfusion of Prematures (TOP) trial, which is designed to determine which of two strategies for treating anemia with blood transfusions is more likely to result in death or neurologic injury in extremely premature infants who develop anemia (low blood hemoglobin, which is found in red blood cells and carries oxygen to the body). In many respects, the ethical lapses in this trial are very similar to those in the SUPPORT study.
The TOP trial began enrolling babies in early 2013 and is ongoing. Infants are being enrolled at as many as 15 major academic medical centers within the Neonatal Research Network, with additional medical centers possibly joining the study in the future. The infants involved weigh less than 2.2 pounds and are born 22 to 29 weeks into the pregnancy. The study is expected to involve 1,824 extremely premature infants.
In the study, half of the infants are randomly assigned to receive transfusions at a high hemoglobin level (liberal transfusion group) and half at a low hemoglobin level (restrictive transfusion group), regardless of their individual needs. Of note, the best available evidence, previously published by some of the TOP trial researchers themselves and extensively cited in the TOP protocol, suggests overall that the restrictive transfusion strategy is more likely to result in neurologic injury and other harms in extremely premature infants.
Yet despite these known risks, the consent forms for the TOP trial have serious deficiencies resembling those found in consent forms used in the SUPPORT study:
- The consent forms fail to inform parents of prior research suggesting that the liberal transfusion approach has more favorable outcomes and that the purpose of the study is in fact to prove this point – which will require exposing more than 900 infants to the restrictive transfusion strategy.
- Of the 17 IRB-approved consent forms obtained by Public Citizen, only one mentions the foreseeable risk of death or disability. Five say the research poses no risk, and 15 conflate risks of the research with risks of routine medical care.
- All but two of the forms fail to explain that part of the primary purpose of the research is to see which transfusion group is more likely to suffer death, and 12 fail to indicate the study’s equally primary goal of seeing which study group shows more signs of neurologic impairment.
On Aug. 22, 2013, Public Citizen sent a letter to HHS Secretary Sebelius urging her to immediately halt the TOP trial and direct OHRP to open an investigation into the trial. It also called for OHRP to develop a plan to contact the parents of subjects already enrolled in the trial and provide them with full information about the risks, purpose and nature of the research.
Furthermore, since this is not the first such lapse in research ethics in a large NIH-funded multicenter trial involving premature babies, Public Citizen’s letter also called for an independent investigation of the HHS system for review and oversight of HHS-funded human subject research, as well as a suspension of any other similar studies currently being funded by NIH or any other HHS agency.
HHS public meeting to discuss consent issues
In its June 5, 2013, letter to UAB, OHRP announced plans to convene an open public meeting as part of a process to develop guidance “on what the rules are with regard to disclosure of risks in randomized studies whose treatments fall within the range of standard of care.” That meeting took place on Aug. 28, 2013.
The highly polarized meeting pitted advocates, physicians, parents of SUPPORT study subjects and bioethicists highly critical of the SUPPORT study against those who are defenders of the study and who endorse efforts to roll back long-existing standards for obtaining informed consent for human subjects research.
Among the first to testify at the meeting were Dr. Michael Carome, director of Public Citizen’s Health Research Group (HRG), and Dr. Sidney Wolfe, HRG founder and senior adviser. Also testifying at the meeting and participating in a midday press conference convened by Public Citizen on the day of meeting were Alice Dreger, professor of clinical medical humanities and bioethics at the Feinberg School of Medicine at Northwestern University; George J. Annas, the William Fairfield Warren Distinguished Professor and Chair in the Department of Health Law, Bioethics & Human Rights at the Boston University School of Public Health; Carrie Pratt and Shawn Pratt, with their 6-year-old daughter Dagen Pratt, who was a baby in the SUPPORT study; and Sharrissa Cook, the mother of another baby in the study.
Carome’s testimony exposed the fallacies that the SUPPORT study interventions represented standard-of-care treatments and that clinical research has entered a new era that needs new regulations and ethical standards. He concluded his testimony with the following comments:
Many critics of OHRP’s actions have sought to blur the line between human subjects research and clinical care and appear to view the process for obtaining informed consent as an unnecessary impediment to conducting clinical trials and advancing medical knowledge. They want to change the rules to satisfy their research needs at the expense of subjects’ rights.
The fact that this meeting is occurring reflects the tremendous influence that NIH, which approved the SUPPORT study and spent more than $20 million for it, has wielded in an effort to undermine OHRP’s authority and reverse OHRP’s findings.
In conclusion, these efforts to weaken human subjects protections must not succeed. Many in the bioethics and research community agree that the deficiencies in the SUPPORT study’s consent forms were obvious and that OHRP was correct in its finding. In the interests of protecting vulnerable human subjects, OHRP must stand its ground.