Informed consent, standard of care debated at OHRP meeting
OHRP will issue new guidance
A late-August Office of Human Research Protections (OHRP) public meeting in Washington, D.C. brought debate from researchers, physicians, and patient advocates on the subject of standard of care research and how IRBs should assess risks in randomized trials.
The public meeting was convened in response to fallout from the 2010 Surfactant, Positive Pressure, and Oxygenation Randomized Trial (Support). The National Institutes of Health (NIH)-funded study included 23 research institutions under the coordination of the University of Alabama at Birmingham (UAB) and tested oxygen levels for nearly 1,300 premature infants. The study intended to find the optimal oxygen concentration for the premature infants. The infants receiving higher levels of oxygen developed retinopathy and other eye disease twice as much as the infants in lower oxygen levels. Those receiving lower oxygen levels had higher rates of brain damage and mortality.
UAB came under fire following the results of the Support study, with the main issue being whether parents were given adequate informed consent of the risks involved. OHRP sent UAB a determination letter in March of this year, stating that while there were no issues with the study design, OHRP found the oxygen saturation levels part of the Support study to be in violation of regulatory requirements of informed consent, neglecting to fully describe the risks of blindness, brain damage, and death for the randomized study, and required corrective action from the institution.1
Bioethics leaders across the country have been sharply divided by the OHRP determination. In the June 20, 2013, issue of the New England Journal of Medicine, 46 bioethics and pediatrics leaders published a letter to the editor in defense of the Support study, urging OHRP to withdraw its decision. "Although we acknowledge that the permission forms could have been improved, we disagree that the random assignment of infants to a high oxygen-saturation level or a low oxygen-saturation level imposed additional risks that the investigators failed to disclose," according to the letter. "The OHRP should not sanction research institutions simply because it disagrees with their assessment of the risks of research but should do so only if it finds that an institution has failed to meet the terms of its federal-wide assurance, such as in the manner in which its institutional review board is constituted or operates."2
OHRP placed enforcement of the corrective action plan on hold pending the issuance of further guidance. The organization planned the public meeting as a way to determine the direction that human research protection programs should take when approving informed consent and determining how federal regulations should be applied to studies with one or more standard of care interventions in which subjects are randomized.
Consent form debate
The public meeting featured speakers on both sides of the Support trial issue. Each of the speaker had seven minutes for presentations before taking panel discussion questions.
"The most important take-home message for OHRP today is that the obvious deficiencies in the Support study consent process signal an urgent need to strengthen informed consent for human subjects research, not weaken it as some in the community are advocating," said Michael Carome, MD, director of the Health Research Group at watchdog organization Public Citizen in Washington, D.C. "Many critics of OHRP’s actions have sought to blur the line between research and clinical care and appear to view the process of obtaining informed consent as an unnecessary impediment to conducting clinical trials and advancing medical knowledge."
"The fact that this meeting is occurring reflects the tremendous influence that NIH, which approved the SUPPORT study and spent nearly $20 million on it, has wielded in an effort to undermine OHRP’s authority and reverse OHRP’s findings," Carome said.
John Lantos, MD, gave a personal account of his twin grandsons born too premature to qualify for the Support study. One died within hours of birth, while the other survived but with severe retinopathy. Had the babies been enrolled in the study, Lantos said, the family would have been outraged at the outcome. But had they read a consent form filled with all potential risks and not enrolled and the babies had the same outcome, no federal regulators would have looked at the consent process.
"Consent forms should explain those real and likely possibilities and if they do not, they are not empowering people to make informed choices; they are scaring them into making uninformed ones," said Lantos, director of the Children’s Mercy Bioethics Center at Children’s Mercy Hospital in Kansas City.
When consent forms overstate the risks of research and don’t say that research subjects might be better off than those not enrolled in the study, Lantos said, the forms are misleading and dangerous. "Misleading inaccuracies push patients away from safe, well-designed studies and towards treatments with unknown and often greater risks and babies die as a result," he said.
One bioethicist stated that the research system is no longer designed to reward those who are "ethically meticulous," saying those who are meticulous experience delays, lower enrollment, and perhaps failure to compete. "In short, the system is set up to allow these ethics problems to keep happening; it may even promote ethical short cuts and missteps," said Alice Dreger, PhD, bioethicist at Northwestern University in Evanston, IL. "If ethical shortcuts and missteps go unpunished, if OHRP fails to enforce findings of wrongdoing, what external incentive is there to be ethically meticulous other than the fear of lawsuits?"
Other speakers expressed concern that there is no standard definition for the term "standard of care."
"Talking about standard of care studies is an inappropriate shortcut that obscures consideration of fundamental elements of ethical research," said Lois Shepherd, JD, a Peter A. Wallenborn, Jr. and Dolly F. Wallenborn Professor of Biomedical Ethics at University of Virginia School of Law. "First, it is not clear what the term standard of care intervention means, nor is there reason to assume so-called standard of care studies merit ethical treatment."
Jeffrey Drazen, MD, editor-in-chief of NEJM, said the definition may be clouded through recordkeeping. "Doctors who do things that are generally accepted by the community are a standard of care. Unfortunately, we don’t often keep meticulous records about what standard of care is, which may lead to many arguments about it in an ex post facto sort of way," Drazen says.
Suggestions for IRBs
Elisa Hurley, MD, education director at Public Responsibility in Medicine & Research (PRIM&R) outlined six questions that PRIM&R recommended IRBs ask when considering protocols and informed consent involving randomized trials:
• Have the investigators established that the medical interventions being compared are within the accepted standard of care and that doubt exists regarding their relative effectiveness?
• How will potential subjects be informed of the risks, benefits, and potential harms of the interventions?
• How will potential subjects be informed that they are being asked to participate in a study comparing two interventions and that if they don’t wish to participate, they will instead receive standard of care? "The key for us in the IRB should be to ensure that the investigator has set forth how subjects come to understand that they have this choice as regards the specific intervention being studied, between remaining in a therapeutic doctor-patient relationship and entering an investigator-subject relationship, in which case their physician won’t routinely be making personalized clinical decisions about the use of interventions in their study," Hurley said.
• How will potential subjects be informed of any available alternatives to the interventions being offered in the study?
• What burdens and potential harms — beyond those inherent in the interventions being compared —are added by participation in the study?
• How will potential subjects be informed of any additional risks? "The IRB must determine whether investigators have thoroughly examined and identified the burdens and potential harm to potential subjects that are added by participation in this study, over and above the risks of receiving either intervention being compared, and that they have developed an adequate description of added risks for the informed consent process," Hurley said.
David Forster, JD, MA, CIP, vice president of compliance at WIRB-Copernicus Group, had this suggestion: "What I would like to propose is that there be guidance from the agencies that is consistent in how we classify and assess risks and benefits of research, all research, and how risks and benefits are presented to subjects in the consent form. But in evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research."
Drazen suggested convening a central IRB that could approve study design, define research questions, and define clinical equilibrium. "I think that there should be an IRB convened specifically with expertise to look at the question that is being asked. And once they have read and said yes, clinical equipoise exists and the method that you’re using to address that question doesn’t contain excess risk for the people in the population, it is well laid out."
There is no set timetable on when to expect new OHRP guidance. Sorting through the key issues and developing new guidance will not happen overnight, said Wanda K. Jones, DrPH, Principal Deputy Assistant Secretary for Health, U.S. Department of Health and Human Services (HHS).
- Determination letter from OHRP to the University of Alabama at Birmingham, March 7, 2013. http://www.hhs.gov/ohrp/detrm_letrs/YR13/mar13a.pdf
- Wilfond BS, et al. The OHRP and SUPPORT. N Engl J Med 2013; 368:e36.