Controversy stimulates informed consent debate
Widespread discussion generated
In May 2013, the U.S. Office for Human Research Protections (OHRP) determined that a large multisite clinical trial comparing the effects of differing levels of oxygen supplementation for neonates failed to obtain proper consent from the parents of enrolled infants in the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT).1,2
The OHRP stated that the amount of oxygen provided to a participant might have been different than the amount that would have been provided had the baby not participated in the study. "Therefore, there might be increased or decreased risk of severe retinopathy of prematurity/blindness, brain injury, or death in either of these two groups, which it stated should have been disclosed in the Risks section of the informed consent form," says Marilyn A. Fisher, MD, MS, associate professor of pediatrics at the Center for Biomedical Ethics Education and Research at Albany (NY) Medical Center.
In a June 2013 letter, a group of bioethicists urged the OHRP to withdraw its notification to the institutions that they failed to meet regulatory informed-consent requirements, in particular regarding reasonably foreseeable risks of enrollment in the study.3 These were some of the group’s concerns about the OHRP’s conclusion:
• Numerous experts disagreed about the OHRP’s claim that subjects in the low oxygen group were at higher risk of dying.
"There were prior studies that showed no increase in mortality from those oxygen levels, including levels considerably below those in the study," says Norman Fost, MD, MPH, professor of pediatrics and bioethics at the University of Wisconsin’s School of Medicine and Public Health in Madison. The study was reviewed by an expert committee at the National Institutes of Health, more than 20 institutional review boards (IRBs), and numerous co-investigators, none of whom agreed with OHRP’s opinion about the risks, he adds.
"Even if there had been evidence prior to the study of increased mortality from the lower oxygen levels, there was no reason for believing infants in the study were more likely to be maintained at the lower levels than infants outside of the study," says Fost.
• The consent form did state that there might be an increased risk of death by joining the study.
This was stated in a section addressing another part of the study — comparing different techniques of assisted ventilation by randomized assignment. "As with most consent forms, this one could have been written more clearly," acknowledges Fost. "But it is not the case that parents who read the consent form would be unaware of the risk of death."
• The OHRP’s decision to charge numerous experts and institutions with non-compliance seemed inappropriate to many critics.
"In the view of the critics, this should be based on something more substantive than a disagreement about the clarity of a consent form, which was approved by dozens of committees including hundreds of thoughtful individuals," says Fost.
Possible turning point
The ORHP subsequently amended the letter. As a result, the investigators have been at least temporarily exonerated of a charge that they failed to comply with federal regulations.
"The institutions involved have been spared from whatever sanctions OHRP might have been considering," says Fost. "Parents involved in the study may get some relief from the concern that the physician investigators caring for their children did not deserve their trust."
The controversy stimulated wide discussion about the OHRP’s approach to compliance issues, however, including the process by which they make these judgments, and the substantive criteria used to distinguish disagreement from non-compliance. "This could be a turning point in longstanding concerns about what many see as a dysfunctional regulatory system, inhibiting and discouraging important research that could benefit future patients," says Fost.
The ability to read and understand the written consent form may be affected by vision, language barriers, intelligence, level of education, amount of time available to peruse the informed consent form, pain, anxiety, and availability of health care professionals and friends or family with whom to discuss the informed consent form, Fisher says.
"Some investigators have gone so far as to administer an exam to potential subjects to ensure that they clearly understand these important issues regarding a proposed study, before allowing enrollment into the study," notes Fisher.
Process often inadequate
Potential research subjects may perceive real or imagined coercion when the study investigator approaching them about study participation is also one of the health care providers caring for the patient. "Potential subjects may fear retribution, in the form of provision of inferior health care, if they decide to not participate in a study," says Fisher.
Additionally, physician investigators may experience a conflict of interest between their desire to administer the therapies in the best interest of each individual patient and their desire to help future patients by enrolling patients into research studies, and to benefit their careers by publishing the study’s results.
"There is a role for bioethicists in the development of, and monitoring of, human research studies," says Fisher. "With regular review of existing studies, bioethicists working on IRB committees may be able to ensure that the rights of human research subjects are protected." Bioethicists working on IRB committees can make suggestions to ensure that all the key elements of the informed consent are met, for example.
It is well-documented that the process for obtaining consent for clinical research, as well as routine clinical care, is often inadequate, says Fost.
"Patients and potential subjects often do not understand the key elements that should inform their decisions," says Fost. "There is no requirement in the regulations to assess or document whether subjects understand these elements, and therefore there is typically no evidence or documentation of whether or not a decision to consent’ to a study is truly informed."
One contributing factor to this gap, says Fost, is the increasing length and complexity of consent forms, driven largely by concerns about being charged with non-compliance and severe sanctions. "There is substantial research on how to obtain more effective and meaningful consent, such as the use of interactive computer programs, or simply using shorter and simpler consent forms," says Fost. "One can hope that the SUPPORT controversy will stimulate discussion that will lead to a more effective consent process."
- Carlo WA, Finer NN, Walsh MC, et al. SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network. Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med. 2010;362(21):1959-1969.
- Kuehn BM. Neonatal trial criticized for inadequate consent. JAMA. 2013;309(20):2087.
- The OHRP and SUPPORT. N Engl J Med 2013. [Epub ahead of print]
- Marilyn A. Fisher, MD, Associate Professor of Pediatrics, Albany (NY) Medical Center. Phone: (518) 262-5421. E-mail: email@example.com.
- Norman Fost, MD, MPH, Professor, Pediatrics and Bioethics, School of Medicine and Public Health, University of Wisconsin, Madison. Phone: (608) 263-8562. E-mail: firstname.lastname@example.org.