Draft Guidance on Disclosing Reasonably Foreseeable Risks in Research Evaluating Standards of Care & The SUPPORT Trial
On October 20, 2014, The Office for Human Research Protections (OHRP) issued a draft guidance document on disclosing reasonably foreseeable risks in research evaluating standards of care. This guidance was issued in the wake of controversy around OHRP’s handling of the SUPPORT trial, and is designed to assist IRBs and researchers in ascertaining which risks must be disclosed in consent forms when the study involves standards of care. The new draft guidance represents an attempt to fulfill the need to set clear expectations how OHRP expects risks of research be evaluated and disclosed.
The SUPPORT Trial
The Surfactant, Positive Pressure, and Oxygenation Randomized Trial’” (SUPPORT) clinical trial examined the amount of supplemental oxygen that should be given to premature babies between 2005 and 2009 by comparting two ranges of oxygen saturations rates that fell within standard of care at the time. OHRP investigated this study and determined subjects were not adequately informed of risks related to the interventions being studied in the SUPPORT trial as required under 45 CFR 46.116(a)(2). Forty-five CFR 46.116(a)(2) requires “disclosure of any reasonably foreseeable risks or discomforts to the subject” as part of the informed consent process.
From very early on it was known that maintaining high levels of oxygen may cause retinopathy of prematurity (ROP) or abnormal growth of blood vessels in the eyes which can damage retinas and impair vision. Infants were randomized to two standard of care ranges of oxygen saturation rates – measured by pulse oximetry between 85% and 95%. The babies in the lower range group had a target saturation of 85% – 89%, those in the higher range group had a target saturation of 91% – 95%. The SUPPORT trial ultimately found that the babies in the higher oxygen saturation range had a higher risk of ROP, and those in the lower saturation range had a higher risk of death.
OHRP’s March 7, 2013 determination letter for the SUPPORT trial finds that the informed consent document associated with the study fell short. OHRP states that it “would have been appropriate for the consent form to explain (i) that the study involves substantial risks, and that there is significant evidence from past research indicating that the level of oxygen provided to an infant can have an important effect on many outcomes, including whether the infant becomes blind, develops serious brain injury, and even possibly whether the infant dies; (ii) that by participating in this study, the level of oxygen an infant receives would in many instances be changed from what they would have otherwise received, though it is not possible to predict what that change will be; (iii) that some infants would receive more oxygen than they otherwise would have, in which case, if the researchers are correct in how they suppose oxygen affects eye development, those infants have a greater risk of going blind; and (iv) 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.”
Critics suggest that OHRP’s treatment of the SUPPORT trial was inappropriate because the consent form adequately discloses the risks of the study. Critics note at the time of the study, there was “no evidence to suggest the increased risk of death with oxygen levels in the lower end of a range viewed by the experts as acceptable,” and effectively, the trial itself is what revealed the risks. The consent form disclosed that there is a higher risk of ROP associated with prolonged exposure to supplemental oxygen, but the benefit of the higher level compared to the lower level of supplemental oxygen was unknown. Regardless of individual opinions on how OHRP should have handled this matter, the SUPPORT trial highlights a need for clear guidance and expectations on how risks should be disclosed in studies involving standard of care, and the new draft guidance is the first step forward.
OHRP’s Draft Guidance
Under 45 CFR 46.111(a)(2), for a study to be approved, the IRB must determine the “[r]isks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. 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). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility.”
OHRP describes that “[r]esearch studies that are designed to evaluate two or more standards of care are often referred to as “comparative effectiveness research” or studies of “the standard of care.” Research comparisons of different standards of care for the same condition are conducted for various reasons, including assessing possible differences in outcomes, risks and benefits between two standards of care. In such studies it is reasonable to expect that one standard of care may be found to be better or worse than another. This may be especially true when a study is designed to target a particular risk for evaluation. The risks associated with the standards of care being compared may differ substantially from each other, as is commonly the case with different accepted ways of treating a medical problem.” 
OHRP defines “standard of care” as “treatments or procedures that have been accepted by medical experts as appropriate treatments or procedures for a given type of disease or condition and are commonly used by healthcare professionals.”  OHRP notes that the evidentiary basis for these standards of care can vary. For example, clinical practice guidelines, which represent standards of care, may be based on evidence from a wide variety and amount of sources, such as properly randomized controlled trials, cohort or case-controlled analytical studies, or opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees.
OHRP notes that studies comparing two or more standards of care may have these unique features:
- The qualities of the risks of each standard of care may be very different (for example, when comparing a surgery to a drug treatment for a condition)
- Each standard of care being evaluated may have different levels or amounts of risk (for example, a surgery may offer a better outcome than the comparator, but there may be a greater risk of a bad outcome). 
OHRP’s general position is that in research studies designed to evaluate the risks of standards of care:
- the risks of standards of care that at least some subjects would be exposed to by participating in a research study that are different from the risks of therapies the subjects would be exposed to outside the study are risks of the research that the IRB must consider when evaluating the research (45 CFR 46.111(a)(2)); and,
- the identified risks the research proposes to evaluate as one of the purposes of the study are reasonably foreseeable risks that generally must be disclosed to prospective subjects when seeking their informed consent (45 CFR 46.116(a)(2)). 
In standard of care studies, OHRP generally considers the risks of a specific standard of care being evaluated to be risks of research if:
- a standard of care that at least some of the individual subjects will be assigned to receive will be different from the standard of care that they would have received if they were not participating in the study, and
- there might be different risks associated with those standards of care. 
Therefore, in such studies, OHRP’s position is that the possible differences in risk being evaluated are considered risks of the research. Studies “designed to evaluate the risks of standards of care often hypothesize that the risks associated with one standard of care being evaluated might be different from the risks associated with another standard of care. The particular risks that the subjects will be exposed to because of being assigned to a specific standard of care are risks the subjects will be exposed to for the sake of the research. 
When a research study assigns the specific version of the accepted standards of care to be used, it is almost certain that at least some of the subjects will receive a different standard of care than they would have received if not participating in the research. Indeed, in the common study design where subjects are randomized equally between two treatments, approximately half of the subjects will be assigned to a treatment different from what they would have otherwise received. 
It is equally important to recognize that the risks of the research do not include the risks that are created by the medical condition for which the person is being treated, or the risks associated with any available standard of care treatment that they would receive for that condition outside of the research.” 
OHRP’s draft guidance takes the position that if a research study examining standards of care includes as a purpose evaluating identified risks associated with those standards of care, the identified risks associated with the standards of care being evaluated that are different from the risks of standards of care at least some of the subjects would be exposed to outside of the research study. Therefore, those risks of the standards of care under evaluation are generally considered by OHRP to be reasonably foreseeable risks of research. “Reasonably foreseeable risks must be described to prospective subjects when seeking their informed consent (45 CFR 46.116(a)(2)). All standards of care do not pose identical risks, either in terms of the nature or the degree of the risks, and individuals often may have reasons to prefer the risks of one standard of care over the risks of another. Disclosing the reasonably foreseeable risks of research to prospective subjects recognizes the ethical obligation to give prospective subjects sufficient information to make a knowledgeable decision about whether or not to participate.” 
OHRP is soliciting comments on the Draft Guidance on Disclosing Reasonably Foreseeable Risks in Research Evaluating Standards of Care through December 23, 2014. For more information regarding when and how to submit comments, go to: http://www.hhs.gov/ohrp/newsroom/rfc/draftstandardreseach.html.
 Draft Guidance On Disclosing Reasonably Foreseeable Risks in Research Evaluating Standards of Care. Available at: http://www.hhs.gov/ohrp/newsroom/rfc/comstdofcare.html. Accessed on November 18, 2014.