Arthur Caplan is a well-known ethicist, the head of the Division of Medical Ethics at New York University’s Langone Medical Center. On June 11, 2013, Caplan posted an article called “Get real: No need to overdo risk disclosure” on the medical website Medscape. According to basic ethical standards, subjects in research projects are supposed to give written informed consent, which means among other things that they are informed of possible risks that a decision to participate in the study might cause. The Office of Human Research Protections (OHRP) of the U.S. Department of Health and Human Services criticized researchers in a large project called SUPPORT for failing to clearly disclose the study’s risks. In his Medscape article, Caplan disagreed with OHRP and argued that strict, inappropriate requirements for consent discourage important research. His sentiments were echoed in a recent editorial in the New England Journal of Medicine, a major respected journal. In contrast, SUPPORT is criticized in a New York Times editorial entitled “An Ethical Breakdown” and by watchdog organizations like the Alliance for Human Research Protection and Public Citizen (many of the critical documents are on the Alliance for Human Research Protection website).
Here’s some background: SUPPORT was a large study of how best to treat very premature babies. These babies often need to be given oxygen to help them breathe. However, if too little oxygen is given, there is a risk of death or brain damage; if there is too much, the babies may develop an eye problem called ROP or blindness. Enter SUPPORT. According to the researchers, their goal was to determine the best oxygen level to get lowest risk of blindness without increased risk of death. This amount had already been narrowed to 85% to 92% oxygen saturation (a measure of the oxygenation of blood) in medical practice; the researchers wanted to find out where within this range is best. Infants in the research were randomly assigned to experimental conditions; in one condition, babies were given enough oxygen to bring the oxygen saturation measure to the lower end of the range (averaging 85%); in the other condition, the higher end (averaging 92%). The researchers found that infants receiving less oxygen did, indeed, have fewer eye problems than did infants given the higher amount, but more of them died.
The critical letter from OHRP stated that the consent forms that the mothers of the babies signed should have clearly stated, but did not, that an increased risk of blindness (for babies in the higher oxygen condition) or death (for babies in the lower oxygen condition) was possible. The ethicist Caplan objected to this. He argued that the researchers were comparing two standard medical practices, since 85% to 92% is the standard range used by doctors. In his view, the current way that doctors decide how much oxygen to use within that range is “a coin flip”; randomly assigning babies to the experimental groups was simply comparing two treatment approaches currently in use to see which one is best and involved no increased risk than the babies would otherwise face. He distinguished this from studies that introduce a new treatment, where informed consent about risks is a different matter. Caplan stated: “I believe that this research is highly ethical” and expressed concern that overly strict rules will hinder needed research. The New England Journal of Medicine editorial also objects to the OHRP letter. The editorial states that the OHRP’s finding that subjects should have been informed of an increased risk of death was based on hindsight. The editorial quotes the researchers, who state that “there was no evidence to suggest an increased risk of death” for infants receiving the lower levels of oxygen before their study was done. The editorial states that OHRP has “cast a pall over the conduct of clinical research” and “strongly disagree[s]” with their letter. SUPPORT, in the editorial’s view is “a model of how to make medical progress.”
What is the controversy? First, with regard to the idea that what was being compared were two versions of standard care, although Caplan does not state this in his article, the OHRP letter specifically addressed this point. In real clinical practice, a range of 85% to 95% exists, but in this study only the extremes were used. As the letter states:
According to the study design, on average, infants assigned to the upper range received more oxygen than average infants receiving standard care, and infants assigned to the lower range received less. Thus the anticipated risks and potential benefits of being in the study were not the same as the risks and potential benefits of receiving standard of care.
Further, in real clinical practice, physicians would be making decisions about where within this range to aim, and how much oxygen a particular infant needed. Caplan assumes that random assignment in the experiment was no different than a physician making a decision. In my view, this is a pretty big assumption. Since the researchers compared infants receiving higher vs. lower levels of oxygen, but did not compare either group with a control group of infants getting real standard care, we do not have evidence whether the babies did better, the same, or worse, than babies given genuine standard care. We know that babies receiving less oxygen in the experiment had fewer eye problems than did babies receiving higher amounts, but we do not have definitive evidence of whether they did better or worse than babies receiving usual care.
With regard to the argument in the Editorial that the OHRP was using hindsight by faulting researchers for not warning of risks that could not be anticipated before the research was done, again, what was in the letter was not cited: the OHRP letter specifically states that the literature had already suggested that death might be a risk of participating in the study:
While it would have been unwarranted to predict, ahead of time, specific outcomes (i.e., which infants developed which outcomes), the researchers had sufficient available information to know, before conducting the study, that participation might lead to differences in whether an infant survived, or developed blindness, in comparison to what might have happened to a child had that child not been enrolled in the study.
In addition, the OHRP letter faulted the researchers for listing possible benefits while not disclosing possible risks in the consent forms:
Although the consent form did not identify a single specific risk relating to the randomization to high or low oxygen ranges, it did include a section that was quite specific in noting possible benefits to participating infants from the change in oxygen ranges. That paragraph observed that “[t]here may be benefits to your child directly, including … a decrease in the need for eye surgery as a result of exposure to oxygen.” It did go on to point out that since it was not known in advance which treatment a particular child would be randomized to, it was “possible that your baby will receive no direct benefit.”
…The form does not say that there may be a greater or lesser risk of death depending on whether the infant is in the lower or upper range group. …While the form says that being in the lower range group may result in the benefit of decreasing the chances of developing severe [eye problems], in the “Possible Risks” section it does not say that being in the upper range group may result in the greater risk.
As I stated above, watchdog groups including the Alliance for Human Research Protection and Public Citizen, a New York Times editorial, and others, have criticized the SUPPORT study as “an ethical breakdown.” The articles by these groups catalog a number of other criticisms and give additional details. For example, in standard medical practice a physician would be evaluating an infant’s need for oxygen in an ongoing manner, but in SUPPORT the physicians were given false readings (depending on the experimental group the baby was assigned to) from instruments measuring oxygen level.
Research is important in making medical progress. No doubt about it. And research with vulnerable people is fraught with ethical dilemmas and problems. It is a truism that the goals of research and clinical care are not the same. However, national reputations of researchers, ethicists, or journals, are not guidelines for what information to trust in evaluating research or deciding to participate in a study.
