“Standard of care” research (also known as “comparative effectiveness” research) is a design that compares two therapies in routine use to determine which has greater benefits or fewer risks.
All institutions that perform this research, including Albert Einstein College of Medicine and its University Hospital, Montefiore Medical Center, face questions about how to handle patient consent. This blog post represents my opinions on the issues, not the official position of Einstein and/or Montefiore.
This type of research has spurred an ongoing controversy following the SUPPORT trial, a study to determine the best oxygen saturation level in extremely premature infants in order to prevent “retinopathy of prematurity,” a condition that can cause blindness. The Office of Human Research Protections (OHRP) of the Department of Health and Human Services imposed sanctions on the lead research institution conducting the study for what the agency said were inadequate informed consent documents.
Criticism over Consent Forms
There followed a spate of editorials and articles in the New England Journal of Medicine (NEJM) and, under what appeared to be pressure from officials at the National Institutes of Health (the sponsor of the SUPPORT study), OHRP withdrew the sanctions but reiterated its criticism of the study’s consent forms. Critics of the OHRP action contended that consent forms for “standard of care” research need not list the risks of any interventions that patients would undergo if not enrolled in the research. One NEJM article stated, “Some of the options for conducting such research take advantage of the fact that there is no additional risk to being randomly assigned to one or another equally well-supported treatment option that falls within the standard range of care in clinical practice.” Those who defend OHRP’s action maintained that the risks even of standard interventions should be disclosed on the consent forms. In late October 2014, OHRP issued “Draft Guidance on Disclosing Reasonably Foreseeable Risks in Research Evaluating Standards of Care,” inviting public comment up to December 23. This guidance reignited the controversy, resulting once again in an editorial in the NEJM and other articles critical of the draft guidance. Among the arguments put forth in NEJM then was that “…the nature of consent, when needed, for research within the standard of care should be fundamentally different from that for research into novel treatments with unknown risks, since standard-of-care research does not expose participants to risk beyond the risk they might be exposed to outside the study.”
The draft guidance says: “OHRP’s general position is that in research studies designed to evaluate the risks of standards of care: (1) 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 [institutional review board] must consider when evaluating the research; and, (2) 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.” In other words, in a randomized, controlled trial studying two “standard of care” interventions, although some participants may receive the treatment they would get outside the study, others will not. An example is a clinical trial to compare a commonly used medical intervention with a standard surgical treatment for the same condition.
IOM Workshop: Pros and Cons
On December 2 and 3, 2014, the Institute of Medicine (IOM) of the National Academies convened a workshop to address the OHRP guidance. Invited speakers and some members of the audience were among the combatants in the ongoing controversy and included authors of the articles published in the NEJM on both sides of the controversy.
I was one of the invited speakers, having been the lead author of one of the published articles. Along with two co-authors and other colleagues, I had argued that the consent documents in the SUPPORT study were flawed by failing to state a number of known risks. My general view of the matter is that consent forms for this type of research must list the risks of interventions, even if those risks are the ones some participants would receive as part of their routine treatment.
At the IOM meeting, I took the role of a hypothetical patient, providing examples of what a prospective research subject would want to know when deciding to enroll in “standard of care” research. I agree with the position OHRP outlined in its draft guidance, in opposition to critics who maintained—in the complete absence of evidence—that the need to disclose the reasonably foreseeable risks of “standard of care” interventions would cause this important type of research to grind to a halt.
The IOM has announced that it will soon make available on its website all the presentations at the December workshop, so readers can evaluate the controversy for themselves.
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This is a controversial topic with which experts such as Dr. Macklin have been grappling for a while, and indeed I am one of those who felt that the SUPPORT trial consent form should have been more forthcoming, since the major risks of treatment–either standard of care or otherwise–could be devastating. However, I think that OHRP has gone too far in attempting to lay new ground rules for all future clinical effectiveness research in which SOC therapies are compared. I thought that the NEJM editorial by Lantos and Spertus (N Engl J Med. 2014 Nov 27;371(22):2129-30) says it best: We must take into account…”the balance of risk and benefit. If adopted, the net result of [the new OHRP] approach will be consent forms that make research seem riskier than it truly is and make existing practices seem safer than they truly are. As a consequence, people will probably refuse to participate in research out of the false belief that, by refusing, they are avoiding risk.” There may not be empirical evidence that research will “grind to a halt,” but these guidelines sure won’t address the woefully low percentage of Americans who participate in clinical research compared to our European counterparts. Hopefully, we will receive OHRP guidance that empowers ethicists and IRBs to make study-by-study judgement calls that will encourage, rather than discourage, clinical effectiveness research.
Professor Macklin is to be commended for speaking out against the ethics violations in the SUPPORT suffocation experiment on premature babies. Unfortunately, she does not go far enough and lets the SUPPORT defenders frame the issue with a faulty argument.
The Office for Human Research Protections (OHRP) has tacitly accepted the position of those defenders that this experiment compared two “standards of care” within the standard range of clinical care. This is a fallacy because that standard is to give premature babies oxygen breathing help so that their blood oxygen levels stays between 85 and 95 percent.
The SUPPORT researchers split this into a low level of 85 to 89 percent and a high level of 91 to 95 percent. Neither of these narrowed ranges was ever a “standard of care”, and the researchers knew that the lower range carried a significantly higher risk of death or severe brain damage which they estimated as 4 percent. They expressed their concern about the safety of the babies in that low-oxygen group but went ahead anyway with their illegal and ethics-violating experiment, lying to the parents and assuring them there was no risk involved.
Some of the researchers had previously written that “defensive documentation” such as the parents’ informed consent would be likely to reduce the number of enrollments and might even prevent the experiment. Indeed, no parent could legally have consented to sacrifice their child’s life for this research because parents are allowed to make decisions on their child’s behalf only to benefit that child.
As a result, there were 23 “extra” deaths in that low-oxygen group, close to the percentage the researchers had predicted. However, the OHRP did not complain about this premeditated killing of babies in the experiment but only to the lack of information about the risks given to the parents.
And now the OHRP is trying to let the researchers get away even with that lying by accepting their defenders’ allegation that they only compared two “standards of care”. For this invented case, the OHRP is trying to rewrite the Nuremberg Code and other ethics mandates by proposing that they only “recommend” informing the parents about the risks instead of insisting that this information was and is mandated by law.
Which means the researchers will not be penalized for having ignored a mere “recommendation” although in reality they broke the laws about informed consent as well as about intentional killing which is also called murder.
This SUPPORT experiment highlights the total failure at all levels of the U.S. health bureaucracy to enforce its own regulations and to protect research subjects.
For instance, the President’s Bioethics Commission made a big show of reassuring the President and the American public that research subjects were now adequately protected from abuses in medical research like the earlier syphilis studies in Guatemala and Tuskegee. However, the Universities led by the Chair and Vice Chair of this Commission had actively participated in this knowingly baby-killing and risk-hiding experiment, and the Commission ignored alerts about this fact.
For a detailed documentation of these dismal failures in the U.S. health system, see
https://retinopathyofprematurity.org/64KnowinglyHarmfulMedicalResearch.htm.
To put this SUPPORT research in perspective, consider that when Saddam Hussein invaded Kuwait, the war-deciding vote in the U.S. Congress was swayed by press reports that his soldiers had ripped 22 premature babies out of their incubators so that they died. These reports turned out later to have been fictitious, but they inflamed the American public and Congress and led to a full-scale war. By contrast, the SUPPORT researchers knowingly killed 23 real American preemies and no one holds them accountable for that crime.