The chief of the National Institutes of Health is disavowing a ruling from the government office that oversees the ethics of human research.
At issue is a controversial study of more than 1,300 severely premature infants. This spring, the federal Office for Human Research Protections criticized the scientists who ran the study for failing to tell parents about the risks their newborn children might face.
"We respectfully disagree," NIH director Dr. Francis Collins and two colleagues say, in an unusual public disagreement within the government over research ethics.
At the same time, the Office for Human Research Protections or OHRP told the University of Alabama at Birmingham, one of the study sites, that it was suspending disciplinary action on the matter until ethics guidelines on such studies are clarified.
The watchdog office also says it won't proceed against sponsors of similar studies for now. But it held open the possibility that the Alabama medical center and 22 other trial sites could still face sanctions. The OHRP is an arm of the Department of Health and Human Services, the NIH's parent agency.
In a commentary published by the New England Journal of Medicine, Collins and company write that "this controversy has alarmed some of the parents of infants who were in the study, confused the biomedical research community, and befuddled IRBs," the Institutional Review Boards that oversee human research at every clinical center.
Collins' coauthors are Kathy Hudson, NIH's deputy director for science, outreach and policy, and Dr. Alan Guttmacher, director of the National Institute of Child Health and Human Development.
The three say they have "a fundamental difference in interpretations" over what doctors knew about how to treat preemies at the time the multicenter study was launched, back in 2004.
The government's research watchdogs say the study's authors should have warned patients that children receiving lower doses of oxygen might be at higher risk of nerve damage and death.
But Collins and other defenders of the study, called SUPPORT, say data available back in 2004 gave "no reason to foresee that infants in one study group would have a higher risk of death that would those in the other group."
The commentary is accompanied by a letter roundly supporting the disputed study that is signed by 46 ethicists and pediatricians.
The ruling of the OHRP is "unfair to the investigators and institutions involved in SUPPORT," the letter says. Allowing it to stand "would...set a precedent that would impede ongoing and future...outcomes studies."
While the letter's signatories say the OHRP "overreaches" in concluding that the study violated federal ethics guidelines, they "acknowledge that the permission forms could have been improved" and "the consent process for clinical research can no doubt be improved."
They did not specify how the SUPPORT study's consent process fell short.
Collins and his colleagues also say the controversy serves as an occasion for "a substantive national dialogue" about "how best to respect and protect participants in research studies conducted within the standard of care and how to define 'reasonably foreseeable risks' in this setting."
The phrase "standard of care" is at the heart of the matter. Basically, the NIH leaders say the SUPPORT controversy raises issues that apply to any research that aims to test and improve accepted medical practice.
Thus, the case could turn out to have far-reaching effects on future clinical research.
To underscore that, HHS announced Wednesday that it plans to hold a public meeting to discuss how federal regulations designed to protect human research subjects should be applied to studies that probe "standard of care treatment."
The upcoming meeting, whose date has not been set, will address how Institutional Review Boards should assess the risks of studies looking at current clinical practice and what "reasonably foreseeable risks" should be disclosed to study volunteers.
OHRP's six-page letter sent Tuesday to Alabama researchers suggests how complicated and subtle an issue this is.
The letter acknowledges that some doctors treating a premature infant might avoid giving oxygen at levels at either end of the range used in the SUPPORT study. But by enrolling their infants in the study, parents were waiving their children's right to such individualized treatment.
"Ultimately, the issues in this case come down to a fundamental difference between the obligations of clinicians and researchers," the OHRP's Lisa Buchanan writes. "Doctors are required, even in the face of uncertainty, to do what they view as being best for their individual patients. Researchers do not have the same obligation."
As a "crucial trade-off" in doing clinical research, Buchanan writes, "society requires that researchers tell subjects how participating in the study might alter the risks to which they are exposed."
Another effect of the controversy: HHS plans to set up a process for researchers and institutions to appeal the rulings of the Office of Human Research Protections "in those situations in which reasonable people disagree about the actions taken."
Currently, there is no appeal from the Office's rulings. Dr. Michael Carome of Public Citizen, an advocacy group that first complained about the SUPPORT study, says the OHRP letter is "an important step toward addressing a highly unethical trial."
But Carome said HHS's decision to allow "current similar trials to continue ... is an abject and unacceptable failure to protect human subjects in clinical trials."
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