OHRP revisits standard of care vs. research issue
Controversy divides bioethics, research community
To some in the research community, the brouhaha over how standard of care is communicated in research consent documents is a tempest in a teapot. For others, it’s a significant problem.
Whichever view one holds, it’s clear that the Office for Human Research Protections (OHRP) is taking the issue and its critics seriously.
In late August 2013, OHRP held a public meeting about standard of care in research, and more than 200 people participated. Also, 75 people posted comments online about the issue.
OHRP will develop guidance about what constitutes reasonably foreseeable risk in research involving standard-of-care interventions and what is required to be disclosed to research subjects, says Diane M. Gianelli, OHRP spokesperson.
"This is an important issue that deserves thoughtful deliberation, so there is no timetable set for releasing the updated guidance," Gianelli says.
There is growing appreciation that the current approach to informed consent has serious flaws, states a letter signed by researchers involved with the Clinical Research Ethics Key Function Committee and the Child Health Oversight Committee of the Clinical and Translational Science Award Consortium (CTSA). The letter was submitted as a comment to OHRP.
"Informed consent documents are lengthy and difficult to understand," the CTSA letter states. "Numerous studies show that people can participate in the informed consent process and yet retain misunderstandings about the most basic facts about the research for which they have given consent."
The OHRP meeting and public debate over the use of standard of care in research resulted from a March 7, 2013, letter OHRP sent to the University of Alabama at Birmingham. The 13-page letter discussed the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) study, which involved 22 sites and was reviewed by at least 23 IRBs. The study enrolled 1,300 infants from 2004 to 2009 and was designed to learn about treatment with continuous positive airway pressure (CPAP) and to determine the appropriate levels of oxygen saturation in extremely low birth weight infants.
The study randomized infants to lower or higher levels of oxygen to test the effects on their survival, neurological development, and the likelihood of developing retinopathy of prematurity (ROP).
OHRP wrote in the letter to UAB that, based on the consent form template and the UAB consent forms, "We determine that the conduct of this study was in violation of the regulatory requirements for informed consent, stemming from the failure to describe the reasonably foreseeable risks of blindness, neurological damage and death."
The OHRP letter further stated that the SUPPORT consent form did not identify a single specific risk relating to the randomization to high or low oxygen ranges, but did include a section with specific information about the possible benefits to participating infants.
More than 40 bioethical and medical experts responded to the letter, urging OHRP to withdraw its notification that SUPPORT failed to meet regulatory informed consent requirements. The bioethicists’ letter was published on June 20, 2013, in the New England Journal of Medicine (NEJM).
"We believe this conclusion was a substantive error and will have adverse implications for future research," the NEJM letter states. "Allowing the decision to stand would be unfair to the investigators and institutions involved in SUPPORT. It would also set a precedent that would impede ongoing and future patient-centered outcomes studies."
That sort of response to OHRP’s letter to UAB is puzzling, says Leonard Glantz, JD, professor of health, law, bioethics and human rights at Boston University, School of Public Health.
"Why do people react this way over such a minor finding?" Glantz says. "When you look at the OHRP letter it’s incredibly gentle."
While the OHRP letter helped launch the broader look at the use of standard of care in research and, more specifically, how it’s handled within informed consent documents, its overall tone is mild, he adds.
OHRP should stand by its letter to UAB and say that standard of care is just like any other research, requiring the same amount of IRB scrutiny, Glantz says.
"When you go to a doctor and you get care, it’s because your doctor thinks it’s good for you," Glantz says. "When your doctor is a researcher and is no longer acting like your doctor, then you need to know that."
OHRP decided to suspend compliance actions against UAB until after the agency issues new guidance to address risks and standard of care. The public meeting in August on the topic was a first step toward creating new guidance.
Several speakers at the public meeting spoke in favor of increased regulatory scrutiny of standard of care in research, and some took issue with OHRP’s critics.
"Soon after OHRP’s findings regarding SUPPORT came to public attention, a group of individuals within the medical research establishment launched a well-orchestrated attack against OHRP in defense of the SUPPORT study," according to Michael Carome of watchdog group Public Citizen in Washington, DC. Carome was the first speaker at the OHRP meeting.
"Many critics of OHRP’s actions have sought to blur the line between research and clinical care and appear to view the process of obtaining informed consent as an unnecessary impediment to conducting clinical trials and advancing medical knowledge," Carome continues. "They want to change the rules to satisfy their research needs at the expense of subjects’ rights."
The people who oppose the OHRP letter appear to oppose research regulation in general, Glantz says.
Research treatment and standard care are different, which is why ethical research requires voluntary informed consent, one expert told OHRP at the August meeting.
"In standard care, as we have heard, a doctor’s fiduciary responsibility is to prescribe treatments that serve each patient’s best interest adjusted in response to each patient’s individual fluctuating need," said Vera Sharav of the Alliance for Human Research Protection in New York City.
"Research treatment is predetermined by a protocol that seeks to resolve uncertainty and contribute generalizable knowledge," Sharav said. "Every patient who is asked to volunteer for research should be informed honestly about potential risk of foregoing individualized care."
Researchers and IRBs should keep in mind the fact that inherent risks in treatment used in standard care may be magnified within the constraints of research, Sharav said.
However, in some comments to OHRP, experts point out that research treatment is not always riskier.
"It is a dangerous and outdated fantasy to simply view research as riskier than conventional treatment," writes John D. Lantos, MD, director of the bioethics center at Children’s Mercy Hospital in Kansas City, and a professor of pediatrics at the University of Missouri in Kansas City.
"Care guided by protocols may be better or worse than care guided by individualized clinical judgment," Lantos adds. "Participation in a research study may increase or decrease some or all of these risks."
The only way investigators and IRBs can ensure that patients make a truly informed choice is to describe risks to potential study subjects in a way that is informative, empowering, clear and comprehensive, Lantos writes.
"And I hope that the federal regulations that come out of hearings like this acknowledge not just the risks of research but also the benefits — and parallel risks of non-validated therapies," he concludes.
Perhaps the real problem with the SUPPORT study was that more than 20 IRBs reviewed it and none had addressed the informed consent problems OHRP found, Glantz says.
"There is a problem when IRBs say, This is a national study; I’m sure it’s fine,’ and then they don’t look too closely," Glantz says.
"You expect investigators to downplay the risk; you never see a proposed form where the risks are exaggerated and the benefits are downplayed, so IRBs should be used to that by now," he adds. "That’s where the failure is."