Kathryn Foxhall

	Criticisms from a federal agency about the informed consent provisions of a study of oxygenation levels for low-birth-weight infants has stirred one of the most prominent medical ethics discussions in recent years. The conversation has gone beyond informed consent in research to look at knowledge and consent in medical practice itself.

	In March of this year, the Office of Human Research Protections (OHRP) within the Department of Health and Human Services determined that “The Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT),” which was done on about 1,300 infants at 22 sites from 2004 to 2009, “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.”

	One of the study’s goals was to “learn the appropriate levels of oxygen saturation in extremely low-birth-weight infants by comparing a lower versus a higher range of levels of oxygen saturation.”

	The OHRP said, among other things, that the template for the study’s consent form section on risks versus benefits did not mention any risks relating to randomizing the babies to higher and lower levels of oxygen, but the form suggested that it was a low-risk study.

	Although it would have been unwarranted to predict which babies would have which outcomes, the OHRP said, there was sufficient information to know “that participation might lead to differences in whether an infant survived or developed blindness” compared with what might have happened if the child were not in the study.

	The OHRP statement stirred significant argument, including a letter in the 

 in which almost 4 dozen experts in ethics and regulatory issues said they disagreed that random assignment of infants carried additional undisclosed risks as compared with standard of care.

	The arguments continued in an August meeting called by OHRP in Washington,

	Nancy Kass, ScD, of the Johns Hopkins Bloomberg School of Public Health, told the meeting that there is a premise in clinical care that because professionals apply the “best knowledge to individual patients’ medical problems,” whatever risks are involved are reasonable trade-offs for the clinical benefits.

	“Ethically, it cannot be defended that we have such different standards for when patients deserve to be given information by trusted health care providers about whether their recommended treatments are risky,” she said.

	Jeffrey Drazen, MD, editor-in-chief of the 

, said that recently when he was working in an intensive care unit, he counted over 50 questions a day that could have been decided with a flip of a coin. “We need to do better than that if we are going to improve our health care system,” he said.

	Jon Tyson, MD, MPH, of the University of Texas Medical School at Houston, noted the 

Institutional Review Board (IRB) Guidebook

 calls experimentation “the use of unproven therapies whether or not research is being performed.”

	“So, babies, whether they were in this trial or not, whichever oxygen saturation goal their physician selected, were experimental subjects whether or not they were research subjects,” he said.

	J. Michael McGinnis, MD, MA, MPP, senior scholar at the Institute of Medicine (IOM), who stressed his statement was not an IOM position, said that research and practice should now be viewed as part of a “continuous cycle of knowledge generation,” and the IOM has called for attention to any regulatory impediments.

	The OHRP referred questions on the issue to a public affairs office that said there would be updated guidance, but is no timetable for its release.

	MS FOXHALL is a freelance health writer in the Washington, DC, area. She has nothing to disclose in regard to affiliations with or financial interests in any organization that may have an interest in any part of this article.

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Questions now address medical ethics regarding risk in clinical care versus risk in research.

Clinical trial for infants did not disclose study risks

In releasing its new report on the childhood immunization schedule, the Institute of Medicine (IOM) emphasizes the safety of the current schedule and says that without epidemiologic or biologic evidence of problems, immunizing children is more important than testing alternative schedules.	 	But at the same time the review says there is little scientific information about the safety of the schedule itself, as opposed to the individual vaccines.“Although each new vaccine is evaluated in the context of the overall immunization schedule that existed at the time of review of that vaccine, elements of the schedule are not evaluated once it is adjusted to accommodate a new vaccine. Thus, key elements of the entire schedule-the number, frequency, timing, order, and age at administration of vaccines-have not been systematically examined in research studies,” says the document.	 	The report was written over the last year by a panel of 14 medical, public health, and legal experts put together by the IOM. It was requested by the US Department of Health and Human Services in light of the concerns of some parents about the timing and number of vaccinations.	 	The committee also says it cannot be sure whether its list of health concerns about the schedule is complete and that some things some stakeholders worry about, such as immunologic, neurologic, and development problems, don’t have well-understood etiologies.	 	It also notes that although most children who have an adverse reaction to an immunization have a preexisting susceptibility, evidence is limited about subpopulations who may be at higher risk of such reactions, such as those with family histories of autoimmune disease or allergies or those born prematurely.	 	The report also points to the difficulty of doing research on the vaccine schedule. It would be unethical, the committee says, to do a randomized, controlled trial to compare fully vaccinated children with unvaccinated children or those vaccinated on an alternative schedule.	 	Saying it is more promising to use secondary analysis of existing data, the panel states the most feasible approach is use of the Vaccine Safety Datalink, a collaboration between the Centers for Disease Control and Prevention and 9 managed care organizations with linked data for monitoring immunization safety and rare events.	 	But even that type of study may be difficult, the report says. Just one of the challenges is the fact that groups of children who are vaccinated on the schedule and those who are not may be different in important ways.	 	The complexity of studying the schedule, the committee notes, is driven by the number of components involved, including the timing of specific vaccines, the relative timing of 2 or more vaccines, the total vaccines given by a particular age, the average age vaccines are given, and the cumulative amount of immune-stimulating content present in all vaccines received.	 	To improve research about the schedule, the committee calls on the National Vaccine Program Office to clarify and standardize definitions of key elements of the schedule, relevant health outcomes, and populations potentially susceptible to adverse events.	 	The problem is not likely to get easier as new vaccines are added in the future, the committee points out, saying that sustained and substantial federal commitment to the research is needed.The report, “The Childhood Immunization Schedule and Safety” (www.iom.edu/Reports/2013/The-Childhood-Immunization-Schedule-and-Safety.aspx), also provides background on the approval process for vaccines, how the schedule is decided, and the various databases and systems for immunization safety surveillance.

	Graduated licensing huge factor in reduced number of crashes

	Over recent decades, motor vehicle death rates for children have plunged downward. That’s a huge health victory, particularly because auto injuries are the number one cause of child deaths.	 	According to the Insurance Institute for Highway Safety (IIHS), since 1975, fatality rates have dropped 75% for infants, 66% for children aged 1 to 3 years, 50% for children aged 4 to 8 years, and 56% for children aged 9 to 12 years.	 	“It’s really a remarkable achievement,” says Anne McCartt, PhD, the IIHS senior vice president for research.	 	A good portion of the drop is because of the overall increased safety for motor vehicle travel for all age groups, driven by factors such as safer roads and vehicles and increased use of safety belts. The age-adjusted motor vehicle death rate for the US resident population was cut nearly in half from 1980 to 2009, from 22.3 to 11.7 per 100,000. Most of the drop occurred before the recession, according to the National Center for Health Statistics, but the larger drops for children have been accomplished also in part by public campaigns and policy changes.	 	A big factor for teenagers, says McCartt, is graduated driver’s licensing, which eases teens into more difficult driving situations and which all states now have in some form.	 	“State after state that implemented graduated licensing studied the effect on crashes and found crash reductions,” notes McCartt.	 	The institute estimated last year that if every state adopted 5 components of the toughest of the graduated licensing laws, the changes would save more than 500 lives and 9,500 collisions: raising the permit age to 16, mandating at least 65 supervised practice driving hours, raising the intermediate license age to 17, restricting nighttime driving, and banning teenaged passengers for teenaged drivers.	 	The decline in deaths for younger children is also impressive. From 1998 to 2006, motor vehicle-occupant fatalities for children aged younger than 13 years dropped at a steady pace-from 1,333 to 1,013-although they had made little sustained progress over the previous 20 years, according to IIHS. Then, in the 4 years from 2006 to 2010, fatalities dropped to 655, although the recession is likely partly responsible.	 	Pedestrian deaths among children dropped from 464 to 209 from 1998 to 2010, according to the IIHS. The Governors Highway Safety Association points out that in recent years, the national Safe Routes to Schools has funded programs in 7,622 schools, but it also notes that children may be walking less. 	 	The 2 biggest factors in this drop for child vehicle occupants, says McCartt, include putting children in child restraints and putting them in the back seat. Can this rate of decline continue, or will we reach some level where further reduction is more difficult?	 	“Probably it will get tougher,” says McCartt. But, she indicates, children are a special group in highway safety: “Most parents want to do the right thing. So it’s a matter of getting them the information. And trying to make things as simple as possible, which we have not done a great job at."	 	Andrea Gielen, ScD, director of the Johns Hopkins Center for Injury Research and Policy, points out that there is still much to be done for children’s motor vehicle safety in general. She would emphasize the proper use of car seats and the fact that there is an enormous need to help parents keep their kids in booster seats until they are ready to fit in adult seat belts.	 	McCartt also stresses that for many of these issues, pediatricians can continue to have an effect because they are authority figures and they see	children frequently.	 	Gielen notes that now with the death rate so low, some people think we can get it to zero. Sweden has made that commitment, and there is increasing interest in this country in taking that step, she says.	 	“We know how to prevent many of the injuries that happen,” she says. “We really should keep at it.”	â¨

IOM advises sustained federal commitment to research on schedule safety

Kathryn Foxhall

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Clinical trial for infants did not disclose study risks

IOM confirms safety of current immunization schedule