Unproven therapies in clinical research and practice: the necessity to change the regulatory paradigm.

In this article, we challenge 2 fundamental assumptions underlying the current regulation of research for unproven therapies: (1) current regulatory practices serve the best interests of patients and (2) standard definitions allow clear demarcation and rational regulation of such therapies in clinical practice, research, and quality improvement (QI) activities. Our goal is to prompt serious consideration of how to better serve all patients, not just research participants, treated with unproven therapies. We begin with a depiction of usual perinatal practices in 2009. Dr Smith, an obstetrician in a major hospital, delivers a 27-weeks’ gestation infant who cries at delivery. As part of long-standing clinical practice Dr Smith immediately clamps the umbilical cord. He then hands the infant to Dr Jones, a neonatologist, for additional care. Later that day, Dr Smith performs an emergency caesarian delivery for fetal distress at 38 weeks’ gestation. The infant does not breathe immediately. Dr Jones initiates resuscitation using 100% oxygen, a practice widely recommended for decades. Neither Dr Smith nor Dr Jones had discussed early cord clamping or resuscitation with 100% oxygen as unproven therapies with the parents. Obstetricians and neonatologists in a perinatal center in the same center proposed large randomized trials to assess delayed cord clamping and use of restricted oxygen concentration during resuscitation. However, they abandoned plans for these trials because of difficulty in meeting stringent institutional review board (IRB) requirements for informed consent. Like many other therapies used in clinical practice, neither early cord clamping nor resuscitation with 100% oxygen ever had proven value by current Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines, US Preventive Task Force Services criteria, or other similar criteria. Systematic reviews now suggest that delayed clamping of the umbilical cord reduces the incidence of brain hemorrhage in preterm infants and indicate that routine use of room air during resuscitation prevents oxidative injury and reduces deaths among term infants, findings that have now changed treatment recommendations, although it is unclear how much usual practice has changed. AUTHORS: Susan H. Wootton, MD,a Patricia W. Evans, MD,b and Jon E. Tyson, MD, MPHac Department of Pediatrics, and Center for Clinical Research and Evidence-Based Medicine, University of Texas Health Science Center, Houston, Texas; and Pediatrix Medical Group, Dallas, Texas