PEDIATRICS Vol. 114 No. 3 September 2004, pp. 859-861 (doi:10.1542/peds.2004-1458)
COMMENTARY |
Resuscitation Research and the Final Rule: Is There an Impasse?
Department of Pediatrics,
University of Michigan,
Ann Arbor, MI 48109-0243
Abbreviations: CA, cardiopulmonary arrest with apnea and loss of palpable pulse • RCT, randomized, clinical trial • IRB, institutional review board
Cardiopulmonary arrest with apnea and loss of palpable pulse (CA) in childhood is a tragic event that often results in either death or poor-quality neurologic survival. This is especially true of CAs occurring in the out-of-hospital setting, where devastating neurologic injury is very common. Until very recently, no therapy had been established to improve neurologic outcome in humans. Two randomized, clinical trials (RCTs) in highly selected adult populations with out-of-hospital CAs reported increased survival and, most importantly, improved neurologic outcomes.1,2 An expert committee concluded that generalization of these findings to all adult or to pediatric CA events should not occur without additional study.3
Unfortunately, major advances in resuscitation of humans have been quite limited over the past 4 decades. The need for RCTs to advance resuscitation science is entering an important period. Promising therapies such as mild hypothermia and vasopressin have been reported recently to improve outcomes in very select adult CA populations.1,2,4 However, many critical questions remain that need urgent study. For example, concerning hypothermia: 1) What is the optimal temperature for therapeutic hypothermia? Does it vary by age group or etiology of CA? 2) What is the duration of the therapeutic window? Are there factors that affect this? 3) What is the optimal duration of hypothermia? No large-scale RCT has been conducted in the nonneonatal pediatric population, and there exists little information on which to make recommendations.
Morris et al5 in this issue of Pediatrics do an excellent job and should receive praise for investigating a hypothetical hypothermia study requiring community consent and reviewing some of the difficult issues related to the use of the "Exception From Informed Consent Requirement for Emergency Research" (Final Rule or 21 CFR 50.24). The Final Rule has been reported to facilitate study of emergency interventions with therapeutic windows of <6 hours.6 Perhaps the most difficult task for investigators associated with the Final Rule is the requirement of a community consultation. For their hypothermia after an in-hospital CA study with a hypothetical 30-minute window of efficacy, the authors report that the consensus for community consultation at their large academic center was to create focus groups, to have publicly displayed information in the form of brochures and posters, and to give a brief discussion with guardians in the immediate postresuscitation period in which an opportunity to decline study participation would exist. This seems quite reasonable; however, in the actual setting of in-hospital CA, it may not always be feasible. Family members may not be available within 30 minutes to begin a therapeutic hypothermia-intervention discussion. Similarly, study investigators may not be available to give a brief verbal-consent discussion, because they might be busy stabilizing the child who was just resuscitated. For patients with general care area CAs or patients with CAs shortly after pediatric intensive care unit admission, the public information may not have been seen, and the families may not be immediately available. A "mock" observational study to determine what proportion of in-hospital CA subjects could actually be enrolled at the author's facility may provide additional useful information. The authors correctly point out that their plan for community consultation would not be suitable for out-of-hospital CAs, which represents the very group that is at greatest risk of death and poor neurologic outcome associated with CA and may have the most to benefit from a hypothermia intervention. A different and more complex community-consultation process would need to be conducted for these patients to participate in a hypothermia study.
Other important issues related to the Final Rule and a hypothermia-for-pediatric-CA trial exist related to the need for multicenter participation to achieve adequate study sample size. In such a trial, each study site would have its own unique institutional review board (IRB) interpretation of the Final Rule. Each site would likely have different requirements requested of the study investigators related to community consultation at their location.7 For example, one center's IRB might require investigators to obtain informed consent prospectively from all high-risk congenital heart disease surgery patients, because this is an easily identified at-risk population in which consent could be obtained prospectively. Another IRB may have different requirements. Another practical issue is that the IRB process would likely to be quite lengthy, because most IRBs are unfamiliar with the special requirements of the Final Rule. In fact, according to the authors,5 who are knowledgeable on the subject, no pediatric RCT using the emergency waiver of informed consent has been performed in the United States since the requirements were established in 1996. A feasibility issue with the Final Rule is that its complex requirements would potentially add significant cost and months of delay in the conduct of important federally sponsored RCTs. It is unlikely in a multicenter RCT that site investigators would have enough protected time to go though the administratively complex and potentially costly process required of the Final Rule. Study funding may need to be secured a priori that would cover the investigator's effort, the administrative support needed for documentation, and costs associated with community consultation. Additional issues have been systematically reviewed and commented on by Biros et al.8
The current Final Rule was a very carefully constructed set of procedures to protect patients with life-threatening emergency conditions from research in which informed consent was not possible. However, the observation that little emergency or resuscitation research without consent has been conducted in the United States since 1996 may suggest that some modifications are required. The recent trend of major CA studies being conducted outside the United States in Europe, Australia, and other locations,1,2,4,9 with US coauthors on occasion,9 may be additional evidence of this. Furthermore, the "Exception From Informed Consent Requirement for Emergency Research" regulations have been identified as one of the major barriers to research in the current National EMS Research Agenda, and steps to address the identified issues have been outlined.10 A thorough review of the existing Final Rule requirements may be in order by the Food and Drug Administration, Office for Human Research Protections, and ultimately Congress that would both continue to rigorously protect study subjects while at the same time permitting highly important research related to resuscitation to be conducted in the United States in a timely manner. Ideas such as creating a national IRB that leads the way in approving up front this uncommon, highly specialized high-risk/high-return research followed by local IRB review with modification as needed could be one of many starting points for discussion.
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FOOTNOTES |
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Accepted Jul 21, 2004.
Address correspondence to Frank W. Moler, MD, MS, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109-0243. E-mail: fmoler{at}umich.edu
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REFERENCES |
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1. The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346 :549 –556
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6. Clifton GL, Knudson P, McDonald M. Waiver of consent in studies of acute brain injury. J Neurotrauma. 2002;19 :1121 –1126[CrossRef][Web of Science][Medline]
7. Alpert S. Implementing the Final Rule [commentary]. Acad Emerg Med. 1999;6 :1188 –1189[Medline]
8. Biros MH, Fish SS, Lewis RJ. Implementing the Food and Drug Administration's Final Rule for waiver of informed consent in certain emergency research circumstances. Acad Emerg Med. 1999;6 :1272 –1282[Web of Science][Medline]
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10. National EMS Research Agenda. Available at: www.nhtsa.dot.gov/people/injury/ems/EMS03-ResearchAgenda/home.htm. Accessed July 2, 2004
PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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