Research in the intensive care unit is a cornerstone for advancing the care of critically ill and injured adults and children. Informed consent is necessary prior to starting research and is categorized in three general areas: informed consent for self-enrollment (when legally competent), informed permission to enroll a family member (surrogate consent), and emergency waiver of consent. Two areas may present challenges in the intensive care unit since they do not follow the usual principles of consent in research: research with children (parental permission) and emergency research, which fall under the umbrellas of surrogate consent and emergency waiver of consent, respectively.
Research with Children
Children by statute generally lack competence, except in specific circumstances. Their decisional capacity increases throughout their development, their maturation and the duration and severity of their disease. By the time they are 11 to 14 years of age, many children may have “adult decisional capacity,” though this may not be recognized by law. Research with children is highly regulated by federal law (Code of Federal Regulations: Title 45, Part 46, Subpart D) and categorized by level of risk, with the lowest level being minimal risk. “The (federal) definition of ‘minimal risk’… should be interpreted as those risks encountered during daily life by normal, average, healthy children living in safe environments or during the performance of routine physical or psychological examinations or tests.”(1)
The research risk is allocated to one of four levels: minimal risk; greater than minimal risk with the prospect of direct benefit to the individual; minor increase over minimal risk without direct benefit to the individual, but likely to yield generalizable knowledge about the disorder or condition; and research not otherwise approvable but which presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children. In the latter category, research protocols must be submitted by the institutional review board (IRB) to the US Food and Drug Administration’s (FDA) Pediatric Ethics Subcommittee, and the final decision is made by the Secretary of Health and Human Services. The permission of one or more parents -- depending on the level of risk -- is required.
Determining what the risk is and how it fits into the aforementioned definition may be difficult. Each step of the protocol must be evaluated for risk. For instance, a magnetic resonance imaging scan in the pediatric intensive care unit may be considered a minimal risk. However, if a critically ill, intubated patient must travel to have that scan, it may not be a trivial risk. The benefits of one procedure are irrelevant to judging the acceptability of another procedure. Also, determining what constitutes normal experiences in life or routine physical or psychological examinations may be difficult. When patients are wards of the state and do not have parents who can legally consent for them, another set of rules applies. An appropriate mechanism is usually required to protect the child, including appointment of an advocate who is neither the guardian nor in loco parentis. The advocate cannot be associated in any way with the research (except as a member of the IRB), the investigators or the guardian organization. On rare occasions, the IRB may waive permission when it is not reasonable (i.e., in cases involving neglected or abused children), but the board must provide an alternative mechanism for protecting the child.
The child’s assent is required when the IRB judges that the individual is capable of providing it. Assent may be waived if the child cannot reasonably be consulted or the intervention or procedure holds direct benefit that is important to the health or well-being of the child and is only available in the context of the research. This is frequently the case in research with cancer drugs and procedures. The American Academy of Pediatrics recommends that the child’s opinion should not be asked unless that opinion would be “seriously weighed,” but dissent for non-therapeutic research should generally be respected.(2) Critically ill children have special issues. These include: a possible perception of coercion since the children are so sick; a strong parental desire to make the treatment team happy; and the overwhelming and stressful nature of the child’s illness, which can make it difficult to assess the efficacy of research-affiliated interventions as they relate to the level of risk and the child’s treatment.
Consent to participate in emergency research is complicated and secondary to the patient’s acute, serious and life-threatening situation. The treatment team must administer the intervention within a limited amount of time, and this frequently presents a roadblock to securing informed consent. Regular treatment is usually administered without consent, but research -- when the therapy is not proven -- can present a much more difficult situation. Treatment of an individual patient can be accomplished, but the collection of data in an organized fashion represents research and so must follow federal rules for approval. IRB approval will likely be necessary not only for the protocol, but also for any subsequent dissemination of the results, since most journals require IRB approval for publication. Automatic defibrillators, “clot-buster” drugs in acute myocardial infarction and hypothermia with acute brain injury have involved the consent for emergency research. The Emergency Preservation and Resuscitation for Cardiac Arrest from Trauma clinical trial in progress underscores the nuances of consent for emergency research.(3)
In the past the practice of deferred consent was frequently utilized, but this required that the risks be minimal, that the waiver not adversely affect the rights and welfare of the subject, and that the research could not be practicably carried out without the waiver. Many of the protocols were not associated with minimal risk and could not be approved and carried out using these guidelines. The federal government instituted a moratorium on these types of research in the 1990s and issued new emergency research regulations in 1996.(4)
The waiver or modification of the requirement for consent prior to starting research requires evidence that the research is needed and that the proposed study subjects would be the only population that could participate. It also requires that informed consent from the subject or legally authorized representative would not be practical. A risk-benefit analysis must show a benefit to the patients. The FDA and the IRB must agree on this process. The situation must be life-threatening, available treatments must be unproven or unsatisfactory, and the collection of valid scientific evidence must be necessary to determine the safety and effectiveness of a particular intervention.
Before initiation of the research, consultations and discussion of the social worth of the study should be held with representatives of the communities in which the clinical investigation will be conducted and from which the subjects will be drawn. One of the three consent documents -- standard consent to research, legally authorized representative permission, or consent or assent after enrollment -- must be respected. Continuation of the investigation would depend on the later consent or assent when available. Regulatory review by the FDA and the principal investigator is necessary early in the study design. A data safety monitoring board must follow the data and approve continuing the protocol on a periodic basis. These regulations clarified some issues, but multiple controversies remain, including the meaning of community consultation and how to do it, a guide to the judgment that consent is truly not practicable, and a framework for assessing research risks and benefits.
Research with child subjects and emergency research without prospective consent are situations that many critical care providers may not be familiar with. Take advantage of any institutional or regulatory resources before initiating studies involving these populations.The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government.
1. US Department of Health and Human Services. Secretary’s Advisory Committee on Human Research Protections (SACHRP). Appendix B. April 18, 2005. http://www.hhs.gov/ohrp/sachrp/sachrpltrtohhssecapdb.html. Accessed August 12, 2014.
2. American Academy of Pediatrics Committee on Bioethics. Informed consent, parental permission, and assent in pediatric practice. Pediatrics. 1995;95:314-317. Available at http://pediatrics.aappublications.org/content/95/2/314.full.pdf+html?sid=98b2bb40-95cb-499f-8da0-c4d0975fc3ef. Accessed August 12, 2014.
3. Acute Care Research. Updated guidance on exception from informed consent for IRBs, clinical investigators, and sponsors. May 1, 2013. Available at http://acutecareresearch.org/news. Accessed August 12, 2014.
4. US Department of Health and Human Services. Informed consent requirements in emergency research. October 31, 1996. Available at http://www.hhs.gov/ohrp/policy/hsdc97-01.html. Accessed August 12, 2014.