clinical research in the intensive care unit ( icu ) setting is essential to ensuring that patients are treated with interventions that are both effective and safe .
unfortunately , lack of clarity as to when research risks are acceptable in relation to anticipated benefits has impeded important clinical trials .
federal regulation governing ' exception from informed consent requirements for emergency research ' considers research risk on the aggregate , and as a result it imposes considerable restrictions on the conduct of research without consent .
recently , the us office for human research protections investigated three ardsnet clinical trials for purportedly exposing trial participants to undue risk . during the protracted review , enrollment in the fluid and catheters treatment trial
if burdensome regulation and unnecessary trial suspension are to be avoided , then clear thinking about research risk is required .
a comprehensive and systematic approach to the ethical analysis of research benefits and harms by institutional review boards ( irbs ) , called component analysis , was recently proposed .
it was endorsed by the us national bioethics advisory commission in its final report and by a number of commentators [ 4 - 6 ] .
the present commentary provides the reader with a brief introduction to component analysis and highlights its application to icu research .
the central insight of component analysis is that clinical research often contains a mixture of study interventions .
therapeutic procedures , such as a particular ventilation strategy , insertion of a pulmonary artery catheter , or administration of a drug , are given with therapeutic warrant .
that is , they are administered on the basis of evidence supporting the expectation that the intervention may benefit the study participant .
nontherapeutic procedures , such as downloading data from monitors , drawing extra blood for pharmacokinetic drug levels , or abstracting information from the patient 's chart , are administered without therapeutic warrant and are performed solely to answer the study question . because therapeutic procedures hold out the prospect of benefit to trial participants and nontherapeutic procedures do not , a separate moral calculus is required for each type of intervention .
clinical equipoise requires in essence that therapeutic procedures in a clinical trial be consistent with competent clinical care .
more formally , it requires that at the start of the trial there exist a state of honest , professional disagreement in the community of expert practitioners as to the preferred treatment .
the irb ensures that this standard is met by reviewing the justification in the study protocol , the relevant literature and , if necessary , the opinions of impartial experts .
therapeutic procedures are acceptable if the irb certifies that there is sufficient evidence supporting each of the procedures such that , were it widely known , expert practitioners would disagree as to the preferred treatment .
nontherapeutic procedures do not offer the prospect of benefit to trial participants and hence a harm  benefit calculus is inappropriate .
risks of nontherapeutic procedures must be minimized consistent with sound scientific design and , furthermore , they must be deemed reasonable in relation to the knowledge to be gained .
the irb ensures the first standard is met by asking whether all nontherapeutic procedures are necessary to answer the study question and , if possible , by identifying procedures that might equally well piggyback on routine clinical interventions .
the second standard requires that the irb judge the scientific and social value of the study to be sufficient to merit the nontherapeutic risks posed to participants .
when clinical research involves members of a vulnerable population , such as pregnant women , prisoners , children , or adults incapable of providing informed consent , additional restrictions may apply .
a threshold may limit the amount of nontherapeutic risk to which vulnerable research participants may be exposed legitimately . in the case of children ,
nontherapeutic risks are limited to a minor increase over minimal risk , that is , a minor increase over the ' risks of daily life ' .
it has been cogently argued that a similar degree of protection ought to be afforded to adults incapable of providing informed consent  a vulnerable group comprising a large proportion of participants in icu research . to determine whether risks associated with nontherapeutic procedures meet this standard , the irb reasons by analogy .
it asks whether risks posed by nontherapeutic procedures are the same as those ordinarily encountered in daily life or are sufficiently similar to those risks .
the irb may deem a study acceptable only if the moral calculi for both therapeutic and nontherapeutic procedures are satisfied .
component analysis allows us to disambiguate this claim , and focus attention on the incremental risk posed to icu patients who enter a clinical study .
clinical equipoise ensures a rough parity in terms of benefit , harm , and uncertainty between the procedures that patients would receive as a part of clinical practice and therapeutic procedures in a clinical trial .
thus , whatever incremental risks are posed to participants stem from nontherapeutic procedures . in icu research , these procedures are commonly limited to downloading data from monitors , abstracting chart information , and a few extra blood tests . in these cases ,
studies are properly understood as posing only minimal risk  a finding with implications for both irb review and the informed consent process .
we argued elsewhere that acute care research in which it is not possible to obtain the consent either of the patient or of their proxy decision maker might proceed under a simplified version of the waiver of consent .
we argue that this approach offers a superior alternative to the unduly restrictive ' exception from informed consent requirements for emergency research ' .
provocatively perhaps , component analysis also suggests a novel approach to informed consent . in this approach ,
the focus is shifted away from the life - threatening complications of the patient 's illness , which are present regardless of whether the patient participates in research , to the incremental risks posed by study participation .
the consent negotiation is thereby allowed to concentrate on the question , ' what difference will it make to me to participate in this study , as opposed to being treated in accordance with routine clinical care ? '
professor weijer 's research is supported by a canadian institutes of health research investigator award and operating grant .
 research in the intensive care unit ( icu ) is commonly thought to pose ' serious risk ' to study participants . 
 this perception may be at the root of a variety of impediments to the conduct of clinical trials in the icu setting . 
 component analysis offers a promising approach to the ethical analysis of icu research . 
 because clinical trials commonly involve a mixture of study interventions , therapeutic and nontherapeutic procedures must be analyzed separately . 
 therapeutic procedures must meet the requirement of clinical equipoise . 
 risks associated with nontherapeutic procedures must be minimized consistent with sound scientific design , and be deemed reasonable in relation to the knowledge to be gained . 
 when research involves a vulnerable population , such as adults incapable of providing informed consent , nontherapeutic risks are limited to a minor increase over minimal risk . 
 understood in this way , the incremental risk posed by participation in icu research may be minimal . 
 this realization has important implications for review by institutional review boards of such research and for the informed consent process . 