Is "rescue" therapy ethical in randomized controlled trials?
OBJECTIVE
There is a commonly held belief that randomized, placebo-controlled trials in pediatric critical care should incorporate "rescue" therapy (open-label administration of active drug) when a child's condition is deteriorating. The ethical, conceptual, and analytic challenges related to rescue therapy in randomized trials can be misrepresented.


METHODS
Narrative review.


METHODS
The ethical basis of rescue therapy, the equipoise concept, and intention-to-treat analysis are examined in the setting of a hypothetical randomized trial comparing corticosteroids vs. placebo in pediatric septic shock.


RESULTS
The perceived need for rescue therapy may be partly motivated by the moral imperative to save a child's life. However, allowing rescue therapy in a trial is misconceived and inconsistent with equipoise regarding the efficacy of the study drug. If rescue therapy is permitted, intention-to-treat analysis can only compare immediate vs. delayed use of the study drug. When rescue therapy is beneficial, the observed treatment effect is substantially diminished from true effect of the study drug, leading to increased sample size and thereby placing more children at risk (18 "excess" placebo-arm deaths occur in our hypothetical example). Analysis of a trial incorporating rescue therapy cannot definitively assess overall efficacy of the agent, or distinguish beneficial or harmful treatment effects related to timing of drug use.


CONCLUSIONS
Although a rescue therapy component in a randomized trial may be perceived as ethically desirable, inconsistency of rescue therapy with full equipoise may itself raise significant ethical concerns. Increased sample sizes expose more children to the risks of study participation, including death. Researchers should be aware that clinical trials designed with rescue therapy cannot definitively determine the beneficial or harmful effects of a treatment per se, and can only assess the effects of delayed vs. immediate provision of the treatment.
Holubkov
Richard
R
Department of Pediatrics, Pediatric Critical Care, University of Utah, Salt Lake City, UT, USA. rich.holubkov@hsc.utah.edu
Dean
J Michael
JM
Berger
John
J
Anand
Kanwaljeet J S
KJ
Carcillo
Joseph
J
Meert
Kathleen
K
Zimmerman
Jerry
J
Newth
Christopher
C
Harrison
Rick
R
Willson
Douglas F
DF
Nicholson
Carol
C
D003422:Critical Care; D032984:Ethics, Research; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D015278:Intensive Care Units, Pediatric; D016032:Randomized Controlled Trials as Topic / Q000941:ethics* / Q000379:methods* / Q000706:statistics & numerical data; D035501:Uncertainty
D005938:Glucocorticoids