A Systematic Review Of The Food And Drug Administration's 'Exception From Informed Consent' Pathway

Health Aff (Millwood). 2018 Oct;37(10):1605-1614. doi: 10.1377/hlthaff.2018.0501.


In 1996 the Food and Drug Administration (FDA) created an "exception from informed consent" (EFIC) pathway for trials conducted on people incapacitated by life-threatening conditions with a therapeutic time window too narrow for reliable surrogate consent. The goals were to promote therapeutic innovation and encourage rigorous but ethical experimentation on this vulnerable population. To evaluate outcomes of this pathway, we reviewed the complete FDA docket of EFIC trials from the past two decades, encompassing forty-one trials. Among the 46,964 patients included in this review, ninety-six percent were enrolled without consent, and fewer than 1 percent withdrew before the primary endpoint. Two (8 percent) of the twenty-four superiority trials demonstrated a benefit from the experimental interventions. Many interventions were associated with adverse effects, including increased mortality, neurological deficits, and myocardial infarctions. Nearly one-third of US patients in EFIC trials were African American. While EFIC trials have yielded medical advances, investigators in future trials must pay better attention to managing withdrawals and ensuring fair demographic representation.

Keywords: Ethical Issues; Minority Health.

Publication types

  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Black or African American / statistics & numerical data
  • Humans
  • Informed Consent*
  • Randomized Controlled Trials as Topic*
  • Research Design / standards*
  • Research Design / trends
  • United States
  • United States Food and Drug Administration*