Study Enrollment When “Preconsent” Is Utilized for a Randomized Clinical Trial of Two Treatments for Acute Agitation in the Emergency Department

Abstract

Background: Acute agitation in the emergency department (ED) represents a danger to both patients and their caregivers. Medication is often needed, and few high-quality randomized trials have evaluated the optimal drugs for this vulnerable population. In the United States, as of 2017, randomized trials of drugs typically cannot be conducted under Waiver of Consent (46 CFR 45.116), and Exception From Informed Consent trials (21 CFR 50.24) are limited to life-threatening conditions, are onerous, and require filing an investigational new drug application with the FDA. We sought to conduct a randomized double-dummy trial of inhaled loxapine versus intramuscular haloperidol + lorazepam for acute agitation in the ED by obtaining consent in advance ("preconsent") in patients at risk of future agitation, allowing study drug administration up to 3 years later if the patient presented with acute agitation.Objective: We sought to report the successful enrollment rate of patients preconsented at an earlier ED visit for this trial.Methods: This was an analysis of patients age 18 to 64 with bipolar I disorder or schizophrenia preconsented for enrollment in the trial (clinicaltrials.gov, NCT02877108) conducted at a single urban academic center seeing approximately 60,000 patients per year. Eligible patients were assessed for capacity to consent by trained research associates, and informed consent was obtained at an ED visit for the possibility of administering drugs for agitation within the next 3 years. In the event the patient later presented to the ED and the attending physician deemed the patient required treatment for acute agitation, preconsent was confirmed and study drug would be administered.Results: Over 67 days, 1,461 patients were screened in the ED, 269 had bipolar I or schizophrenia, 194 of whom had a contraindication to inhaled loxapine leaving 75 eligible patients; preconsent was obtained in 43 patients. Four additional patients who had not preconsented were consented for the trial in real time (three by surrogate, one patient had capacity while agitated) resulting in a total of 47 consented patients. Of these 47, a total of 12 were later removed from the study: 10 patients had unrecognized exclusion criteria for inhaled

Advance consent for participation in randomised controlled trials for emergency conditions: a scoping review

“…Two of the articles were commentaries 24 25 ; one was a consensus statement 26 ; one consisted of semistructured interviews 27 ; one was a historical review 28 ; and one was a cohort study. 29 Specific conditions addressed included acute psychiatric illnesses (n=2), 24 29 pneumonia (n=1) 27 and stroke (n=1). 25 Two articles did not mention specific conditions 26 28 but rather addressed emergency conditions in general.…”

In reply:

“…We studied whether agitated patients had capacity to consent, using a standardized capacity tool 5 ; whether legally authorized representative consent was feasible 4 ; and whether obtaining "preconsent" (rather than prospective consent) could be used. 6 The findings from these studies all clearly demonstrated that meaningful informed consent is not practical or ethical in this population, and that these alternative consent methods are also not plausible.…”

Randomized Double‐blind Trial of Intramuscular Droperidol, Ziprasidone, and Lorazepam for Acute Undifferentiated Agitation in the Emergency Department

“…We sought to enroll them ahead of time in an RCT that would compare two treatment regimens, should they have a future visit for acute agitation; this approach was suggested by the FDA. When this methodology was used, we screened 1,461 patients and were unable to enroll a single patient via “preconsent.” 51 Even if enough resources were available to utilize LARs, preconsent, and consent tools each to maximum capacity, the resulting study would likely contain highly biased data. As such, it is likely a waiver or EFIC will be needed to obtain high‐quality data to inform practice and improve care for these patients.…”