Exception From Informed Consent Enrollment in Three Hemorrhagic Shock Trials

INTRODUCTION

Exception from informed consent is a vital mechanism used to enroll participants in emergency care trials when prospective consent is not practicable.¹ Exception from informed consent trials have reshaped trauma and emergency care by identifying life-saving interventions.² Because of the necessary adaptation of the traditional consent process, exception from informed consent studies must meet appropriately stringent criteria (Table) and are preceded by a robust public disclosure and community consultation process.¹ When a subject presents to care and meets eligibility criteria, they are enrolled under exception from informed consent and study interventions occur. Subsequently, when feasible and appropriate, the patient or their legally authorized representative is approached for consent to continue participation.¹ Exception from informed consent trials remain relatively uncommon, and studies describing participation and timeliness of the consent process are sparse.

Table.

Exception from Informed Consent Criteria.

Criteria1	Definition
Situation	Situation must be urgent/emergent/life-threatening requiring immediate intervention that will be unduly affected by delay
Feasibility	Consent must not feasible due to patient incapacity
Available interventions	Available interventions/therapeutics are unproven or not satisfactory
Necessity	Collection of evidence on intervention is necessary to determine safety and efficacy
Benefit	Intervention must offer possibility of direct benefit to subjects
Pre-identification	No possible way to pre-identify eligible subjects
Risk	Risk of intervention is comparable to available therapies or reasonable in relation
Impracticability	Study could not be performed without waiver
Public disclosure and community consultation	Public disclosure (one-way communication for transparency) community consultation (two-way communication) is supported by current literature1

METHODS

We performed a secondary analysis of subjects enrolled at one institution into 3 randomized clinical trauma trials: PAMPer, STAAMP, and PPOWER.^3–5 The main outcomes were the proportion of exception from informed consent-enrolled subjects retained in the trial after consent to continue participation, time to consent or notification, and withdrawal of previously given consent. Local study protocols mandated daily approach for consent by physician beginning on day of injury through study completion; legally authorized representative was defined per state regulation. The same study team conducted all trials. Data were summarized, and descriptive statistics were conducted using R version 4.5.0. This analysis followed Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines and was approved by the institutional review board (STUDY 25040051).

RESULTS

In 992 participants (Figure), 97.8% (970/992) consented to continue participation after exception from informed consent enrollment. Of subjects who regained decisionmaking capacity before a legally authorized representative was available, 99.6% (519/521) consented to continue participation. When a legally authorized representative was available while the subject lacked capacity (212/941), 100% of legally authorized representatives (212/212) consented to continue participation. Per study protocols, these patients were assessed daily for decisionmaking capacity and when appropriate were approached for consent on behalf of themselves; after regaining capacity, 91.9% (195/212) affirmed consent in concordance with their legally authorized representative’s prior decisionmaking. For 51/992 the person providing consent was not specified. The remainder of the subjects remained incapacitated without a legally authorized representative, were discharged or died prior to admission, and received written notification of enrollment (Appendix E1, available at http://www.annemergmed.com); none requested study withdrawal (184/184; 100%). Only 4/992 (0.40%) subjects could not be contacted in any manner. The median time to consent (n=894) was 1.0 day (1.0 to 3.0). There was no difference in time to consent provided by a legally authorized representative (n=210) (1.0 day [1.0 to 2.0]) versus subject (n=519) (1.0 day [1.0 to 2.0]). The rate of consent did not differ by patient sex, race, ethnicity, or age.

Figure.

Subject consent and eligibility. LAR, legally authorized representative.

DISCUSSION

Exception from informed consent facilitates the conduct of high-quality clinical research and ensures a robust consent discussion with participants and/or legally authorized representatives that is not rushed or coercive, and is informative regarding interventions, guarantee of usual clinical care, and exception from informed consent processes such as community consultation.¹ Rates of consent were high in these 3 trauma trials, concordant with the existing exception from informed consent literature.⁶ Prior studies have shown differential acceptance rates of the exception from informed consent mechanism based on patient race and sex which was not the case in our study, perhaps due to the extent of community outreach prior to study initiation and positive relationship between research team and participants.⁶ Time to consent was short (median 1 day), and almost all subjects or legally authorized representatives were able to be reached or notified; the frequency and speed with which families are approached and offered the first feasible opportunity for discontinuation of participation engenders further trust. Further, surrogates generally had accurate substituted judgment as shown by the lack of withdrawal of previously given legally authorized representative consent.

Generalizability is limited due to specific interventions, patient characteristics in this catchment area, single institution, and imbalanced sample size between trials. Data were presumed missing at random but may affect results. Due to high consent rates, conclusions about withdrawal of consent are not possible; reason for refusal was not recorded.

Timely engagement of participants/legally authorized representatives enrolled under exception from informed consent was feasible, and rate of continuation was high across key demographics. Legally authorized representatives made representative decisions on behalf of subjects in most cases. More work is needed to confirm these finding in larger cohorts, to include variable types of trials, and to better understand the effects of factors not studied here including level of education, socioeconomic status scoring, and demographics of participants in the consent process.

Data sharing statement:

The data underlying this study are not publically available due to privacy and regulatory restrictions. Deidentified data may be made available from the corresponding author upon reasonable request and subject to institutional review and data use agreements.

All authors attest to meeting the four ICMJE.org authorship criteria: (1) Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; AND (2) Drafting the work or revising it critically for important intellectual content; AND (3) Final approval of the version to be published; AND (4) Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.