Abbreviations
AMI: acute myocardial infarction; CS: cardiogenic shock; EFIC: exception from informed consent; LAR: legally authorized representative
Acute myocardial infarction (AMI), cardiogenic shock (CS), and other cardiac emergencies have high morbidity and mortality and require rapid intervention to achieve optimal outcomes. Randomized trials are the reference standard for evaluating the safety and efficacy of such therapies. Ordinarily, enrollment in trials requires prospective consent with adequate time for participants to consider participation. This may not be feasible during emergencies. Patients and families often report difficulty giving meaningful informed consent because of time pressure, emotional stress, and medical complexity.
Although international trials have evaluated promising AMI-CS interventions, no U.S. trial has completed enrollment in this population in over 25 years. In part, this reflects the challenges of conducting time-sensitive research in CS, a heterogenous population in which the feasibility of obtaining prospective consent varies. In AMI-CS, the need for timely intervention and frequent impairment of patients’ decision-making capacity may limit the feasibility of obtaining meaningful informed consent.
In this viewpoint, we clarify the role of Exception from Informed Consent (EFIC) in U.S. trials evaluating emergency cardiac interventions, with a focus on its application in studies of acute therapeutic interventions for AMI-CS. We describe key regulatory requirements and ethical safeguards relevant to its use in this context. We also address other regulatory frameworks sometimes cited when prospective consent is not feasible and describe their potential limitations in greater-than-minimal risk interventional studies in this population. Our goal is to clarify how EFIC may be used in time-sensitive research settings such as AMI-CS while maintaining appropriate protections for patient autonomy.
Federal human subjects regulations include provisions that allow certain emergency research to proceed without prospective informed consent through EFIC, when specific criteria are met. For FDA-regulated research, these requirements are described in 21 CFR 50.24. For research regulated by the U.S. Department of Health and Human Services (HHS), a similar pathway exists through a Secretarial waiver of informed consent for certain emergency research.
These criteria include, among other requirements, a life-threatening condition for which available treatments are unproven or unsatisfactory, a narrow therapeutic window, infeasibility of obtaining consent from the patient or a legally authorized representative (LAR) within that window, the prospect of direct benefit from the intervention, and that the research could not practicably be conducted without such waiver. Whether a trial may use EFIC depends on how all required criteria are met in the context of study design and timing of the intervention.
EFIC has been used to enroll patients with AMI in prior emergency research. However, its use in U.S. AMI-CS trials remains limited. EFIC provides a regulatory pathway that may permit certain greater-than-minimal-risk trials to proceed when prospective consent is not feasible.
EFIC includes ethical safeguards intended to support patient autonomy and transparency. These safeguards include community consultation and public disclosure before site initiation, respect for any objection from the patient or family member before enrollment, and notification to patients or LAR after enrollment, as soon as feasible.
Community consultation is not a form of group consent, but a structured process to inform local communities about the study and solicit meaningful feedback. After study completion, investigators must disclose results to the same communities.
During research using EFIC, important safeguards include the requirement to seek prospective consent when feasible. When prospective consent cannot be obtained, investigators must make reasonable efforts to provide an “opportunity to object” before the research intervention is initiated. This allows the patient, family member, or LAR to express their wishes, and any objection will be respected. The ability to object reflects a lower threshold than informed consent and serves as an important safeguard to respect autonomy. In AMI-CS, where patients are often unable to participate in decision-making, this safeguard can help ensure that known objections, when they can be identified, are respected despite the time-sensitive nature of the intervention.
EFIC protocols must include postenrollment notification once the patient or LAR can be contacted and able to engage. This provision ensures transparency and provides an opportunity to share study information and address questions as soon as feasible. In some AMI-CS trials where additional procedures or follow-up activities remain after the initial intervention, consent for continued participation may be sought after enrollment.
Trials enrolling patients with AMI-CS under EFIC build on extensive prior experience in emergency research, including studies in out-of-hospital cardiac arrest, traumatic brain injury, and other life-threatening conditions requiring rapid care. Historically, implementation of trials using EFIC has been associated with substantial delays, in part due to the time needed for community consultation and public disclosure. Our recent experience applying EFIC in patients with AMI-CS suggests that centralized approaches with shared infrastructure may reduce these barriers.
Other regulatory frameworks that may allow research enrollment when prospective informed consent is not feasible are sometimes discussed in emergency research, , but they have limited applicability to U.S. trials evaluating acute therapeutic interventions in AMI-CS. In selected studies in the U.S., institutional review boards (IRBs) may approve a waiver of prospective consent based on the rationale that the study presents no more than minimal risk and meets all other criteria. FDA 21 CFR 56.102(i) and HHS 45 CFR 46.102(j) regulations define minimal risk as:
“Research activities where the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”
This definition does not typically apply to trials evaluating life-saving therapies for AMI-CS. Even when trials compare existing standards of care, interventions may differ in risk profiles and expected outcomes. Patients randomized in such trials may receive an intervention they would not otherwise receive outside the study. Outcomes may also be affected by research assignment and its timing (eg, screening for eligibility could delay time-sensitive care). Participants may therefore experience increased risks attributable to research participation, which must be evaluated as research-related risks. Accordingly, most AMI-CS trials evaluating acute interventions would be unlikely to meet the criteria for a minimal-risk waiver of consent.
Some lower-risk study designs, including certain diagnostic validation studies, may meet criteria for minimal risk, depending on the nature of the intervention and study procedures. Recent discussions in the emergency research literature have explored whether minimal-risk waivers may be applicable in certain comparative effectiveness trials involving treatments already used in clinical care. However, how these discussions may translate to emergency research in patients with AMI-CS remains uncertain, and federal guidance on this issue is limited. Determinations regarding minimal risk, therefore, rely on IRB interpretation of existing regulations and guidance. In FDA-regulated research, investigators may also seek protocol-specific consultation with the FDA when there is uncertainty about whether a study may qualify for a minimal-risk waiver of consent or whether EFIC should be used.
In emergency research where prospective consent is not feasible, international variation in policies and procedures for trial enrollment has been well documented. These differences reflect how countries approach consent in time-sensitive research. Several approaches used in other countries are not permitted under current U.S regulations. Deferred consent, in which consent is sought after the intervention, has been used in some countries to enroll patients with AMI-CS outside the U.S. but is not permitted under current U.S. regulations. This approach may introduce bias if risk profiles of participants who provide postenrollment consent differ from those who do not. In contrast, EFIC may include a plan to seek consent for continued participation after enrollment, which applies prospectively to future study-related activities but not retroactively for research procedures already performed.
Some trials outside the U.S. permit enrollment based on a two-physician model, in which two clinicians agree that enrollment is appropriate. This model is not recognized as a valid mechanism for research enrollment in the U.S. In the U.S., the term “two-physician consent” is sometimes used informally in limited medical situations, typically when two physicians are required to certify a diagnosis or determine eligibility for a medical intervention. In these situations, physicians verify a diagnosis or eligibility, not consent on the patient’s behalf.
In the U.S., common law, case law, and some state statutes recognize the principle of implied consent in emergency clinical care. This allows physicians to initiate treatment when patients lack decision-making capacity, no legally recognized surrogate is available, and delay would jeopardize the patient’s health. However, implied consent for emergency clinical care does not extend to research participation, which requires distinct ethical and regulatory protections.
AMI-CS is a time-sensitive condition in which generating rigorous evidence remains challenging. EFIC provides a U.S. regulatory pathway that permits enrollment in certain greater-than-minimal-risk research without prospective consent in such time-sensitive, life-threatening settings. Other regulatory approaches, including minimal risk waivers, may be applicable in selected lower-risk study designs, but their role in trials evaluating acute therapeutic interventions in AMI-CS is limited. Improving outcomes for patients with AMI-CS requires trial enrollment approaches that are aligned with existing U.S. regulatory pathways. Clarifying the role of EFIC in this context, including its associated ethical considerations, may help support the conduct of these studies in the U.S.
