What is the Current Emergency Consent Procedure in the Context of Acute Stroke Trials?

Our experience is framed by the context of acute stroke trials. In acute ischemic stroke, an artery in the brain becomes blocked and the brain begins to die, with the region of dysfunctional but surviving brain converting to dead brain the longer it is deprived of blood flow.^{Reference Heran, Lindsay and Gubitz1} Treatment with thrombolysis and/or thrombectomy must be administered as quickly as possible to save viable brain and maximize patient outcomes. It is typical to initiate treatment within 30 minutes of a patient’s arrival in the emergency department. Every 10 minutes that treatment administration is delayed leads to a reduction in approximately 2 healthy life months.^{Reference Almekhlafi, Goyal and Dippel2} Considering that a typical consent conversation in acute stroke trials takes 20–30 minutes,^{Reference Lindley, Kane, Cohen and Sandercock3} delaying treatment to obtain consent costs the potential research participant an average of 4–6 months of health. Moreover, Canadian best practice guidelines emphasize that consent is not required in the emergency treatment of patients with acute ischemic stroke, meaning that there is no such delay when administering treatment in the context of routine clinical care.^{Reference Heran, Lindsay and Gubitz1} Consequently, and in accordance with the TCPS-2 consideration on informed consent for research in emergency situations where the research participant lacks capacity, modern clinical trials in acute stroke care have developed novel approaches to consent, most notably, deferral of consent. Deferral of consent refers to a process in which patients eligible for participation in a trial, usually in a time-sensitive emergency, are enrolled without first gaining individual or surrogate decision-maker consent. Consent is then obtained as soon as possible after the fact from the participant (if they have regained capacity) or from their substitute decision-maker. Our group has conducted dedicated empirical research into both the ethical acceptability and operational performance of deferral of consent in acute stroke trials. The findings are consistent and convergent: deferral of consent is broadly acceptable to participants enrolled in acute stroke clinical trials^{Reference Shamy, Dewar and Deschaintre4} and meaningfully reduces time-to-treatment compared to standard prospective consent approaches. Taken together, these findings establish that deferral of consent eliminates consent as a barrier to trial participation without disadvantaging those enrolled. Participants receive care that is equivalent to what they would receive outside a trial context.

What Criteria for Emergency Consent Procedures are Outlined in the Proposed Regulations?

The proposed regulations would permit an exception to documented informed consent only when justified, a notion we fully support. Our concern is with establishing the proper mechanism to correctly identify when consent may be deferred. The proposed regulations place heavy emphasis on the concept of “potential direct benefit” as the qualifying condition for emergency enrollment with deferred consent. We respectfully submit that this is the wrong axis upon which to apply regulatory scrutiny. All interventions have the potential of direct benefit; hence, the statement as written adds little in the way of protection. Rather, this requirement seems to be suggesting that the experimental treatment must demonstrate potential direct benefit that is greater than that of the control treatment. However, this expectation is inappropriate: it echoes the well-known ethical fallacy of the “therapeutic misconception.” If it is known ahead of time that the potential direct benefit of the experimental treatment exceeds that of the control treatment, then conducting the trial would be unethical because the patients not receiving the experimental treatment would be knowingly harmed by their participation in the trial. A clinical trial should be done specifically because the potential for benefit of one treatment vs another is unknown.

How Do We Propose to Modernize the Criteria for Emergency Consent Procedures?

When a participant cannot consent, the question that most demands regulatory attention is not “might this intervention help?” but “might this intervention harm?” The appropriate higher standard for emergency enrollment is therefore a harm-minimization standard: a requirement that the intervention not expose participants to risks beyond those they would face in routine clinical care.^{Reference Shamy, Dewar and Deschaintre4}

This reframing has several important advantages. It is conceptually precise, identifies the specific vulnerability created by the deferral of consent, and addresses it directly. It is design-agnostic and applies equally to superiority trials, non-inferiority trials, equivalence trials and trials evaluating safety or operational outcomes, without arbitrarily excluding any class of legitimate scientific inquiry or any condition, whether or not a standard of care exists. And it is operationally implementable: sponsors and research ethics boards can evaluate it concretely against existing clinical practice standards.

We therefore propose that the criteria for emergency enrollment be reorganized around the following two conditions:

1. 1. Evidence-based uncertainty: The trial sponsor must put forward a reasonable evidence-based argument that there is uncertainty regarding the experimental intervention relative to the comparator. This uncertainty should be understood broadly, encompassing superiority, non-inferiority or equivalence with respect to safety, tolerability, ease of use or other clinically meaningful outcomes. It can be operationalized by requiring the sponsor to conduct or cite a systematic review of the relevant literature. If this condition is met, then there is genuine reason to believe that the participant will not be harmed by receiving the experimental intervention, given available knowledge.

2. 2. Harm minimization: Research participation must not expose participants to risks that exceed those associated with routine clinical care. This is the central and non-negotiable condition for bypassing consent. It can be operationalized by requiring the sponsor to document three key elements: first, that the safety profile of the intervention, as established by existing evidence, is consistent with or does not meaningfully exceed the risks of standard clinical management; second, that the patient is not deprived of standard of care interventions; and third, that the study procedures do not themselves impose a meaningful risk of harm. Reference to current Canadian clinical practice guidelines, or where absent, documented current clinical practice, should be required to fulfill these criteria.

Together, these criteria achieve what the proposed language attempts: a substantively higher standard appropriate to the gravity of deferring consent. The distinction is one of emphasis and precision. By centering the framework on harm rather than benefit, the Regulations would protect participants where protection is most needed – while preserving the full range of scientifically important and ethically sound trial designs that emergency research requires.

Identification of a Substitute Decision-Maker

We welcome the proposed Regulations’ recognition that consent from a substitute decision-maker should be sought where possible in emergency circumstances. We would like to propose clarification on the meaning of “where possible” in practice, as the current language leaves this phrase undefined in ways that could have significant and unintended clinical consequences. We suggest that the Regulations make explicit what is implied but not stated: that the obligation to seek a substitute decision-maker should be determined by whether one is immediately present at the bedside, and not by whether one might be located through additional effort. In other words, a representative who is immediately present at the bedside should be involved in decision-making about trial participation. If a representative is not immediately present at the bedside, then efforts to locate, identify, and communicate with this representative should not be undertaken, and enrollment should proceed according to approved emergency procedures.

The rationale for this approach is an extension of the harm-minimization principle established above. In time-sensitive emergency conditions, searching for an absent substitute decision-maker is itself a source of potential harm. It introduces treatment delay that carries measurable clinical cost. Moreover, qualifying a substitute decision-maker is not a simple task: it requires establishing identity, relationship, knowledge of the patient’s wishes, legal authority, and willingness to act. In aggregate, this process can significantly delay treatment.

We recognize that urgency varies by condition, intervention, and therapeutic window, and that this consideration does not apply uniformly across all emergency research contexts. We therefore acknowledge that the Regulations could make explicit that the extent of effort required to identify and engage a substitute decision-maker should be condition-, treatment-, and time-dependent, either through Health Canada defining specific thresholds for particular emergency conditions, or by requiring investigators to justify and define their approach within the trial protocol, subject to research ethics board approval. In all cases, the goal is the same: to respect patient autonomy where possible, while ensuring that the mechanisms for doing so do not become a source of harm.

Content of Written Consent Forms in Emergency Conditions

We would like to clarify that, under emergency conditions in which consent is being sought from a capable patient or a present substitute decision-maker, the written information that must be conveyed should be rationalized. As currently written, the same content would need to be shared with the patient or substitute decision-maker in emergency conditions as under regular conditions. This requirement is a meaningful impediment to clinical trial conduct in emergencies. As cited in the current regulations, a potential trial participant or their substitute decision-maker would need to be informed of 22 separate topics. The list of topics, without any trial-specific content, is over 500 words long (i.e. 2 standard double-spaced pages) and takes over 3 minutes to read. It is important to note that this list of topics is itself NOT evidence-based, meaning no study has ever been done to prove that potential participants want to know all this information before deciding about trial participation in an emergency. And, in fact, several studies have suggested that they want to know significantly less.^{Reference Seeger, Palacek, Cummings, Dewar and Shamy5}

Hence, we propose that the written content to be communicated in the context of participation in a clinical trial in an emergency condition should be limited to a few short statements about a select number of items (see Figure 1). It should not take more than 2–3 minutes to conduct a consent conversation in a medical emergency. Anything more than this could meaningfully impact patient outcomes.

Figure 1.

Key topics for research consent in medical emergencies.

Figure 1. Long description

This long description includes a table that lists example phrasing to the nine key topics topics : 1. The person’s diagnosis. 2. That this diagnosis is a medical emergency, and decision-making must occur quickly. 3. That the person is eligible for participation in a trial. 4. The treatments being compared in the trial. 5. That there is uncertainty about the treatments being investigated in the trial. 6. That the person will receive care that is otherwise consistent with standard of care and the alternative to participation in the trial is routine standard of care. 7. The major risk(s) of trial participation, if any are known or suspected. 8. That the decision to participate in the trial is theirs, and that they may change their mind at any time. 9. That any and all further information about the trial will be made available as quickly as possible after trial participation is decided.

The principles and practices suggested in this analysis are based on the approach towards deferred consent that was successfully used in the Canada-wide Alteplase Compared to Tenecteplase Trial, which was approved by 22 research ethics boards across Canada.^{Reference Shamy, Dewar and Deschaintre4} It also serves as the blueprint for the consent approach used in the ACT-GLOBAL trial, which is currently enrolling participants at 13 sites across Canada and around the world.

This public comment submitted is fully endorsed by the Canadian Neurological Sciences Federation and the Canadian Stroke Consortium.