The threshold for honouring objections in research is low

There are two strong reasons for having a low threshold for honouring objections to EFIC research. First, while some have argued that limited obligations to participate in some research may exist, it is widely accepted and ensconced in international guidelines and regulations that participation in clinical research—especially with novel interventions—is generally non-obligatory and is not like public health efforts, for example. As a result, informed consent by a patient or surrogate is usually required for enrolment, and refusals are typically honoured, regardless of whether a patient or surrogate understands the study. In other words, capacity for consent must be demonstrated in order to allow enrolment, a requirement traditionally grounded in the principle of respect for persons.5 6 There is generally no threshold for honouring objections to enrolment.

Second, EFIC is permitted in emergencies because consent is not possible, not because consent is not important. If consent could be practicably obtained for enrolment in a randomised trial of a new drug for cardiac arrest or traumatic brain injury, it would be required. Most EFIC studies typically involve an investigational intervention and are rarely what most IRBs would consider to be minimal risk.7 It is true that US EFIC regulations contain additional protections; they require that risks be reasonable, that a prospect of direct benefit be present, that a situation be life threatening, and that existing therapy is in some way inadequate. However, the EFIC mechanism is ultimately allowed when studies cannot be conducted with capacitated patients.8 If consent were possible, the default position would become non-enrolment as in other settings.

Recognising that EFIC is grounded in practical considerations makes it clear that a low threshold for honouring objections to enrolment in EFIC studies is ethically appropriate. However, an objector may be uninformed, have marginal capacity or lack a connection to the patient that would provide insight into the patient’s wishes regarding enrolment. Some individuals should not be given an opportunity to object, and some objections should not be honoured. Identifying these situations will be the focus of this paper.

The relevance of the research-clinical care distinction

In clinical emergency medicine, interventions are often performed over objections of incapacitated patients or surrogates. An agitated patient with haemorrhagic shock from a gunshot wound might be taken to surgery against his will because it is known that the operation is necessary to save his life and it is unclear whether his objection is genuine. These decisions are governed by determinations of the patient’s best medical interests.9 Some may argue that the EFIC trial scenario is analogous. Because EFIC trials require a potential for direct benefit in order to be approved, and because existing therapy must be considered unsatisfactory or unproven, EFIC enrolment may be considered to be in a patient’s best interests.

We agree that EFIC trial participation, in some circumstances, may represent the best chance for a good outcome. However, the distinction between clinical care and research is relevant. EFIC trials must have a favourable risk-benefit ratio and, in the presence of equipoise, may be consistent with clinical obligations, but they remain trials. Study interventions are typically not standard of care, and sufficient uncertainty must be present for randomisation to be ethical. In other words, all treatment arms must be considered consistent with patients’ interests; all patients must receive care consistent with standard practice. Despite a prospect of benefit, enrolment in an ethical randomised trial—in which legitimate uncertainty exists—over an objection by a patient (or someone who knows the patient) is difficult to justify based on best interests grounds. If the treatment being tested were known to be in patients’ best interests, the trial would not be ethical to conduct in the first place.

Objections should be honoured when they undermine the assumption that participation does not conflict with enrolled patients’ values or interests

The most promising answer to when objections should be honoured lies in the underlying ethical justification for EFIC research. Interestingly, the EFIC regulations do not offer an explicit ethical argument for why EFIC is acceptable other than to articulate that emergency research is important and that consent is impractical. The regulations do incorporate protections related to risk and benefit and require community engagement. However, addressing objections to enrolment requires an understanding of the ethical basis of EFIC enrolment.

Several accounts have been put forth regarding the justification of EFIC. Some have emphasised clinical equipoise and the absence of significant non-therapeutic research risks.10 11 If these conditions apply, there are unlikely to be strong reasons why most patients would object to enrolment. In a comprehensive analysis of the ethical justification for EFIC, Largent et al argue more explicitly that an important condition is that ‘there is no compelling reason to think that participation in research conflicts with enrolled patients’ values or interests.’12 This condition, we believe, offers instructive guidance regarding how objections should be approached. The additional protections in the EFIC regulations help to ensure that approvable trials are ones to which most patients are unlikely to object. However, this assumption is probabilistic. If a patient, LAR, family member or friend expresses an objection, this assumption may be undermined for that patient, and the justification for enrolment may not hold.

The key question in addressing objections to EFIC enrolment is thus whether the objection overturns the assumption that participation does not conflict with the patient’s values or interests. We consider three different cases of objection in order to examine when this assumption is or is not undermined.

Case 1

A patient with suspected myocardial infarction is eligible for a prehospital EFIC study. The patient is conscious and awake but is having active chest pain. After being told that patients in this system are routinely being enrolled in a study testing a new treatment for heart attack, he states he does not want to be included.

This situation is straightforward. With a responsive patient, investigators need not depend on the assumption that he is unlikely to object. His objection undermines that assumption, even if his understanding is minimal. For these reasons, some EFIC studies have offered patients the opportunity to opt out of inclusion and honour all refusals. In the Out-of-Hospital Administration of Intravenous Glucose-Insulin-Potassium in Patients with Suspected Acute Coronary Syndrome trial,13 for example, investigators incorporated a brief assent script to allow refusal in a prehospital acute coronary syndrome trial. In addition to being conceptually sound, this approach has empirical support. Although some may believe that patients may not want to make such decisions in the context of stressful emergencies, evidence suggests they value the opportunity to refuse, even in emergency situations with diminished understanding.14 15

While this case may not seem controversial, this approach is not universal, and few attempts to offer opportunities to object have been described. In a recent trial of anticoagulation in acute myocardial infarction in the UK, for example, no opportunity to object was offered despite potentially capacitated patients.16–18 Honouring this patient’s refusal thus requires acceptance of the view that uninformed refusals have ethical force. After all, this patient’s refusal is not rooted in any understanding of this trial, and it is far from clear that he is capacitated to provide consent. Willingness to honour the refusal thus establishes an important baseline for cases that are not as intuitively obvious.

Case 2

There is no LAR available for a patient with traumatic injury and haemorrhagic shock, but a non-LAR family member is contacted via phone. When telling the family member what is occurring, should the investigator offer an opportunity to object over the phone?

The US regulations specifically state that an opportunity to object to trial enrolment should be offered if a family member (not an authorised surrogate) is present at the hospital within the therapeutic window for an EFIC trial. This case asks whether geographic proximity matters. Having accepted in the last case that uninformed refusals can be appropriate, it is not clear why the fact that the family member is not physically present should affect a decision about whether to offer an opportunity to object or to honour a refusal of enrolment. An available family member allows investigators to involve someone with potential knowledge of the patient’s wishes in the enrolment decision rather than relying on a population-based assumption of non-objection. There is no clear reason why the lack of physical presence of the family member is ethically determinative.

The challenge in this case is more about practicality. The opportunity to object to a trial should not be offered without some discussion of relevant clinical information. An investigator should not say ‘your family member is going to be included in a study of a new treatment unless you object, but we can’t tell you what is happening medically.’ This is an important detail, as some hospitals have restrictive policies regarding sharing of clinical information over the phone. These policies are grounded in the view that remote communication may pose risks to the family member (eg, driving to the hospital) and may not be in patients’ interests. Clinical disclosure policies are outside the scope of this paper, but addressing incompatibilities between such policies and the desire to engage surrogates in research decisions is important for hospitals doing EFIC research to confront.4

An additional challenge is that investigators should make clear to family members that they are not being asked to provide informed consent but that patients are being enrolled in this trial at that institution. The default position in an EFIC study when an authorised surrogate is not present remains enrolment. The family member is simply given the ability to opt out on behalf of the patient if they believe the patient would not want to be included. Follow-up discussion and an informed consent must happen with an LAR or patient as soon as possible.

How best to communicate the nuances of offering an opportunity to object (as opposed to asking for consent) has not, to our knowledge, ever been studied, and there are logistical challenges related to contacting family members who are not present. Research teams should not delay care or enrolment inappropriately and can only make reasonable efforts. Moreover, the nature of the intervention being studied—particularly its potential risks—factor into assessing the ethical importance of contacting a family member immediately. These concerns may affect the approach in a given trial, but they do not detract from the basic ethical argument that remote family members (or other appropriately connected individuals) should be given the opportunity to object when feasible.

Case 3

A patient has suffered traumatic brain injury, and her roommate is present at the hospital. The investigator is talking with the roommate about what is happening and discloses that the patient is being enrolled in a clinical trial. The roommate states that the patient would not want any kind of experimental drug.

In many places, a roommate or friend does not have a legally defined relationship with the patient and does not qualify as an authorised surrogate. The decision regarding whether to involve these individuals in decisions and whether to honour objections on behalf of the patient can thus become complicated. The EFIC guidance document only discusses family members and gives no recommendations regarding other friends and bystanders.1 Two related but separable issues arise: whether to offer the friend the opportunity to object and whether to act on an objection raised spontaneously.

Whether to offer the roommate an opportunity to object is highly contextual. Some roommates are little more than acquaintances and are inappropriate to act as an agent for the patient in any capacity. Others are deeply connected—more than most family members—and may be ethically valid surrogates. Unfortunately, figuring out the context of the roommate’s relationship to the patient may be impossible in emergency settings. For this reason, it is reasonable for investigators to default to local legal standards of surrogate authority as a matter of policy. This avoids placing healthcare decision-making responsibility on an individual who may have little knowledge about the patient’s wishes and interests and gives investigators a consistent default practice. That said, if it is immediately clear that a roommate’s relationship is substantial, it seems ethically justifiable to offer an opportunity to object to enrolment.

Even if an opportunity to object is not solicited, the roommate may learn about EFIC trial inclusion (through actions of staff or direct communication) and state an objection to enrolment that suggests the trial does not align with the patient’s values or interests. To take an extreme example, one can imagine that the patient had a parent who died while participating in a clinical trial and swore never to enrol in research. We believe there is an ethical responsibility to honour that objection. A policy of not honouring such objections—based purely on the roommate’s lack of LAR status—seems inconsistent with the EFIC justification and likely to generate problematically unwanted enrolment. Moreover, it may create situations in which investigators practise diminished transparency in order to avoid a confrontational situation. A lack of transparency and perception of secrecy by investigators and clinicians could have negative implications for public trust in healthcare and research.

Concerns about offering or honouring the roommate’s objection are legitimate. The roommate may make a decision that is later discovered not to reflect the patient’s wishes. That decision may have real consequences if the study intervention is beneficial. However, there are three reasons why this does not constitute a reason to over-ride the objection. First, though EFIC creates a default of enrolment, it does not create an obligation to enrol an individual in a clinical trial or ground a best interests argument to over-ride an objection. As articulated earlier, despite a prospect of benefit, randomised trials are only justified when sufficient uncertainty (clinical equipoise) exists. A patient receiving the current standard of care is not deprived of known effective therapy. Second, enrolment over the objection of someone who knows the patient violates a component of the ethical justification for EFIC (that enrolment does not likely conflict with the patient’s values or interests). Finally, research occurs in a public context, and practices that involve over-riding objections to enrolment by individuals like this roommate seem likely to jeopardise the trust on which the research enterprise depends.