In emergency trials applying for an exception from informed consent (EFIC), the US Food and Drug Administration (FDA) requires transparency, achieved through consultation with community members, before clinical investigators can enroll patients without informed consent. Feldman et al1 provide a review of surveys intended to achieve these consultations. Their results contribute to the literature by indicating the persistent gap between our goals and the imperfect surveys that have been reported.
Voluntary informed consent is the usual prerequisite for the ethical conduct of research involving human subjects,2,3 although some question its legitimate existence.4 Feldman et al desire a “clearer understanding of the population surveyed and attitudes elicited.”1 This reasonable goal does not seem achievable with the available information. Despite the herculean effort of a single investigator analyzing nearly 16 000 pages of survey material, the inferences from these data remain limited. The wide variability of community consultation methods makes it nearly impossible to perform any detailed analysis of the EFIC process or its outcomes. Survey data are inconsistently reported, with varied approaches for community surveys. Even simple key demographic information, such as age, could not be analyzed owing to inconsistencies between trial surveys. Because of these limitations, there is no clear way to assess the efficacy of community consultation using current survey methods.
While the results of the study by Feldman et al1 demonstrate inequalities between survey respondents and study participants, these results should be interpreted with caution. The survey questions used for EFIC trials are often unvalidated instruments that could include important sources of bias. Some questions had multiple components, which suggests they were likely substandard with respect to phrasing or framing. Because of the inconsistencies of these questions, data extraction by a single author could also introduce inadvertent bias.
Feldman et al1 recognize this limitation and highlight the need for validated survey instruments, but the process of validation raises interesting challenges for community consultation. Validating a survey typically requires establishing an expert committee to design appropriate questions, conducting a pilot survey, and then applying principle component analysis to iteratively refine the survey. When the goal is to find out what the community wants from a study, who is the expert? How do we address the scenario where a community member offers passionate responses to a pilot survey question that is later discarded? The community may get exhausted with the iterative refinement of questions. As these surveys are specific to individual studies, there is little ability to reuse a validated survey for a future study. Given the considerable cost, limited budget, and limited timeline in conducting an EFIC trial, there seems to be no robust process for validating community consultation within the current framework of emergency clinical trials. Even if surveys were standardized and validated, it is unclear how the results would impact the EFIC process. There is no guidance for investigators on how to use survey information to influence the subsequent trial design and execution in the community. What would the threshold for EFIC approval or changes be? Would groups with low survey acceptance rates be excluded from participation in the proposed emergency clinical trial? The results of the article by Feldman et al1 point out the need for more clarification by the FDA.
Community respondents in the study by Feldman et al1 were selected by random and by convenience sampling. Because the convenience sampling details were not addressed and likely unknown to the authors (and possibly the investigators of the EFIC trials), it is difficult to know how well these samples generalized and represented the communities. Consequently, the inferences we might draw from the article by Feldman et al1 are limited. Some surveyed groups (specifically African American individuals and men) were underrepresented relative to their enrollment in EFIC trials and less likely to approve of EFIC.1 The authors concluded that EFIC surveys must become more inclusive. Regardless of better sampling and more inclusive surveys, past observations that general community members are not representative of patients with critical illnesses will still present a challenge. The demographic composition of patients with critical illnesses differs from the general population with regard to sex, race, and socioeconomic status.5,6 It is not clear how to address this inequality. Should we weight survey answers by respondent group? It seems unfair to seek community consultation and then assign unequal value to answers from different groups, even if it appears more likely that those groups will require care in an emergency department or intensive care unit.
Even if we were able to create a valid instrument and conduct surveys in an ideally composed survey group, how good is the wisdom of the crowd? Community consultation can also lead to harms or irrational decisions. Vaccines offer significant health benefits and some harms, but some jurisdictions have elected not to mandate vaccines because of the exaggerated perception of harms raised by ill-informed community members. Conversely, the introduction of automobile airbags, which can and do save lives but can also cause harm, occurred without the approval of community members. It is possible to imagine public resistance to airbags if their adoption relied on community consultation. Paradoxically, while most respondents in the surveys Feldman et al1 analyzed were willing to approve the initiation of trials in their community without prospective consent, only approximately half were willing to endorse the principle behind EFIC. This may reflect the common irrationality of human decision-makers and raised the following question: is the community the correct adjudicator of such studies? The legal and regulatory answer is yes, although there is likely more uncertainty from scientific and ethical perspectives. Is surrogate consent of any sort appropriate for trials? Family members often provide surrogate consent in emergent situations. Yet for interventional studies, family members’ ability to predict the patient’s wishes were no better than random.7 Knowing this, we doubt that a member of the community would fare any better in guessing a stranger’s preference. The legal burden of community consultation for EFIC may seem inclusive in principle, but in the end, someone besides the patient is deciding his or her fate and participation in a potentially high-risk study.
Despite the irrationalities that can arise from community consultation, we cannot forgo it. As Feldman et al1 point out, a key goal of community consultation is fostering public trust. We need a high bar to conduct human subjects research, even with informed consent, so the imperatives to forgo informed consent must be compelling, explicit, and well articulated to the involved community. We need guidance from the FDA for more explicit methods on conducting community consultations and how their results should inform subsequent EFIC trial design and execution. We need not only valid survey instruments but also methods to assess the efficacy of community consultation. We need these considerations, which have both ethical and scientific implications, applied to EFIC clinical investigations. We believe the results of Feldman et al1 point to the need for more detailed consideration and clarification of FDA goals.
Published: July 24, 2019. doi:10.1001/jamanetworkopen.2019.7569
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Lanspa MJ et al. JAMA Network Open.
Corresponding Author: Alan H. Morris, MD, Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center, 5121 S Cottonwood St, Sorenson Heart & Lung Center, Sixth Floor, Murray, UT 84157-7000 (firstname.lastname@example.org).
Conflict of Interest Disclosures: Dr Fan reported receiving personal fees from Abbott Laboratories, ALung Technologies, and MC3 Cardiopulmonary during the preparation of this article. No other disclosures were reported.
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Lanspa MJ, Fan E, Morris AH. How Should We Apply the Wisdom of the Crowd to Clinical Trials With Exception From Informed Consent? JAMA Netw Open. Published online July 24, 20192(7):e197569. doi:10.1001/jamanetworkopen.2019.7569
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