Hospital-acquired bacterial pneumonia (HABP) is the most common hospital-acquired infection, the most common cause of hospital-onset sepsis, and a highly morbid complication for patients.1 The estimated mortality rate is between 15% and 30% for both ventilated and nonventilated patients.2,3 There is consequently a pressing need for better strategies to prevent and treat this condition. In practice, however, it is very difficult and expensive for investigators to enroll adequate numbers of patients into pneumonia treatment studies. Barriers include the limited amount of time available to consent patients given the importance of treating serious infections immediately, patients’ limited capacity to consider research questions or give informed consent if they are in respiratory distress or delirious, and the difficulty of imposing on caregivers with research questions when their loved ones have just taken a turn for the worse. The high cost of conducting HABP trials (estimated at approximately $90 000 per patient) is driven at least in part by the complexity and difficulty of identifying and enrolling eligible patients.4
The qualitative study by Corneli and colleagues5 includes a thoughtful and informative description of one potential strategy to mitigate the HABP enrollment paradox (HABP is a common high-stakes infection but trial enrollment is very limited). Investigators from the Clinical Trials Transformation Initiative, a public-private partnership between the US Food and Drug Administration and Duke University, conducted formative interviews with a range of stakeholders to explore the feasibility and acceptability of enrolling patients at risk for pneumonia into treatment studies for pneumonia before they develop pneumonia. Participants included 18 patients at risk of pneumonia, 12 caregivers, 10 institutional review board members, 7 investigators, and 5 study coordinators. Participants were drawn from centers across the United States, although there was limited diversity—all patients were white, more than 80% had been to college, and all but 2 had chronic lung disease.
The potential advantages of advance enrollment are manifold. It provides patients, caregivers, clinicians, and study staff more time to contemplate and discuss the proposed study and to complete enrollment without the pressure of having to treat immediately. This is important because investigators have reported that more than 50% of patients with HABP are excluded from treatment trials because they receive nonstudy antibiotics before investigators have time to enroll them.6 Advance consent could allow patients the opportunity to consider the risks and benefits of participating in a treatment trial when they are clinically stable rather than fighting respiratory distress or slipping into delirium. Likewise, caregivers may be better positioned to weigh risks and benefits when they are not dealing with the stress of a new complication of care.
The investigators reported that patients and caregivers were universally receptive to the idea of being approached to enroll in a trial for the treatment of a condition that was not yet present. One-third of patients thought that it might be anxiety provoking to learn of their risk for pneumonia, and some patients and caregivers speculated that they might be too focused on their current condition to contemplate enrolling in a trial for a future, theoretical complication. Other patients, however, noted that they already knew they were at risk for pneumonia and some even welcomed the opportunity to learn about and discuss this risk in advance, particularly if paired with information about what the clinical team might be doing to prevent pneumonia.
Similarly, institutional review board members acknowledged the potential advantages of early enrollment for patients, caregivers, and investigators and did not express any ethical concerns with the model. There were differences of opinion among respondents about whether and how to reconfirm consent if the patient did develop pneumonia. Some felt this was not necessary, some felt there should be a conversation, others felt it was sufficient merely to inform patients or their representatives that they were about to receive study medication. The investigators concluded that advance consent is ethical, well received by patients and caregivers, and feasible for study staff to implement.
One concern that the investigators alluded to but did not discuss in detail is the mathematics of enrollment. The incidence of HABP is only about 1%.1 This means that if the investigators enroll unselected inpatients, the enrollment to randomization ratio will be about 100 to 1, a ratio that calls into question the efficiencies investigators hope to realize through advance consent. The obvious solution is to selectively enroll high-risk patients. The same study team has separately reported preliminary figures on the efficiency of limiting screening to intensive care unit patients on mechanical ventilation or high levels of supplemental oxygen alone; 11% of this population developed pneumonia, allowing for a much more promising enrollment to randomization ratio.6
Another potential solution to the inefficiency of advance consent is to consider integrating advance consent for a pneumonia treatment trial with consent for related studies such as diagnostic biomarkers and new prevention strategies. Likewise, several investigative teams could consider combining resources and seeking advance consent for multiple potential complications of hospitalization at the same time to increase the probability that the patient will enter at least 1 trial before discharge (eg, sepsis, pneumonia, Clostridium difficile infection, delirium).
One subtle issue worth contemplating is whether advance enrollment creates a subconscious incentive for investigators to downplay pneumonia prevention efforts. It is difficult to imagine investigators or clinicians consciously minimizing prevention, but this potential conflict of interest should at the very least be acknowledged and mitigated by requiring independence between clinical and investigative personnel. Another subtle question is whether foreknowledge that a patient has consented to participate in a pneumonia study creates a subconscious incentive to diagnose pneumonia more freely. The diagnostic criteria for pneumonia are notoriously subjective (eg, radiographic infiltrates) and nonspecific (eg, fever, leukocytosis, infiltrates, and positive respiratory cultures).7-9 It is therefore possible that advance consent might lead to randomizing more borderline cases of pneumonia, which could in turn bias treatment studies toward the null.
All told, advance consent appears to be a promising new option to help tackle the HABP enrollment paradox. It would be very informative to see a randomized clinical trial of early enrollment vs postdiagnosis enrollment to determine which model leads to more patients being randomized and which model is associated with the best ratio of study staff effort and cost to randomization. In the interim, investigators and regulators are continuing to explore other potential solutions to facilitate HABP treatment trials such as simplifying informed consent, minimizing exclusion criteria, allowing a limited period of treatment with nonstudy antibiotics prior to enrollment, and defining new end points to maximize both power and clinical significance.10
Published: December 14, 2018. doi:10.1001/jamanetworkopen.2018.5821
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Klompas M. JAMA Network Open.
Corresponding Author: Michael Klompas, MD, MPH, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, 401 Park Dr, Ste 401 E, Boston, MA 02215 (firstname.lastname@example.org).
Conflict of Interest Disclosures: None reported.
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Klompas M. Tackling the Hospital-Acquired Pneumonia Enrollment Paradox. JAMA Netw Open. 2018;1(8):e185821. doi:10.1001/jamanetworkopen.2018.5821
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