Navigating the Informed Consent Process When Using Innovative Surgery

Case Presentation

An 8-month-old boy with complex congenital heart disease and tracheobronchomalacia has spent his entire life in the intensive care unit at an academic tertiary care children’s hospital. He is tracheostomy dependent with high ventilator settings and tenuous respiratory status requiring increased doses of sedatives and occasional paralytic medications during repeated life-threatening respiratory events. A novel 3-dimensional (3D) airway splint, developed and manufactured at the university, is being piloted to treat severe tracheobronchomalacia. His family hopes this would allow him to wake up and smile. How should the involved clinicians and researchers navigate the informed consent process?

(The University of Michigan’s IRBMED deems deidentified case reports as exempt from formal review.)

Point: The informed consent process in the setting of a novel surgically implanted device for a life-threatening condition without established alternative treatment is primarily centered on clinical risks, benefits, and alternatives.

The 3-D printed airway splint is an example of surgical innovation.¹ Surgical innovation often takes place when a novel approach is developed to treat pathology that does not otherwise have an adequate alternative. This innovation affords patients the opportunity for treatment of a condition that may not otherwise be available while potentially facing unknown (and possibly considerable) risk. Historically, it has been difficult to develop controlled clinical trials for novel surgical procedures due to underpowered studies, significant crossover between groups, and challenges with objective comparison of outcomes. Studying novel surgical treatments of rare diseases compounds the challenges of clinical trial development, as the number of potential enrollees is frequently insufficient to adequately power a study.

Surgical innovation is ever more complicated due to the nature of surgery itself. Surgeons are constantly changing technique and striving to improve technology and practice. As such, the question of when innovation becomes “research” is tricky. In short, at the point whereby the creation of generalizable knowledge is anticipated, innovation should typically be viewed as research.²

A patient-specific 3D-printed bioabsorbable airway splint may provide an alternative option to patients who have failed standard treatment and are at risk for severe morbidity and mortality associated with tracheobronchomalacia. This bioabsorbable splint is created based on a computed tomography scan that creates a 3D representation of the airway. Then, with a multidisciplinary team, a personalized splint is designed and manufactured so as to be placed on the extraluminal surface of the involved airway.

Expanded access (EA), also referred to as “compassionate use,” is a Food and Drug Administration (FDA) mechanism by which patients with serious or life-threatening conditions for which there is no approved treatment may access novel investigational drugs, biologics, or medical devices. The benefits of the proposed drug/device must outweigh the risks to that patient or group of patients. This EA can be applied at the individual patient level as well as a patient population.³ EA requires an application to and approval from the FDA and an institutional review board (IRB).⁴

Obtaining informed consent in this setting is complicated due to the conflation of clinical care and research, with each directed at different primary goals. Traditionally, clinicians are expected to solely focus on the best possible outcome for the patients they are treating. Researchers, on the other hand, are primarily focused on creating generalizable knowledge to help all patients. Of course, these goals may be more or less divergent, especially when surgeon-scientists are acting in both capacities.⁵

In clinical care, the informed consent process centers on a specific individual. Risks, benefits, alternatives, and tradeoffs are wholly centered on the patient. For example, a proven airway intervention, such as a tracheotomy, involves discrete consideration of clinical risks, benefits, and alternatives. But in clinical research, risks and benefits are generally considered on the population level, balanced across all potential subjects. Thus, research subjects are inherently more vulnerable, as their well-being, while still a major consideration, is not the only or in fact the primary outcome of interest. As a result, how this information is shared and navigated with patients versus subjects as part of the informed consent process reflects these differences, as discussed below, with regard to framing around the medical decision itself vs a decision to participate in research.⁶ In all aspects of these discussions, it behooves professionals to employ strategies to improve information transmission and facilitate mutual understanding and communication, such as including using simple verbal and written language, and the teach-back method.

From a governance standpoint, the resolution is rather straightforward. The EA regulations require that informed consent be obtained from the patients or their legally authorized representative per 21 CFR Part 50.⁷ Part 50 is “informed consent of human subjects,” and thus an IRB-approved written research informed consent is obligatory. In addition, as a prerequisite to undergoing surgery, a clinical informed consent process is also required. So, to participate in a surgically innovative procedure under the EA program, both clinical and research informed consent processes and written documents are necessary.

But it is not so simple. While both documents need to be signed, the tenor of the process and conversation is dynamic and not siloed. With the use of EA, there is a natural transition away from a research-based discussion with the patient and family toward a clinical discussion and informed consent process. This is focused on presenting the proposed benefits, as well as the risks and negative outcomes that may occur with this unproven intervention.

Another significant challenge of this informed consent process through EA is the inherent vulnerability of a patient who has exhausted standard treatment or does not have a proven treatment available. This baby has a disease process with significant morbidity and a very real risk of death with or without surgery. With a vulnerable family, clinicians must be open and understanding but not underestimate the potential of false hope when desperate people feel that they have no other options and see unproven innovative procedures as their only hope.

Part of the solution requires focusing specifically on goals. In this case, the parents are praying to see their child wake up and smile. Contextualizing these goals and the likelihood of achieving them requires much more nuance than simply explaining the details of the surgery and the splint itself. This involves pediatric intensivists and palliative care experts, in addition to the likely panoply of experts participating in the care of this medically complex infant. The splint may be but one part of a much larger discussion. As such, this is, fundamentally, a clinical conversation, and informed consent is most properly centered on a clinical informed consent emphasis.

Counterpoint: The informed consent process in the setting of a novel surgically implanted device for a life-threatening condition without established alternative treatment is primarily centered on the experimental and unproven nature of the therapy.

For this infant with life-threatening tracheobronchomalacia with no proven treatment options, the FDA’s EA program provides a nexus between research, clinical care, and surgical innovation. EA offers a unique opportunity for patients to receive investigational drugs, biologics, and medical devices that would otherwise not be available to them. There is the potential to simultaneously offer additional choices to patients with otherwise no options and in the same setting continue to push the field forward in helping future patients.

This regulated arena has a scripted protocol that is, fundamentally, in line with clinical research consent processes. To proceed along the EA platform, the team must apply for and obtain FDA approval, as well as apply through their local IRB to obtain approval for the treatment and/or intervention, including review of the informed consent documentation. The FDA specifies that the “informed consent means that the purpose of the research is explained to the participant, including what their role would be and how the trial or study will work … to help ensure the patient understands the nature of the investigational medical product for the proposed treatment.”⁸

There are compelling historical reasons for why clinical research is regulated differently from clinical care. Henry Beecher⁹ presented these concerns in his landmark 1966 publication. Epic ethical lapses, from Tuskegee to Guatemala, have reinforced the susceptibility of research subjects to both explicit and implicit harms, as well as the compelling need that the research community has to protect vulnerable populations.¹⁰ The Belmont report and resultant human subjects research regulations subsequently standardized how we consider such threats to patients, subjects, and the clinical research enterprise.

But in clinical care, there are generally not prospective regulations that can be penalized by mere breach. Rather, clinical care is more often enforced by a tort-law medical malpractice system that generally requires an injury to occur. In addition, a lack of clinical informed consent is often not considered an injury in and of itself. So, clinical research clearly has different standards for enforcement and for informed consent. But how should clinicians and researchers balance their duties to patients and patients’ best interests, within goals of the research and the long-term best interest of the public?

This confusion also affects how patients understand the goals of and reasons to participate in research.¹¹ The therapeutic misconception reflects the mistaken belief that enrolling in research will provide a direct clinical benefit. This is more nuanced than a basic misunderstanding. It relates to people’s underlying beliefs and faith in the medical establishment as well.¹² When presenting an investigational drug or device, this is often interpreted with hope and optimism by the patient and family.¹³ But this hope and optimism may be overestimated. For example, a surgical trial involving a test between a novel procedure and an accepted standard will have an informed consent process predicated upon equipoise and the unknown incremental benefit of the innovative option, but in the case of a novel device for an otherwise untreatable condition as in this case, there is no such comparison.

It is for this reason that it is imperative that the informed consent process stress the unproven and experimental nature of the intervention, lest we exacerbate therapeutic misconception. Realistic goals are critical; the informed consent process thereby needs to make quite clear exactly what, how, and why a potential intervention is being offered and how likely any individual benefit is to accrue to the individual patient. The consenting individual is also tasked with providing a robust discussion of the goals of the surgical intervention. These may include gathering data in hopes of helping future patients and may engender further testing along with inherent incremental risks that go beyond what would happen in the course of typical clinical care.

There are also formidable concerns with potential or perceived conflicts of interest that affect informed consent. Researchers may benefit from successful outcomes. This may manifest via academic recognition, additional grants, or even financial rewards if they have a corporate stake in the experimental intervention. This becomes an even greater issue if the surgeon-scientist who is conflicted also is the actual surgeon who is involved in care delivery.

Although it is impossible to completely remove inherent conflicts of interest in these situations, several steps mitigate these issues. Involvement of the FDA and IRB requires additional levels of regulatory scrutiny that go beyond what occurs in clinical care. In some cases, separation of the potentially conflicted team member from the informed consent process (or at least some components of it) would also be appropriate. At a minimum, disclosures of such conflicts will need to be transparently shared. Either way, these conflicts arise out of the need to recognize that consent must abide by research regulations that are appropriately stricter than their clinical counterparts. As such, the research informed consent framework supersedes how to approach this family even when the novel surgical procedure is not part of a formal research study.

Surgical innovation using the EA program represents a thoughtful balance between patient/family choices, our duty to potential future patients, and the regulatory landscape in which we practice. The informed consent process represents an amalgam of standard clinical components, as well as clinical research regulations that necessarily meet a higher standard and level of scrutiny. As such, our obligations as researchers, clinicians, and our dual roles as both, highlight the need for us to uphold the highest levels of morality, ethics, and professionalism.