© Springer-Verlag Berlin Heidelberg 2014
Ahmed Ammar and Mark Bernstein (eds.)Neurosurgical Ethics in Practice: Value-based Medicine10.1007/978-3-642-54980-9_1616. Research Ethics
(1)
Division of Neurosurgery, University of Toronto, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada
(2)
Department of Surgery, University of Toronto, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada
(3)
Division of Neurosurgery, Toronto Western Hospital, University of Toronto, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada
16.1 Introduction
Research ethics deals with the ethical principles and challenges of conducting biomedical research (Weijer et al. 1997). Although spanning every part of the research process, from study design to publication of results, at the root of ethical research practice is the protection of the subject and of the population at large. To guide researchers, an influential report known as the Belmont Report was published in 1979, which outlined three basic principles of ethical research practice: beneficence, justice, and autonomy (Beauchamp 2004; Sims 2010). Autonomy means that the individual’s ability to make free and informed decisions should be respected at all times and that as much information as necessary is provided prior to deciding to enroll in a study. Beneficence means that researchers should attempt at all times to maximize benefit to participants and minimize risk. Finally, justice means that research studies should not exclude populations from participation and should be as inclusive as possible, and the benefits of research should be evenly and widely, that is, fairly, distributed. These are all key components to value-based medicine.
Clinical neurosurgical research has many challenges, including complex populations, rare life-threatening illnesses, and clinical pictures that often fluctuate over time. Many of these practical challenges also translate into ethical challenges, wherein researchers attempt to balance their duties as clinicians with their duties as investigators, often treating patients and studying them at the same time (Bernstein 2003, 2006). The cornerstone of clinical research is trust: patients’ trust that investigators will consider and respect their safety and well-being, investigators’ trust in the validity of others’ findings and their data, and society’s trust that research resources will be properly allocated and findings used to benefit society at large (Council 2009).
To help understand the ethical challenges of clinical neurosurgical research, this chapter reviews important principles related to research practice in neurosurgical populations. We highlight the pertinent ethical challenges in the field that raise important questions about how to best safeguard patient and subject well-being. We begin by describing two cases that highlight key ethical principles and challenges that are common in neurosurgical practice and research.
16.2 Illustrative Cases
Case 1 (Conflict of Interest)
A neurosurgeon is interested in the complication rate associated with a cervical spine artificial disc that she has been using for the last 10 years. She intends to perform a retrospective chart review as well as informally assess patient attitudes toward the surgery when they are seen in clinic. Although the study is not industry sponsored, the neurosurgeon previously served as a consultant for the artificial disc manufacturer but is now no longer involved with the company. Is IRB approval required to perform this noninvasive study? Is there a possible conflict of interest (COI), and if so, how can it be managed?
Case 2 (Extremely Vulnerable Patient)
A therapy has been proposed for recurrent glioblastoma multiforme (GBM) that would see wafers containing a novel chemotherapy compound implanted into the intraoperative surgical bed following a subtotal resection. Investigators are hoping to recruit eight patients for a phase I pilot trial. Preclinical models identified only mild adverse events associated with the investigated compound, although its effects in humans are not known. While obtaining informed consent, the investigator is told by a patient, “I’m desperate! I’m willing to try any treatment that might work.” Should this patient be enrolled in the study? What challenges to the consent process would a trial like this pose?
16.3 Approach to the Cases
Case 1
Although the study in question is technically “noninvasive” and will utilize only medical records and informal discussions with patients, it nevertheless necessitates institutional review board (IRB) approval. The IRB is an independent committee that regulates the ethical conduct of research and safeguards the privacy and safety of patients and caregivers. The neurosurgeon has a valid question related to outcomes of a novel surgical procedure that has the potential to change practice patterns. As a result, there is societal and academic validity to the question. Their previous involvement with the company, however, raises the possibility that a conflict of interest may be present that could influence their objectivity. The presence of COI requires careful management which begins with full and early disclosure. The surgeon should report any relationship, current or previous, with the company to the IRB and outline this involvement in the informed consent form. Further, the researcher should abstain from conducting patient interviews herself about the surgery, given the potential risk for more subtle COI related to her role as the clinician, which could influence patient responses. A third-party investigator or research assistant should conduct these interviews, which would ideally be formally structured and held at a different setting than the surgical clinic.
Case 2
The objective of a phase I trial is to establish the safety and tolerability of a novel intervention, not the establishment of efficacy. In the described study, preclinical evidence has suggested the compound’s safety that now needs to be tested in humans. Provided proper IRB approval and oversight, such a study would be a critical first step in developing a new treatment. It is important, however, for patients to be aware that they are participating in research, not treatment. The therapeutic misconception is when patients believe that the investigations and interventions they will be or are receiving are designed specifically for as part of treatment, when in fact, they are enrolled in a structured clinical trial designed to answer a research question. The patient in this case should have the objectives of “treatment” and “research” explained to them and that they will be enrolling in the latter, not the former. The consent challenges in this case relate to the complexity of the trial, the futility of current treatments for a condition with universally poor prognosis, and the desperation of the patient. Careful communication, with no medical jargon and in the presence of a caregiver or family member, would help optimize the consent process.
16.4 Discussion
16.4.1 Societal and Academic Value of Research
Research is vital for the advancement of any field, and neurosurgery is a clear example. Advances in trauma, vascular, spinal, oncologic, and functional neurosurgery have all been made as a direct result of highly controlled and well-designed clinical studies. Examples include the use of temozolomide for glioblastoma multiforme (Stupp et al. 2005), the use of carotid endarterectomy in symptomatic carotid stenosis (Ferguson et al. 1999), and early surgery for traumatic spinal cord injury (Fehlings et al. 2012). Such trials have changed the practice of neurosurgeons and have added much to the field and to the treatment of neurosurgical patients globally.
Assessing the value of research is therefore an important component of ethical research practice, not least because patients can be exposed to significant risk (Emanuel et al. 2000; Bernstein 2006; Bernstein and Upshur 2003). As a result, a fundamental ethical principle for research in neurosurgery is that the research question being asked, or intervention being proposed, should be of some scientific and ultimately societal value. The role of the investigator, therefore, is in large part to clearly describe the objectives of the trial, both to the IRB and to eligible subjects. For example, phase I trials are designed to assess safety and feasibility and not to evaluate efficacy. Such trials recruit small numbers of patients, are open-label, and often have no placebo or control arm. The objectives of this type of study are very different from a phase III study, where the goal is to establish efficacy. These trials recruit large numbers of patients, involve a control arm with which to compare results, and can often involve multiple centers and treatment sites. Both types of trials are key to the treatment development process, but have very different objectives: safety and efficacy, respectively.
The societal value of research is fundamental to neurosurgical research because resources are also not equally distributed. Investigators must avoid unnecessary use of human and financial resources for research projects that would not add value to the scientific or clinical community. The balance between risk and potential benefit must consider both the individual and the community, and the value to the broader patient and medical community should be factored into the design of study protocols.
16.4.2 Research Ethics Approval
An independent ethics review of a study protocol is a critical feature of good ethical practice and should be universally applied (Cook et al. 2013; Upshur 2011). The purpose of the Institutional Review Board (sometimes called Research Ethics Board) is to ensure the minimization of undue risk to subjects and to bring protocols and informed consent forms in line with universal ethical principles, such as patient autonomy and justice. By design, IRBs are multidisciplinary and are consisting of a committee of clinicians, allied health professionals, legal representatives, and community members. IRBs are typically affiliated with academic institutions, but their independence and separate oversight are fundamental to their role.
IRB review is often divided along two streams: a delegated, expedited stream and a “full-board,” more comprehensive review. The former is reserved for studies that pose relatively low or no risk for study subjects, such as retrospective chart reviews, as well as some interview or survey studies. Often, a single or small group of ethics review professionals will review such studies and work closely with the investigator to ensure that both institutional and general ethical requirements are met. More comprehensive reviews, involving the entire IRB committee, are reserved for larger studies where there is more potential risk and/or features of a study that could in some way violate basic ethical principles of beneficence and/or nonmaleficence. Clinical trials, from phase I to III, will usually undergo a full review, a process that can take much time and effort on the part of both the IRB and the investigator. This is a critical component of neurosurgical research, as the IRB is the “gatekeeper” for potential ethical transgressions, whether intentional or unintentional. The IRB will ensure, among other things, that proper and understandable language is used in consent forms and may also, for example, request elimination of a placebo or control arm, if the scientific rationale is not provided.
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