As a first step, what must be done before enrolling a young child in a research protocol?

Ethics of Research in the Neonatal Intensive Care Unit

Clinical research on sick newborn infants is required to advance clinical care; improvements in the practice of clinical neonatology would not occur without such research. Research in children, let alone newborn infants, has historically been difficult to justify. Until more recently, a very protectionist view prevailed, such that studies in children were justified only if they were unsuitable in adults. This perspective has changed, reflecting the move from the dominance of beneficence or protectionism toward vulnerable groups, such as infants, to a stance based more on the principle of justice as the important consideration whereby individuals who are the subject of a treatment should have an equal opportunity to share the benefits of human research. This move is also a reflection of the fact that newborns have been harmed by the adaptation of results of treatment in other groups being applied to them without adequate research.

Despite the imperative for research, there are many challenges to neonatal research.77 It is difficult to obtain “authentic,” morally valid, informed consent from parents, because this requires surrogate decision making by anxious and stressed decision makers, often following an unanticipated, acute emergency. In addition, parents are often young, healthy members of society with little prior medical exposure and familiarity with the concept of medical research. Language and cultural and religious diversity add further complexity, and the act of soliciting consent itself often further exacerbates parental stress. Parents or guardians feel beholden to the caregivers of their vulnerable infants, and in cases in which the relationship between caregiver and researcher is unclear, there is the potential for “therapeutic misconception” (i.e., attributing therapeutic intent to research).

It may also be disturbing for parents to learn that there is much uncertainty about neonatal practice, such that their confidence in NICU caregivers may be diminished. Before discussing informed consent in neonatal research, other more general issues facing the ethical conduct of research need to be ensured, including the scientific value and validity of the study proposal, the existence of clinical equipoise in randomized trials, the distinction between therapeutic and nontherapeutic research (where the study would not lead to direct benefit for that infant), the existence of any potential conflicts of interest or financial incentives, and the overall risk/benefit analysis of the research proposal.

Informed consent is enshrined as a foundational cornerstone of the ethical practice of protecting human subjects from research risk.69 The four domains within informed consent are (1) disclosure of information, (2) understanding, (3) competence or capacity, and (4) voluntariness or freedom to choose. Decisions that adults make on their own are morally robust, but decisions made for others cannot have the same degree of authenticity and are necessarily less valid in children.69 Despite these challenges, it is widely accepted that neonatal research investigators have the obligation to obtain truly informed parental consent. Golec and colleagues described various models of consent in neonatal research44; this includes the standard model in which parents are solicited when their infant becomes eligible for a study, given written and verbal information, encouraged to ask questions, and required to sign a consent form. Other means of obtaining consent have included a steplike process of consent3; advanced consent, in which parents are approached in anticipation that their infant may meet inclusion criteria at a later date; emergency consent; and randomization without consent, in which randomization occurs before potential participants are approached, and only participants allocated to experimental therapies are informed of the trial and invited to give or withhold consent (Zelen randomization).128 The individuals allocated to continue with standard therapies are not informed that they are trial participants at that stage.

Definitional Issues

Is TM a highly prevalent phenomenon among patient-subjects? Critics note that this depends on how TM is defined and measured.

Jonathan Kimmelman argued that TM as initially propounded by Appelbaum and colleagues focuses on ‘confusion within a protocol’ rather than ‘confusion about protocol.’ TM as confusion within a protocol is manifested as the failure to recognize limitations on individualized care and treatment that are inherent in certain clinical research methods and procedures because they do not operate on the principle of personal care. Nevertheless, many commentators on TM have claimed that patient-subjects harbor TM if they misestimate the therapeutic potential or benefits of participating in trials with particular objectives and designs, such as early phase clinical research. Arguably, TM is recorded or argued to be prevalent in Phase I cancer drug trials in part because misestimation of medical benefits was incorporated into the definition and measurement of TM in many of the empirical studies on consent to Phase I cancer trials. That benefit misestimation is seen by many commentators as within the conceptual boundaries of TM is not surprising given that two of the originators and main proponents of the concept, Appelbaum and Lidz (together with Thomas Grisso), went on to develop a qualitative measure of TM with two equally weighted bases. Patient-subjects manifest TM when they express (1) an incorrect belief that their individual needs will determine assignment to treatment conditions or lead to modification of the treatment regime, denoted as TM1, and (2) an unreasonable or unrealistic appraisal of the nature or likelihood of medical benefit because of a misperception of the nature of the research activity, denoted as TM2. Under TM2, research subjects are confused about the medical benefits (and risks) of participating in a clinical research setting or design per se. Conducting interview studies with more than 200 patients from 44 clinical research studies, the authors found that 31% of subjects had TM1, 51% had TM2, and more than 60% were judged to have TM on one or both of these bases. The incorporation of benefit misestimation therefore has considerable impact on quantifying the presence of TM in research subjects and, consequently, its generalizability to different research subject populations and research settings.

The incorporation of benefit misestimation into TM has also led to the consideration of TM influencing decisions of trial enrollment for other stakeholders in clinical research, such as proxy decision makers. Parents who enroll their sick children in pediatric clinical trials are said to harbor TM when they have great hopes and expectations of medical benefit for their children as an outcome of the research project. Various writers have also charged investigators with TM when they, in recommending or enrolling patients to participate in a certain clinical research project, sincerely (but inaccurately) claim that the experimental therapeutic intervention is equivalent to standard therapy or when they express ‘undue’ optimism for the experimental intervention’s prospects of medical benefit for patient-subjects. In fact, some writers argue that the entire clinical research community – investigators, regulatory agencies, government and industry sponsors, and patient advocates – harbors a ‘collective’ therapeutic misconception. The brandings of clinical research projects reflect a degree of truth for this view. Terms that suggest that clinical research equates to effective or optimal care, such as ‘MIRACL’ (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering) or ‘PROVED’ (Prospective Randomized Study of Ventricular Failure and the Efficacy of Digoxin), are typical labels for clinical trials used in recruitment advertisements (especially for industry-sponsored research).

In addition to the issue of prevalence, the inclusion of unrealistic expectations or misestimation of benefits into TM to measure its presence in patient-subjects impacts the assessment of when informed consent has been compromised. Consider informed consent for Phase I cancer drug trials. Most cancer patients are motivated to participate in a cancer drug trial because of the possibility of receiving direct medical benefit. However, as mentioned previously, the probability of medical benefit for those participating in such trials is very low. As such, TM in patient-subjects participating in Phase I cancer drug trials is said to be ethically very troubling for informed consent because research subjects’ expectations or estimations of direct medical benefit are unlikely to be met within the parameters of trial purpose and design. In fact, the subjects face unknown risks, such as a chance – albeit a very low one (< 1%) – of toxicity-related death. This presents an ethical conundrum. Do Phase I cancer drug trials, or Phase I clinical trials in general, trade on the false hopes of a vulnerable population? Does any clinical research project, for that matter, exploit patient-subjects whenever subjects misestimate medical benefits because misestimation undermines the autonomy of a decision to participate in research?

Sam Horng and Christine Grady have argued for the need to make a neat conceptual distinction between TM and ‘therapeutic misestimation.’ This distinction allows us to know when informed consent is compromised to the extent that we should be ethically concerned. For Horng and Grady, TM should simply be defined as the conflation of clinical research with therapy. Therapeutic misestimation, on the other hand, should be defined as the underestimation of risks or overestimation of benefits or both. In their view, these are different phenomena of misunderstandings that affect patients’ consideration of and decisions on trial participation in different ways and to different degrees of ethical significance.

According to Horng and Grady, although therapeutic misestimation can coexist with TM in the minds of subjects, it need not be so. Therapeutic misestimation therefore need not come together with or stem from TM. A research subject can fully understand the nature or intent of a clinical trial while still misestimating the probability of medical benefits or risks. Conversely, a patient-subject can have a realistic expectation of medical benefits and risks while conflating the nature of clinical research with the nature of clinical therapy. For the authors, therapeutic misestimation is less problematic than TM because it is a misrepresentation of an aspect (i.e., the probability of benefit and/or risk) of the option of research participation rather than a misrepresentation of the option itself. However, therapeutic misestimation undercuts decision making regarding trial participation in an ethically worrisome way if the misestimation of benefit and/or risk is very large and is the primary factor in a subject’s trial enrollment – for example, when a subject gives an estimate of a 50% chance of a direct medical benefit as his or her chief reason for participating in a Phase I oncology trial.

One must be careful, however, taking cues from philosophy of language, that the research subject’s estimation may reflect a belief-type expression of probability rather than a frequency-type expression of probability. Frequency-type probability expressions state as a matter of fact the relative number of times that some outcome occurs in a large number of relevantly similar trials. Belief-type probability statements express a person’s level of confidence or certainty about an outcome in light of relevant reasons or evidence that supports such confidence or certainty, including frequency-type probability. Thus, although a research subject may be aware that only 5 of 100 patients treated in a Phase I oncology trial will experience some clinical benefit, he or she may rationally believe in a 50% chance of being one of the five who benefit clinically, especially when there is some reason to believe that the statistics may not apply to his or her unique condition. Even in the absence of sound evidence for such a belief, patient-subjects may not be irrational in expressing a 50% chance of receiving direct medical benefit in a Phase I trial, depending on what they want to achieve with such utterances. Expressing a 50% chance of direct medical benefit may be a performative way for the patient-subject to sustain hope for cancer cure or remission. The value of hope, what Horng and Grady call ‘therapeutic optimism,’ is that it can contribute positively to the therapeutic process. Thus, a patient-subject’s quality of life may be improved by not giving up this chance, no matter how low it is objectively speaking in terms of statistics. Moreover, as a product of one’s individual values, attitude toward life, and cultural upbringing, therapeutic optimism does not undercut the autonomy of a decision to participate in research – even in early phase research – when the subject has carefully taken into account the low (frequency) probability of clinical benefit against risk and has appreciated the consequences of choosing participation over nonparticipation.

Nevertheless, the inclusion of therapeutic misestimation into the definition of TM remains a subject of disagreement and contention. Some commentators argue that although a conceptual distinction can be maintained between TM and therapeutic misestimation, it is unwise to make a clear distinction at the practical level because therapeutic misestimation is frequently a phenomenological manifestation of TM. However, there is agreement on the need to move beyond the impasse to find a definition that can consistently be used to empirically determine and evaluate TM across the heterogeneity of clinical trial designs and settings and also to assess its impact on informed consent. This aligns with the goal of determining sources of TM, which can include shortcomings in informed consent documents and the discussion process, and testing interventions to reduce or dispel TM. (Suggested interventions include the use of neutral educators who have no affiliation with the research project to disclose information to potential subjects and the provision of financial compensation to impress upon subjects that they are providing a social service by volunteering for clinical research.) To this end, Henderson et al. propose a consensus definition of TM: TM exists when individuals do not understand that the defining purpose of clinical research is to produce generalizable knowledge, regardless of whether the patient-subjects may potentially benefit from the intervention under study or from other aspects of the clinical trial.

Conclusion

Pediatric clinical trials present some of the most challenging ethical issues in modern medicine. Children are inherently vulnerable, and yet they are in need of the best, most effective, and least toxic therapies. Much is at stake in childhood cancer. New therapies are developed through research, and yet in pediatric trials, the person who is experiencing the risk is not the same person who is deciding whether the child participates. Many questions will require further thought and discussion and empiric research for the questions amenable to such approaches. Children do not have legal status as decision makers, and yet persons who care for children in pediatric clinical trials know how mature a child's perception can be, even that of a young child. What weight should be given to their opinions? More globally, how should we respond to the disparity of wealth in prioritizing pediatric research goals, even within the boundaries of a developed nation? How should we navigate cultural and political differences that influence the ethical considerations in international clinical trials?

Advancing excellent care of children around the world who have catastrophic diseases such as cancer depends upon clinical trials. Good clinical trials require ethical decision making at every level. Two questions regarding advances in therapy for childhood cancer must always be asked at the same time: “Whatcan be done next?” and “Whatshould be done next?” The means for answering the first question is scientific. The means for answering the second question is often more philosophical, drawing on many sources of wisdom and insight that are not intrinsically scientific in their approach. History has taught us that scientific advances without ethical considerations can become horrific. Similarly, wisdom without scientific advances cannot further the effort to cure sick children. Medical science committed to ethical research offers the best possibility for continuing to advance the care of children with cancer.

6.2.6 Therapeutic misconception and medical innovations

Therapeutic misconception, in different senses, may be involved in the later stages of the translation. It means roughly that patients may be led to believe—by the information provided or in other ways—that safety studies will provide some therapeutic benefit for them. This may, in turn, lead to lobbying by patient organizations for more translational research. And such lobbying may increase therapeutic misconceptions, etc. (Magnus, 2010).

The ISSCR guidelines stress that it is important that medical innovations do not become short cuts to avoid formal first-in-human trials. Otherwise, medical innovation using SC therapies “may exploit desperate patients, undermine public trust in SC research and unnecessarily delay better designed clinical trials” (ISSCR, 2008). Detailed conditions for medical innovations are therefore proposed in these guidelines.

3.6 Autonomy Versus Therapeutic Misconception

According to Lidz and Applebaum, therapeutic misconception occurs “when a research subject fails to appreciate the distinction between the imperatives of clinical research and of ordinary treatment, and therefore inaccurately attributes therapeutic intent to research procedure” (Lidz and Appelbaum, 2002). The therapeutic misconception may be caused by the patient's expectations that the investigation will act in his/hers best interest even during a clinical trial, by the lack of understanding regarding the concept of randomization, by treatment constraints associated with clinical trials, or by a wish that the study will be beneficent to them (Byrne and Thompson, 2006). There are two main responses to therapeutic misconception: to accept it as an inevitable consequence of clinical trials or to implement measures whose purpose is to reduce it, including the use of the “neutral discloser,” rewriting the informed consent forms, changes in the information algorithm used by physicians when trying to enroll a patient in a clinical trial, changes in monetary rewards, and research advertisements (Emanuel, 2008, pp. 633–644). Therapeutic misconception is especially high in fields in which the patients are highly vulnerable like oncology or psychiatry (Hostiuc, 2015). We believe that surgery could also fit in this category as a patient scheduled for a surgical procedure most likely expects a direct benefit resulting from the intervention. Moreover, sometimes even the proper information might not change his/her preconception regarding the clinical utility of the surgery. Therefore, to minimize therapeutic misconception, subjects must be explicitly informed about the sham surgery and the understanding by the subjects of this issue should be tested explicitly before they sign the informed consent.

The above-presented list is by no means exhaustive; it shows, however, the complexity of the problem and the difficulties of its ethical analysis. A series of guidelines have been developed regarding the possibility of using placebo (sham surgeries) in research, of which one of the easiest and most useful for surgical investigators is the one by Tenery et al., who based their ethical analysis on the following elements: (1) Placebo-controlled trials should only be used in surgery if there are no other designs that could lead to the necessary information. (2) Special care should be given to the obtaining of the informed consent. The potential subjects should clearly know the risk and the particularities of each arm of the study, with an emphasis on the interventions that would/would not be performed. It is recommended for a third party (not the investigator) to obtain the informed consent. (3) Placebo controls should not be used when the investigators investigate the usefulness of a slightly modified surgical procedure. (4) Placebo controls should be allowed when a surgical procedure is developed for an affliction for which there is no surgical treatment, or if the efficiency of the standard surgical procedure is questionable, and if it is known that the affliction is potentially influenced by placebo, or if the risks of the placebo intervention are small. (5) If the surgical treatment has high risks, and the standard, nonmedical treatment is efficient and acceptable to the patients, it should be offered in all the arms of the study (2002). Additionally, we believe that a first step should consist of a proper analysis of the acceptability of the sham surgery by potential subjects. Moreover, specific measures should be taken to minimize issues like coercion generated by potential collateral benefits, or therapeutic misconception.

71.3.7 Therapeutic Misconception?

In research enrolling patients as subjects, the therapeutic misconception is the tendency to view research as treatment, to blur the distinction between research and treatment, and/or to have unreasonably high expectations of direct benefit from receiving the experimental intervention or unreasonably to discount the risks of harm. First identified by Paul Appelbaum and colleagues some 30 years ago [33], the therapeutic misconception is most often attributed to patient-subjects, but it is vital to recognize that it is also common in investigators and oversight bodies [34]. The therapeutic misconception is of concern because it may adversely affect understanding about the nature of the research and the likelihood that the experimental intervention will be beneficial for subjects. It thus might, but does not necessarily, compromise decision-making by patient-subjects. More importantly, it might also influence how investigators describe the research to potential subjects in the informed consent process, as well as how oversight bodies like IRBs, and even study sponsors, view the research [35–37].

In early stage research, available information about potential benefit is limited at best, but the goal of the line of research is to demonstrate clinical benefit. When potential subjects are patients with the disease or condition that the experimental intervention is ultimately intended to treat, an unintended consequence may unfortunately result: the mistaken belief that, if healthy volunteers are not enrolled, it is because they cannot benefit, but because patients will be enrolled, they stand at least some chance to benefit, almost by definition—especially when no good standard treatment exists [15,27,38]. In such cases, all involved are hoping that a new, untried intervention will offer some benefit that standard treatment cannot provide [34]. Although this hope is understandable, the resulting therapeutic misconception may have significant distorting effects on decision-making.

The surgical component of regenerative medicine/transplantation research may increase the risk of therapeutic misconception. Surgery, like chemotherapy, is generally not practiced on healthy volunteers, and a surgical intervention is difficult to limit to safety considerations in an early stage trial [4]. Moreover, randomized trials are unlikely to be feasible even at later stages of research involving regenerative medicine and organ transplantation, with the possible exception of some comparative effectiveness trials. Thus, hopes of benefit are likely to exist for all involved in early stage organ regeneration research. To reduce the therapeutic misconception, those hopes must be acknowledged and directly addressed.

It is not yet clear how best to identify the therapeutic misconception and assess its effects on decision-making in clinical research [39]. However, the likelihood of the therapeutic misconception in patient-subjects enrolled in early stage research can be considerably reduced if it is addressed and reduced in investigators and IRB members, so that the consent form and process provide clear, accurate, and realistic information about the potential for direct benefit [27,36]. Second, the possibility of the therapeutic misconception should never automatically disqualify patients as potential subjects, especially when vague or misleading information about potential benefit has contributed to their views. Hope for benefit is not always therapeutic misconception; it is acceptable, even desirable to hope for benefit if you do not expect it. Patient-subjects who are confident that they will experience benefit may be expressing a degree of optimism that is unproblematic in context [40,41].

4.3 Willingness to participate in investigational treatments and therapeutic misconception

Since novel neurosurgical or neurotechnological treatments are not typically offered until standard medical management has been exhausted, it is common for vulnerable populations such as families affected by intractable epilepsy to reach a state of desperation. Desperation puts patients at an even greater risk for vulnerability, as it may impact their ability to properly weigh the risks and benefits of a novel treatment.

Patients often demonstrate a therapeutic misconception when they fail to recognize the competing obligations of their care physician as both clinical investigator and primary caregiver, and that the intervention being offered usually has no proven benefit or superiority as of yet (Appelbaum & Grisso, 1988; Appelbaum, Lidz, & Grisso, 2004; Lidz, Appelbaum, Grisso, & Renaud, 2004). Vulnerable patient populations who may hold negative views regarding their health are at particular risk of the therapeutic misconception (Goebel, von Harscher, & Mehdorn, 2011). One report suggests that individuals should understand the following five dimensions of investigational therapies in order to mitigate therapeutic misconception: (i) scientific purpose, to benefit future patients; (ii) study procedures, that are not necessary for patient care; (iii) uncertainty, which is greater than standard treatments; (iv) adherence to protocol, which is more strict than standard treatments; and (v) clinician as investigators, and the ethical tension that exists in the dual roles of the treating physician (Henderson et al., 2007).

Enrolling Human Research Subjects

One of the bedrock principles of research ethics is that human subjects with decisional capacity must provide their voluntary informed consent before participating in a scientific study. Informed consent for research is founded upon the basic ethical principle of respect for persons. Often, however, researchers and regulators slip into an overly legalistic understanding of informed consent as a mechanism for avoiding institutional liability. Also, often most of the emphasis during subject enrollment is on the informed consent document itself and not enough on the quality of communication during the course of the informed consent interview. To uphold the ethical principle of respect for persons, investigators and regulators should focus on ways to assess the quality of the research volunteers’ understanding of what is proposed by the research team. Unfortunately, research regulators tend to require only that the wording of the informed consent document meets the review board’s approval and that there is documentation that the patient has agreed to participate in the study (i.e., that he or she has signed the consent form).

Clinician–scientists should evaluate subject comprehension during informed consent discussions and elicit from prospective subjects concerns that might alter enrollment decisions. In studies involving risky interventions such as those used in early phase anticancer trials, this should involve a “teach back” method for assessing understanding, either through a short written test or an oral quiz, to determine whether the patient truly comprehends key issues covered in the consent process. Key issues include patient understanding of study procedures and their attendant risks, alternatives to study participation (including standard treatment), and the right to withdraw from the study at any time [15].

Early phase trials of anticancer gene transfer strategies confront two particular consent challenges. The first is therapeutic misconception, which has traditionally been understood in the bioethics as a research subject’s false belief that “every aspect of the research project to which he had consented was designed to benefit him directly” [29]. Subjects who operate under this false belief may not adequately understand how research procedures, such as randomization, might antagonize patient interests in having their allocation deliberately chosen.

The second consent challenge is therapeutic misestimation, which refers to the tendency of some patients to overestimate the therapeutic benefits associated with trial participation. According to some studies, advanced cancer patients in early phase studies are prone to overestimating the therapeutic benefits associated with trial participation [30]. Unfortunately, such false beliefs can be perpetuated during the subject enrollment process. For instance, a review of 321 gene transfer research consent forms (69% of which were for cancer trials) revealed that study benefits were widely described in overstated and vague language. To help reduce the threat of therapeutic misconception, some have recommended that researchers should avoid misleading “treatment” implications by consistently using “research” terminology when referring to experimental interventions, patient subjects, and investigators [31].

Some may argue that therapeutic misestimation is merely one version of therapeutic misconception; however, we believe there are good reasons to view these concepts separately [32]. One fruitful way to think about therapeutic misconception is that it may often cause patients to overestimate the personal benefits of participating in a clinical trial. However, one should not forget the important point that misestimation can also occur independently of therapeutic misconception, as may be the case when subjects comprehend that the study is designed to expand generalizable knowledge and yet overestimate the possible benefits of trial participation (however remote these benefits may be). Indeed, we should admit that even investigators and regulators may themselves harbor beliefs that misestimate the potential benefits of a study in question.

In essence, therapeutic misconception and misestimation are matters of having inaccurate information and beliefs, the presence of which undermines the autonomy of a patient’s choice to consent to research participation. Of course, the issue of therapeutic misconception and misestimation can be quite complicated for certain types of research. If a randomized trial is in clinical equipoise, then all subjects in a trial should be receiving interventions that are either consistent or believed to be competitive with standard of care. Nevertheless, subjects should understand that some procedures in the study, such as extra blood draws or tumor biopsies, are performed solely to address scientific questions. Similarly, we suggested previously that IRBs should balance risks of drug delivery in early phase anticancer trials against their knowledge value rather than therapeutic value. Nevertheless, there can be legitimate reasons why subjects with advanced illness might perceive early phase trial participation as a therapeutic endeavor [33]. In judging whether consent is valid, the task for researchers is to distinguish between inaccurate understandings of the protocol (i.e., failure to understand that allocation will be determined by randomization, or inaccurate, population-level estimates of the probability of benefit) and legitimate reasons why subjects might harbor expectations of therapeutic benefit (i.e., faith or a belief in the power of positive thinking).

Closely related to these complications is the issue of therapeutic hope. Therapeutic hope is not the same as therapeutic misconception. Therapeutic hope is a notion that has received far less attention than therapeutic misconception [34]. Some cancer patients might be motivated to participate in gene transfer clinical trials not by false beliefs about the exploratory nature of this research but, rather, by hopes for what the research could yield for themselves or other patients like them. In these cases, the concept of a therapeutic misconception may not provide the best tool for ethical analysis. Therapeutic hope can exist in cases in which there is a very slim chance that volunteering for a particular research protocol could lead to physical improvements for the patient, even if the study is not actually designed to produce health benefits for the research subject. In these situations, it is not easy to talk patients out of participating in research, particularly if it is not certain that the study intervention would have zero chance of improving the patient’s condition. Therapeutic hope survives wherever there exists even the most remote chance of benefit. Therapeutic hope, like therapeutic misconception, may turn out to be ethically problematic because it can leave the patient subject vulnerable to exploitation. The cure for therapeutic misconception is to correct the patient’s false beliefs. The cure for therapeutic hope, however, is not so obvious. Indeed, some may question whether therapeutic hope undermines the voluntariness of a patient research subject’s choice or whether it can be consistent with voluntary informed consent. Some may even go so far as to argue that squelching therapeutic hope shows a lack of full respect for persons; others may hold the exact opposite view.

Conditions for informed consent

Respect for persons and their autonomy is recognized and addressed through obtaining informed consent. This tenant of ethical conduct prescribes that the participant involved in research has capacity to consent, understands the full nature of the research, the potential benefits, and risks, is willing to participate, and offers consent free of coercion. Truly informed consent also explores subjects’ motivations to participate, possible therapeutic misconceptions, and willingness for long-term participation. Conditions for informed consent in psychiatric DBS and other investigational uses include the following recommendations: participants should possess decisional capacity (Nuttin et al., 2002, 2003; Kuhn et al., 2009; Rabins et al., 2009; Carter et al., 2011), incorporate disclosure of potential long-term consequences of DBS (Rabins et al., 2009), understand that psychiatric DBS subjects (e.g., depressed patients) may continue to possess decisional capacity despite severity and intractability of the disease (Rabins et al., 2009; Dunn et al., 2011), incorporation of caregivers in the informed consent process (Rabins et al., 2009; Mian et al., 2010), use of a standard consent document (Rabins et al., 2009) and demonstration of the worth of methods applied in the informed consent process (Lipsman et al., 2010), attention paid to the potential effects of desperation on informed consent (Dunn et al., 2011), and the potential occurrence of therapeutic misconception (Rabins et al., 2009).

Assessment of benefit