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W2023851710 abstract "Geron, a California-based for-profit biotechnology company, plans to launch a multicenter phase 1 study for human embryonic stem cell therapy (GRNOPC1) as soon as the Food and Drug Administration (FDA) releases its approval for the Investigational New Drug application [1]. The study will seek to enroll newly injured patients with “complete” thoracic (ASIA A) spinal cord injuries (SCIs; T3-T10) who will agree to have GRNOPC1 surgically injected into the lesion area 7 to 14 days after injury. Geron is not alone and will undoubtedly be joined by other research companies during the next decade who are similarly racing to develop and test treatment interventions for SCI. Thus, it is imperative that rehabilitation professionals become proficient with the ethics of phase 1 research studies. To review, the intent of phase 1 research is to delimit the safety, pharmacodynamics, and toxicity of a new drug or intervention. To place in context, phase 2 research focuses on efficacy, dosing, and continued safety monitoring; phase 3 focuses on larger scale, usually multicenter testing for efficacy; and phase 4 is for postmarketing safety monitoring [2]. Although a benefit to an individual patient is always desired, it is not the purpose or stated intention of phase 1 research. This definition is important because it raises fundamental questions about the informed consent process for research in phase 1 studies. Some of the most elegant work on this issue has been with oncology patients [3] who have exhausted all therapeutic treatment options and may still be desperate for treatment alternatives and desire their enrollment in phase 1 research. (The reasons for participation vary, and hope of benefit may not always be the case. Some subjects may choose to do so for altruistic reasons and contribute to medical research so that others in the future might benefit.) For phase 1 research to proceed, the investigators most petition the FDA for an Investigational New Drug application and show that the intervention has evidence of benefit (usually through animal studies), is believed to be safe, and the potential benefit of the treatment outweighs the risk of the trials. In addition to issues of informed consent, a related but more specific concern is that therapeutic misconception may occur. Therapeutic misconception is the belief or hope, on the part of the subject, that direct benefit will accrue when it is neither expected nor the intent of the research [4]. Even when the subject has been explicitly informed otherwise, therapeutic misconception can and does occur. The psychological reasons posited are complex. Social scientists who study informed consent in phase 1 research have found that some subjects still believe, even when told otherwise, that doctors would not recommend an intervention that is likely to cause harm and unlikely to cause direct benefit. Those in the physical medicine and rehabilitation field will soon be facing these issues with phase 1 research in patients with SCI. For newly injured patients, the question arises of whether it is possible to obtain truly informed consent for phase 1 research, particularly so early after onset of the SCI. The concerns about informed consent are laid out by Dr Frederic Gilbert in an excerpt of his commentary at the Bioethics Forum website: Even if Geron has taken appropriate measures to ensure that the design for this first-in-human trial is both scientifically valid and reasonably safe, patients still may not appreciate the risks of harm that they are assuming at the time of enrollment. Recent spinal cord injury patients may be legally competent, but may not be able to make meaningfully autonomous decisions regarding participation in the proposed Phase 1 trial owing to the complexity of the research and the short time between acute injury and trial participation. Consent to research participation must be sought and obtained 7 to 14 days after what will have been a traumatic, life-changing injury. How can Geron avoid exploiting the hopes of patients? Informed consent is an important mechanism for respecting patient autonomy, but this may be insufficient under the circumstances [5]. To help us think about these issues, I have invited a distinguished panel of experts to provide commentary, including 3 SCI physicians (Drs. Stenson, Chen, and Tansey), 2 SCI psychologists (Drs. Kerkhoff and Butt), and a lawyer who also has lived with quadriplegia for more than a decade (Mr. Gallegos). Edward Wirth MD, PhD, the Medical Director of Regenerative Medicine at Geron Corporation, also was invited to write a commentary but declined. The whole team at Geron is working fulltime to complete the tasks necessary to get the hold on the approval lifted. As always, we invite your responses and thoughts. The first 2 weeks after an acute traumatic SCI are understandably an emotional time for the patient and family. Those patients with neurologically complete SCI—once their spines are considered stable—are not offered any medical or surgical intervention with the expectation of improving their strength, sensation, or function. The recovery process becomes, to a large extent, a waiting game from early on, with the patient and clinician alike hoping and looking for meaningful change in neurologic status. We are often asked by our patients in the months after injury what the latest trials are, what new interventions are available, whether there is anything else available to them to improve their neurologic condition. They ask about stem cells. Some have read about them on the Internet, of miraculous recoveries in other countries. Some actually travel to other countries and have received untested treatments at great personal expense with limited observable outcomes. At this point, Geron is about to embark on the first step in a long journey of discovery regarding the potential role of stem cells in SCI. The phase 1 trial, although absolutely necessary, is not a trial that will establish the effect of the stem cell intervention on outcomes of patients with SCI. Because this trial will establish safety and tolerable dosing parameters, there is an inherent component of risk. The 7 to 14 days after injury is a difficult time to expect someone to be able to process the full scope of what they are being asked to participate in and the possible implications in terms of health risks and potential exclusion from future trials or interventions. In this trial, Geron is planning to recruit up to 10 patients who will have the choice to do something besides wait and watch. Even when patients are fully informed of the aim of the phase 1 trial, the fact of this study is that it offers a tangible option that the patient and his or her family will be able to undertake. There will likely be some hope behind their decisions to participate in the trial. However, we don't believe that this therapeutic misconception negates the process of informed consent. If there has been a rigorous process of providing the patients the information and asking them to reiterate what they understand from what's been offered, there's not much more that can be done besides aborting the study. Understanding that there is such a notion as therapeutic misconception, what are the alternatives for the investigator? The time frame of the study design was not arbitrarily chosen. There are data in animals on which the timing of the trial is based. That the time frame occurs during an emotionally charged period of time is perhaps a difficult hurdle but one that should not be insurmountable. In comparison, although the disease course is markedly different from SCI, phase 1 trials involving patients with terminal cancers also are being conducted during an emotionally charged period of time. Conducting a search of stem cells and SCI on Google, one finds many links, among which are the following: “New stem cell treatment for spinal cord injury. We can help!” and “Find out how spinal cord injury patients have improved today.” If one views the websites, there are descriptions of the procedures, graphs of improvement, and testimonials from people who have had such treatments. The centers are not in the United States, and there is information about price, along with the disclaimer that there is no guaranteed success with treatment. The way that the information is presented is clearly tugging at the emotions of those patients who want a choice for a treatment that they may have heard about in the news media but have not personally been offered by their own physician. There has been talk about the potential promise of stem cell treatments for at least a decade. The word is out enough to entice injured patients to seek out unproven methods at great personal expense. However, the presentation that a researcher gives regarding participation in a phase 1 trial is not akin to the promises on websites that make unsubstantiated claims and operate for profit. The researcher may have a vested interest in enrolling participants for the sake of the study, which should be kept in mind, but the presentation of the risks and benefits should be as neutral and thorough as possible. In other words, the potential benefits of the trial should not be exaggerated [1]. Similarly, if potential participants believe that there is no harm in the trial because participation is being recommended by a physician, it would be best for a researcher who is divorced from that patient's immediate clinical care to discuss the risks and benefits and obtain informed consent. Clearly, patients are seeking interventions. Whether it is in the context of a thoughtful and well-run clinical trial or an option found via Google, patients will seek it out. When it was announced last January that Geron had received approval to move ahead with the trial, the company's phone system crashed under the burden of calls it received from patients who wanted to be included in the trials [2]. Presumably, these were patients at all stages of injury. Although there may be no way of completely removing the therapeutic misconception in trial participation at any stage after SCI—including the vulnerable period in the first 2 weeks after injury—to simply not offer because of a mistrust of the patient's motivation to participate may be an error on the side of paternalism. And it may ultimately push patients towards a more “unsanctioned” approach to stem cell treatment. Cellular transplantation therapy for SCI has been studied in animal models for some time, and recently a booming medical tourism business has developed in which patients travel to centers around the world to receive transplants of various cell types. Lacking is scientific evidence of safety or clinically significant recovery, yet U.S. patients sometimes feel that they have no choice but to pursue these unproven therapies, often at great cost and risk, because there have not been FDA-approved clinical trials in the United States. With the Proneuron trial [1] and now the Geron study, this situation is changing. An ethical discussion of new human research needs to begin with an assessment of the potential for clinical efficacy, even if phase 1 trials are only about safety. This assessment needs to critically understand the biological problem, the animal model results, and the likelihood those results will translate to humans. The greatest biological problem in SCI is the loss of axons conducting signals up and down the spinal cord, followed by neuronal loss at the injury level, and then loss of glia with some demyelination of remaining axons. Cell transplantation in SCI should, therefore, not be thought of as “cell replacement” therapy, as might be envisioned for Parkinson disease. It is theoretically possible that transplanted cells of some pluripotency could differentiate into neurons to replace missing cells at the level of injury and/or form “bridging circuits” to restore function across the level of injury, but there is no neurophysiologic evidence that this occurs. Some cell transplants alter the anatomy and chemical nature of the injury site, providing a bridge and/or permissive environment for the “holy grail” of SCI repair, long tract regeneration. With current interventions, unfortunately, large numbers of axons do not regenerate for long distances in animal models, making it unlikely this will be a significant mechanism of neural repair in the larger human spinal cord. Problems that also remain include determining how to direct regenerating axons to their targets, how to achieve synaptogenesis there, and how to integrate new connections with infrainjury circuitry that has already undergone plastic changes after supraspinal inputs were lost. It is also not likely that remyelinating a small number of demyelinated axons will have a significant effect on functioning in SCI. It is true, with stem cells guided to differentiate along an oligodendrocyte lineage, like Geron's GRNOPC1 cells, remyelination can be observed in animals that improve their stepping after treatment, but this finding is probably not a causal relationship. During the days to weeks of oligodendrocyte cell death after untreated SCI, animals actually improve their locomotor function. If remyelination were a great target for functional recovery in human SCI, 4-aminopyridine would likely have greater clinical effect [2] and the FDA trial in SCI would have been successful. So how do those animals getting cell transplants get better? In favor of cell transplantation in SCI is the fact that most stem or progenitor cells are great sources of a cocktail of “good humors,” including growth factors, neuromodulators, and other chemical signals that may explain the positive animal studies. It is possible these substances limit secondary damage in subacute SCI, resulting in some long tract sparing. It is also possible that remaining pathways undergo sprouting or synaptic strengthening at their targets to recover additional functioning. Finally, there could be enhanced plasticity at infrainjury neural circuitry to improve recovery. These mechanisms have not often been investigated in the animal models, but they are important to understand because of the differences between humans and the animal models. In complete SCI in animals, training can improve locomotor recovery, but this is not true in humans, suggesting that we can count on less from our infrainjury neural circuitry for functional recovery. A treatment that works in rats at that level, therefore, may not help humans. Incomplete injuries in humans, however, do show improvement both spontaneously and with therapy, suggesting the importance of remaining connections to supraspinal centers. We should remember that although approximately 50% of SCI patients are “complete” by clinical ASIA testing, approximately 60% to 80% of those can be shown to be neurophysiologically “discomplete,” with some preserved supraspinal influence over distal spinal functions [3, 4]. If cell transplantation therapies are to be effective in patients, they may have to preserve more long tract axons or encourage them to have greater distal effects through sprouting or synaptic strengthening. The “discomplete” patients are important to remember when the initial clinical studies performed in “complete” patients are interpreted. The ethical discussion then turns to patient expectations, informed consent, and future implications. Previously, we told patients that the lack of federal funding for stem cell research was precluding the discovery of treatments, but now the expectation is that a lifted ban on funding for research today should result in a new therapy tomorrow. Although we are now ready to study the safety of a stem cell transplantation strategy in SCI, we have to combat patient hope or expectation that some therapeutic benefit may result during a phase 1 trial. There is also the concern that asking patients to enroll in such clinical trials in the acute injury period, when patient and family education has just begun and hopes and fears are at the peak of urgency, may preclude truly ethical research. The only solution to combat unrealistic expectations is education, both about the process of clinical research and the specific therapy at hand. The International Collaborative to Cure Paralysis has an excellent informational paper and question checklist that all patients and families should be given when they are asked about participating in SCI research [5]. Patients and families need to be told that “desperation is not an indication” and that, although time is short, careful pessimistic consideration is what's needed. They also need to consider the long-term implications, including that participation in the current trial might actually result in a worsening of the current clinical condition or preclude participation with future trials or other interventions. Even in the face of good education, there remains the possibility of misplaced optimism for psychological reasons. Although this issue is a difficult one, it is not new and has been addressed in other studies, including ones that have had to provide education, carry out informed consent, and enroll patients in time periods of only minutes to hours, such as in acute stroke trials [6]. It is not clear that there has been significant psychological damage to patients as a result in those studies. Ethicists and clinicians need to remember that the patients' alternatives to participating in FDA-approved trials of cellular transplantation for SCI in the United States, even with the risk of unrealistic patient expectations, include nonscientific, for-profit, stem cell tourism. This option is clearly a greater source of ethical dilemmas and has been addressed by leaders in the field [7, 8]. All said, it is this commentator's opinion that there is reasonable scientific rationale to carry forward with a quality phase I trial like Geron's and that it can proceed on adequate ethical grounds if good educational processes are followed, if not for the reason that some of the ethical alternatives are worse. The procedures and requirements of a phase 1 study of human embryonic stem cell therapy with a markedly delimited eligibility window raise significant questions about the achievement of formal versus effective informed consent [1]. The purpose of phase 1 research is the determination of safety, pharmacokinetics, and toxicity of a new drug or intervention. In addition, the typical precursors to a phase 1 study are solely animal-based ones that are believed to be safe and possess potential benefit. Specifically, the nature of traumatic SCI and the complex processes attendant to acute medical stabilization during the immediate period after trauma pose many challenges to securing both formal and effective consent. Formal consent can be secured if decision-making capacity is addressed in the procedural manner outlined by Appelbaum and Roth [2], with a clinically derived decision regarding capacity to consent at a given point in time. Specifically, these primary components include understanding relevant information, appreciation of one's medical situation and its consequences, manipulating choices rationally, and communicating choices. However, effective consent requires control over decisional biases of the potential research participants, including limited available information related to the decision (both research protocol and implications of new SCI), unawareness of relevant decision-making criteria (expected effects of new procedure, possible complications), time constraints (narrow treatment window in the midst of acute injury stabilization), and limited memory/recall of provided information (effects of medication, possible concurrent concussion/TBI complications) [1]. The ability of the researchers to manage potential decisional biases that could compromise valid consent within the necessary constraints of the intensive care medical system remains an open question. In addition, these issues must be considered in the context of the cognitive, behavioral and emotional factors impacting individuals with acute traumatic spinal cord injuries. Patients experiencing traumatic SCI are subjected to significant physical, cognitive, and emotional distress during the incident and acute medical management of their injury. Decisions to participate in research during this stressful period of time will doubtlessly be influenced by physical factors (eg, sensory and motor alterations, pain, respiratory compromise, sleep disturbance), cognitive factors (the authors of some studies note up to a maximum of 50% of traumatic SCI evidence cognitive compromise with or without a documented loss of consciousness with presumption of postconcussion effects; other posttrauma cognitive issues could include delirium and induced sedation, to name a few), and emotional and behavioral factors (eg, anxiety, dysphoria, possible acute stress disorder, substance abuse history) [3]. Further, the dynamic nature of the interplay among internal physiologic and emotional states occurring within the pressured environment of intensive care introduces variability in clinical presentation, such that successful formal consent obtained on one occasion may be suspect at a later time. Serial assessment of capacity is required to establish a pattern of responding across time that can be judged reliable for consent. In addition, the nature of disclosure of the details of the research project requires the skills of an experienced clinician because of the variable nature of the patient's capacity to consent during acute medical management of SCI. This provided information must be consistent in its content, often a problematic issue within the context of multiple health-care providers within the intensive care environment. Finally, the potential participant's awareness of the complex nature of SCI, treatment, prognosis, and so on requires repeated educational interventions that can often extend throughout tertiary rehabilitation care. The implications of SCI are difficult to fathom absent time to reflect in the context of a recovery trajectory within which to set realistic personal expectations. A characteristic of the relationship between patient and health-care provider, especially in an intensive care environment, is one of essential dependence. In many cases, the patient is literally dependent upon the treatment team for survival. The demand characteristics of the treatment situation most often result in compliant behavior necessary to allow required treatment. Indeed, the relational differential between patient and health-care provider can compromise autonomous choice [4], an essential difference between mere assent and true informed consent. The patient with an SCI must implicitly trust the treatment team with her/his life during this critical period of medical stabilization. To approach a patient during this stressful and uncertain time to participate in an invasive experimental procedure, the researcher must have a significant level of confidence that the potential participant can appreciate the consequences of such a decision, understand the substantial risks (inherent in a phase 1 human trial safety trial), and deliver a consistent valid consent. There will likely be negative bias toward consent introduced in the study if a researcher, not part of the cadre of familiar professionals rendering daily treatment and care, approaches the patient. In contrast, if a clinician−researcher is tasked with securing consent, the fine line between providing necessary information in an objective manner and exerting unintended coercion becomes blurred from the perspective of the necessarily dependent patient. Finally, this topic is one with which the first author is familiar from the clinician's point of view. In 2000, I was fortunate to be able to work with 2 patients admitted to my inpatient rehabilitation facility who had been participants in a postacute SCI fetal neural tissue to spinal syrinx implantation project at the University of Florida [5]. These research participants were admitted to the rehabilitation center for several weeks after surgery for medical monitoring and as part of a standardized performance measurement protocol peripherally linked to the study. In both instances, the research participants were hopeful for a curative outcome, despite the reality of the project being a phase 1 feasibility and safety study. They clearly recalled the consent explanation of the project methods and goals, simultaneously minimizing/failing to recall the attendant risks, agreeing to participate in hopes of receiving benefit from this early phase procedure—an example of therapeutic misconception [6]. None of these participants presented with evidence of anxiety, depression, or cognitive impairments related to their traumatic injuries or other evidence of maladjustment to their SCI. Nonetheless, their recall of the consent process revealed decisional biases on the basis of minimizing risks and placing significant hope on the possibility that stem cell proliferation into their spinal cord might trigger functional improvement. The supplemental issue is how this type of research impacts the understanding of acute rehabilitation and accommodating to the consequences of SCI. These authors fully support the necessity of well-grounded and judicious research in service of moving the field of SCI treatment forward. These types of ventures only serve to augment our knowledge base and aid the patients and families we serve. However, there are not often clearly defined or black-white answers in the realm of bioethics, especially in light of phase 1 human trials. As a result, true informed consent must be predicated upon the idiosyncrasies of the patient and aforementioned contextual variables described. Only via a vigorous attentiveness to the components of true informed consent can this side of the equation be satisfied. Principal investigators take their research subjects as they find them. Given that, obtaining informed consent from recent spinal cord-injured subjects is improbable. Recent spinal cord-injured subjects must be considered a vulnerable population requiring additional safeguards to protect them against therapeutic misconception and the inherent influence of white coat principal investigators; but even then, informed consent will be highly improbable, regardless how thoughtful and deliberate institutional review boards are in designing an informed consent process for this (GRNOPC1) phase 1 research study. In formulating this opinion, I have reflected, in part, upon my personal experiences, as I have been living with the effects of a SCI now for 13 years. A SCI resulting in paralysis is life altering and life threatening. A SCI unexpectedly occurs within a fraction of a second, and unlike chronic life-threatening diseases and conditions, there is no opportunity for the injured or their family to prepare for the devastating immediate reality of living with paralysis and its complications. Instantaneously upon injury, all aspects of your life, as you previously knew them abruptly halt and remain suspended in whatever polished or unpolished form they may be in at the time. At that moment, whatever dreams and aspirations you had for yourself or for your family are shattered. The informed consent requirements were written with the premise, jurisprudentially, that every adult of “sound mind” has a right to determine what will be done with his or her own body. Recently injured, your mind is far from being sound. One to two weeks after injury, incessantly, you mentally relive the circumstances that caused the injury, contemplating what you could have done differently. Deep depression and grief lead to thoughts of suicide, or regret (and in some instances, guilt) for having survived. Feelings of worthlessness, fear, shame, anger, and despair exist. When you are not focusing on yourself, your thoughts are of your family. How will you be able to take care of them? What kind of father can you be? Will they still want you? The initial nights are restless. When your eyes close, the shooting, the crash, the fall, are all replayed in slow motion and you vividly recall the trauma of being prepped for surgery—helplessly lying still while a team of physicians forcefully yank your arms towards your feet as a metal brace with weights is being screwed into your skull to immobilize your spine. Just when sleep sets in, you are awakened every 3 hours by rotating teams of strangers whom, while taking vitals and adjusting your body's position to prevent pressure sores, intrusively query how “it” happened. In between intrusive visits, you are awakened by sharp, throbbing pain from one or all of the four screws bolted into your skull to support a cage that serves to stabilize your fused spine. The initial mornings are emotional, frustrating, and humiliating. You abruptly awake as you sense probing eyes peering and hovering over you. Physiatrists and their residents grab limbs and digits asking for movement. Every inch of your body is pricked with a pin as you are cruelly quizzed to identify “sharp” from “dull;” the proctor smiles politely when repeatedly asked if you answered correctly. The physiatrist patiently explains the difference between “complete” and “incomplete,” and yet again answers what degree of functional recovery to expect. You nevertheless pepper him with the same questions, hoping to elicit different answers. As the physiatrist and his crew moves on, a team of nurse assistants then follow to clean, dress, and feed you. You are completely dependent upon others for every basic function. You are then netted and hoisted into a wheelchair, forced to confront the day. In the daylight, every sound is amplified, and every sensation is heightened as each nerve in your body is hypersensitive. A breeze leads to uncontrollable lingering shivers. Blackouts are triggered performing the simplest activities, like sipping water through a straw. Frustration and resignation build as during each of those initial days in physical and occupational therapy you are made acutely aware of what you cannot do; resentment sets in at the sight of what others can do. A sense of desperation exists, where you will do anything to reverse your new reality. Like the Federal Common Rule, the FDA rules for consent in clinical research permit principal investigators to obtain the informed consent of the subject's legal representative if the subject is unable to. However, just as with subjects, principal investigators take their subjects' legal representatives as they find them. If a subject's legal representative is the subject's spouse or a parent, their mental states are as fragile as the subject's, and they are as frantic to find a cure as the subject himself. Since 2005, the median age at injury is 40.2 years and SCIs occur predominantly to men, who account for 80.8% of all reported injuries [1]. If we accept the premise that men are the primary breadwinner and household head, the subject's wife has a sense of desperation, hopelessness, and vulnerability. In those initial days, wives grieve. The subject's parents' mental and emotional states are similar to the subject's wife. The shock and gravity of the subject's condition can either result in a closer bond between the subject and his wife or family, or, sadly, outright rejection and abandonment by either one or both; there is no in between. It is well established that given the nature of the physician−patient relationship, patients may have difficulty distinguishing between the physician's professional medical advice on the one hand and a commercial sales pitch on the other. (As a result “white coat” marketing is regulated and closely scrutinized by the Federal Trade Commission and the Health and Human Services Office of Inspector General.) In the initial days after SCI, the subjects and their familial legal representatives are so fraught with grief and desperation that they would be willing to try anything available that may lead to a cure. Having said all that, it's critical, in my (admittedly, self-serving) opinion, to advance any research that will lead to therapies that will one day restore functional recovery in patients with SCIs. Thus, if an institutional research board approves this research, to protect this vulnerable population, they should narrow the defined subject population to recently SCI patients 18 years and older who have legal representatives and design and implement an informed consent process that: (1) requires the translation of the informed consent document into different languages and grade levels to enhance the understanding of what will be a ethnic and educational diverse subject population, (2) require the informed consent document to clearly and unambiguously state the absence of a “direct subject benefit,” (3) appoints an independent subject advocate (who can communicate with subjects and their legal representatives in their native languages) who would have the authority to deny a subject's participation in the research if a lack of understanding of the absence of a “direct subject benefit” manifests, (4) requires that any contact between an investigator and subjects occur only in the presence of the subject advocate and the subjects' legal representatives; and (5) requires an investigator to wait for initial contact with subjects and their legal representatives 4 to 5 days after injury to present the research study and to read (or have read) to the subjects and their legal representatives, in their native languages, the informed consent document; requires the investigator to meet with subjects and their legal representatives 7 to 8 days after injury for purposes of answering their questions and again reviewing the informed consent document, and finally, which precludes enrollment in the study until 11 to 12 days after injury." @default.
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