Abstract: Photo by Diana Polekhina on Unsplash ABSTRACT Randomized placebo-controlled trials are often used in clinical research, though there are ethical concerns regarding their use. The Food and Drug Administration (FDA) has rejected international stances on placebo-controlled trial use in favor of the bioethical principles of autonomy, beneficence, nonmaleficence, and justice. The FDA permits placebo-controlled trials in three circumstances: when there are no established treatments available when their use would be of negligible harm to the patient, and when there are compelling reasons for their use. However, in some cases, the FDA’s approval of placebo-controlled trials violates bioethical principles. Ultimately, the FDA should overhaul its practices regarding the use of placebo-controlled trials. INTRODUCTION Randomized placebo-controlled clinical trials (PCTs) are considered the most rigorous method of understanding the efficacy of an intervention and, as a result, are widely used in clinical research.[1] However, there are ethical concerns regarding placebo controls, including their use in the study of deadly diseases or when effective treatments already exist, though poor oversight and lax rules have largely permitted PCT research, even under those conditions.[2] The FDA prefers PCTs for most interventional research and considers them essential to test the efficacy of drugs. Between 2006-2011, 40 percent of FDA-approved clinical trials used a placebo alone for comparison. The FDA has been lagging in altering its policies regarding PCTs, only advising against PCT research in select oncological cases for the first time in 2019 in a nonbinding guidance. It is our belief that the FDA should change its approach and prohibit the use of placebo controls in clinical trials where effective treatments already exist. l.     Brief History of PCTs and the FDA In contemporary research practices, PCTs are used to evaluate whether an intervention is effective by comparing it to a control group that received a treatment designed to have no real effect (placebo). Throughout the 20th century there have been numerous bioethical tragedies, including but not limited to the Holocaust and the Tuskegee Syphilis Study.[3] These and other transgressions have become an impetus for establishing ethical research standards preventing human exploitation in the name of science. The Declaration of Helsinki, adopted in 1964, a nonbinding instrument, restricts the use of PCTs. Clause 33 of the Declaration of Helsinki states that new medical interventions should be tested against previously demonstrated interventions and placebos should be used only if there is no existing intervention with narrow exceptions. Clause 33 says the effectiveness of a new intervention must be tested against those of the best current proven intervention (s), except in the following circumstances: Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention. Extreme care must be taken to avoid abuse of this option.[4] The FDA has largely ignored this and deemed placebo controls the gold standard, stating that “PCTs are necessary to control for placebo effect of investigational medicinal product.”[5] The FDA has even refused to approve drugs that are tested against established treatments instead of against placebos, notably atenolol.[6] By stretching the “methodological” exception and failing to define harm reasonably, the FDA does not meet the spirit behind Helsinki’s conditions for allowing PCTs. When the Declaration of Helsinki was revised in 2000 to increase restrictions, the Director of Medical Policy for the FDA’s Center for Drug Evaluation and Research considered it “unpardonable” and abandoned any compliance with it in 2008.[7] The FDA’s past statements and actions have supported its belief that drug approval hinges on the use of placebos. While the FDA has rejected the Declaration of Helsinki’s stance on placebos, it has remained faithful to the guidelines of other bioethical codes such as the International Ethical Guidelines for Biomedical Research Involving Human Subjects and the Council for International Organization of Medical Science’s guidelines for biomedical research involving human subjects. The International Ethical Guidelines for Biomedical Research Involving Human Subjects permits PCTs if the consequences are negligible, when methodologically advantageous, and when responses have been historically erratic.[8] The Council for International Organization of Medical Science’s guidelines for biomedical research involving human subjects echoed the Declaration of Helsinki in guideline 11, stating that a “‘placebo may be used: When there is no effective intervention; when withholding an established, effective intervention would expose to, at most temporary discomfort, or delay in relief symptoms; when use of an established, effective intervention as comparator would not yield scientifically reliable results and the use of the placebo would not add risk of serious or irreversible harm to subjects.”[9] The Belmont Report notes three ethical principles: beneficence, respect for persons (autonomy), and justice. The Common Rule requires IRBs for human research and reflects principles noted in the Belmont Report. The Belmont Report covers three applications of its principles:  Informed consent, selection of research subjects, and risk-benefit assessments.[10] In 1979, Beauchamp and Childress established the four principles approach to bioethics including autonomy, beneficence, nonmaleficence, and justice. While PCTs were not mentioned in these reports, the principles in them permit placebo controls as long as subjects are informed of the risks of participating and risks are minimized. The FDA has since followed that approach. These guidelines have made PCTs ethically ambiguous, and there are moral counterpoints to be made. ll.     FDA-PCT Conditions The FDA has permitted PCT use under three conditions. The first condition is when there is no proven intervention for the medical condition under the study. This means treatment has either not been found for a disease or has not yet been translated into clinical practice and is not controversial. The second condition is when there is negligible harm to the patient from delaying or forgoing an available treatment. In this scenario, a placebo is not suspected to cause damage and the available treatment is meant for mild conditions that pose low-risk adverse effects, which is said to justify its use. The final condition is when there are compelling methodologic reasons for the use of the placebo. This scenario is for situations where outcomes fluctuate for complex reasons making other research methods likely to be unreliable. This condition for PCT use is also justified when it is not possible to administer the intervention to the experimental group because of economic, social, or administrative factors, in which case it is believed to be better to have results of some kind than none at all.[11] We will argue each condition is unethical to the current degree it is practiced. lll.     Condition One: Lack of Established Treatment Placebo use in cases where no established treatment exists would not typically be considered unethical. However, placebos continue to be used in numerous clinical trials approved by the FDA, many of which already have standard interventions.[12] In addition, the la ck of head-to-head drug trials, in favor of placebo, has had no benefit on clinical guidelines and practices. The direct comparison of drugs in head-to-head trials gives physicians and buyers a better understanding of the effectiveness of a drug and allows for the creation of more robust clinical guidelines. Instead, under the PCT model, the market is saturated with a plethora of drugs to choose from. While each one may be better than placebo, it can be difficult to understand how each treatment compares to another, which may be harmful to patients. A recent study has shown that nearly 90 percent of new drugs do not perform better than existing options.[13] There is an ethical cost to be considered when devoting financial resources and effort to create new drugs that are inferior to existing treatments and have not led to changes to clinical practice. While the FDA claims to follow the bioethical principles of beneficence and nonmaleficence, its choice of approving treatments through placebo controls, despite the existence of standard interventions, counters these guidelines. lV.     Condition Two: Negligible Harm from Delayed Treatment The International Ethical Guidelines for Biomedical Research Involving Human Subjects argues that placebos are acceptable if there is only “temporary discomfort or a delay in relief of symptoms,” a stipulation that the FDA follows. However, what constitutes temporary is arbitrary, as there is no absolute reference of time prescribed, nor is there a defined proportion relative to total life expectancy available. For example, many patients in trials for terminal illnesses have a limited therapeutic window and a reduced life expectancy, so they value time differently from someone with a non-terminal illness. Additionally, there is no consensus of what constitutes harm when withholding treatment; placebos are often used in trials for major depressive disorder, yet this population has statistically higher rates of self-harm and suicide without treatment compared to the general population.[14] Serious risks can be incurred due to a placebo intervention by not offering experimental treatment, without excusing the psychological harm withholding a treatment may have on a patient should it be unblinded. Nevertheless, the FDA has used the umbrella term of “temporary discomfort” to justify the widespread use of PCTs, but the vagueness of this language results in human suffering. V.     Condition Three: Compelling Methodological Reasoning Finally, the FDA authorizes placebo use in cases where for compelling scientifically sound methodological reasons, the use of placebo is necessary to determine the efficacy or safety of an intervention, and the parties who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. The condition includes cases where PCT is believed to be necessary to demonstrate efficacy, such as in trials of psychoactive drugs where evidence is inconsistent due to disease heterogeneity and demonstrating equivalence to an established treatment is insufficient. There are also arguments that PCTs, while not necessary, may be beneficial in generating socially valuable knowledge. However, whether a placebo control demonstrates efficacy is not sufficient to justify its use. When considering the ethical use of PCTs, investigators must weigh the social value gained against the risks of no treatment in the control. Unfortunately, the risk-benefit analysis is often controversial. For example, in 2001, the FDA initially responded positively to a placebo-controlled trial of Surfaxin in infants with acute respiratory distress syndrome in Latin America. However, the trial was deemed exploitative by a public watch group when it was revealed that the drug was already FDA-approved in the United States, and the manufacturer of that drug was undertaking another study with the same drug in Europe without any placebos. To justify withholding treatment from a vulnerable population in a developing country, the manufacturer stated that they would be providing a drug that would otherwise be unavailable to many participants, and the risks would be compensated by upgrades to the host country’s medical infrastructure. Despite the FDA’s initial approval and the manufacturer’s attempt to quell public outcry, objections by the public led to the removal of the placebo arm from the trial. While the FDA believes there may be methodologically compelling reasons to utilize PCTs, they have demonstrated a lack of judgment necessary to balance the gains against their inherent losses, requiring the public to step in. CONCLUSION Based on the ambiguous bioethical guidelines that the FDA follows, and the moral justifications described in this paper, its preference of PCTs is unethical. We suspect the overreliance of PCTs has resulted in harm to research participants and the general population, which is why the FDA should change its policy. We propose that PCTs be used only for diseases that lack an established treatment, as decreed by Clause 33 of the Declaration of Helsinki. Other measures that would satisfy Clause 33, the Belmont Report, and the Common Rule are the use of large retrospective observational trials for comparison rather than a prospective placebo group. Ultimately, it is ethically necessary that the FDA modify its practices regarding drug approval and more stringently scrutinize PCTs as well as adopt more favorable approaches to other comparative models. Acknowledgments We sincerely thank Dr. Gregory James Smith, JD, DBE for his patience and guidance in both the research and writing of this paper. - [1] Simmonds A. Ethics of placebo-controlled trials in developing countries: The Search for Standards and Solutions. The Morningside Review. https://journals.library.columbia.edu/index.php/TMR/article/view/5507. Published May 1, 2011. Accessed April 21, 2022; Millum J, Grady C. The ethics of placebo-controlled trials: Methodological Justifications. Contemporary Clinical Trials. 2013;36(2):510-514. doi:10.1016/j.cct.2013.09.003; Center for Drug Evaluation and Research. Institutional Review Boards (IRBs) and Protection of Human Subjects in Clinical Trials. U.S. Food and Drug Administration. https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/institutional-review-boards-irbs-and-protection-human-subjects-clinical-trials. Published September 11, 2019. Accessed April 21, 2022. [2] Keränen T, Halkoaho A, Itkonen E, Pietilä A-M. Placebo-controlled clinical trials: How trial documents justify the use of randomisation and Placebo. BMC Medical Ethics. 2015;16(1). doi:10.1186/1472-6939-16-2; Feifel D. The use of placebo-controlled clinical trials for the approval of psychiatric drugs: part I-statistics and the case for the "greater good.” Psychiatry (Edgmont). 2009;6(3):41-43; van der Graaf R, Rid A. Placebo-controlled trials, ethics of. International Encyclopedia of the Social & Behavioral Sciences. 2015:164-173. doi:10.1016/b978-0-08-097086-8.11011-6; Ibrahim MS, Ovosi JO, Bello-Ovosi BO. Randomized controlled trials: Ethical and scientific issues in the choice of placebo or active control. Annals of African Medicine. 2017;16(3):97-100. doi:10.4103/aam.aam_211_16; Sorscher S, AbuDagga A, Almashat S, Carome M, Wolfe S. Placebo-only-controlled versus active-controlled trials of new drugs for nine common life-threatening diseases. Open Access Journal of Clinical Trials. 2018;Volume 10:19-28. doi:10.2147/oajct.s156054; Mezher M. FDA finalizes guidance on placebos and blinding for cancer trials. Regulatory Affairs Professionals Society (RAPS). http://www.raps.org/news-and-articles/news-articles/2019/8/fda-finalizes-guidance-on-placebos-and-blinding-fo. Published August 28, 2019. Accessed April 21, 2022. [3] WMA Declaration of Helsinki – ethical principles for medical research involving human subjects. The World Medical Association. http://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Published July 9, 2018. Accessed April 21, 2022. [4] WMA Declaration of Helsinki, Clause 33. [5] Ovosi JO, Ibrahim MS, Bello-Ovosi BO. Randomized controlled trials: Ethical and scientific issues in the choice of placebo or active control. Ann Afr Med. 2017;16(3):97-100. doi:10.4103/aam.aam_211_16; Rothman KJ, Michels KB. The continuing unethical use of placebo controls. New England Journal of Medicine. 1994;331(6):394-398. doi:10.1056/nejm199408113310611 [6] Rothman KJ, Michels KB. The Continuing Unethical Use of Placebo Controls. New England Journal of Medicine.1994;331(6):394-98. doi:10.1056/nejm199408113310611 [7] Hollon T. FDA uneasy about placebo revision. Nature Medicine. 2001;7(1):7-7. doi:10.1038/83389 [8] International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS; 1993. https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf. Accessed April 21, 2022. [9] Ovosi JO, Ibrahim MS, Bello-Ovosi BO. Randomized controlled trials: Ethical and scientific issues in the choice of placebo or active control. Ann Afr Med. 2017;16(3):97-100. doi:10.4103/aam.aam_211_16 [10] The Belmont Report Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, D.C: U.S. Government Print. Off; 1978. Accessed April 21, 2022. Office for Human Research Protections (OHRP); Federal Policy for the Protection of Human Subjects ('Common Rule'). HHS.gov. https://www.hhs.gov/ohrp/regulations-and-policy/regulations/common-rule/index.html. Published June 16, 2021. Accessed April 21, 2022. [11] Millum J, Grady C. The ethics of placebo-controlled trials: Methodological justifications. Contemporary Clinical Trials. 2013;36(2):510-514. doi:10.1016/j.cct.2013.09.003; Center for Drug Evaluation and Research. Institutional Review Boards (IRBs) and Protection of Human Subjects in Clinical Trials. U.S. Food and Drug Administration. https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/institutional-review-boards-irbs-and-protection-human-subjects-clinical-trials. Published September 11, 2019. Accessed April 21, 2022. [12] Center for Drug Evaluation and Research. New drug therapy approvals 2020. U.S. Food and Drug Administration. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2020#first-in-class. Published January 8, 2021. Accessed April 21, 2022. [13] Light DW, Lexchin J, Darrow JJ. Institutional corruption of pharmaceuticals and the myth of safe and effective drugs. Journal of Law, Medicine & Ethics. 2013;41(3):590-600. doi:10.1111/jlme.12068 [14] Lahey T. The ethics of clinical research in low- and middle-income countries. 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Abstract: Photo 190773207 / Transplant Medicine © Victor Moussa | Dreamstime.com ABSTRACT Xenotransplant research offers hope to individuals waiting for vital organ transplants. Nascent first-in-human xenotransplantation research trials present unique ethical challenges which may translate into obligations for researchers and special considerations for institutional review boards (IRBs). Contextual vulnerability is an important consideration in reviewing proposed subject selection methods. Some recipients are uniquely prone to receiving an unfair offer to enroll in an experimental clinical trial when excluded from allograft waitlists due to psychosocial or compliance evaluations. These exclusions represent an allocational injustice. Enrolling research subjects subjectively excluded from allotransplantation into xenotransplant research is not a mechanism of fair access but rather an exploitation of an unjustly option-constrained vulnerable group by the clinical transplant system. Carefully considering contextual vulnerability can help researchers and IRBs clarify eligibility criteria for xenograft clinical trials. A requirement for simultaneous allograft co-listing can safeguard the interests of vulnerable potential subjects. INTRODUCTION In the United States, the supply of allogeneic, or human-derived, organs and tissues from living donors and cadavers available for transplant into critically ill individuals is inadequate.[i] Physicians refer only half of potentially eligible patients for transplant evaluation, and the clinical transplant team ultimately waitlists less than 30 percent.[ii] Waitlists are lengthy for those who make it through the evaluation process, and many individuals die while waiting for a transplant.[iii] In contrast to allogeneic transplants, xenotransplantation, from the prefix, xeno- meaning foreign, is the process of taking live organs or tissues from an animal for surgical placement into a human recipient. Xenografts are typically sourced from porcine animals (domestic pigs) or non-human primates (baboons) and range from simple tissues like corneas to complex vital organs like hearts, lungs, or kidneys. Scientists have explored xenotransplantation methods for decades, but research with vital organ xenotransplants has been in largely haphazard and non-controlled studies, which demonstrated only short-duration survival for recipients.[iv] Recent advances using gene modification and improved immunosuppression in single-patient attempts to transplant porcine organs into brain-dead human recipients have presented more realistic human-environment models; however, these modified xenografts have still functioned only for very short durations.[v] The limited bioethics discourse on xenotransplantation centers primarily on the ethical use of high-order animals and the risks of zoonotic infectious disease spread.[vi] Bioethics pays insufficient attention to the potential for exploitation of vulnerable individuals in need of a transplant amid growing interest in phase I clinical trials in living human subjects. Clinician-investigators in contemporary literature repeatedly recommend that these trials enroll subjects who are medically eligible for, but effectively excluded or outright denied access to, an allograft.[vii] The Food & Drug Administration (FDA) recommends xenotransplants be limited to subjects with serious or life-threatening diseases for whom adequately safe and effective alternative therapies are not available.[viii] The ethically salient difference between the investigator and the regulatory recommendations is why alternatives are not available to potential subjects: because transplant centers have subjectively denied access or because there is a clinical contraindication that proves prohibitively risky.  In a notable single-patient emergency use authorization, physician-investigators offered a genetically modified porcine heart to a living male recipient after denying him access to the waitlist for a human-donor heart, citing a history of non-compliance.[ix]  This case suggests that a person denied access to a transplant waitlist due to subjective compliance criteria is an appropriate research subject. The physician-investigators failed to acknowledge how offering a xenotransplant to a contextually vulnerable subject is potentially unfair. Contextual vulnerability is a specific feature of a research environment that increases a subject’s risk of harm. Bioethics discourse must address this vulnerability within the transplant research environment. This paper describes the current transplant system’s use of subjective evaluation criteria, particularly psychosocial support and compliance. Subjective evaluation criteria perpetuate discriminatory medical biases rather than advance the transplant system’s goal of additional life-years gained. Researchers designing contro lled human subject trials and institutional review boards (IRBs) reviewing and approving proposed protocols must consider how disparate waitlisting practices unjustly preclude some patients from a fair opportunity to access an allograft and impacts their participation in research. It is unethical for physician-investigators to intentionally take advantage of this vulnerability, creating an exploitative and unethical transaction.[x] Protocol inclusion criteria requiring proof of simultaneous allograft listing is a feasible procedural safeguard to protect research subjects’ interests. I.     Injustices in Organ Allocation Solid organ allocation systems are varied but aim for equity and efficiency in granting individuals with similar claims a fair opportunity to access the scarce resource. Allocation decisions attempt to maximize the common good of additional life-years gained.[xi] The federal oversight of allograft allocation in the US uses objective clinical metrics like blood type, immune compatibility, body size, and geographic distance to match organs to recipients to increase both graft and patient survival.[xii] Transplant centers additionally use their own evaluations to waitlist patients. Although variation exists between transplant center criteria across more objective measurements, such as lab values and concurrent diseases, significant inconsistencies arise in how they incorporate subjective factors like compliance with medical recommendations, psychosocial support, and intellectual disability into the review process.[xiii] Only 7 percent of renal transplant programs use formal criteria for subjective psychosocial assessments, while no pediatric solid organ transplant programs use formal, explicit, or uniform review to assess developmental delays and psychosocial support.[xiv] Failing to establish uniform definitions and inconsistently applying evaluation criteria in the review of potential transplant candidates introduce bias into listing practices.[xv] The center they present to and the variable evaluative criteria the center uses may discount an individual’s claim to a fair opportunity to access a scarce resource. Labeling a patient non-compliant can preclude both a referral to and placement on a waitlist for potentially suitable recipients. Compliance considerations presuppose that graft longevity will be jeopardized by an individual’s failure to adhere to pre- and post-transplant regimens. It is necessary to distinguish individuals who are intentionally non-adherent to treatment regimens and demonstrate willful disregard for medical recommendations from those who are involuntarily non-adherent due to barriers that limit full participation in care plans. The former would not be offered a spot on the waitlist for an allograft, nor would investigators offer them a spot in a xenotransplantation research study. Significant and repeated refusals to participate in treatment plans would confound the ability of researchers to collect necessary data and perform the safety monitoring required by early-phase clinical trials. Enrolling subjects who are medically eligible for a traditional transplant but denied access requires a population that is suitably compliant to participate in a clinical trial reliably and safely yet judged not worthy of receipt of a standard allograft during the evaluation process.  The latter population is most disadvantaged by compliance judgments and unsubstantiated outcome predictions. Multi-center research studies have found that moderate non-adherence to immunosuppression regimens is not directly associated with poor kidney transplant outcomes.[xvi] Nor are intellectual and developmental disabilities, conditions for which transplant centers may categorically refuse evaluation, clear indicators of an individual’s ability to comply with treatment regimens.[xvii] Large cohort studies of both pediatric kidney and liver transplant recipients found no correlation between intellectual disability and graft or patient survival.[xviii] Rather, it is the perpetuation of medical biases and quality-of-life judgments that presumptively label specific populations poor transplant candidates or label their support systems insufficient, notwithstanding data demonstrating their ability to achieve successful transplant outcomes.[xix] Variability in compliance assessments and psychosocial support criteria allows medical biases to persist and disproportionately impedes waitlist access to patients from underserved populations.[xx] Low-income Medicaid patients are 2.6 times more likely to be labelled non-compliant as privately insured patients.[xxi] Additionally, the medical records of Black patients are 2.5 times more likely to contain negative descriptors like non-compliant, non-adherent, aggressive, unpleasant, and hysterical than those of white patients.[xxii] The higher prevalence of stigmatizing, compliance-based language in the medical records of minority, economically disadvantaged, and disabled persons decreases the likelihood that they will be recommended for a transplant, referred for an evaluation, placed on a waiting list, or ultimately receive a transplant.[xxiii] These populations are at heightened risk of being used in ethically inappropriate ways by xenograft research that capitalizes on this precluded access. II.     Defining Vulnerability Subjective evaluation criteria in allograft waitlisting disproportionately impact some populations. This precluded access to waitlists increases their vulnerability to experience harm in experimental xenotransplant research. Fair subject selection requires the development of specific and appropriate inclusion and exclusion criteria designed to address and minimize known subject vulnerabilities.[xxiv] This process begins with physician-investigators designing research trials and IRB review of proposed trials in which some or all potential subjects are vulnerable.[xxv] The literature has no consensus on defining vulnerability in the clinical or research setting.[xxvi] Prominent guidelines such as the Common Rule and the Declaration of Helsinki focus on a categorical, consent-based approach to assessing vulnerability.  The capacity to provide freely given consent is a necessary prerequisite for ethical human subject research. Still, consent alone is insufficient to establish ethical permissibility or assure that a research transaction is fair.[xxvii] Harm can occur even with informed consent if it results from coercion, undue influence, or exploitation.[xxviii] Subjects have limited ability to avoid exploitation and act as an autonomous moral agents under such circumstances. Categorical assessments label groups whose members share salient features, such as prisoners or children, as vulnerable. This shared characteristic may compromise their capacity for free consent and autonomous ability to protect their interests. Although widely used, broad categorizations create monolithic views of populations but lack clarity as to why a particular feature makes one vulnerable or what a given characteristic decidedly renders one vulnerable to.[xxix] Individuals broadly vulnerable in society, such as the severely economically disadvantaged or incarcerated, are not necessarily vulnerable as research subjects in a given proposed trial.[xxx] Categorical vulnerability is insufficient to recognize that research-related harm is specific to a particular subject potentially participating in a given protocol at a definite time and place. III.     Assessing for Contextual Vulnerability Ensuring ethical consent, therefore, requires more than an accounting of capacity, competency, and freedom from coercion. This requires looking beyond voluntariness to ask whether the research offer is fair. Contextual vulnerability recognizes and addresses how some subjects are at a heightened risk of being used in ethically inappropriate ways due to research-specific situations and environments.[xxxi] Contextual vulnerability derives from a specific feature of the research environment that increases a subject’s risk of harm rather than an intrinsic categorical condition of that subject. Accounting for contextual vulnerabilities is necessary because it is ethically unsound for a competent subject to give voluntary consent to an offer that is nonetheless unfair or exploitative.[xxxii] Potential subjects excluded from accessing an allograft are contextually vulnerable in a research environment that may view their diminished range of choice as an opportunity for experimental research enrollment. Proposals to exploit or take advantage of this vulnerability places these individuals at a heightened risk of research-related harm. IV.     Exploitative Transactions in Xenotransplant Research In the landmark single-patient case in Maryland, a genetically modified porcine heart was offered to the subject only because he was denied access to the allograft waitlist due to a history of noncompliance with a recommended medical regimen.[xxxiii] Physician-investigators did not define how they evaluated compliance, nor did they elaborate on how this claim demonstrated the subject’s clear and convincing contraindication to receive a conventional cardiac allograft.  The subject was presented with a so-called Hobson’s choice, in which there is the illusion of free choice but ultimately there is no real choice as only one outcome, the acceptance of the experimental xenograft, is permitted; access to other choices, such as pursuing standard of care waitlisting, have been removed.[xxxiv] This case set a precedent for researchers and IRBs to view individuals denied access to conventional allografts as an appropriate subject population without acknowledgment of how this transaction is consensually exploitative. Consensual exploitation occurs when researchers intentionally and wrongfully take advantage of a subject’s vulnerability.[xxxv] In the cardiac xenotransplant case, the application of subjective evaluation criteria created a unique contextual vulnerability specific to transplant waitlist practices. Investigators took advantage of the subject’s diminished ability to access the heart transplant waitlist to obtain consent for the xenotransplant procedure. Researchers have no obligation to repair unjust conditions that they bear no responsibility for causing.[xxxvi] The wrongfulness in this case is how subjective compliance-based waitlisting criteria precluded the subject from accessing the heart transplant waitlist and denied him fair consideration in accessing the standard clinical option. Then, the transplantation team exploited this disadvantage they were morally responsible for creating. The subject agreed to the terms for an experimental and high-risk xenograft from a place of vulnerability due to the diminished range of choice specifically constructed by the policy and actions of the transplant center. The options offered by the physician-investigators to the patient were manipulated to promote the research system’s interests through the production of new scientific knowledge, not necessarily the subject’s conception of his own good.[xxxvii] V.     Recommendation for Simultaneous Allograft Listing Ethical research design calls for assessments of which vulnerabilities and in which contexts researchers and IRBs ought to offer additional safeguards. Subjects should be clinically suitable to produce robust, reliable, and generalizable scientific knowledge and be presented with a fair research offer. Researchers and IRBs can achieve this through an inclusion criterion requiring that a subject has previously been placed on and maintains a spot on a waitlist for a conventional allograft. Investigators and IRBs must ensure that subjects are selected based on scientific rationale, not because they are easy to recruit due to a compromised or vulnerable position.[xxxviii] Evidence of simultaneous allograft listing would provide verification that a researcher expects a potential subject to survive the burdens of an experimental xenotransplant procedure. Individuals of advanced age or with severe life-limiting comorbidities separate from their end-stage organ failure are less likely to survive after receiving an allograft or a research xenograft. These subjects would not produce valuable data in service to the study’s endpoints or knowledge generalizable to broader patient populations.  Requiring evidence of simultaneous allograft listing fulfills the ethical requirement that subjects who withdraw consent are not worse off than if they had not pursued research enrollment.[xxxix] If a subject withdraws consent before receiving a xenograft, their continued place on a waitlist ensures that their fair opportunity claim to an allograft has been maintained. Simultaneous allograft waitlisting excludes contextually vulnerable subjects clinically suitable to receive a graft but denied access to a waitlist. This inclusion criteria provides an additional safeguard against unfairly capitalizing on a subject’s marginalized status. Requiring simultaneous allograft listing will narrow the potential subject population to those clinically suitable and well situated to receive a fair opportunity to enroll in research: individuals listed for an allograft but significantly unlikely to receive or to benefit from that allograft. This potential subject population includes individuals with broadly reactive antibodies who are unlikely to match to a donor organ and individuals with anatomical contraindications who face prohibitive risks with standard allografts or bridging therapies.[xl] This subject population aligns with the FDA recommendation to enroll subjects for whom safe and effective alternatives are not available.[xli] These individuals have not had their claim to a fair opportunity transgressed by a subjective evaluation process, nor has their interest in accessing a scarce resource been unjustly discounted.[xlii] Neither the individual nor the transplant clinicians are responsible for creating a clinical or statistical disadvantage to receiving a standard allograft. An offer of research enrollment extended to this population has not been manipulated to favor one party over the other, but rather appropriately considers the interests of both parties.[xliii] Researchers have an interest in identifying subjects capable of producing scientifically valuable knowledge. Potential subjects have an interest in exploring alternatives to the high morbidity of a traditional allograft.  This subject population retains the autonomous choice to pursue a standard-of-care allograft or to enroll in xenograft research. Having few treatment options available does not inexorably undermine the voluntariness of research consent or increase vulnerability.[xliv] The consent transaction is not exploitative or unfair because the transplant system is not responsible for creating this diminished range of choice. Simultaneous allograft listing represents an eligibility criterion that responds to and limits the products of subjective decisions from unjustly impacting trial enrollment. VI.     Counterargument: Is Something Better Than Nothing? Some may argue that for medically exigent individuals in need of a transplant, any option to participate in research is better than no option. Autonomy and dignity, however, are not advanced when an inability to access the standard of care compels a subject’s decision to pursue experimental research. An offer of research enrollment that is unfair or exploitative remains unethical regardless of whether the subject stands to benefit. Nor should benefit be expected in early-phase research. The goals of phase I research are primarily to collect short-term safety, toxicity, dosing, and pharmacologic data, not to provide efficacious treatment.[xlv] Expanding access to experimental research trials cannot be conflated with fair access to equitable health care.[xlvi] Broadened access alone does not produce a more ethical research environment. Excluding contextually vulnerable subjects from research should not be the end goal, but rather a necessary interim to call attention to the need to redress biases and existing injustices in transplant access. Research that targets a population’s vulnerability serves to enable the continuation of unjust systems. CONCLUSION In summary, the urgent and significant clinical need for transplantable organs cannot undermine the requirements of ethical research design and conduct. Fair subject selection is a requirement of ethical clinical research.[xlvii] Potential subjects enrolled in upcoming xenograft research must be selected for their ability to answer the scientific objectives of a proposed study and must have the capacity to provide freely given informed consent within a fair research environment. Denying access to allotransplants for subjective psychosocial or compliance-based claims creates contextual vulnerability specific to transplant research that perpetuates the unfairness of the organ allocation system. Ethical research that produces valuable scientific knowledge cannot exploit the rights or interests of subjects in the process. A look beyond categorical vulnerability to contextual vulnerability highlights this currently overlooked area of exploitation. - [i]  “Organ Donation Statistics,” Health Resources and Services Administration, accessed April 18, 2022, https://www.organdonor.gov/learn/organ-donation-statistics. [ii] Schold, J.D. et al., “Barriers to Evaluation and Wait Listing for Kidney Transplantation,” Clinical Journal of the American Society of Nephrology 6, no. 7 (2011): 1760-67. [iii]  Abouna, G.M. “Ethical Issues in Organ Transplantation,” Medical Principles and Practice 12, no. 1 (2003): 54-69. [iv]  Anderson, M. “Xenotransplantation: A Bioethical Evaluation,” Journal of Medical Ethics 32, no. 4 (2006): 205-8. [v]  Lambert, J. “What Does the First Successful Test of a Pig-to-Human Kidney Transplant Mean?,” ScienceNews, October 22, 2021, https://www.sciencenews.org/article/xenotransplantation-pig-human-kidney-transplant.; Koplon, S. “Xenotransplantation: What It Is, Why It Matters and Where It Is Going,” UAB News, February 17, 2022, https://www.uabmedicine.org/-/xenotransplantation-what-it-is-why-it-matters-and-where-it-is-going. [vi]  Anderson, supra; Daar, A.S. “Ethics of Xenotransplantation: Animal Issues, Consent, and Likely Transformation of Transplant Ethics,” World Journal of Surgery 21, no. 9 (1997): 975-82.; Kim, M.K., et al., “The International Xenotransplantation Association Consensus Statement on Conditions for Undertaking Clinical Trials of Xenocorneal Transplantation,” Xenotransplantation 21, no. 5 (2014): 420-30. [vii]  Abouna, supra; Pierson, R.N., et al., “Pig-to-Human Heart Transplantation: Who Goes First?,” American Journal of Transplantation 20, no. 10 (2020): 2669-74. [viii]  Food and Drug Administration, Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans (Silver Spring, MD, 2016), 43, https://www.fda.gov/media/102126/download. [ix]  Wang, W., et al., “First Pig-to-Human Heart Transplantation,” Innovation (Camb) 3, no. 2 (2022): 100223. [x]  Carse, A.L. and Little, M.O. “Exploitation and the Enterprise of Medical Research,” in Exploitation and Developing Countries, ed. J. S. Hawkins and E. J. Emanuel (Princeton, NJ: Princeton University Press, 2008), 206-45. [xi]  Halpern, S.D. and Goldberg, D.“Allocating Organs to Cognitively Impaired Patients,” New England Journal of Medicine 376, no. 4 (2017): 299-301. [xii] “How We Match Organs,” United Network for Organ Sharing, accessed April 18, 2022, https://unos.org/transplant/how-we-match-organs/. [xiii] UW Medicine Harborview Medical Center – UW Medical Center University of Washington Physicians, Selection Criteria: Kidney Transplant Recipient (Seattle, WA, 2019), 1-3, https://www.uwmedicine.org/sites/stevie/files/2020-11/UW-Medicine-Kidney-Selection-Criteria-UH2701.pdf; Penn Medicine, Kidney Transplant Selection Criteria (Philadelphia, PA: Hospital of the University of Pennsylvania), 1-2. https://www.pennmedicine.org/media/documents/instructions/transplant/kidney_transplant_selection_criteria.ashx. [xiv]  Dudzinski, D.M. “Shifting to Other Justice Issues: Examining Listing Practices,” American Journal of Bioethics 4, no. 4 (2004): 35-37.; Richards, C.T., et al., “Use of Neurodevelopmental Delay in Pediatric Solid Organ Transplant Listing Decisions: Inconsistencies in Standards Across Major Pediatric Transplant Centers,” Pediatric Transplant 13, no. 7 (2009): 843-50. [xv]  Dudzinski, supra. [xvi]  Israni, A.K., et al., “Electronically Measured Adherence to Immunosuppressive Medications and Kidney Function after Deceased Donor Kidney Transplantation,” Clinical Transplantation 25, no. 2 (2011): 124-31. [xvii]  National Council on Disability, Organ Transplant Discrimination against People with Disabilities (Washington, DC, 2019), 25-35, https://ncd.gov/sites/default/files/NCD_Organ_Transplant_508.pdf.; Halpern and Goldberg, supra. [xviii]  Wightman, A., et al., “Prevalence and Outcomes of Renal Transplantation in Children with Intellectual Disability,” Pediatric Transplantation 18, no. 7 (2014): 714-19.; Wightman, A., et al., “Prevalence and Outcomes of Liver Transplantation in Children with Intellectual Disability,” Journal of Pediatric Gastroenterology and Nutrition 62, no. 6 (2016): 808-12. [xix]  Richards et al., supra; Godown, J., et al., “Heart Transplantation in Children with Down Syndrome,” Journal of the American Heart Association 11, no. 10 (2022): e024883. [xx]  Silverman, H. and Odonkor, P.N. “Reevaluating the Ethical Issues in Porcine-to-Human Heart Xenotransplantation,” Hastings Center Report 52, no. 5 (2022): 32-42. [xxi]  Sun, M., et al., “Negative Patient Descriptors: Documenting Racial Bias in the Electronic Health Record,” Health Affairs 41, no. 2 (2022): 203-11. [xxii]  Ibid. [xxiii]  Dudzinski, supra; Garg, P.P., et al., “Reducing Racial Disparities in Transplant Activation: Whom Should We Target?,” American Journal of Kidney Diseases 37, no. 5 (2001): 921-31. [xxiv]  Emanuel, E.J., et al., “What Makes Clinical Research Ethical?,” JAMA 283, no. 20 (2000): 2701-11. [xxv]  45 C.F.R. 46.111(b). [xxvi]  Hurst, S.A. “Vulnerability in Research and Health Care; Describing the Elephant in the Room?,” Bioethics 22, no. 4 (2008): 191-202. [xxvii]  The Nuremberg Code, Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law 2, no. 10: 181-2 (Washington, DC: U.S. Government Printing Office, 1949); Kipnis, K. “Vulnerability in Research Subjects: A Bioethical Taxonomy. Ethical and Policy Issues in Research Involving Human Participants.,” in Ethical and Policy Issues in Research Involving Human Participants,  (Bethesda, MD: National Bioethics Advisory Commission, August 2001), G1-G13. [xxviii]  Dickert, N. and Grady, C. “Incentives for Research Participants,” in The Oxford Textbook of Clinical Research Ethics, ed. E. J. Emanuel et al. (Oxford University Press, 2008), 386-96. [xxix]  Gordon, B.G. “Vulnerability in Research: Basic Ethical Concepts and General Approach to Review,” Ochsner Journal 20, no. 1 (2020): 34-38. [xxx]  Kipnis, supra. [xxxi]  Hurst, supra. [xxxii]  Lamkin, M. and Elliott, C. “Avoiding Exploitation in Phase I Clinical Trials: More Than (Un)Just Compensation,” Journal of Law, Medicine & Ethics 46, no. 1 (2018): 52-63.; Jansen, L.A. “A Closer Look at the Bad Deal Trial: Beyond Clinical Equipoise,” Hastings Center Report 35, no. 5 (2005): 29-36. [xxxiii]   Wang et al., supra; Silverman and Odonkor, supra. [xxxiv]   Silverman and Odonkor, supra. [xxxv]   Carse and Little, supra. [xxxvi]   Wertheimer, A. “Exploitation in Clinical Research,” in The Oxford Textbook of Clinical Research Ethics, ed. E. J. Emanuel et al. (Oxford University Press, 2008), 201-210. [xxxvii]   Brock, D.W. “Philosophical Justifications of Informed Consent in Research,” in The Oxford Textbook of Clinical Research Ethics, ed. E. J. Emanuel et al. (Oxford University Press, 2008), 606-612. [xxxviii]   Council for International Organizations of Medical Sciences, International Ethical Guidelines for Health-Related Research Involving Humans (Geneva: World Health Organization, 2016), https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf. [xxxix]  Ibid. [xl]  Pierson et al., supra. [xli]  Food and Drug Administration, supra. [xlii]  Hurst, supra. [xliii]  Kipnis, supra. [xliv]  Hawkins, J.S. and Emanuel, E.J. “Introduction: Why Exploitation?,” in Exploitation and Developing Countries, ed. J. S. Hawkins and E. J. Emanuel (Princeton, NJ: Princeton Universiy Pres, 2008), 1-20. [xlv]  Muglia, J.J. and DiGiovanna, J.J. “Phase 1 Clinical Trials,” Journal of Cutaneous Medicine and Surgery 2, no. 4 (1998): 236-41. [xlvi] Dresser, R. “The Role of Patient Advocates and Public Representatives in Research,” in The Oxford Textbook of Clinical Research Ethics, ed. E. J. Emanuel et al. (Oxford University Press, 2008), 231-41. [xlvii] MacKay, D. and Saylor, K.W. “Four Faces of Fair Subject Selection,” The American Journal of Bioethics 20, no. 2 (2020): 5-19.