The history of drug/vaccine development has included major advances guided primarily by risk/benefit analyses concerning the innovative agent, not by evidence-based clinical trials (Phase I–IV). Because the approval for new drugs is hindered under the present process, the system requires restructuring. The Phase I/II study period should be more flexible, using the “environment of knowledge” about the new agent, plus risk/benefit assessments. Phase III, as presently constructed, does not add new adverse events data, it provides (...) a narrower profile of drug efficacy than properly done Phase II studies, and placebo-controlled trials continue to raise unresolved ethical and social issues. Phase III studies should be abandoned for most drugs, and substituted with properly powered Phase II doseranging studies plus careful post-marketing surveillance. Phase III should be a penalty for poor drug development, not a regulatory requirement. (shrink)

Most phase III clinical trials today are explanatory. Because explanatory, or efficacy, trials test hypotheses under “ideal” conditions, they are not well suited to providing guidance on decisions made in most clinical care contexts. Pragmatic trials, which test hypotheses under “usual” conditions, are often better suited to this task. Yet, pragmatic, or effectiveness, trials are infrequently carried out. This mismatch between the design of clinical trials and the needs of health care (...) professionals is frustrating for everyone involved, and explains some of the challenges inherent in attempts to enhance knowledge translation and encourage evidence-based practice. The situation is more than simply frustrating, however; it is potentially unethical. Clinical trials must be socially valuable in order to (1) warrant the risks they impose on human research subjects and (2) fairly and efficiently assess new clinical interventions. Most bioethicists would agree that trials that have no social value, for instance, because their results do not have the potential to advance clinical care, should not be performed. What is less widely appreciated is that given limited research resources, trials that are more socially valuable should be preferred to trials that are less socially valuable when all else is equal. With respect to clinical trial design, I argue that while explanatory trials often have some social value, many have less social value than their pragmatic counterparts. On the basis of this general ethical assessment, I provide a preliminary defense of the position that clinical researchers should aim to conduct pragmatic trials, that is, that researchers face a burden of justification related to any idealizing elements added to trial designs. (shrink)

Phase I clinical trials are the first stage of testing new pharmaceuticals in humans. The majority of these studies are conducted under controlled, inpatient conditions using healthy volunteers who are paid for their participation. This article draws on an ethnographic study of six phase I clinics in the United States, including 268 semistructured interviews with research staff and healthy volunteers. In it, I argue that an institutional banalization of risk structures the perceptions of research staff and (...) healthy volunteers participating in the studies. For research staff, there are three mechanisms by which risk becomes banal: a perceived homogeneity of studies, Fordist work regimes, and data-centric discourse. For healthy volunteers, repeat study participation contributes to the institutional banalization of risk both through the process of desensitization to risk and the formation of trust in the clinics. I argue that the institutional banalization of risk also renders invisible ethical concerns about exploitation of underprivileged groups in pharmaceutical research. (shrink)

ABSTRACTRelatively little has been written about the ethics of conducting early phase clinical trials involving subjects from the developing world. Below, I analyze ethical issues surrounding one of gene transfer’s most widely praised studies conducted to date: in this study, Italian investigators recruited two subjects from the developing world who were ineligible for standard of care because of economic considerations. Though the study seems to have rendered a cure in these two subjects, it does not appear to (...) have complied with various international guidelines that require that clinical trials conducted in the developing world be responsive to their populations’ health needs. Nevertheless, policies devised to address large scale, late stage trials, such as the AZT short‐course placebo trials, map somewhat awkwardly to early phase studies. I argue that interest in conducting translational research in the developing world, particularly in the context of hemophilia trials, should motivate more rigorous ethical thinking around clinical trials involving economically disadvantaged populations. (shrink)

Research to improve the health of pregnant and fetal patients presents ethical challenges to clinical investigators, institutional review boards, funding agencies, and data safety and monitoring boards. The Common Rule sets out requirements that such research must satisfy but no ethical framework to guide their application. We provide such an ethical framework, based on the ethical concept of the fetus as a patient. We offer criteria for innovation and for Phase I and II and then for Phase (...) III clinical trials to improve the health of pregnant patients and of fetal patients and also criteria to responsibly manage the transition from investigation to clinical practice. Basing ethical criteria for research involving pregnant women on the ethical concept of the fetus as a patient insulates the proposed ethical framework and therefore research on pregnant women from the divisive and politicized concepts and discourses of personhood, fetal rights, and unborn child. (shrink)

Research to improve the health of pregnant and fetal patients presents ethical challenges to clinical investigators, institutional review boards, funding agencies, and data safety and monitoring boards. The Common Rule sets out requirements that such research must satisfy but no ethical framework to guide their application. We provide such an ethical framework, based on the ethical concept of the fetus as a patient. We offer criteria for innovation and for Phase I and II and then for Phase (...) III clinical trials to improve the health of pregnant patients and of fetal patients and also criteria to responsibly manage the transition from investigation to clinical practice. Basing ethical criteria for research involving pregnant women on the ethical concept of the fetus as a patient insulates the proposed ethical framework and therefore research on pregnant women from the divisive and politicized concepts and discourses of personhood, fetal rights, and unborn child. (shrink)

The ethical treatment of cancer patientsparticipating in clinical trials requiresthat patients are well-informed about thepotential benefits and risks associated withparticipation. When patients enrolled in phaseI clinical trials report that their chance ofbenefit is very high, this is often taken as evidence of a failure of the informed consent process. We argue, however, that some simple themes from the philosophy of language may make such a conclusion less certain. First, the patient may receive conflicting statements from multiple (...) speakers about the expected outcome of the trial. Patients may be reporting the message they like best. Second, there is a potential problem of multivocality. Expressions of uncertainty of the frequency type can be confused with expressionsof uncertainty of the belief type. Patients may be informed using frequency-type statements and respond using belief-type statements. Third, each speech episode involving the investigator and the patient regarding outcomes may subservemultiple speech acts, some of which may beindirect. For example, a patient reporting ahigh expected benefit may be reporting a beliefabout the future, reassuring family members,and/or attempting to improve his or her outcome by apublic assertion of optimism. These sources oflinguistic confusion should be considered injudging whether the patient's reported expectation isgrounds for a bioethical concern that there hasbeen a failure in the informed consent process. (shrink)

In her article, Pascale Hess raises the issue of whether her proposed model may be extrapolated and applied to clinical research fields other than stem cell-based interventions in the brain (SCBI-B) (Hess 2012). Broadly summarized, Hess’s model suggests prioritizing efficacy over safety in phase 1 trials involving irreversible interventions in the brain, when clinical criteria meet the appropriate population suffering from “degenerative brain diseases” (Hess 2012). Although there is a need to reconsider the traditional phase (...) 1 model, especially with respect to first-in-human clinical trials involving novel technologies, the question arises as to whether it is appropriate to advocate for a new model that prioritizes efficacy over safety across all phase 1 clinical research trials involving irreversible interventions in the brain. -/- . (shrink)

Background: One of the ethical imperatives for a valid consent process in clinical medication trials is that the process be guided by and recorded in an informed consent document (ICD). Concerns have been expressed, however, about readability and participant understanding of ICDs, which are often 10–20 pages long. Objective measures of readability and understanding have been used to support these concerns in several articles, but surprisingly the voice of trial participants on ICDs has not been heard in previous (...) studies. Hence, this study compares participants' subjective views on readability and their understanding of ICDs with those ICDs' objective readability scores. It also evaluates whether family, friends, and additional aids would foster better understanding of the ICD. Methods: Sixty current trial participants rated the readability and their understanding of deidentified standard ICDs. These had been sourced from two multicenter international Phase III trials on medication for diabetes mellitus and cancer. Results: Less than 10% of participants considered the ICDs difficult to read or difficult to understand in spite of objective readability scores at levels of about 12th grade education, but about a quarter considered the ICDs to be too technical. Participants gave mixed responses about friends or family members helping or the need for videos, pictures, additional reading material, and frequently answered questions (FAQ) sheets as an aid to their understanding. Conclusions: These findings suggest individual clinical trial participants should be engaged on their views of an ICD, for doing so is part of informed consent as a process rather than consent being merely focused on written information. Such participant-specific engagement should guide whether family and friends, videos, pictures, additional reading material, and FAQ sheets would be of assistance in improving understanding. (shrink)

Lowering compensation to research subjects to protect them from “undue inducement” is a misguided attempt to shoehorn a concern about exploitation into the framework of autonomy. We suggest that oversight bodies should be less concerned about undue influence than about exploitation of subjects. Avoiding exploitation in human subjects research requires not only increasing compensation, but enhancing the dignity of research participation.

In phase I clinical trials, healthy volunteers are dosed with investigational drugs and subjected to blood draws and other bodily monitoring procedures. In exchange, they are paid. Healthy volunteers are, in a very direct sense, selling access to their bodies for pharmaceutical companies and their associates to run drugs through. In his ethnographic study of socalled professional guinea pigs, Roberto Abadie writes, "Paid volunteers are well aware of the demand for an idealized, perfectly healthy volunteer. They also (...) realize that their body is a valued commodity in clinical trials research". It is perhaps surprising, then, that commodification is little discussed in the bioethics literature on phase I... (shrink)

Optogenetics is being optimistically presented in contemporary media for its unprecedented capacity to control cell behavior through the application of light to genetically modified target cells. As such, optogenetics holds obvious potential for application in a new generation of invasive medical devices by which to potentially provide treatment for neurological and psychiatric conditions such as Parkinson's disease, addiction, schizophrenia, autism and depression. Design of a first-in-human optogenetics experimental trial has already begun for the treatment of blindness. Optogenetics trials involve (...) a combination of highly invasive genetic and electronic interventions that results in irreversible and permanent modifications of an individual's nervous system. Given its novelty, its uncertain benefit to patients, and its unique risk profile of irreversible physiological alteration, optogenetics requires a reassessment of the ethical challenges for protecting human participants in clinical trials, particularly at formative stages of clinical evaluation. This study explores the evolving ethical issues surrounding optogenetics’ potential harm to participants within trial design, especially focusing on whether Phase 1 trials should incorporate efficacy as well as safety endpoints in ways that are fair and respectful to research trial participants. (shrink)

Decentralized clinical trials (DCTs) have the potential to advance the conduct of clinical trials, but raise several ethical issues, including obtaining valid informed consent. The debate on the ethical issues resulting from digitalization is predominantly focused on direct risks relating to for example data protection, safety, and data quality. We submit however, that a broader view on ethical aspects of DCTs is needed to touch upon the new challenges that come with the DCT practice. Digitalization has (...) impacts that go beyond its direct purposes, by shaping behaviors, experiences, social relations, and values. We examine four elements of the informed consent procedure that are affected by DCTs, while taking these soft impacts of technologies into account: (i) informing participants and testing understanding, (ii) freedoms in relation to responsibilities and burdens, (iii) trust in participant-researcher relations, and (iv) impacts on the concept of privacy. Our analysis reveals that a broad view is key for optimal conduct of DCTs. In addition, it provides insight into the ethical impacts of DCTs on informed consent. Technologies such as DCTs potentially have profound impacts which are not immediately addressed by the existing regulatory frameworks, but nonetheless important to recognize. These findings can guide future practices of DCTs to foster the important values of clinical research in this novel approach for conducting clinical trials. (shrink)

In clinical trials, it is common practice to follow up significant interactions between the factors under investigation with subgroup analyses. Such analyses pose at least two analytical and interpretational challenges. The first challenge is that performing multiple subgroup analyses increases the likelihood of obtaining spuriously significant results. This has been acknowledged and relevant guidance exists in the medical literature. The second challenge is that the effects that are obtained at the level of subgroup are composite. This has yet (...) to be fully acknowledged and discussed in the context of medical research. This paper aims to fill this lacuna. Using a simple additive model, we use recent findings from the CHARISMA trial on the efficacy of clopidogrel in addition to aspirin in the treatment of patients at risk for atherothrombotic events to demonstrate quantitatively the composition of effects at the level of subgroups. In the simplest case of a design involving an interaction (two crossed factors, with two levels each, i.e. a 2 x 2 design), effects at the level of subgroup consist of influences that stem (i) from the incidence of the measured outcome in the study population as a whole; (ii) from the factor of interest (e.g. treatment vs. placebo); (iii) from the second factor (e.g. patient group membership); (iv) from the interaction between the two factors; and (v) from random error in the measured outcome. The value of the approach illustrated here is that it is generalizable to any research design irrespective of its complexity and that it prompts clinicians to consider the multiple causality underlying medical research findings. (shrink)

Participants in clinical research sometimes view participation as therapy or exaggerate potential benefits, especially in phase I or phase II trials. We conducted this study to discover what methods might improve cancer patients’ understanding of early-phase clinical trials. We randomly assigned 130 cancer patients from three U.S. medical centers who were considering enrollment in a phase I or phase II cancer trial to receive either a multimedia intervention or a National Cancer (...) Institute pamphlet explaining the trial and its purpose. Intervention participants were 32 times more likely to believe that the trial’s purpose was to examine safety and 60 % less likely to believe they would experience long-term benefit or cure. There was no difference in enrollment decision. However, while patients’ understanding of the trial’s purpose improved and expectations of long-term benefit diminished, half the respondents still believed they would experience long-term benefit or cure from participation. Therefore, we conclude that multimedia interventions such as this one may help oncologists to explain the risks and benefits of early-phase cancer trials in a way that patients can more easily understand, helping them to make more informed decisions about participation. But further research into other factors that influence patients’ beliefs about the outcome of enrollment is needed, both to modify the interventions and to determine how malleable patient beliefs are. (shrink)

We explored the comprehension of the informed consent in 77 cancer patients previously enrolled in randomised phase II or phase III clinical trials, between March and July 2011, at the San Raffaele Scientific Institute in Milano. We asked participants to complete an ad hoc questionnaire and analysed their answers. Sixty-two per cent of the patients understood the purpose and nature of the trial they were participating in; 44% understood the study procedures and 40% correctly listed at (...) least one of the major risks or complications related to their participation in the trial. We identified three factors associated with comprehension of the informed consent: age, education and type of tumour/investigator team. We suggest several possible improvements of how to obtain informed consent that will increase patient awareness, as well as the validity and effectiveness of the clinical trials. (shrink)

Altruism is a well-established reason underlying research participation. Less is known about altruism in adolescent-parent decision-making about clinical trials enrolling healthy adolescents. This qualitative investigation focused on identifying spontaneous statements of altruism within adolescent-parent (dyadic) discussions of participation in a hypothetical phase I clinical trial related to adolescent sexual health. Content analysis revealed several response patterns to each other’s altruistic reasoning. Across 70 adolescent-parent dyads in which adolescents were 14 to 17 years of age and 91% (...) of their parents were mothers, a majority (61%) of dyadic discussions included a statement reflecting altruism. Parents responded to adolescents’ statements of altruism more frequently than adolescents responded to parents’ statements. Responses included: expresses concern, reiterates altruistic reasoning, agrees with altruistic reasoning, and adds to/expands altruistic reasoning. Since an altruistic perspective was often balanced with concerns about risk or study procedures, researchers cannot assume that altruism will directly lead to study participation. Optimizing the informed consent process for early phase clinical trials involving healthy adolescents may include supporting parents to have conversations with their adolescents which will enhance their capacity to consider all aspects of trial participation. (shrink)

Clinical trials in developing countries are often beset by ethical problems that would be considered unresolvable in countries like Australia and the U.S. Nevertheless, such trials continue to go ahead throughout Asia, Africa and South America, and are often conducted in ways that could be considered to be unethical. In this article I discuss two issues, focussing on an HIV preventative trial of a vaginal gel, the Nonoxynol 9 phase three trial being held in Kenya. The (...) first of these is what makes such a trial unethical given that it has approval from the WHO and seemingly conforms with acceptable standards of consent. The second issue involves using material from such trials, if we accept that they were conducted unethically. (shrink)

This study appeared in full in the last issue of Research Ethics Review (2009; 5(1): 26). SB, a 21-year-old healthy male, volunteered to take part in a phase I randomized, double-blind, placebo-controlled drug interaction study. The trial compound was a CNS-active drug currently under development for a range of CNS indications. The trial–which was not ‘first in class’ or ‘first in man’ –comprised two residential seven-day study periods with a washout period in between. Three days after the end of (...) the first study period the volunteer developed an acute, severe psychosis that warranted hospitalization. (shrink)

The transition of novel and potentially promising medical therapies into their initial human clinical trials can engender conflicting pressures. On the one side, because Phase I trials raise greater ethical and human protection challenges than later stage clinical trials, there is a need to proceed cautiously. This is particularly the case for Phase I trials with a novel therapy being tested in humans for the first time, usually termed first-in-human (FIH) trials, (...) especially if the FIH trial involves significant risks. On the other side, scientists interested in having their research validated, corporations with a financial interest in the field, and potential patients and patient support groups desirous of having .. (shrink)

Clinical trials of novel agents often present several layers of ethical challenge. Because time and resources for ethical and safety review are limited, how investigators, IRBs, and regulators allocate attention to a trial's various safety dimensions itself represents a critical ethical question. In what follows, I use the example of a Parkinson's disease gene transfer trial to show how risks involving unknown probabilities or outcomes (ambiguity), might sometimes draw attention away from risks that involve known probabilities or outcomes. (...) This potentially undermines the goal of ‘systematic and nonarbitrary analysis of risk’ during ethical review. To counteract the possible effects of such attention biases, I propose that reviewers develop ‘cognitive aids’ like lists and, where appropriate, set aside time to discuss non-ambiguous risks. I also propose further research for addressing and understanding how attention allocation, emotion, and ambiguity influence ethical decision-making. (shrink)

This article empirically examines how healthy volunteers evaluate and make sense of the risks of phase I clinical drug trials. This is an ethically important topic because healthy volunteers are exposed to risk but can gain no medical benefit from their trial participation. Based on in-depth qualitative interviews with 178 healthy volunteers enrolled in various clinical trials, we found that participants focus on myriad characteristics of clinical trials when assessing risk and making enrolment (...) decisions. These factors include the short-term and long-term effects; required medical procedures; the type of trial, including its design, therapeutic area of investigation, and dosage of the drug; the amount of compensation; and trust in the research clinic. In making determinations about the study risks, participants rely on information provided during the consent process, their own and others’ experiences in clinical trials, and comparisons among studies. Our findings indicate that the informed consent process succeeds in communicating well about certain types of risk information while simultaneously creating lacunae that are problematically filled by participants through their collective experiences and assumptions about risk. We discuss the ethical implications of these findings and make recommendations for improving the consent process in healthy volunteer trials. (shrink)

While risk of harm is an important focus for whether clinical research on humans can and should proceed, there is uncertainty about what constitutes harm to a trial participant. In Phase I trials on healthy volunteers, the purpose of the research is to document and measure safety concerns associated with investigational drugs, and participants are financially compensated for their enrollment in these studies. In this article, we investigate how characterizations of harm are narrated by healthy volunteers in (...) the context of the adverse events they experience during clinical trials. Drawing upon qualitative research, we find that participants largely minimize, deny, or re-attribute the cause of these AEs. We illustrate how participants' interpretations of AEs may be shaped both by the clinical trial environment and their economic motivation to participate. While these narratives are emblematic of the larger ambiguity surrounding harm in the context of clinical trial participation, we argue that these interpretations also problematically maintain the narrative of the safety of clinical trials, the ethics of testing investigational drugs on healthy people, and the rigor of data collected in the specter of such ambiguity. (shrink)

Background: The approval of a research ethics committee and obtaining informed consent from patients could be considered the main issues in the ethics of research with human beings. The aim of this study was to assess both methodological quality and ethical quality, and also to assess the relationship between these two qualities in randomised phase III cancer trials.Method: Methodological quality and ethical quality were assessed for all randomised controlled trials published in 10 international journals between 1999 and (...) 2001 .Results: The mean Jadad score was 9.86 ± 1.117. The methodological quality was poor in 75 RCTs . The mean Berdeu score was 0.42 ± 0.133. The mean ethical quality score for poor methodological quality RCTs was 0.39 ± 0.133; it was 0.43 ± 0.133 for good methodological quality RCTs . There was improvement in ethical quality according to the year of commencement of the trials . There was no correlation between methodological quality and the number of participating patients , between ethical quality and the number of participating patients , or between ethical quality and methodological quality . ICP and REC approval were not obtained for 21 and 77 trials respectively.Conclusion: The association between methodological quality and the reporting of ethical requirements probably reflects the respect shown for patients during the whole research process. These results suggest that closer attention to the conduct of clinical research, as well as the reporting of its ethical aspects, is needed. (shrink)

The focus on translational research in clinical trials has the potential to generate clinically relevant genetic data that could have importance to patients. This raises challenging questions about communicating relevant genetic research results to individual patients. An exploratory pharmacogenetic analysis was conducted in the international ovarian cancer phase III trial, AGO-OVAR 16, which found that patients with clinically important germ-line BRCA1/2 mutations had improved progression-free survival prognosis. Mechanisms to communicate BRCA results were evaluated, because these findings may (...) be beneficial to patients and their families. Communicating individual BRCA results was not anticipated during clinical trial design. Consequently, options were not available for patients to indicate their preference for receiving their individual results when they signed pharmacogenetic informed consent. Differences in local requirements, clinical practice, and opinion regarding the ethical aspects of how to convey genetic results to patients are all potential barriers to returning individual BRCA results to patients. Communicating the aggregate BRCA result from this study provided clinical investigators with a mechanism to disseminate the overall study finding to patients while taking individual circumstances, local guidelines and clinical practice into account. This study illustrates the importance of increasing the clarity and scope of informed consent and the need for patient engagement to ensure clinical trial participants can indicate their preference regarding receipt of potentially important individual pharmacogenetic results. This study was registered in the NCT Clinical Trial Registry under NCT00866697 on March 19, 2009, following approval from participating ethics committees. (shrink)

We studied changes in eligibility criteria--the largest impediment to patient accrual--in two samples of clinical trials. Trials from the NSABP (National Surgical Adjuvant Breast and Bowel Program) and POG (Pediatric Oncology Group) were analyzed. After eliminating duplications, the criteria in each protocol were enumerated and classified according to a novel schema. NSABP trials contained significantly more criteria than POG trials, and added precision criteria (making study populations homogeneous) at a faster rate than POG studies. The (...) difference between NSABP studies (explanatory trials) and POG studies (pragmatic trials) suggest that large numbers of eligibility criteria are not necessary for quality studies. We recommend that: (1) the inclusion/exclusion criteria distinction be abandoned; (2) eligibility criteria be explicitly justified; (3) the need for each criterion be assessed when new trials are planned; (4) criteria in phase III trials restricting patient accrual be minimized; and (5) further research be done to assess the impact of criteria on generalizability. (shrink)

Nanomedicine is a rapidly growing field in the academic as well as commercial arena. While some had predicted nanomedicine sales to reach $20.1 billion in 2011, the actual growth was much more rapid, with the global nanomedicine market being valued at $53 billion in 2009, and forecast to increase at an annual growth rate of 13.5% to reach more than $100 billion in 2014. In 2006, more than 130 nanotechnology-based drugs and delivery systems had entered preclinical, clinical, or commercial (...) development. The European Medicines Agency reviewed 18 marketing authorization applications for nanomedicines in 2010. In 2011, 22 drugs that had been approved by the FDA, and 87 Phase I and Phase II clinical trials were listed in the U.S. National Institutes of Health data base, www.clinicaltrials.gov. Although the fastest growing areas of nanomedicine are applications in medical imaging and diagnosis using contrast-enhancing agents, most nanomedicine research and commercialization is in the area of cancer drug therapy, including nano gold shells. (shrink)

James E Cooper¹, Uwe Christians², Alexander C Wiseman¹¹Division of Renal Diseases and Hypertension, Transplant Center, ²iC42 Integrated Solutions in Systems Biology for Clinical Research and Development, University of Colorado Denver, Aurora, CO, USA: Everolimus is a novel target of rapamycin -I analog that has recently been approved in combination with cyclosporine A and steroids for use in the prevention of organ rejection in kidney transplant recipients. Compared with rapamycin, everolimus is characterized by a shorter half-life and improved bioavailability. Prior (...) to US Food and Drug Administration approval, a number of Phase II and III clinical trials were undertaken to evaluate the effectiveness of everolimus in combination with calcineurin inhibitors for preventing acute rejection and promoting allograft survival in kidney transplant recipients. In this report, we review the pharmacokinetic properties of everolimus, the clinical efficacy studies that led to its approval for use in kidney transplantation, as well as reported data on patient safety and tolerability associated with its use.Keywords: mTOR inhibitors, kidney transplantation, everolimus. (shrink)

There are more large-scale pregnancy trials that implement lifestyle interventions than ever before; yet, there is a dearth of information on pregnant peoples’ experiences in such trials. Contemporary lifestyle pregnancy trials draw on epigenetics and DOHaD research to design and justify prenatal interventions on the material environment to reduce health risks in future generations. This article draws on ethnographic data from a prenatal trial in the United Kingdom and focuses specifically on the experiences of pregnant participants during (...) the intervention phase. In this article, I develop the politics of postgenomic reproduction as a feminist and critical race framework to examine the complex and mercurial stakes of contemporary pregnancy trials. I argue that narratives of control and responsibility in epigenetic models are echoed and preceded by participants’ own embodied experience. The pregnant narratives show at once how their bodies are exposed to unpredictable and uncontrollable environmental exposures and that they are required to respond as if they have absolute control and responsibility. Attending to trial participants’ narratives from a feminist and critical race framework reveals how individualized lifestyle interventions are deeply political and racial, and carry implications for how pregnancy trials influence postgenomic reproduction. (shrink)

In this essay, I argue that at least in two phases of pharmaceutical research, especially while assessing the adequacy of the accumulated data and its interpretation, the influence of non-epistemic values is necessary. I examine a specific case from the domain of pharmaceutical research and demonstrate that there are multiple competing sets of values which may legitimately or illegitimately influence different phases of the inquiry. In such cases, the choice of the appropriate set of values—epistemic as well as non-epistemic—should be (...) made on the basis of the set’s viability to promote specific epistemic and social aims of the research, in the case at hand, rather than other competing aims. I put forth an account which addresses two philosophically significant and interrelated questions in the context of values in science debates: which aim should be prioritized when there are different stakeholders who try to achieve competing but, sometimes, conflicting goals; and what should be the criteria according to which the prioritization of a particular goal over other competing goals can be determined? I argue that both these questions can be addressed by invoking the principle of non-arbitrariness and the mere means principle and self-determination right. The philosophical import of raising and addressing these questions from an ethical perspective is that this approach leads to a better understanding of problems in today’s pharmaceutical research and guides us in efforts to alleviate these problems. (shrink)

ABSTRACT I argue that this examination and appreciation for the shift to abductive reasoning should be extended to the intersection of neuroscience and novel brain-computer interfaces too. This paper highlights the implications of applying abductive reasoning to personalized implantable neurotechnologies. Then, it explores whether abductive reasoning is sufficient to justify insurance coverage for devices absent widespread clinical trials, which are better applied to one-size-fits-all treatments. INTRODUCTION In contrast to the classic model of randomized-control trials, often with a (...) large number of subjects enrolled, precision medicine attempts to optimize therapeutic outcomes by focusing on the individual.[i] A recent publication highlights the strengths and weakness of both traditional evidence-based medicine and precision medicine.[ii] Plus, it outlines a tension in the shift from evidence-based medicine’s inductive reasoning style (the collection of data to postulate general theories) to precision medicine’s abductive reasoning style (the generation of an idea from the limited data available).[iii] The paper’s main example is the application of precision medicine for the treatment of cancer.[iv] I argue that this examination and appreciation for the shift to abductive reasoning should be extended to the intersection of neuroscience and novel brain-computer interfaces too. As the name suggests, brain-computer interfaces are a significant advancement in neurotechnology that directly connects someone’s brain to external or implanted devices.[v] Among the various kinds of brain-computer interfaces, adaptive deep brain stimulation devices require numerous personalized adjustments to their settings during the implantation and computation stages in order to provide adequate relief to patients with treatment-resistant disorders. What makes these devices unique is how adaptive deep brain stimulation integrates a sensory component to initiate the stimulation. While not commonly at the level of sophistication as self-supervising or generative large language models,[vi] they currently allow for a semi-autonomous form of neuromodulation. This paper highlights the implications of applying abductive reasoning to personalized implantable neurotechnologies. Then, it explores whether abductive reasoning is sufficient to justify insurance coverage for devices absent widespread clinical trials, which are better applied to one-size-fits-all treatments.[vii] ANALYSIS I. The State of Precision Medicine in Oncology and the Epistemological Shift While a thorough overview of precision medicine for the treatment of cancer is beyond the scope of this article, its practice can be roughly summarized as identifying clinically significant characteristics a patient possesses (e.g., genetic traits) to land on a specialized treatment option that, theoretically, should benefit the patient the most.[viii] However, in such a practice of stratification patients fall into smaller and smaller populations and the quality of evidence that can be applied to anyone outside these decreases in turn.[ix] As inductive logic helps to articulate, the greater the number of patients that respond to a particular therapy the higher the probability of its efficacy. By straying from this logical framework, precision medicine opens the treatment of cancer to more uncertainty about the validity of these approaches to the resulting disease subcategories.[x] Thus, while contemporary medical practices explicitly describe some treatments as “personalized”, they ought not be viewed as inherently better founded than other therapies.[xi] A relevant contemporary case of precision medicine out of Norway focuses on the care of a patient with cancer between the ventricles of the heart and esophagus, which had failed to respond to the standard regimen of therapies over four years.[xii] In a last-ditch effort, the patient elected to pay out-of-pocket for an experimental immunotherapy (nivolumab) at a private hospital. He experienced marked improvements and a reduction in the size of the tumor. Understandably, the patient tried to pursue further rounds of nivolumab at a public hospital. However, the hospital initially declined to pay for it given the “lack of evidence from randomised clinical trials for this drug relating to this [patient’s] condition.”[xiii] In rebuttal to this claim, the patient countered that he was actually similar to a subpopulation of patients who responded in “open‐label, single arm, phase 2 studies on another immune therapy drug” (pembrolizumab).[xiv] Given this interpretation of the prior studies and the patient’s response, further rounds of nivolumab were approved. Had the patient not had improvements in the tumor’s size following a round of nivolumab, then pembrolizumab’s prior empirical evidence in isolation would have been insufficient, inductively speaking, to justify his continued use of nivolumab.[xv] The case demonstrates a shift in reasoning from the traditional induction to abduction. The phenomenon of ‘cancer improvement’ is considered causally linked to nivolumab and its underlying physiological mechanisms.[xvi] However, “the weakness of abductions is that there may always be some other better, unknown explanation for an effect. The patient may for example belong to a special subgroup that spontaneously improves, or the change may be a placebo effect. This does not mean, however, that abductive inferences cannot be strong or reasonable, in the sense that they can make a conclusion probable.”[xvii] To demonstrate the limitations of relying on the abductive standard in isolation, commentators have pointed out that side effects in precision medicine are hard to rule out as being related to the initial intervention itself unless trends from a group of patients are taken into consideration.[xviii] As artificial intelligence (AI) assists the development of precision medicine for oncology, this uncertainty ought to be taken into consideration. The implementation of AI has been crucial to the development of precision medicine by providing a way to combine large patient datasets or a single patient with a large number of unique variables with machine learning to recommend matches based on statistics and probability of success upon which practitioners can base medical recommendations.[xix] The AI is usually not establishing a causal relationship[xx] – it is predicting. So, as AI bleeds into medical devices, like brain-computer interfaces, the same cautions about using abductive reasoning alone should be carried over. II. Responsive Neurostimulation, AI, and Personalized Medicine Like precision medicine in cancer treatment, computer-brain interface technology similarly focuses on the individual patient through personalized settings. In order to properly expose the intersection of AI, precision medicine, abductive reasoning, and implantable neurotechnologies, the descriptions of adaptive deep brain stimulation systems need to deepen.[xxi] As a broad summary of adaptive deep brain stimulation, to provide a patient with the therapeutic stimulation, a neural signal, typically referred to as a local field potential,[xxii] must first be detected and then interpreted by the device. The main adaptive deep brain stimulation device with premarket approval, the NeuroPace Responsive Neurostimulation system, is used to treat epilepsy by detecting and storing “programmer-defined phenomena.”[xxiii] Providers can optimize the detection settings of the device to align with the patient’s unique electrographic seizures as well as personalize the reacting stimulation’s parameters.[xxiv] The provider adjusts the technology based on trial and error. One day machine learning algorithms will be able to regularly aid this process in myriad ways, such as by identifying the specific stimulation settings a patient may respond to ahead of time based on their electrophysiological signatures.[xxv] Either way, with AI or programmers, adaptive neurostimulation technologies are individualized and therefore operate in line with precision medicine rather than standard treatments based on large clinical trials. Contemporary neurostimulation devices are not usually sophisticated enough to be prominent in AI discussions where the topics of neural networks, deep learning, generative models, and self-attention dominate the conversation. However, implantable high-density electrocorticography arrays (a much more sensitive version than adaptive deep brain stimulation systems use) have been used in combination with neural networks to help patients with neurologic deficits from a prior stroke “speak” through a virtual avatar.[xxvi] In some experimental situations, algorithms are optimizing stimulation parameters with increasing levels of independence.[xxvii] An example of neurostimulation that is analogous to the use of nivolumab in Norway surrounds a patient in the United States who was experiencing both treatment-resistant OCD and temporal lobe epilepsy.[xxviii]Given the refractory nature of her epilepsy, implantation of an adaptive deep brain stimulation system was indicated. As a form of experimental therapy, her treatment-resistant OCD was also indicated for the off-label use of an adaptive deep brain stimulation set-up. Another deep brain stimulation lead, other than the one implanted for epilepsy, was placed in the patient’s right nucleus accumbens and ventral pallidum region given the correlation these nuclei had with OCD symptoms in prior research. Following this, the patient underwent “1) ambulatory, patient-initiated magnet-swipe storage of data during moments of obsessive thoughts; (2) lab-based, naturalistic provocation of OCD-related distress (naturalistic provocation task); and (3) lab-based, VR [virtual reality] provocation of OCD-related distress (VR provocation task).”[xxix] Such signals were used to identify when to deliver the therapeutic stimulation in order to counter the OCD symptoms. Thankfully, following the procedure and calibration the patient exhibited marked improvements in their OCD symptoms and recently shared her results publicly.[xxx] In both cases, there is a similar level of abductive justification for the efficacy of the delivered therapy. In the case study in which the patient was treated with adaptive deep brain stimulation, they at least had their neural activity tested in various settings to determine the optimum parameters for treatment to avoid them being based on guesswork. Additionally, the adaptive deep brain stimulation lead was already placed before the calibration trials were conducted, meaning that the patient had already taken on the bulk of the procedural risk before the efficacy could be determined. Such an efficacy test could have been replicated in the first patient’s cancer treatment, had it been biopsied and tested against the remaining immunotherapies in vitro. Yet, in the case of cancer with few options, one previous dose of a drug that appeared to work on the patient may justify further doses. However, as the Norwegian case presents, corroboration with known responses to a similar drug (from a clinical trial) could be helpful to validate the treatment strategy. (It should be noted that both patients were resigned to these last resort options regardless of the efficacy of treatment.) There are some elements of inductive logic seen with adaptive deep brain stimulation research in general. For example, abductively the focus could be that patient X’s stimulation parameters are different from patient Y’s and patient Z’s. In contrast, when grouped as subjects who obtained personalized stimulation, patients X, Y, and Z demonstrate an inductive aspect to this approach’s safety and/or efficacy. The OCD case holds plenty of abductive characteristics in line with precision medicine’s approach to treating cancer and as more individuals try the method, there will be additional data. With the gradual integration of AI into brain-computer interfaces in the name of efficacy, this reliance on abduction will continue, if not grow, over time. Moving forward, if a responsive deep brain stimulation treatment is novel and individualized (like the dose of nivolumab) and there is some other suggestion of efficacy (like clinical similarities to other patients in the literature), then it may justify insurance coverage for the investigative intervention, absent other unrelated reasons to deny it. III. Ethical Implications and Next Steps While AI’s use in oncology and neurology is not yet as prominent as its use in other fields (e.g., radiology), it appears to be on the horizon for both.[xxxi] AI can be found in both the functioning of the neurotechnologies as well as the implementation of precision medicine. The increasing use of AI may serve to further individualize both oncologic and neurological therapies. Given these implications and the handful of publications cited in this article, it is important to have a nuanced evaluation of how these treatments, which heavily rely on abductive justification, ought to be managed. The just use an abductive approach may be difficult as AI infused precision medicine is further pursued. At baseline, such technology relies on a level of advanced technology literacy among the general public and could exclude populations who lack access to basic technological infrastructure or know-how from participation.[xxxii] Even among nations with adequate infrastructure, as more patients seek out implantable neurotechnologies, which require robust healthcare resources, the market will favor patient populations that can afford this complex care.[xxxiii] If patients already have the means to pay for an initial dose/use of a precision medicine product out of pocket, should insurance providers be required to cover subsequent treatments?[xxxiv] That is, if a first dose of a cancer drug or a deep brain stimulator over its initial battery life is successful, patients may feel justified in having the costs of further treatments covered. The Norwegian patient’s experience implies there is a precedent for the idea that some public insurance companies ought to cover successful cancer therapies, however, insurance companies may not all see themselves as obligated to cover neurotechnologies that rely on personalized settings or that are based on precision/abductive research more than on clinical trials. CONCLUSION The fact that the cases outlined above rely on abductive style of reasoning implies that there may not be as strong a justification for coverage by insurance, as they are both experimental and individualized, when compared to the more traditional large clinical trials in which groups have the same or a standardized protocol (settings/doses). If a study is examining the efficacy of a treatment with a large cohort of patients or with different experimental groups/phases, insurance companies may conclude that the resulting symptom improvements are more likely to be coming from the devices themselves. A preference for inductive justification may take priority when ruling in favor of funding someone’s continued use of an implantable neurostimulator. There are further nuances to this discussion surrounding the classifications of these interventions as research versus clinical care that warrant future exploration, since such a distinction is more of a scale[xxxv] than binary and could have significant impacts on the “right-to-try” approach to experimental therapies in the United States.[xxxvi] Namely, given the inherent limitations of conducting large cohort trials for deep brain stimulation interventions on patients with neuropsychiatric disorders, surgically innovative frameworks that blend abductive and inductive methodologies, like with sham stimulation phases, have traditionally been used.[xxxvii] Similarly, for adaptive brain-computer interface systems, if there are no large clinical trials and instead only publications that demonstrate that something similar worked for someone else, then, in addition to the evidence that the first treatment/dose worked for the patient in question, the balance of reasoning would be valid and arguably justify insurance coverage. As precision approaches to neurotechnology become more common, frameworks for evaluating efficacy will be crucial both for insurance coverage and for clinical decision making. ACKNOWLEDGEMENT This article was originally written as an assignment for Dr. Francis Shen’s “Bioethics & AI” course at Harvard’s Center for Bioethics. I would like to thank Dr. Shen for his comments as well as my colleagues in the Lázaro-Muñoz Lab for their feedback. - [i] Jonathan Kimmelman and Ian Tannock, “The Paradox of Precision Medicine,” Nature Reviews. Clinical Oncology 15, no. 6 (June 2018): 341–42, https://doi.org/10.1038/s41571-018-0016-0. [ii] Henrik Vogt and Bjørn Hofmann, “How Precision Medicine Changes Medical Epistemology: A Formative Case from Norway,” Journal of Evaluation in Clinical Practice 28, no. 6 (December 2022): 1205–12, https://doi.org/10.1111/jep.13649. [iii] David Barrett and Ahtisham Younas, “Induction, Deduction and Abduction,” Evidence-Based Nursing 27, no. 1 (January 1, 2024): 6–7, https://doi.org/10.1136/ebnurs-2023-103873. [iv] Vogt and Hofmann, “How Precision Medicine Changes Medical Epistemology,” 1208. [v] Wireko Andrew Awuah et al., “Bridging Minds and Machines: The Recent Advances of Brain-Computer Interfaces in Neurological and Neurosurgical Applications,” World Neurosurgery, May 22, 2024, S1878-8750(24)00867-2, https://doi.org/10.1016/j.wneu.2024.05.104. [vi] Mark Riedl, “A Very Gentle Introduction to Large Language Models without the Hype,” Medium (blog), May 25, 2023, https://mark-riedl.medium.com/a-very-gentle-introduction-to-large-language-models-without-the-hype-5 f67941fa59e. [vii] David E. Burdette and Barbara E. Swartz, “Chapter 4 - Responsive Neurostimulation,” in Neurostimulation for Epilepsy, ed. Vikram R. Rao (Academic Press, 2023), 97–132, https://doi.org/10.1016/B978-0-323-91702-5.00002-5. [viii] Kimmelman and Tannock, 2018. [ix] Kimmelman and Tannock, 2018. [x] Simon Lohse, “Mapping Uncertainty in Precision Medicine: A Systematic Scoping Review,” Journal of Evaluation in Clinical Practice 29, no. 3 (April 2023): 554–64, https://doi.org/10.1111/jep.13789. [xi] Kimmelman and Tannock, “The Paradox of Precision Medicine.” [xii] Vogt and Hofmann, 1206. [xiii] Vogt and Hofmann, 1206. [xiv] Vogt and Hofmann, 1206. [xv] Vogt and Hofmann, 1207. [xvi] Vogt and Hofmann, 1207. [xvii] Vogt and Hofmann, 1207. [xviii] Vogt and Hofmann, 1210. [xix] Mehar Sahu et al., “Chapter Three - Artificial Intelligence and Machine Learning in Precision Medicine: A Paradigm Shift in Big Data Analysis,” in Progress in Molecular Biology and Translational Science, ed. David B. Teplow, vol. 190, 1 vols., Precision Medicine (Academic Press, 2022), 57–100, https://doi.org/10.1016/bs.pmbts.2022.03.002. [xx] Stefan Feuerriegel et al., “Causal Machine Learning for Predicting Treatment Outcomes,” Nature Medicine 30, no. 4 (April 2024): 958–68, https://doi.org/10.1038/s41591-024-02902-1. [xxi] Sunderland Baker et al., “Ethical Considerations in Closed Loop Deep Brain Stimulation,” Deep Brain Stimulation 3 (October 1, 2023): 8–15, https://doi.org/10.1016/j.jdbs.2023.11.001. [xxii] David Haslacher et al., “AI for Brain-Computer Interfaces,” 2024, 7, https://doi.org/10.1016/bs.dnb.2024.02.003. [xxiii] Burdette and Swartz, “Chapter 4 - Responsive Neurostimulation,” 103–4; “Premarket Approval (PMA),” https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P100026. [xxiv] Burdette and Swartz, “Chapter 4 - Responsive Neurostimulation,” 104. [xxv] Burdette and Swartz, 126. [xxvi] Sean L. Metzger et al., “A High-Performance Neuroprosthesis for Speech Decoding and Avatar Control,” Nature 620, no. 7976 (August 2023): 1037–46, https://doi.org/10.1038/s41586-023-06443-4. [xxvii] Hao Fang and Yuxiao Yang, “Predictive Neuromodulation of Cingulo-Frontal Neural Dynamics in Major Depressive Disorder Using a Brain-Computer Interface System: A Simulation Study,” Frontiers in Computational Neuroscience 17 (March 6, 2023), https://doi.org/10.3389/fncom.2023.1119685; Mahsa Malekmohammadi et al., “Kinematic Adaptive Deep Brain Stimulation for Resting Tremor in Parkinson’s Disease,” Movement Disorders 31, no. 3 (2016): 426–28, https://doi.org/10.1002/mds.26482. [xxviii] Young-Hoon Nho et al., “Responsive Deep Brain Stimulation Guided by Ventral Striatal Electrophysiology of Obsession Durably Ameliorates Compulsion,” Neuron 0, no. 0 (October 20, 2023), https://doi.org/10.1016/j.neuron.2023.09.034. [xxix] Nho et al. [xxx] Nho et al.; Erik Robinson, “Brain Implant at OHSU Successfully Controls Both Seizures and OCD,” OHSU News, accessed March 3, 2024, https://news.ohsu.edu/2023/10/25/brain-implant-at-ohsu-successfully-controls-both-seizures-and-ocd. [xxxi] Awuah et al., “Bridging Minds and Machines”; Haslacher et al., “AI for Brain-Computer Interfaces.” [xxxii] Awuah et al., “Bridging Minds and Machines.” [xxxiii] Sara Green, Barbara Prainsack, and Maya Sabatello, “The Roots of (in)Equity in Precision Medicine: Gaps in the Discourse,” Personalized Medicine 21, no. 1 (January 2024): 5–9, https://doi.org/10.2217/pme-2023-0097. [xxxiv] Green, Prainsack, and Sabatello, 7. [xxxv] Robyn Bluhm and Kirstin Borgerson, “An Epistemic Argument for Research-Practice Integration in Medicine,” The Journal of Medicine and Philosophy: A Forum for Bioethics and Philosophy of Medicine 43, no. 4 (July 9, 2018): 469–84, https://doi.org/10.1093/jmp/jhy009. [xxxvi] Vijay Mahant, “‘Right-to-Try’ Experimental Drugs: An Overview,” Journal of Translational Medicine 18 (June 23, 2020): 253, https://doi.org/10.1186/s12967-020-02427-4. [xxxvii] Michael S. Okun et al., “Deep Brain Stimulation in the Internal Capsule and Nucleus Accumbens Region: Responses Observed during Active and Sham Programming,” Journal of Neurology, Neurosurgery & Psychiatry 78, no. 3 (March 1, 2007): 310–14, https://doi.org/10.1136/jnnp.2006.095315. (shrink)

The Ebola epidemic that broke out inWest Africa West AfricaAfrica towards the end of 2013 had been brought under reasonable control by 2015. The epidemic had severely affected three countries. This case study is about a phase I/II clinical trial Phase I/II clinical trial of a candidate Ebola virus vaccine in 2015 in a sub-Saharan AfricanSub-Saharan Africa country which had not registered any cases of the Ebola virus disease. The study was designed as a randomized double-blinded (...) trialRandomized double blinded trial. It was sponsored and funded by one of the biggest Northern multinational pharmaceutical companiesPharmaceutical companies. The protocol received ethics clearance from the relevantNational Ethics Committee national ethics committeeEthics committee. The study was coordinated and managed at the local branch of a big Northern diagnostic laboratoryDiagnostic laboratory and a laboratory of a local regional hospital. The overall study was a multi-countryMulti-country, multi-siteMulti-site trial aimed at recruiting a total of 3,000 research participantsResearch participants across four or five sub-Saharan African countries. For this country, the recruitmentRecruitment sites were two big cities, each aiming to recruit 200 participants: adults at the first site and childrenChildren at the second. The target sampleSample size was almost achieved at the first site but, before the study commenced at the second site, some members of raised the alarm that the governmentGovernment was carelessly risking the health, safetySafety and lives of citizens in the cause of an unproven vaccine that could precipitate a public health disaster. The trial was immediately suspended. A commentary on this case, and on the importance of trustTrust, is provided by Katharine Browne and Doris Schroeder at the end of this chapter. It highlights differences between this case and a phase I Ebola vaccine trial in CanadaCanada in 2014. (shrink)

In many research studies, tumor biopsies are an unavoidable requirement for achieving key scientific aims. Yet some commentators view mandatory research biopsies as coercive and suggest they should be optional, or at least optional until further data are obtained regarding their scientific usefulness. Further complicating the ethical picture is the fact that some research biopsies offer a potential for clinical benefit to trial participants. We interviewed and surveyed a convenience sample of participants in phase I clinical (...) class='Hi'>trials at a single institution. Our primary aim was to describe phase I participants’ understanding of whether a research biopsy offered them the prospect of medical benefit. We also endeavored to describe participants’ views about biopsies—specifically, the benefits of biopsies, if any, and whether biopsies were acceptable, risky, or discouraged trial participation. Finally, we collected data on demographics and attitudes to see if any strong correlations with misunderstanding, acceptability, or riskiness existed. Overall, the respondents tended to view research biopsies as acceptable, though they did not succeed in identifying the lack of benefit of a research biopsy. These findings call for renewed efforts in consent conversations and documents to carefully describe the benefits, or lack thereof, of research biopsies. (shrink)

Tremendous development in recent medical science and the consequent discoveries resulting in successful prevention and also cure of different diseases are shared by clinical research involving the human volunteers. Preceding the trials in the human subjects, and to ensure safety, the proposed drug and other interventions are either tested in animals (vivo) or in laboratory (vitro) to evaluate initial safe starting dose for the human beings and to key out the benchmarks for the clinical monitoring for the (...) potential unfavorable effects. These pre human trials might not necessarily protect against the untoward effects in the human beings as happened in the case of thalidomide tragedy, which caused disability and killed thousands of babies born to the mothers, those who took this medicine. Use of healthy human volunteers in the preliminary experiments or phase I clinical trials either reduces or excludes risks of subsequent undesirable effects in the future trails (1). Phase-1 trials are conducted in order to test the safety, reactions and immunogenicity of vaccines in volunteers. Novel treatments for the cancer are first tested in phase 1 trials enrolling the patients with advanced disease, who have exhausted the standard treatment options. Phase-1 oncology trials are the pivot point in the translation of new cancer therapies from bench to bedside. Nevertheless, these trials remain ethically controversial. The controversy stems from the fact that, classically, phase-1 oncology clinical trials involve first-in-human testing of experimental treatment candidates in patients with a terminal diagnosis, who typically have exhausted standard treatment options. Commentators on the ethics of phase-1 clinical trials make diametrically opposed claims about the prospect of direct medical benefit from participation in these trials-benefits that can be attributed to receiving the experimental treatment intervention. One camp of benefit skeptics, inhabited mainly by bioethicists, characterizes this form of research as lacking any reasonable prospect of direct medical benefit. They see an ethical cloud hovering over phase-1 trials, because the vast majority of patients volunteer for phase-1 trials out of a motivation to receive medical benefit. In the view of these skeptics, such patients therefore harbor a ‘therapeutic misconception’ about research participation. This misconception calls into question the validity of informed consent and thereby undercuts the ethical basis of these trials (2). In this paper, I will discuss the ethical justification of the participation of human volunteers in phase-1 trials. (shrink)

One of the most pressing ethical challenges facing phase I cancer research centres is the process of informed consent. Historically, most scholarship has been devoted to redressing therapeutic misconception, that is, the conflation of the nature and goals of research with those of therapy. While therapeutic misconception continues to be a major ethical concern, recent scholarship has begun to recognise that the informed consent process is more complex than merely a transfer of information and therefore cannot be evaluated only (...) according to how well an individual understands such information. Other components of decision-making operate independently of understanding and yet still may compromise the quality of informed consent. Notable among these components is unrealistic optimism, an event-specific belief that one has a better chance of receiving benefit than others similarly situated. In this article, we consider responses to interviews with parents who had recently completed an informed consent conference for enrolling their child in a phase I cancer clinical trial to examine how this influence manifests and how investigators might address it during informed consent. (shrink)

Unrealistic optimism is a bias that leads people to believe, with respect to a specific event or hazard, that they are more likely to experience positive outcomes and/or less likely to experience negative outcomes than similar others. The phenomenon has been seen in a range of health-related contexts—including when prospective participants are presented with the risks and benefits of participating in a clinical trial. In order to test for the prevalence of unrealistic optimism among participants of early-phase oncology (...) trials, we conducted a survey with patients over 18 years of age who were enrolled in a phase I, phase I/II, or phase II clinical cancer trial in the New York City area between August 2008 and October 2009. Participants in our study were asked to compare their own chances of experiencing a range of risks and benefits related to the trial they were enrolled in with the chances of the other trial participants. We found a significant optimistic bias in their responses. Respondents tended to overestimate the benefits of the trial they were enrolled in and underestimate its risks. In addition, we found no significant relationship between respondents’ understanding of the trial’s purpose and how susceptible they were to unrealistic optimism. Our findings suggest that improving the consent process for oncology studies requires more than addressing deficits in understanding. (shrink)

Within the world of pharmacology, the male body has traditionally been taken as the biological norm. Coupled with this, concern about danger to the unborn foetus has meant that, until very recently, ‘women of childbearing potential’ were routinely excluded from most of the early phases of clinical drug testing. Consequently, most drugs tested during Phase I trials were initially carried out on healthy male volunteers. During subsequent phases when drugs were tested on patients, women remained largely under-represented. (...) As a result, some drugs prescribed for women have later been discovered to be lacking in efficacy, and women are more likely to suffer adverse drug reactions than men. The exclusion of women during the early phases of clinical drug trials has now been lifted and drugs are currently being more widely tested on women. This paper examines the differing political and ethical positions adopted by the pharmaceutical industry, drug regulators, pharmacologists, women's groups and patient activists in relation to the exclusion and inclusion of women in clinical drug trials. (shrink)

BackgroundCentral to ethically justified clinical trial design is the need for an informed consent process responsive to how potential subjects actually comprehend study participation, especially study goals, risks, and potential benefits. This will be particularly challenging when studying deep brain stimulation and whether it impedes symptom progression in Parkinson’s disease, since potential subjects will be Parkinson’s patients for whom deep brain stimulation will likely have therapeutic value in the future as their disease progresses.MethodAs part of an expanded informed consent (...) process for a pilot Phase I study of deep brain stimulation in early stage Parkinson’s disease, an ethics questionnaire composed of 13 open-ended questions was distributed to potential subjects. The questionnaire was designed to guide potential subjects in thinking about their potential participation.ResultsWhile the purpose of the study (safety and tolerability) was extensively presented during the informed consent process, in returned responses 70 percent focused on effectiveness and 91 percent included personal benefit as potential benefit from enrolling. However, 91 percent also indicated helping other Parkinson’s patients as motivation when considering whether or not to enroll.ConclusionsThis combination of responses highlights two issues to which investigators need to pay close attention in future trial designs: (1) how, and in what ways, informed consent processes reinforce potential subjects’ preconceived understandings of benefit, and (2) that potential subjects see themselves as part of a community of Parkinson’s sufferers with responsibilities extending beyond self-interest. More importantly, it invites speculation that a different paradigm for informed consent may be needed. (shrink)

Objectives: There are indications that institutional review board members do not find it easy to assess the risks and benefits in medical experiments, although this is their principal duty. This study examined how IRB members assessed the risk/benefit ratio of a specific phase II breast cancer clinical trial.Participants and methods: The trial was evaluated by means of a questionnaire administered to 43 members of IRBs at six academic hospitals and specialised cancer centres in the Netherlands. The questionnaire addressed: (...) identification and estimation of inconvenience, toxicity, psychosocial distress, and benefits of trial participation to patients; identification and estimation of benefits to future patients and medical science; assessment of the trial’s RBR; and assessment of its ethical acceptability.Results: Most IRB members expected trial participation to involve fairly or very serious inconvenience, fairly severe to sometimes life-threatening toxicity, and serious psychological and social consequences. Conversely, the perceived likelihood of benefits to patients was modest. Most regarded the study as important, and the balance between risks and benefits to be favourable, and believed that the protocol should be approved. The IRB members’ final judgement on the trial’s ethical acceptability was significantly correlated with their RBR assessment of the protocol.Conclusions: Because most patients who participate in clinical trials hope this will prolong their lives, it is suggested that patient information should better describe the anticipated benefits—for example, the likelihood of prolonging life. This would allow patients to make decisions regarding participation based on realistic expectations. (shrink)

The recent review by Monrad1 presents several issues about secondary vaccine trials. It lays out the case in which a vaccine has been tested through phases I–III and is being deployed. Subsequently, consideration is being given to conducting ‘trials for another vaccine for the pathogen’. Monrad states: ‘In summary, we may say that researchers have strong prima facie reasons not to conduct a secondary vaccine trial.’ Monrad discusses several factors meriting careful consideration about the need for developing (...) and testing more than one vaccine: relative efficacy, length of immunity, adverse reactions, ease of storage and administration, economic and logistical factors. What is not addressed are the ethical duties that exist when there are competing phase III vaccine candidates for COVID-19. We have serious concerns about potential ethical inadequacies about these ongoing trials and …. (shrink)

What kind of patients may be recruited to early clinical trials of xenotransplantation? This is discussed under the assumption that the risk of viral infection to the public is non-negligible. Furthermore, the conditions imposed by the Helsinki declaration are analysed. The conclusion is that only patients at risk of dying and with no alternative treatment available should be recruited to xenotransplantation trials in the early phase. For some of the less dangerous cell or islet cell xenotransplantation (...) other categories might be recruited. The risk of cell and islet cell xenotransplantation should, however, be weighted against the development of other technologies.In order to safeguard the public, the opt-out clause in the Helsinki declaration should not be fully applied. Legally binding rules on obligatory monitoring and restrictions should be imposed—before clinical trials start. Journal of Medical Ethics. (shrink)

Our society has long sanctioned, at least tacitly, a degree of conflict of interest in medical practice and clinical research as an unavoidable consequence of the different interests of the physician or clinical investigator, the patient or clinical research subject, third party payers or research sponsors, the government, and society as a whole, to name a few. In the past, resolution of these conflicts has been left to the conscience of the individual physician or clinical investigator (...) and to professional organizations. The public is no longer willing to allow health care providers to wholly govern their own conflicts of interest for several reasons. These include: new forms of health care financing and delivery that provide innovative and lucrative opportunities for physician or insurer enrichment at patient expense; the increased importance of commercial research support as peer-reviewed governmental research support has decreased; evidence that physicians and clinical investigators too frequently resolve conflicts of interest in their own favor; and a general societal mistrust of authority. This volume represents a multidisciplinary effort, drawing from philosophy, medicine, law, economics and public policy to identify and categorize conflicts of interest in medical practice and clinical research, and, where possible, to offer a mechanism for resolving them. Part I addresses conflicts of interest from a theoretical perspective, offering basic concepts and analytical frameworks. The second part discusses two topics prominent in current health care policy debates--self-referral and financial incentives to limit care. Part III examines conflicts of interest generated by pharmaceutical industry involvement in clinical practice and research. The final section deals with conflicts of interest in clinical research in several contexts, including institutional reviews boards, clinical trials, Cooperative Research and Development Agreements between government and private researchers, brokerage of research subjects by Contract Research Organizations, and cost-effectiveness studies. (shrink)

Objective To evaluate the questions asked during the informed consent process by adult and adolescent participants as well as their parents in five interventional regulatory studies conducted at our center from 2018 to 2019. Methods The study protocol was approved by Institutional Ethics Committee [EC/OA-116/2019]. Consent narratives in the source documents for the studies were evaluated. Questions asked were classified as per Indian Council of Medical Research’s (ICMR) guidelines (2017). We evaluated total number of questions, nature of questions and whether (...) there was an association between education, gender, phase of trials, physician taking consent and number questions being asked. Results A total of five studies that had N = 297 consent narratives were evaluated. Narratives of n = 284 adult participants/Guardians and of n = 13 children were analysed. A total of 374 questions were asked of which children asked only 10 questions. A total of 131/284 (40%) of the participants did not ask any question. Among the participants who asked questions, the majority132/171 (77%) participants asked about risks related to investigational products followed by questions related to study procedures 83/171 (49%). Participants/guardians with higher education (relative to those who were educated upto the secondary school and primary school) and those who consented for Phase III studies (relative to Phase I studies) asked significantly more questions (p < 0.0001). Conclusion A majority of the queries were related to the risks associated with the investigational products. Educational status and the Phase of the trial were found to be significantly associated with the number of questions being asked. (shrink)

BackgroundIn clinical research, obtaining informed consent from participants is an ethical and legal requirement. Conveying the information concerning the study can be done using multiple methods yet this step commonly relies exclusively on the informed consent form alone. While this is legal, it does not ensure the participant’s true comprehension. New effective methods of conveying consent information should be tested. In this study we compared the effect of different methods on the knowledge of caregivers of participants of a (...) class='Hi'>clinical trial on Pemba Island, Tanzania.MethodsA total of 254 caregivers were assigned to receive (i) a pamphlet (n = 63), (ii) an oral information session (n = 62) or (iii) a pamphlet and an oral information session (n = 64) about the clinical trial procedures, their rights, benefits and potential risks. Their post-intervention knowledge was assessed using a questionnaire. One group of caregivers had not received any information when they were interviewed (n = 65).ResultsIn contrast to the pamphlet, attending an information session significantly increased caregivers’ knowledge for some of the questions. Most of these questions were either related to the parasite (hookworm) or to the trial design (study procedures).ConclusionsIn conclusion, within our trial on Pemba Island, a pamphlet was found to not be a good form of conveying clinical trial information while an oral information session improved knowledge. Not all caregivers attending an information session responded correctly to all questions; therefore, better forms of communicating information need to be found to achieve a truly informed consent. (shrink)

In the beginning of the COVID pandemic, researchers and bioethicists called for human challenge trials to hasten the development of a vaccine for COVID. However, the fact that we lacked a specific, highly effective treatment for COVID led many to argue that a COVID challenge trial would be unethical and we ought to pursue traditional phase III testing instead. These ethical objections to challenge trials may have slowed the progress of a COVID vaccine, so it is important (...) to evaluate their merit. One common way of doing so is to make an analogy to other social practices that are relevantly similar and which we currently sanction. We submit that non-directed live organ donation (NDLOD) is a promising analogy. After arguing that the risks to volunteers for each activity appear similar, we explore potential disanalogies that would undermine the comparison. We note that there are differences in both the kind and certainty of benefit secured by NDLOD compared to challenge trials. We conclude these differences are insufficient to make NDLOD permissible and challenge trials impermissible. Ultimately, if we think the risks associated with NDLOD are ethically permissible, then we should think the same of the risks associated with COVID challenge trials. (shrink)

The recent TeGenero phase I trial of a novel monoclonal antibody in healthy volunteers produced a drastic inflammatory reaction in participants receiving the experimental agent. Commentators on the ethics of the research have focused considerable attention on the role of financial considerations: the for-profit status of the biotechnology company and Contract Research Organization responsible respectively for sponsoring and conducting the trial and the amount of monetary compensation to participants. We argue that these financial considerations are largely irrelevant and distort (...) ethical appraisal of this tragic research. Except for administering the antibody to all 6 participants nearly simultaneously, the trial appears to fulfill all of the critical ethical requirements for clinical research—social value, scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent, and respect for enrolled participants. (shrink)