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 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)

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)

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)

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)

Relatively 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)

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)

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)

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)

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)

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)

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)

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)

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)

This paper explores the connection of offshoring and outsourcing to nonconsensual global pharmaceutical trials in low-income countries. After discussing reasons why the topic of nonconsensual offshored clinical trials may be overlooked in bioethics literature, I suggest that when pharmaceutical corporations offshore clinical trials today, nonconsensual experiments are often foreseeable and not simply the result of aberrant ethical conduct by a few individuals. Offshoring of clinical trials is structured so that experiments can be presented as health care (...) in a unique form of outsourcing from the host country to pharmaceutical corporations. Bioethicists’ assessments of the risks and potential benefits of offshore corporate pharmaceutical trials should therefore systematically include not only the hoped for benefits and the risks of the experimental drug but also the risk that subjects will not have consented, as well as the broader international consequences of nonconsensual experimentation. (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)

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)

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)

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 (...) class='Hi'>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)

Background: Informed consent in clinical research is mandated throughout the world. Both patient subjects and investigators are required to understand and accept the distinction between research and treatment.Aim: To document the extent and to identify factors associated with therapeutic misconception in a population of patient subjects or parent proxies recruited from a variety of multicentre trials .Patients and methods: The study comprised two phases: the development of a questionnaire to assess the quality of informed consent and a survey of (...) patient subjects based on this questionnaire.Results: A total of 303 patient subjects or parent proxies were contacted and 279 questionnaires were analysed. The median age was 49.5 years, sex ratio was 1 and 61% of respondents were professionally active. Overall memorisation of the oral or written communication of informed consent was good , and satisfaction with the process was around 70%. Therapeutic misconception was present in 70% of respondents, who expected to receive better care and ignored the consequence of randomisation and treatment comparisons. This was positively associated with the acuteness and severity of the disease.Conclusion: The authors suggest that the risk of therapeutic misconception be specifically addressed in consent forms as an educational tool for both patients and investigators. (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)

Clinical trials and other forms of evaluation of medical treatment are held to give an objective assessment of the 'clinical effectiveness' of the medical treatments under evaluation. This kind of evaluation is central to the evidence-based medicine movement, as it provides a basis for the rational selection of treatment. The ethical status of randomised clinical trials is widely agreed to depend crucially upon the state of equipoise regarding which of two treatments is more effective in a defined (...) population. However, the meaning and nature of 'clinical effectiveness' are unclear. in this paper, I discuss the proposals to define clinical effectiveness as a relational property and as an intrinsic property, and the way effectiveness may supervene upon more fundamental physical properties of treatments. I discuss whether effectiveness is a single property or a family of properties; the types of outcome which can be explained by effectiveness properties; and the relationship between 'objective' and 'preference' outcomes. This paper suggests that while it may be possible to put clinical effectiveness on a proper metaphysical footing, in practice the language of clinical effectiveness is more properly a topic of the human sciences than of the natural sciences. (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)

Physician‐investigators face the daunting task of enrolling desperate patients into Phase I cancer trials that are not meant to be therapeutic. Patients doggedly regard the trials as therapeutic, and researchers tend to collaborate in their confusion by glossing the trials’ true purposes and noting the occasional benefit that subjects accidentally receive. The disparity between hope and fact must be redressed by degrees, from many angles at once.

Clinical trials and other forms of evaluation of medical treatment are held to give an objective assessment of the ‘clinical effectiveness’ of the medical treatments under evaluation. This kind of evaluation is central to the evidence-based medicine movement, as it provides a basis for the rational selection of treatment. The ethical status of randomised clinical trials is widely agreed to depend crucially upon the state of equipoise regarding which of two (or more) treatments is more (or most) (...) effective in a defined population. However, the meaning and nature of ‘clinical effectiveness’ are unclear. in this paper, I discuss the proposals to define clinical effectiveness as a relational property and as an intrinsic property, and the way effectiveness may supervene upon more fundamental physical properties of treatments. I discuss whether effectiveness is a single property or a family of properties; the types of outcome which can be explained by effectiveness properties; and the relationship between ‘objective’ and ‘preference’ outcomes. This paper suggests that while it may be possible to put clinical effectiveness on a proper metaphysical footing, in practice the language of clinical effectiveness is more properly a topic of the human sciences than of the natural sciences. (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)

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 many cases, the “therapeutic misconception” may be an unavoidable part of the imperfect process of recruitment and consent in medical researchPaul Appelbaum, Loren Roth, and Charles Lidz coined the term “therapeutic misconception” in 1982.1 They described it as the misconception that participating in research is the same as receiving individualised treatment from a physician. It referred to the research subject’s failure to appreciate that the aim of research is to obtain scientific knowledge, and that any benefit to the subject (...) is a by-product of that knowledge. More recent studies by Appelbaum and Lidz have shown that this phenomenon is just as pervasive now as it was twenty four years ago.2 The problem pertains not to any duty of care for researchers but to participants’ unfounded belief in the therapeutic potential of research.3 It is especially acute in phase I oncology trials, which aim to test the toxicity and highest tolerable dose of anticancer drugs.To remedy this situation, many have argued that both clinicians and researchers need to do more in explaining to subjects the differences between experimental research and standard care. Clinicians and researchers recruiting potential subjects for research must present information about the expected risks and benefits of participation in research in a more realistic and straightforward way.4 In one recent examination of consent forms for phase I oncology trials, Sam Horng et al found that, in the section on “benefit”, only one of 272 forms stated that the subjects were expected to benefit. They also found that 11 consent forms stated clearly that subjects would not benefit, 25 forms communicated uncertainty about benefit, and 5 forms said nothing about the chance of benefit. Interestingly, 139 forms alluded to the …. (shrink)

It is not uncommon for multiple clinical trials at the same institution to recruit concurrently from the same patient population. When the relevant pool of patients is limited, as it often is, trials essentially compete for participants. There is evidence that such a competition is a predictor of low study accrual, with increased competition tied to increased recruitment shortfalls. But there is no consensus on what steps, if any, institutions should take to approach this issue. In this article, we (...) argue that an institutional policy that prioritises some trials for recruitment ahead of others is ethically permissible and indeed prima facie preferable to alternative means of addressing recruitment competition. We motivate this view by appeal to the ethical importance of minimising the number of studies that begin but do not complete, thereby exposing their participants to unnecessary risks and burdens in the process. We then argue that a policy of prioritisation can be fair to relevant stakeholders, including participants, investigators and funders. Finally, by way of encouraging and helping to frame future debate, we propose some questions that would need to be addressed when identifying substantive ethical criteria for prioritising between studies. (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)

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)

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)

Many commentators have expressed concern that large investments in biomedical research over the past two decades have not been translated effectively into clinical applications. In its Critical Path Report, the Food and Drug Administration characterized the problem as a “technological disconnect between discovery and the product development process,” and documented that the number of investigational new drugs submitted to the agency had declined “significantly” since 2000. Along a similar vein, another study found that only five of 101 basic science (...) studies showing significant therapeutic promise were successfully translated into clinical applications.This perceived translational lag is stimulating a shift toward human testing of study interventions earlier in the drug development process. One indication of this trend is a recent guidance encouraging sponsors to pursue human “exploratory” studies before embarking on phase I trials. (shrink)

ABSTRACT Many recent articles argue that participants who seroconvert during HIV prevention trials deserve treatment when they develop AIDS, and there is a general consensus that the participants in HIV/aids treatment trials should have continuing post‐trial access. As a result, the primary concern of many ethicists and activists has shifted from justifying an obligation to treat trial participants, to working out mechanisms through which treatment could be provided. In this paper I argue that this shift frequently conceals an important assumption: (...) that if there is an obligation to supply treatment, then any party who could provide it may be prevailed upon to discharge the obligation. This assumption is false. The reasons why trial participants should get ART affect who has the duty to provide it. We should not burden governments with the obligations of sponsors, nor researchers with the obligations of the international community. And we should not deprive a group of treatment because their need is less salient than that of research participants. Insisting otherwise may lead to people being wrongfully deprived of access to antiretrovirals. (shrink)

Clinical investigators must engage in just subject recruitment and selection and avoid unduly influencing research participation. There may be tension between the practice of keeping payments to participants low to avoid undue influence and the requirements of justice when recruiting normal healthy volunteers for phase 1 drug studies. By intentionally keeping payments low to avoid unduly influenced participation, investigators, on the recommendation or insistence of institutional review boards, may be targeting or systematically recruiting healthy adult members of lower (...) socio-economic groups for participation in phase 1 studies. Investigators are at risk of routinely failing to fulfill the obligation of justice, which prohibits the systematic targeting and recruiting of subjects for reasons unrelated to the nature of the study. Insofar as we take seriously the obligation to engage in just subject recruitment and selection, I argue that we must acknowledge the implications low payments might have for subject recruitment and selection and examine the effect of low payments. If low payments de facto target the less well-off for phase 1 studies, we must defend the priority ranking of the obligation to avoid undue influence over the obligation of justice or adopt an alternative recruitment approach. This paper identifies a number of alternatives to the current system of low-value payments to research participants. (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)

As the_number of clinical trials continues to grow, there is an increasing need for education and training in the field. The clinical research climate is less forgiving of errors and oversights and therefore requires more knowledge of regulations and requirements. This brand new edition details new laws and regulations in protecting children participating in clinical trials and how a new focus on privacy of individual health information in the United States has changed how medical records are handled. (...) Includes a manual for investigators, research nurses and study coordinators with minimal experience or who are new to clinical research An easy-to-read and open text design using ‘sidebars’ of examples and information boxes related to the main text Includes a list of Frequently Asked Questions and Glossary Duke Clinical Research Institute is the world’s largest academic clinical research organisation and is well known and respected within the clinical research community. (shrink)

Unrealistic therapeutic beliefs are very common—the majority of patient-subjects enrol in phase 1 trials seeking and expecting significant medical benefit, even though the likelihood of such benefit has historically proven very low. The high prevalence of therapeutic misestimation and unrealistic optimism in particular has stimulated debate about whether unrealistic therapeutic beliefs in early-phase clinical trials preclude adequate informed consent. We seek here to help resolve this controversy by showing that a crucial determination of when such therapeutic beliefs (...) are ethically problematic turns on whether they are causally linked and instrumental to the motivation to participate in the trial. Thus, in practice, it is ethically incumbent on researchers to determine which understanding and beliefs lead to the participant’s primary motivation for enrolling, not to simply assess understanding, beliefs and motivations independently. We further contend that assessing patient-subjects’ appreciation as a component of informed consent—it is already an established component of decision-making capacity assessments—can help elucidate the link between understanding-beliefs and motivation; appreciation refers to an individual’s understanding of the personal significance of both the medical facts and the experience of trial participation. Therefore, we recommend that: in addition to the usual question, ‘Why do you want to participate in this trial?’, all potential participants should be asked the question: ‘What are you giving up by participating in this trial?’ and researchers should consider the settings in which it may be possible and practical to obtain ‘two-point consent’. (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)

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)

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)

Ethical reasons are presented for requiring 1) that a proposal for a clinical trial should be accompanied by a thorough review of all previous trials that have examined the same and closely related questions, and 2) that a trial should be approved by a research ethics committee only if the investigator undertakes to register it in an appropriate register of clinical trials as soon as one exists.

The volume of clinical research is increasing exponentially—far beyond our ability to process and absorb the results. Given this situation, it may be beneficial to consider reducing the flow at its source. In what follows, I will motivate and critically evaluate the following proposal: researchers should conduct fewer clinical trials. More specifically, I c onsider whether researchers should be permitted to conduct only clinical research of very high quality and, in turn, whether research ethics committees should prohibit (...) all other, lower-quality research, even when it might appear to meet some minimal ethical standard. Following a close analysis of the social-value requirement of ethical clinical research, I argue that this proposal is defensible. The problem identified in this paper has two parts, quantity and quality, and some clarification is needed about the latter because “quality” is a highly contested term in the medical literature. When some scholars advocate for high-quality trials, they mean large-scale, simple, explanatory randomized controlled trials. Others, including myself, have defended a different characterization of high-quality research that tends more toward pragmatic trial design and the use of methods other than RCTs. Pragmatic trials aim to provide evidence that directly supports clinical decision-making in “usual” care settings. Unlike explanatory trials, which aim to abstract away from particular settings and patients, in the hopes of creating ideal conditions for the success of an intervention, pragmatic trials deliberately pursue knowledge of high applicability, through the use of representative subjects, clinically important questions, flexible treatment protocols, patient-oriented outcome measures, and so on. I see applicability as a marker of high-quality research. The context in which research is meant to be applied should be the context in which new interventions are evaluated. (shrink)

ABSTRACT This paper is intended to stimulate debate amongst stakeholders in the international research community on the topic of returning individual genetic research results to study participants. Pharmacogenetics and disease genetics studies are becoming increasingly prevalent, leading to a growing body of information on genetic associations for drug responsiveness and disease susceptibility with the potential to improve health care. Much of these data are presently characterized as exploratory (non‐validated or hypothesis‐generating). There is, however, a trend for research participants to (...) be permitted access to their personal data if they so choose. Researchers, sponsors, patient advocacy groups, ethics committees and regulatory authorities are consequently confronting the issue of whether, and how, study participants might receive their individual results. Noted international ethico‐legal guidelines and public policy positions in Europe and the United States are reviewed for background. The authors offer ‘Points‐to‐Consider’ regarding returning research results in the context of drug development trials based on their knowledge and experience. These considerations include: the clinical relevance of data, laboratory qualifications, informed consent procedures, confidentiality of medical information and the competency of persons providing results to participants. The discussion is framed as a benefit‐to‐risk assessment to balance the potential positive versus negative consequences to participants, while maintaining the integrity and feasibility of conducting genetic research studies. (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)

LANGUAGE NOTE | Document text in Chinese; abstract also in English. 以新冠疫苗I期試驗的健康受試者為研究對象，基於深度訪談和虛擬民族志研究方法，採用NVivo11軟體進行編碼分析，發現健康受試者的參與動機多為積極動機，在抉擇過程中曾面臨內外矛盾而深陷糾結與掙扎。文章歸 納出新冠疫苗受試者抉擇過程不同階段的動機與行為特點，即：萌生想法——躍躍欲試的受試者；進退狐疑——踽踽獨行的受試者；備受煎熬——忐忑不安的受試者；解惑釋疑——篤定前行的受試者。旨在真實地還原健康受試者 的抉擇過程，消除社會偏見，為健康受試者和I期試驗去除污名，提升公眾的認知，增强健康受試者的認同感和歸屬感。 Taking the Phase I trial of the 2019-nCoV vaccine as a case study, this paper examines the motivational and psychological development and behavioral patterns of healthy volunteers who participate in different phases of clinical trials for vaccines. The findings of a series of in-depth interviews and virtual ethnographical studies show that participation in a clinical trial such as that for the 2019-nCoV vaccine is a difficult (...) choice for volunteers, as it entails exposure not only to medical risks but also to social prejudice. The paper provides a detailed account of how the volunteers for the Phase I 2019-nCoV vaccine trials made their choice to participate and how they overcame various doubts and fears to serve as responsible research partners. (shrink)

The article presents the advantages and limitations of adaptive clinical trials for assessing the effectiveness of medical interventions and specifies the conditions that contributed to their development and implementation in clinical practice. I advance two arguments by discussing different cases of adaptive trials. The normative argument is that responsible adaptation should be taken seriously as a new way of doing clinical research insofar as a valid justification, sufficient understanding, and adequate operational conditions are provided. The second argument (...) is historical. The development of adaptive trials can be related to lessons learned from research in cases of urgency and to the decades-long efforts to end the productivity crisis of pharmaceutical research, which led to the emergence of translational, personalized, and, recently, precision medicine movements. (shrink)