Exclusion of Women from Phase I Trials: Perspectives from Investigators and Research Oversight Officials.

Over the past 30 years, progress has been made in increasing women's representation in clinical research. However, women continue to be underrepresented in phase I clinical trials-those trials that test the safety and tolerability of investigational drugs, often on healthy individuals. As sex-based differences in adverse drug reactions are often linked to drug dose, pivotal safety information in phase I trials is often insufficiently-and inequitably-captured for females. Yet there has been little attention to how clinical investigators and those charged with overseeing the ethical conduct of these trials perceive the barriers to women's inclusion in phase I trials. To address this gap, we report on 22 interviews with U.S. phase I investigators and institutional review board (IRB) members. Our findings indicate that although these investigators and IRB members acknowledged the importance of including women in clinical trials, they justified women's exclusion from phase I trials by citing the need to manage their reproductive potential. In particular, we identified four key themes that informants used to warrant women's exclusion from phase I trials: the structure of the drug-development system itself, fears about risks to potential fetuses, distrust of women to prevent pregnancy, and concerns about risks and burdens to institutions from resulting pregnancies. We argue that these rationales reflect structural and cultural barriers to women's inclusion in clinical research that ultimately fail to respect female research participants as persons, highlighting the need for broad-based solutions.

"Death and Taxes": Why Financial Compensation for Research Participants is an Economic and Legal Risk.

In the US, research payments are technically taxable income. This article argues that tax liability is a form of possible economic and legal risk of paid research participation. Findings are presented from empirical research on Phase I healthy volunteer trials. The article concludes by discussing the implications of these findings for the informed consent process, as well as for broader ethical issues in whether and how payments for research participation should be regulated.

Global Efforts to Protect Healthy Volunteers.

Clinical trials on healthy volunteers generate unique ethical challenges both because participants accept potential physical risks without the possibility of direct medical benefit and because participants' financial motivations to enroll in trials could lead to their exploitation. Despite the large volume of published empirical studies and ethical analyses of healthy volunteer research, there has been little concerted effort to change how healthy-volunteer research is overseen or regulated. A new collaborative effort to do so is the VolREthics (Volunteers in Research and Ethics) Initiative. Launched in 2022, this initiative brings together an international community to engage questions about how healthy volunteers could best be protected from the risks of harm and exploitation while the validity of clinical trials is optimized.

Mission Creep or Mission Lapse? Scientific Review in Research Oversight.

BACKGROUND: The ethical use both of human and non-human animals in research is predicated on the assumption that it is of a high quality and its projected benefits are more significant than the risks and harms imposed on subjects. Yet questions remain about whether and how IRBs and IACUCs should consider the scientific value of proposed research studies. METHODS: We draw upon 45 interviews with IRB and IACUC members and researchers with oversight experience about their perceptions of their own roles in reviewing the quality and value of scientific protocols. Interview transcripts were memoed to highlight specific findings, which were then used to identify key themes through an iterative process. RESULTS: IRB and IACUC members expressed broad trust in the need for and value of research, and they often assumed that protocols had social value or that prior review, especially when associated with funding, affirmed both the rigor and merit of those protocols. Some oversight members also took an explicit stance against scientific review by stating that such review is not within the regulatory mandates governing their parts in the oversight system. Yet other interviewees expressed uneasiness about the current paradigm for evaluating the quality and overall value of science, suggesting that IRB and IACUC members perceive gaps in the oversight systems. CONCLUSIONS: These findings reveal many similarities in how IRB and IACUC members understand the roles and limitations of their respective oversight committees. We conclude with a discussion of how the lack of a clear mandate regarding scientific review within US federal regulations may undermine ethical engagement of whether human and animal research is scientifically justified, resulting in a "mission lapse" wherein no organizational body is clearly responsible for ensuring that the research being conducted has the potential to advance science and benefit society.

Ethical Criteria for Improved Human Subject Protections in Phase I Healthy Volunteer Trials.

Phase I healthy volunteer trials test the safety and tolerability of investigational pharmaceuticals. In them, participants are exposed to study-drug risks without the possibility of direct medical benefit and typically must spend days or weeks in a residential research facility. Monetary payments are used to incentivize enrollment and compensate participants for their time. Together, these features of phase I healthy volunteer trials create a research context that differs markedly from most other clinical research, including by enrolling disproportionate numbers of economically disadvantaged people of color as participants. Due to these unique trial features and participation patterns, traditional biomedical research oversight offers inadequate ethical and policy guidance for phase I healthy volunteer research. This article details five ethical criteria crafted to be responsive to the particularities of this type of research: translational science value, fair opportunity and burden sharing, fair compensation for service, experiential welfare, and enhanced voice and recourse.

Gendered Logics of Biomedical Research: Women in U.S. Phase I Clinical Trials.

Despite the importance of including diverse populations in biomedical research, women remain underrepresented as healthy volunteers in the testing of investigational drugs in Phase I trials. Contributing significantly to this are restrictions that pharmaceutical companies place on the participation of women of so-called childbearing potential. These restrictions have far-reaching effects on biomedical science and the public health of women. Using 191 interviews collected over 3 years, this article explores the experiences of 47 women who navigate restrictions on their participation in U.S. Phase I trials. Women in this context face a number of contradictory criteria when trying to enroll, which can curtail their participation, justify additional surveillance, and deny pregnant women reproductive agency. The pharmaceutical industry's putative protections for hypothetical fetuses exacerbate inequalities and attenuate a thorough investigation of the safety of their drugs for public consumption. We use the framework of "anticipatory motherhood" within a gendered organizations approach to make sense of women's experiences in this context.

Translational science: a survey of US biomedical researchers' perspectives and practices.

This national survey aimed to identify how biomedical researchers using vertebrate animals viewed issues of significance for translational science, including oversight and public engagement, and to analyze how researcher characteristics and animal model choice correlate with those views. Responses from 1,187 researchers showed awareness of, and concerns about, problems of translation, reproducibility and rigor. Surveyed scientists were nevertheless optimistic about the value of animal studies, were favorable about research oversight and reported openness with non-scientists in discussing their animal work. Differences in survey responses among researchers also point to diverse perspectives within the animal research community on these matters. Most significant was variability associated with the primary type of animal that surveyed scientists used in their work. Other significant divergence in opinion appeared on the basis of professional role factors, including the type of degree held, workplace setting, type of funding, experience on an institutional animal care and use committee and personal demographic characteristics of age and gender.

Healthy volunteers in US phase I clinical trials: Sociodemographic characteristics and participation over time.

BACKGROUND: Increasing the diversity of research participants is an important focus of clinical trials. However, little is known regarding who enrolls as healthy volunteers in Phase I clinical trials, which test the safety and tolerability of investigational new drugs. Despite the risk, healthy volunteers can derive no medical benefit from their participation, and they are financially compensated for enrolling. OBJECTIVE: This study's purpose is to describe sociodemographic characteristics and clinical trial participation histories of healthy people who enroll in US Phase I trials. METHODS: The HealthyVOICES Project (HVP) is a longitudinal study of healthy individuals who have enrolled in Phase I trials. We describe self-reported sociodemographic information and Phase I trial history from HVP recruitment (May-December 2013) through the project's end three years later (December 2016). Trial experiences are presented as medians and quartiles. RESULTS: The HVP included 178 participants. Nearly three-fourths of participants were male, and two-thirds were classified as racial and ethnic minorities. We found that some groups of participants were more likely to have completed a greater number of clinical trials over a longer timeframe than others. Those groups included participants who were male, Black, Hispanic, 30-39-years-old, unemployed, had received vocational training in a trade, or had annual household incomes of less than $25,000. Additionally, the greater the number of clinical trials participants had completed, the more likely they were to continue screening for new trials over the course of three years. Participants who pursued clinical trials as a full-time job participated in the greatest number of trials and were the most likely to continuing screening over time. IMPLICATIONS: Participation as a healthy volunteer in US Phase I trials is driven by social inequalities. Disadvantaged groups tend to participate in a greater number of clinical trials and participate longer than more privileged groups.

Speculating on Precarious Income: Finance Cultures and the Risky Strategies of Healthy Volunteers in Clinical Drug Trials.

Speculation has become a normalized occupational strategy and quotidian economic rationality that extends throughout society. Although there are many contemporary articulations of speculation, this article focuses on contract labor as a domain of financialization. Seen through this lens, contract labor can be understood as a speculative investment strategy wherein individuals leverage whatever assets they have at their disposal-savings, time, bodily health-to capture economic advantages. In particular, we explore the speculative practices of healthy individuals who enroll in pharmaceutical drug trials as their primary or critical source of income. Mobilizing speculative logics to maximize the money they can earn from their clinical trial participation, these contract workers employ what we term a future-income-over-immediate-pay calculus. This speculative calculus valorizes fictional projections of significant long-term future income over present financial opportunities. For the economically precarious individuals in our study, we argue that rather than effectively increasing their income, speculation on contract work serves a compensatory function, providing an important-but ultimately inadequate-sense of control over market conditions that thrive upon workers' economic insecurity.

Phase I trial compensation: How much do healthy volunteers actually earn from clinical trial enrollment?

BACKGROUND/AIMS: Financial compensation for research participation is a major focus of ethical concern regarding human subject recruitment. Phase I trials are sometimes considered to be a lucrative source of income for healthy volunteers, encouraging some people to become "professional guinea pigs." Yet, little is known about how much these clinical trials actually pay and how much healthy volunteers earn from them. METHODS: As part of a mixed-methods, longitudinal study of healthy volunteers, we required participants to complete clinical trial diaries, or surveys that captured detailed information about screening and enrollment in Phase I trials. Over a 3-year period, participants provided information online or via telephone about each clinical trial for which they screened (e.g. the clinic name, the study's therapeutic area, the length of the trial, the number of nights spent in the clinic, and the study compensation), and whether they qualified for trial inclusion. Clinical trial diaries generated data about whether participants continued to screen for and enroll in clinical trials and how much money they earned from their participation. RESULTS: 131 participants routinely completed clinical trial diaries or confirmed that they had not screened for any new clinical trials. Together, these participants screened for 1001 clinical trials at 73 research facilities during a 3-year period. Overall, the median clinical trial compensation was US$3070 (range = US$150-US$13,000). Participants seeking new healthy volunteer trials tended to screen for three studies per year, participate in one or two studies, and earn roughly US$4000 annually. Participants who were unemployed earned the most income from clinical trials compared to those with full-time or part-time jobs, and those individuals whom we label "occupational" participants because of their persistent pursuit of clinical trials earned more than people who screened occasionally. Notably, the median annual trial compensation was well below US$10,000 for all employment groups, and most occupational healthy volunteers also earned less than US$10,000 each year. The 10% of participants who earned the most had a median annual income of US$18,885 from clinical trials, and there was significant volatility in these individuals' earnings from year to year. CONCLUSION: Despite the perception that Phase I enrollment can generate significant earnings, it was exceedingly rare for anyone in this study to make more than US$20,000 in a single year, and unusual to earn even between US$10,000 and US$20,000. From an ethics perspective, individual trials might appear to unduly induce enrollment by offering significant sums of money, but given our findings, the larger problem for low-income participants may be the unrealistic perception that clinical trials alone could be a way of earning a living.

Biomedical Researchers' Perceptions of the NIH's Sex as a Biological Variable Policy for Animal Research: Results from a U.S. National Survey.

Background: In 2015, the National Institutes of Health (NIH) established a policy on sex as a biological variable (SABV) in an effort to address the overrepresentation of men and male animals in biomedical research and the lack of attention to sex-based responses to medical treatments. However, questions remain regarding how U.S. biomedical researchers perceive the impact of the SABV policy on their own research and on translational science more broadly. Materials and Methods: A national survey of U.S. scientists who use vertebrate animals in their research was conducted. Respondents were asked how they select and use animal species as model organisms as well as how they perceive the impact of the SABV policy on their research practices. Results: Almost all respondents reported that they had previously heard of the NIH SABV policy, and over one-third had altered their study designs to comply with the policy. There were robust differences in perceptions of the SABV policy based on researchers' primary species of model organism. However, there was no significant difference in the likelihood of researchers analyzing their results by sex based on whether they had received recent NIH funding. Conclusions: While many researchers report adhering to the SABV policy requirements, more work needs to be done to ensure that the policy is being evenly applied to researchers using all types of animal models and that researchers adhere to the policy after receiving NIH funding, particularly in terms of reporting on and analyzing SABV in their study findings for publication.

Inter-rater reliability of care home staff's proxy judgements with residents' assessments of their own health-related quality of life: an analysis of the PATCH trial EQ-5D data.

OBJECTIVES: to compare care staff proxies with care home residents' self-assessment of their health-related quality of life (HRQoL). METHODS: we assessed the degree of inter-rater reliability between residents and care staff proxies for the EQ-5D-5L index, domains and EQ Visual Analogue Scale at baseline, 3 months and 6 months, collected as part of the PATCH trial. We calculated kappa scores. Interpreted as <0 no agreement, 0-0.2 slight, 0.21-0.60 fair to moderate and >0.6 substantial to almost perfect agreement. Qualitative interviews with care staff and researchers explored the challenges of completing these questions. RESULTS: over 50% of the HRQoL data from residents was missing at baseline compared with a 100% completion rate by care staff proxies. A fair-to-moderate level of agreement was found for the EQ-5D-5L index. A higher level of agreement was achieved for the EQ-5D-5L domains of mobility and pain. Resident 'non-completers' were more likely to: be older, have stayed a longer duration in the care home, have lower Barthel Index and Physical Activity and Mobility in Residential Care (PAM-RC) scores, a greater number of co-morbidities and have joined the trial through consultee agreement. Interviews with staff and researchers indicated that it was easier to rate residents' mobility levels than other domains, but in general it was difficult to obtain data from residents or to make an accurate proxy judgement for those with dementia. CONCLUSIONS: whilst assessing HRQoL by care staff proxy completion provides a more complete dataset, uncertainty remains as to how representative these values are for different groups of residents within care homes.

Evaluating the National Institutes of Health's Sex as a Biological Variable Policy: Conflicting Accounts from the Front Lines of Animal Research.

Background: Since the National Institutes of Health (NIH) Revitalization Act of 1993, focus on the equitable inclusion of women in clinical research has been ongoing. NIH's 2015 sex as a biological variable (SABV) policy aims to transform research design, analysis, and reporting in the preclinical sphere by including male and female organisms in vertebrate animal research as well as human studies. However, questions remain regarding how researchers and members of research oversight committees perceive the value and need of the SABV policy. Materials and Methods: Based on 62 interviews with animal researchers and oversight personnel, we analyze what the animal research community knows about the policy and sees as the benefits and challenges of implementation. Results: We found that the 62 interviewees disagreed about the need for the policy, with some being supportive and others questioning whether the policy is based on science or is politically motivated. There were also tensions in how interviewees conceptualized the challenges to and resources needed for implementing the SABV policy. For instance, while some thought implementation would require a significant increase in numbers of animals used for each study, others explicitly rejected this claim. Conclusions: We conclude by discussing the practical and social implications of our findings about the views of members of the animal research community regarding the SABV policy.

Sacrificial Labour: Social Inequality, Identity Work, and the Damaging Pursuit of Elusive Futures.

This article explores the relationship between personal sacrifice and identity work within conditions of profound structural insecurity. We develop the concept of sacrificial labour to describe how individual self-sacrifice aligns workers' identities to the needs of organizations while gradually foreclosing the actualization of individuals' desired future selves. Drawing upon qualitative data from a longitudinal study of healthy individuals who enrol in paid clinical trials for the pharmaceutical industry, we make two contributions to the identity-work literature. First, we argue that the ongoing project of building stable and secure identities may become damaging when structural and cultural conditions defy even provisional, fragile attainment of this goal. Second, we reflect on how racialization and social marginalization erode identities and constrain possibilities for identity recuperation. Whereas the identity-work literature often focuses on the agential accomplishments of individuals, we provide a troubling account of how persistent social and economic inequalities confound identity realization efforts.

A posture and mobility training package for care home staff: results of a cluster randomised controlled feasibility trial (the PATCH trial).

BACKGROUND: provision of care for care home residents with complex needs is challenging. Physiotherapy and activity interventions can improve well-being but are often time-limited and resource intensive. A sustainable approach is to enhance the confidence and skills of staff who provide care. This trial assessed the feasibility of undertaking a definitive evaluation of a posture and mobility training programme for care staff. DESIGN AND SETTING: a cluster randomised controlled feasibility trial with embedded process evaluation. Ten care homes in Yorkshire, United Kingdom, were randomised (1:1) to the skilful care training package (SCTP) or usual care (UC). PARTICIPANTS: residents who were not independently mobile. INTERVENTION: SCTP-delivered by physiotherapists to care staff. OBJECTIVES AND MEASUREMENTS: key objectives informed progression to a definitive trial. Recruitment, retention and intervention uptake were monitored. Data, collected by a blinded researcher, included pain, posture, mobility, hospitalisations and falls. This informed data collection feasibility and participant safety. RESULTS: a total of 348 residents were screened; 146 were registered (71 UC, 75 SCTP). Forty two were lost by 6 months, largely due to deaths. While data collection from proxy informants was good (>95% expected data), attrition meant that data completion rates did not meet target. Data collection from residents was poor due to high levels of dementia. Intervention uptake was variable-staff attendance at all sessions ranged from 12.5 to 65.8%. There were no safety concerns. CONCLUSION: care home and resident recruitment are feasible, but refinement of data collection approaches and intervention delivery are needed for this trial and care home research more widely.

Disadvantaged, Outnumbered, and Discouraged: Women's Experiences as Healthy Volunteers in U.S. Phase I Trials.

While enormous strides have been made in the representation of women in clinical trials, the percentage of women enrolling in Phase I trials still remains low, which both raises public health concerns about the safety of new drugs and social justice concerns regarding their inclusion in research. As part of a longitudinal study of healthy volunteers in the United States, our inquiry aimed to examine impediments to women enrolling in Phase I trials as well as their experiences participating in these studies at residential research clinics. We analyzed 111 semi-structured interviews conducted with 47 women who had enrolled in at least one Phase I trial. Our study indicates that women face discrimination during all stages of their participation in Phase I trials from their ability to qualify for studies, the treatment they receive in the clinic facilities, and a lack of social support. Specifically, we found that (1) study designs disadvantage participants of childbearing potential, (2) women feel vulnerable in the clinic space when outnumbered by men, and (3) heterosexual women are often discouraged from participation by their husbands or significant others. Placing these findings within the scholarly literature on barriers to women's clinical trial participation, we argue that diverse strategies attending both to physiological and social factors are needed to combat inequalities in U.S. Phase I trial participation.

Picking and Choosing Among Phase I Trials : A Qualitative Examination of How Healthy Volunteers Understand Study Risks.

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.