How informative were early SARS-CoV-2 treatment and prevention trials? a longitudinal cohort analysis of trials registered on ClinicalTrials.gov.

BACKGROUND: Early in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic. METHODS: Based on prespecified eligibility criteria, we created a cohort of Phase 1/2, Phase 2, Phase 2/3 and Phase 3 SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We excluded trials evaluating behavioural interventions and natural products, which are not regulated by the U.S. Food and Drug Administration (FDA). We evaluated trials on 3 criteria of informativeness: potential redundancy (comparing trial phase, type, patient-participant characteristics, treatment regimen, comparator arms and primary outcome), trials design (according to the recommendations set-out in the May 2020 FDA guidance document on SARS-CoV-2 treatment and prevention trials) and feasibility of patient-participant recruitment (based on timeliness and success of recruitment). RESULTS: We included all 500 eligible trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.9% (95% Confidence Interval 23.7-36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%. CONCLUSIONS: Less than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic.

Ethics of Pharma Clinical Trials in the Era of Precision Oncology.

Pharmaceutical industry clinical trials are ethically problematic: human research subjects are being used as a means to the end of demonstrating statistically significant efficacy of novel anticancer agents to achieve regulatory registration and marketing approval. Randomized controlled trial design is inequitable since control arm patients are denied access to the postulated best treatment. Most pharma studies do not provide clinically meaningful benefit of increased overall survival and enhanced quality of life (QOL) to cohorts and are not reliably generalizable to real-world patients. Precision oncology now enables prospective identification of patients expressing a specific cancer biomarker to determine their particular eligibility for evaluation of efficiency of molecular-targeted treatments. A patient-centered approach, collecting prospective real-world data in large populations, could provide real-world evidence of cost-effective, sustained clinical benefits of survival and QOL, while preserving the ethical beneficent compact between patient and doctor.

Informal professionalization of healthy participants in phase I clinical trials in Russia.

BACKGROUND: Previous social science research has shown how some healthy phase I trial participants identify themselves as workers and rely on trials as a major source of income. The term "professionalization" has been used to denote this phenomenon. PURPOSE: We aim to examine a component of healthy trial participants' professionalization that has not yet been systematically studied: how repeat phase I trial participants develop and claim expertise that distinguishes them from others and makes them uniquely positioned to perform high-quality clinical trial labor. We also aim to explain the significance of these research results for protection of healthy participants in phase I trials. METHODS: This qualitative exploratory study was conducted in Russia, in two phase I trial units. It involved semi-structured interviews with 28 healthy trial participants with varying lengths of experience in trials, observations of work done in trial units, and interpretive conversations with investigative staff. RESULTS: Interviewed healthy individuals who repeatedly participate in phase I trials describe developing knowledge and skills that involve appreciating the meaning of trial procedures, coming up with techniques to efficiently follow them, organizing themselves and others in the course of a trial, and sharing tacit ways of doing trial work well with other less experienced participants. Our results suggest that a prerequisite for such expertise-centered professionalization is the emergence of a positive identity linked to seeing value in trial participation work. A crucial component of professionalization thus understood is the development of a work ethic that entails caring about results and being reliable partners for investigators. LIMITATIONS: The attitudes and behaviors presented in this article are not suggested to be universally shared among healthy trial participants, but rather represent a particular instance of professionalization that coexists with other views and tactics. CONCLUSIONS: A way of better protecting healthy trial participants begins with recognizing their skills, knowledge, and the centrality of the contribution they are making to pharmaceutical research. Currently, the expertise of experienced trial participants is recognized on the work floor only; therefore, the professionalization we described is informal. Yet, the informal professionalization process is inherently risky as it does not involve any change in the formal conditions of trial participants' work. Instituting formal measures for protecting healthy trial participants as skilled workers combined with recognition of their expertise is essential.

"Paid to Endure": Paid Research Participation, Passivity, and the Goods of Work.

A growing literature documents the existence of individuals who make a living by participating in phase I clinical trials for money. Several scholars have noted that the concerns about risks, consent, and exploitation raised by this phenomenon apply to many (other) jobs, too, and therefore proposed improving subject protections by regulating phase I trial participation as work. This article contributes to the debate over this proposal by exploring a largely neglected worry. Unlike most (other) workers, subjects are not paid to produce or achieve anything but to have things done to them. I argue that this passivity is problematic for reasons of distributive justice. Specifically, it fails to enable subjects to realize what Gheaus and Herzog call "the goods of work"-a failure not offset by adequate opportunities to realize these goods outside of the research context. I also consider whether granting subjects worker-type protections would accommodate this concern.

Informed consent for early-phase clinical trials: therapeutic misestimation, unrealistic optimism and appreciation.

Unrealistic therapeutic beliefs are very common-the majority of patient-subjects (up to 94%) 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: (1) 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 (2) researchers should consider the settings in which it may be possible and practical to obtain 'two-point consent'.

Innovation in oncology clinical trial design.

Progress in and better understanding of cancer biology causes a shift in cancer drug development: away from the evaluation of drugs in large tumour histology defined patient populations towards targeted agents in increasingly heterogeneous molecularly defined subpopulations. This requires novel approaches in clinical trial design by academia and industry, and development of new assessment tools by regulatory authorities. Pharmaceutical industry is developing new targeted agents generating many clinical studies, including target combinations. This requires improved operational efficiency by development of innovative trial designs, strategies for early-stage decision making and early selection of candidate drugs with a high likelihood of success. In addition, patient awareness and ethical considerations necessitate that agents will be rapidly available to patients. Regulatory Authorities such as the European Medicine Agency and national agencies recognise that these changes require a different attitude towards benefit-risk analysis for drug approval. The gold standard of randomised confirmatory Phase III trials is not always ethical or feasible when developing drugs for treatment of small cancer populations. Alternative strategies comprise accelerated approval via conditional marketing approval, which can be granted in the EU based on small non-randomised Phase II trials. The paper describes innovative trial designs with their pros and cons and efforts of pharmaceutical industry and regulatory authorities to deal with the paradigm shift. Furthermore, all stakeholders should continue to share their experiences and discuss problems in order to understand the position and concerns of the other stakeholders to learn from each other and to progress the field of novel oncology clinical trial design.

Parental Experiences of Child Participation in a Phase I Pediatric Oncology Clinical Trial: "We Don't Have Time to Waste".

Children with cancer are only eligible for phase I clinical trials (P1Ts) when no known curative therapy remains. However, the primary aims of P1Ts are not focused on directly benefiting participants. This raises ethical concerns that can be best evaluated by exploring the experiences of participants. An empirical phenomenology study, using an adapted Colaizzi method, was conducted of 11 parents' lived experiences of their child's participation in a pediatric oncology P1T. Study findings were that parents' experiences reflected what it meant to have a child fighting to survive high-risk cancer. Although elements specific to P1T participation were identified, more pervasive was parents' sense of running out of time to find an effective treatment and needing to use time they had with their child well. Even though some problems were identified, overall parents did not regret their child's P1T participation and would recommend P1Ts to other parents of children with cancer.

"My Body is One of the Best Commodities": Exploring the Ethics of Commodification in Phase I Healthy Volunteer Clinical Trials.

In phase I clinical trials, healthy volunteers are dosed with investigational drugs and subjected to blood draws and other bodily monitoring procedures while they are confined to clinic spaces. In exchange, they are paid. These participants are, in a direct sense, selling access to their bodies for pharmaceutical companies and their associates to run drugs through. However, commodification is rarely investigated as an ethical dimension of phase I trial participation. We address this gap in the literature by bringing the voices of phase I healthy volunteers into conversation with philosophical perspectives on body commodification. Querying the intersection of commodification and phase I clinical trials illuminates important features of healthy volunteers' experiences, disentangles commodification from a dominant narrative about exploitation, and brings focus to the question of what, if any, market norms will best protect the multiple ways in which healthy volunteers' welfare is impacted by clinical trial participation.

Well-Being of Child and Family Participants in Phase 1 Pediatric Oncology Clinical Trials.

PROBLEM IDENTIFICATION: Pediatric oncology phase 1 clinical trials (P1Ts) are essential to developing new anticancer therapies; however, they raise complex ethical concerns about balancing the need for this research with the well-being of participating children. The purpose of this integrative review was to synthesize and appraise the evidence of how P1T participation, which begins with consent and ends with the transition off the P1T, can affect the well-being (either positively or negatively) of children with cancer. The Resilience in Individuals and Families Affected by Cancer Framework, which has an outcome of well-being, was used to synthesize findings. LITERATURE SEARCH: Articles on the experiences of child (n = 21) and adult (n = 31) P1T participants were identified through systematic searches. DATA EVALUATION: Articles were evaluated on rigor and relevance to P1T participant experiences as high, medium, or low. SYNTHESIS: Minimal empirical evidence was found regarding the effect of P1T participation on the well-being of children with cancer. Adult P1T participant experiences provide insights that could also be important to children's P1T experiences. IMPLICATIONS FOR PRACTICE: To achieve a balanced approach in P1T consent discussions, nurses and healthcare providers who work with children considering participation in a P1T should share the potential effect of participation on participants' well-being.

Serial Participation and the Ethics of Phase 1 Healthy Volunteer Research.

Phase 1 healthy volunteer clinical trials-which financially compensate subjects in tests of drug toxicity levels and side effects-appear to place pressure on each joint of the moral framework justifying research. In this article, we review concerns about phase 1 trials as they have been framed in the bioethics literature, including undue inducement and coercion, unjust exploitation, and worries about compromised data validity. We then revisit these concerns in light of the lived experiences of serial participants who are income-dependent on phase 1 trials. We show how participant experiences shift attention from discrete exchanges, behaviors, and events in the research enterprise to the ongoing and dynamic patterns of serial participation in which individual decision-making is embedded in collective social and economic conditions and shaped by institutional policies. We argue in particular for the ethical significance of structurally diminished voluntariness, routine powerlessness in setting the terms of exchange, and incentive structures that may promote pharmaceutical interests but encourage phase 1 healthy volunteers to skirt important rules.

First-in-human Phase 1 CRISPR Gene Editing Cancer Trials: Are We Ready?

A prospective first-in-human Phase 1 CRISPR gene editing trial in the United States for patients with melanoma, synovial sarcoma, and multiple myeloma offers hope that gene editing tools may usefully treat human disease. An overarching ethical challenge with first-in-human Phase 1 clinical trials, however, is knowing when it is ethically acceptable to initiate such trials on the basis of safety and efficacy data obtained from pre-clinical studies. If the pre-clinical studies that inform trial design are themselves poorly designed - as a result of which the quality of pre-clinical evidence is deficient - then the ethical requirement of scientific validity for clinical research may not be satisfied. In turn, this could mean that the Phase 1 clinical trial will be unsafe and that trial participants will be exposed to risk for no potential benefit. To assist sponsors, researchers, clinical investigators and reviewers in deciding when it is ethically acceptable to initiate first-in-human Phase 1 CRISPR gene editing clinical trials, structured processes have been developed to assess and minimize translational distance between pre-clinical and clinical research. These processes draw attention to various features of internal validity, construct validity, and external validity. As well, the credibility of supporting evidence is to be critically assessed with particular attention to optimism bias, financial conflicts of interest and publication bias. We critically examine the pre-clinical evidence used to justify the first-inhuman Phase 1 CRISPR gene editing cancer trial in the United States using these tools. We conclude that the proposed trial cannot satisfy the ethical requirement of scientific validity because the supporting pre-clinical evidence used to inform trial design is deficient.

First-in-human HIV-remission studies: reducing and justifying risk.

Interest and excitement surround the possibility of developing measures that produce sustained or permanent HIV remission in infected individuals. First-in-human (FIH) trials are one step in exploring this possibility. Initial human trials raise the usual ethical issues associated with human research, and a set of distinct issues. Because the potential direct benefits to FIH trial volunteers will be either small or non-existent, trial risks must be justified by the social value of the information the trials are expected to produce. To minimise and justify risks, researchers must have solid preclinical evidence that FIH trials will be safe and produce information relevant to human health improvements. Researchers must also adopt adequate study safeguards to protect FIH subjects. An ethically defensible study population must be selected as well.