Incidental findings in human subjects research: Is ignorance really bliss?

<p>Human subjects research has the potential to produce information beyond the aims of the research study. This information may, nevertheless, have health or reproductive significance for the research participant. With the development of sophisticated technologies, these occurrences, known as incidental findings (IFs), are becoming increasingly common. As yet, however, there is no consensus on how IFs in human subjects research should be managed. This paper examines the current law and guidelines relating to human subjects research, and in doing so determines that research participants are inadequately informed about IFs. Consequently, their ability to make an informed choice about and provide informed consent to research procedures is compromised. After addressing the ethical and practical issues most salient to IFs, a framework for their management is developed. The framework sets out the information that should be discussed with research participants during the informed consent process. Recommendations for how this framework should be implemented are then made. The paper concludes that guidelines establishing minimum standards for communicating the possibility and presence of IFs are urgently required so that the rights of research participants are sufficiently protected.</p>

Incidental findings in human subjects research: Is ignorance really bliss?

<p>Human subjects research has the potential to produce information beyond the aims of the research study. This information may, nevertheless, have health or reproductive significance for the research participant. With the development of sophisticated technologies, these occurrences, known as incidental findings (IFs), are becoming increasingly common. As yet, however, there is no consensus on how IFs in human subjects research should be managed. This paper examines the current law and guidelines relating to human subjects research, and in doing so determines that research participants are inadequately informed about IFs. Consequently, their ability to make an informed choice about and provide informed consent to research procedures is compromised. After addressing the ethical and practical issues most salient to IFs, a framework for their management is developed. The framework sets out the information that should be discussed with research participants during the informed consent process. Recommendations for how this framework should be implemented are then made. The paper concludes that guidelines establishing minimum standards for communicating the possibility and presence of IFs are urgently required so that the rights of research participants are sufficiently protected.</p>

261 A functional genetic screen uncovers regulators of intratumoral macrophage function and reveals CD24 as a novel target for cancer immunotherapy by macrophages

BackgroundCancer cells are capable of evading clearance by macrophages through the overexpression of anti-phagocytic, innate immune checkpoint molecules called ‘don’t eat me’ signals, including CD47,1 PD-L1,2 and MHC class I.3 Monoclonal antibodies that antagonize the interaction of ‘don’t eat me’ signals with their macrophage-expressed receptors have demonstrated therapeutic potential in several cancers. However, variability in the magnitude and durability of the responses to these agents has suggested the presence of additional, as yet unknown innate immune checkpoints. Here, we present a functional screening platform which identifies tumor-specific regulators of intratumoral macrophage function. We show that CD24 is a dominant innate immune checkpoint in many solid tumors, including ovarian cancer and breast cancer.4MethodsBy applying our screening method, we uncovered the novel innate immune checkpoint molecule, CD24. To characterize the role of CD24 as a macrophage checkpoint, we leveraged the MCF-7 human xenograft tumor model and the ID8 syngeneic ovarian cancer tumor model. We evaluated the anti-tumor effect of CD24 antagonism through genetic ablation experiments in addition to therapeutic CD24 monoclonal antibody (mAb) blockade. We also utilized primary human immune cells and tumor specimens to assess the effect of CD24 blockade either alone or in combination with additional tumor-targeting antibodies.ResultsWe demonstrate that CD24 promotes immune evasion through its interaction with the inhibitory macrophage receptor Siglec-10. Genetic ablation of either CD24 or Siglec-10, as well as blockade of the CD24–Siglec-10 interaction using monoclonal antibodies, robustly augmented the phagocytosis of all CD24-expressing human tumors that we tested. Therapeutic blockade of CD24 resulted in a macrophage-dependent reduction of tumor growth in vivo and an increase in survival time. The therapeutic efficacy of anti-CD24 mAbs was enhanced when combined with a second anti-tumor antibody. In particular, dual treatment of HER2-positive breast cancers with anti-CD24 mAb and trastuzumab, augmented phagocytosis relative to either treatment alone, even among cancers with inherent trastuzumab resistance (figure 1).Abstract 261 Figure 1Macrophage checkpoints are therapeutic targets. (A) There are four defined innate immune checkpoint signaling axes which exist between macrophages and cancer cells, which all rely on ITIM or ITSM signaling on the cytoplasmic side of the macrophage. (B) Phagocytosis of BT-474 (n = 8 donors) in the presence of anti-CD24 mAb, anti-HER2 mAb or dual treatment, compared with IgG control.ConclusionsThese data reveal CD24 as a highly expressed, anti-phagocytic signal in several cancers, and demonstrate the therapeutic potential for CD24 blockade in cancer immunotherapy, either alone or in combination with existing anticancer treatments. Collectively, this work suggests a new paradigm that innate immune checkpoints are redundant and employed in a tissue-specific and even tumor-specific manner, and makes clear the need to measure the collective expression of these ‘don’t eat me’ signals in order to optimize patient responses to both innate and adaptive immunotherapies.ReferencesMajeti R, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 2009;138: 286–299. Gordon SR, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 2017;545:495–499.Barkal AA, et al. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat Immunol 2018;19:76–84.Barkal AA, Brewer RE, Markovic M, Kowarsky MA, Barkal SA, Zaro BW, Krishnan V, Hatakeyama J, Dorigo O, Barkal LJ, Weissman IL. CD24 signaling through macrophage siglec-10 is a new target for cancer immunotherapy. Nature 2019;572:392–396.Ethics ApprovalThe Human Immune Monitoring Center Biobank and the Stanford Tissue Bank all received IRB approval from the Stanford University Administrative Panels on Human Subjects Research and complied with all ethical guidelines for human subjects research to obtain samples from patients with ovarian cancer and breast cancer, and received informed consent from all patients.

Guidelines, Codes, and Regulations

Research involving human subjects is increasingly global in scope. This research is governed by over 1,000 guidelines, codes, and regulations spanning 130 countries. While there have been some attempts to construct international codes of conduct, particularly in the area of biomedical research, the reality is that these universal codes are superimposed over national and institutional norms, resulting in idiosyncrasies and discrepancies. Even within the United States as a single example, human subjects research is subject to a “patchwork quilt” of regulation, depending on the nature of the research and the source of funding. This chapter will provide an overview of these governing standards, recounting their historical evolution, discussing their key elements, and describing the challenges faced by researchers, sponsors, and regulatory bodies who must navigate this landscape.

Survey Fraud and the Integrity of Web-Based Survey Research

Compared to traditional paper surveys, online surveys offer a convenient, efficient, and socially distant way to conduct human subjects research. The popularity of online research has grown in recent decades. However, without proper precautions, false respondents pose a serious risk to data integrity. In this paper, we describe our research team’s own encounter with survey fraud, steps taken to preserve the integrity of our study, and implications for future public health research.

Historical Foundations

This chapter considers the history of the rise of ethical concerns in the public health movement and epidemiology, which is the study of the distribution and determinants of disease in human populations. It explains that epidemiology is a basic science in public health. It also provides an overview of early developments in public health and ethics. The chapter looks at recent developments, including the origins of bioethics, regulatory safeguards for human subjects research, public health ethics, and contemporary epidemiological ethics. It begins with the end of the Middle Ages, wherein few advances were made in public health except for the control of a very limited number of communicable diseases achieved through the segregation and quarantine of persons thought to be infectious.

A call for structured ethics appendices in social science papers

Ethics in social science experimentation and data collection are often discussed but rarely articulated in writing as part of research outputs. Although papers typically reference human subjects research approvals from relevant institutional review boards, most recognize that such boards do not carry out comprehensive ethical assessments. We propose a structured ethics appendix to provide details on the following: policy equipoise, role of the researcher, potential harms to participants and nonparticipants, conflicts of interest, intellectual freedom, feedback to participants, and foreseeable misuse of research results. We discuss each of these and some of the norms and challenging situations of each. We believe that discussing such issues explicitly in appendices of papers, even if briefly, will serve two purposes: more complete communication of ethics can improve discussions of papers and can clarify and improve the norms themselves.

Use of Template Documents with Guidance to Improve the Quality of Human Subjects Research Protocol Submissions to a Thai Research Ethics Committee

A pre–post study was conducted to evaluate the utility of template documents specifically created to assist research protocol submissions to a Thai research ethics committee (REC). A total of 172 protocols during the 2014–2016 preintervention period were matched to 172 protocols during the 2017–2019 postintervention period by type of principal investigator and REC review category. The intervention was associated with a significant reduction in initial REC requirement deficiencies in the information sheet and informed consent form, resubmission turn-around time by the principal investigator, and time form protocol submission to REC approval. The most significant postintervention improvements were for information about the consent process and listed risks of study participation. In this study, utilization of a structured protocol template with guidance instructions was associated with measurable improvement in the quality of research protocol submissions and REC review process.