Enabling patient-reported outcome measures in clinical trials, exemplified by cardiovascular trials

Objectives There has been limited success in achieving integration of patient-reported outcomes (PROs) in clinical trials. We describe how stakeholders envision a solution to this challenge. Methods Stakeholders from academia, industry, non-profits, insurers, clinicians, and the Food and Drug Administration convened at a Think Tank meeting funded by the Duke Clinical Research Institute to discuss the challenges of incorporating PROs into clinical trials and how to address those challenges. Using examples from cardiovascular trials, this article describes a potential path forward with a focus on applications in the United States. Results Think Tank members identified one key challenge: a common understanding of the level of evidence that is necessary to support patient-reported outcome measures (PROMs) in trials. Think Tank participants discussed the possibility of creating general evidentiary standards depending upon contextual factors, but such guidelines could not be feasibly developed because many contextual factors are at play. The attendees posited that a more informative approach to PROM evidentiary standards would be to develop validity arguments akin to courtroom briefs, which would emphasize a compelling rationale (interpretation/use argument) to support a PROM within a specific context. Participants envisioned a future in which validity arguments would be publicly available via a repository, which would be indexed by contextual factors, clinical populations, and types of claims. Conclusions A publicly available repository would help stakeholders better understand what a community believes constitutes compelling support for a specific PROM in a trial. Our proposed strategy is expected to facilitate the incorporation of PROMs into cardiovascular clinical trials and trials in general.

Part VIII Accountability for Displacement and Refugee Rights Violations, Ch.62 Restitution and Other Remedies for Refugees and Internally Displaced Persons

This chapter explores restitution and other remedies for refugees and internally displaced persons (IDPs). Most refugees and IDPs never receive any formal redress for the wrongs they have suffered. Yet over the past 30 years, significant progress has been made in advancing international norms on remedies for refugees and IDPs, and experiences in countries from Bosnia and Kosovo to Rwanda and Iraq have strengthened understanding of the challenges involved in translating these principles into practice. Efforts have focused predominantly on the restitution of housing, land, and property (HLP), with the assumption that this is the most pertinent remedy for forced migrants, particularly because it may help enable return as the ‘preferred’ solution to displacement. The chapter assesses these developments and the state of research on this pivotal challenge. It reviews the approaches taken in major peace treaties, court decisions, and standards. The chapter then reflects on five intertwined challenges: (i) developing appropriate data collection techniques and evidentiary standards; (ii) balancing the rights of ‘secondary occupants’ and people in protracted displacement; (iii) mitigating risks associated with HLP restitution; (iv) developing a better understanding of how gender, race, class, and other intersecting power relations influence redress; and (v) moving beyond a narrow focus on property restitution to consider the wider range of losses associated with displacement.

What makes the securities criminal law system of the United States work: 'All-embracing' 'blanket' securities crimes and the linked enforcement framework

The article explores the key factors that make the securities criminal law of the United States (US), as one of the integral building blocks of the capital markets and securities regulatory system, efficient. This includes the role and characteristics of sectoral (blanket) all-embracing securities crimes enshrined into the federal securities statutes, their nexus with general crimes, the close cooperation of the Securities Exchange Commission (SEC) and prosecutorial offices, the applicable evidentiary standards, and the fundamental policies undergirding these laws. The rich repository of US experiences should be instructive not only to the Member States of the European Union (EU) striving to forge deeper capital markets but also to those endeavoring to accede the EU (e.g., Serbia), or to create deep capital markets for which efficient prosecution of securities crimes is inevitable.

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

The challenges in the diagnosis, prognosis, and monitoring of Gaucher disease (GD), an autosomal recessive inborn error of glycosphingolipid metabolism, can negatively impact clinical outcomes. This systematic literature review evaluated the value of glucosylsphingosine (lyso-Gb1), as the most reliable biomarker currently available for the diagnosis, prognosis, and disease/treatment monitoring of patients with GD. Literature searches were conducted using MEDLINE, Embase, PubMed, ScienceOpen, Science.gov, Biological Abstracts, and Sci-Hub to identify original research articles relevant to lyso-Gb1 and GD published before March 2019. Seventy-four articles met the inclusion criteria, encompassing 56 related to pathology and 21 related to clinical biomarkers. Evidence for lyso-Gb1 as a pathogenic mediator of GD was unequivocal, although its precise role requires further elucidation. Lyso-Gb1 was deemed a statistically reliable diagnostic and pharmacodynamic biomarker in GD. Evidence supports lyso-Gb1 as a disease-monitoring biomarker for GD, and some evidence supports lyso-Gb1 as a prognostic biomarker, but further study is required. Lyso-Gb1 meets the criteria for a biomarker as it is easily accessible and reliably quantifiable in plasma and dried blood spots, enables the elucidation of GD molecular pathogenesis, is diagnostically valuable, and reflects therapeutic responses. Evidentiary standards appropriate for verifying inter-laboratory lyso-Gb1 concentrations in plasma and in other anatomical sites are needed.

Who Is an Indian Child? Institutional Context, Tribal Sovereignty, and Race-Making in Fragmented States

Despite growing interest in state race-making, we know little about how race-making plays out in the everyday practice of policy governance. To address this gap, I examine the implementation of the Indian Child Welfare Act (1978), which sought to end generations of state policies that denied tribal sovereignty and forcibly removed Native children from their tribes. ICWA’s protections extend to children based on tribal citizenship, not racial status. Marshalling 40 years of archival data from the government agencies charged with ICWA enforcement, I analyze how ICWA implementers determine a child’s Indian status. I find that authorities routinely eschew the requirement to treat Indian as a citizenship category, re-defining it as a race. Yet whether and how state actors racialize Indianness varies by the institutional contexts in which they work. Comparing state child welfare agencies, state courts, and federal courts, I identify three institutional characteristics that organize race-making practices: evidentiary standards, record-keeping requirements, and incentive structures. These characteristics influence whether state decision-makers operationalize “Indian” as a racial category and the cognitive and ideological processes that undergird their classifications. I also demonstrate that changes in these institutional characteristics yield concomitant shifts in whether and how state agents engage in racialization.

Justifications, Excuses, and Affirmative Defenses

A defendant who admits to having committed an offense may nevertheless be acquitted if he can provide a legally cognizable justification or excuse for his actions by raising an affirmative defense. This article explains how affirmative defenses generate social benefits in the form of avoided unnecessary punishment. It then asks what kind of evidentiary standards must be used in order to balance these benefits against potential social costs arising from frivolous defense claims. It thereby provides an economic rationale for the uniformity across US jurisdictions in allocating the burden on the prosecution to prove the commission of the offense, as well as the variation across states in the standards of proof they use in determining the validity of affirmative defenses. The analysis also explains why mere assertions of undeterrability should not be considered as affirmative defenses. (JEL K00, K14, K40, K41, K42)