Algorithmic identification of persons with dementia for research recruitment: ethical considerations.

Underdiagnosis, misdiagnosis, and patterns of social inequality that translate into unequal access to health systems all pose barriers to identifying and recruiting diverse and representative populations into research on Alzheimer's disease and Alzheimer's disease related dementias. In response, some have turned to algorithms to identify patients living with dementia using information that is associated with this condition but that is not as specific as a diagnosis. This paper explains six ethical issues associated with the use of such algorithms including the generation of new, sensitive, identifiable medical information for research purposes without participant consent, issues of justice and equity, risk, and ethical communication. It concludes with a discussion of strategies for addressing these issues and prompting valuable research.

Digital Health Technologies in Clinical Trials: An Ontology-Driven Analysis to Inform Digital Sustainability Policies.

BACKGROUND: Digital health technologies (DHTs) can facilitate the execution of de-centralized trials that can offer opportunities to reduce the burden on participants, collect outcome data in a real-world setting, and potentially make trial populations more diverse and inclusive. However, DHTs can also be a significant source of electronic waste (e-waste). In recognition of the potential health and environmental impact from DHT use in trials, private and public institutions have recently launched initiatives to help measure and manage this e-waste. But in order to develop sound e-waste management policies, it will be necessary to first estimate the current volume of e-waste that results from the use of DHTs in trials. MATERIALS AND METHODS: A Web Ontology Language (OWL)-compliant ontology of DHTs was created using a list of 500 DHT device names derived from a mixture of public and private sources. The U.S. clinical trials registry, ClinicalTrials.gov, was then queried to identify and classify trials using any of the devices in the ontology. The ClinicalTrials.gov records from this search were then analyzed to characterize the volume and properties of trials using DHTs, as well as estimating the total volume of individual DHT units that have been provisioned (or are planned to be provisioned) for clinical research. RESULTS: Our ontology-driven search identified 2326 unique clinical trials with a reported "actual" enrollment of 200,947 participants and a "planned" enrollment of an additional 4,094,748 participants. The most-used class of DHTs in our ontology was "wearables," (1852 trials), largely driven by the use of smart watches and other wrist-worn sensors (estimated to involve 149,391 provisioned devices). The most-used subtype of DHTs in trials was "subcutaneous" devices (367 trials), driven by the prevalent use and testing of glucose monitors (estimated to involve 17,666 provisioned devices). CONCLUSION: Thousands of trials, involving hundreds of thousands of devices, have already been completed, and many more trials (potentially involving millions more devices) are planned. Despite the great opportunities that are afforded by DHTs to the clinical trial enterprise, if the industry lacks the ability to track DHT use with sufficient resolution, the result is likely to be a great deal of e-waste. A new ontology of DHTs, combined with rigorous data science methods like those described in this paper, can be used to provide better information across the industry, and in turn, help create a more sustainable and equitable clinical trials enterprise.

Opioid Use Disorder Treatments: An Evidence Map.

BACKGROUND: Evidence maps are emerging data visualization of a systematic review. There are no published evidence maps summarizing opioid use disorder (OUD) interventions. AIM: Our aim was to publish an interactive summary of all peer-reviewed interventional and observational trials assessing the treatment of OUD and common clinical outcomes. METHODS: PubMed, Embase, PsycInfo, Cochrane Central Register of Clinical Trials, and Web of Science were queried using multiple OUD-related MESH terms, without date limitations, for English-language publications. Inclusions were human subjects, treatment of OUD, OUD patient or community-level outcomes, and systematic reviews of OUD interventions. Exclusions were laboratory studies, reviews, and case reports. Two reviewers independently scanned abstracts for inclusion before coding eligible full-text articles by pre-specified filters: research design, study population, study setting, intervention, outcomes, sample size, study duration, geographical region, and funding sources. RESULTS: The OUD Evidence Map (https://med.nyu.edu/research/lee-lab/research/opioid-use-disorder-treatment-evidence-map) identified and assessed 12,933 relevant abstracts through 2020. We excluded 9455 abstracts and full text reviewed 2839 manuscripts; 888 were excluded, 1591 were included in the final evidence map. The most studied OUD interventions were methadone (n = 754 studies), buprenorphine (n = 499), and naltrexone (n = 134). The most common outcomes were heroin/opioid use (n = 708), treatment retention (n = 557), and non-opioid drug use (n = 368). Clear gaps included a wider array of opioid agonists for treatment, digital behavioral interventions, studies of OUD treatments in criminal justice settings, and overdose as a clinical outcome. CONCLUSION: This OUD Evidence Map highlights the importance of pharmacologic interventions for OUD and reductions in opioid use. Future iterations will update results annually and scan policy-level interventions.

Ethical considerations within pragmatic randomized controlled trials in dementia: Results from a literature survey.

Introduction: This review aims to describe the landscape of pragmatic randomized controlled trials (RCTs) in the context of Alzheimer's disease (AD) and related dementias with respect to ethical considerations. Methods: Searches of MEDLINE were performed from January 2014 until April 2019. Extracted information included: trial setting, interventions, data collection, study population, and ethical protections (including ethics approvals, capacity assessment, and informed consent). Results: We identified 62 eligible reports. More than two-thirds (69%) included caregivers or health-care professionals as research participants. Fifty-eight (94%) explicitly identified at least one vulnerable group. Two studies did not report ethics approval. Of 57 studies in which patients were participants, 55 (96%) reported that consent was obtained but in 37 studies (67%) no mention was made regarding assessment of the patients' capacity to consent to research participation. Discussion: Few studies reported protections implemented when vulnerable participants were included. Shortcomings remain when reporting consent approaches and capacity assessment.

Informed consent in pragmatic trials: results from a survey of trials published 2014-2019.

OBJECTIVES: To describe reporting of informed consent in pragmatic trials, justifications for waivers of consent and reporting of alternative approaches to standard written consent. To identify factors associated with (1) not reporting and (2) not obtaining consent. METHODS: Survey of primary trial reports, published 2014-2019, identified using an electronic search filter for pragmatic trials implemented in MEDLINE, and registered in ClinicalTrials.gov. RESULTS: Among 1988 trials, 132 (6.6%) did not include a statement about participant consent, 1691 (85.0%) reported consent had been obtained, 139 (7.0%) reported a waiver and 26 (1.3%) reported consent for one aspect (eg, data collection) but a waiver for another (eg, intervention). Of the 165 trials reporting a waiver, 76 (46.1%) provided a justification. Few (53, 2.9%) explicitly reported use of alternative approaches to consent. In multivariable logistic regression analyses, lower journal impact factor (p=0.001) and cluster randomisation (p<0.0001) were significantly associated with not reporting on consent, while trial recency, cluster randomisation, higher-income country settings, health services research and explicit labelling as pragmatic were significantly associated with not obtaining consent (all p<0.0001). DISCUSSION: Not obtaining consent seems to be increasing and is associated with the use of cluster randomisation and pragmatic aims, but neither cluster randomisation nor pragmatism are currently accepted justifications for waivers of consent. Rather than considering either standard written informed consent or waivers of consent, researchers and research ethics committees could consider alternative consent approaches that may facilitate the conduct of pragmatic trials while preserving patient autonomy and the public's trust in research.

A review of pragmatic trials found a high degree of diversity in design and scope, deficiencies in reporting and trial registry data, and poor indexing.

OBJECTIVE: We established a large database of trials to serve as a resource for future methodological and ethical analyses. Here, we use meta-data to describe the broad landscape of pragmatic trials including research areas, identification as pragmatic, quality of trial registry data and enrolment. STUDY DESIGN AND SETTING: Trials were identified by a validated search filter and included if a primary report of a health-related randomized trial published January 2014-April 2019. Data were collated from MEDLINE, Web of Science, ClinicalTrials.gov, and full text. RESULTS: 4337 eligible trials were identified from 13,065 records, of which 1988 were registered in ClinicalTrials.gov. Research areas were diverse, with the most common being general and internal medicine; public, environmental and occupational health; and health care sciences and services. The term "pragmatic" was seldom used in titles or abstracts. Several domains in ClinicalTrials.gov had questionable data quality. We estimated that one-fifth of trials under-accrued by at least 15%. CONCLUSION: There is a need to improve reporting of pragmatic trials and quality of trial registry data. Under accrual remains a challenge in pragmatic RCTs despite calls for more streamlined recruitment approaches. The diversity of pragmatic trials should be reflected in future ethical analyses.

Heterogeneity of antidiabetic treatment effect on the risk of major adverse cardiovascular events in type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: We explored whether clinically relevant baseline characteristics of patients with type 2 diabetes can modify the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on the risk of major adverse cardiovascular events (MACE). METHODS: We investigated Medline and EMBASE through June 2019. We included randomized clinical trials reporting the effect of GLP-1 RA or SGLT-2i on MACE in subgroups of patients with type 2 diabetes, identified through key baseline factors: established cardiovascular disease; heart failure; chronic kidney disease; uncontrolled diabetes; duration of diabetes; hypertension; obesity; age; gender and race. Hazard ratios (HRs) and 95% confidence intervals (CIs) from trials were meta-analyzed using random-effects models. RESULTS: Ten trials enrolling 89,790 patients were included in the analyses. Subgroup meta-analyses showed a 14% risk reduction of MACE in patients with established cardiovascular disease [GLP1-RA: HR, 0.86 (95% CI, 0.80-0.93); SGLT-2i: 0.86 (0.80-0.93)], and no effect in at-risk patients without history of cardiovascular events [GLP1-RA: 0.94 (0.82-1.07); SGLT-2i: 1.00 (0.87-1.16)]. We observed a trend toward larger treatment benefits with SGLT-2i among patients with chronic kidney disease [0.82 (0.69-0.97)], and patients with uncontrolled diabetes for both GLP1-RA or SGLT-2i [GLP1-RA: 0.82 (0.71-0.95); SGLT-2i: 0.84 (0.75-0.95)]. Uncontrolled hypertension, obesity, gender, age and race did not appear to modify the effect of these drugs. CONCLUSIONS: In this exploratory analysis, history of cardiovascular disease appeared to modify the treatment effect of SGLT2i or GLP1-RA on MACE. Chronic kidney disease and uncontrolled diabetes should be further investigated as potential effect modifiers.

Ethical and Regulatory Issues for Embedded Pragmatic Trials Involving People Living with Dementia.

Embedded pragmatic clinical trials (ePCTs) present an opportunity to improve care for people living with dementia (PLWD) and their care partners, but they also generate a complex constellation of ethical and regulatory challenges. These challenges begin with participant identification. Interventions may be delivered in ways that make it difficult to identify who is a human subject and therefore who needs ethical and regulatory protections. The need for informed consent, a core human subjects protection, must be considered but can be in tension with the goals of pragmatic research design. Thus it is essential to consider whether a waiver or alteration of informed consent is justifiable. If informed consent is needed, the question arises of how it should be obtained because researchers must acknowledge the vulnerability of PLWD due in part to diminished capacity and also to increased dependence on others. Further, researchers should recognize that many sites where ePCTs are conducted will be unfamiliar with human subjects research regulations and ethics. In this report, the Regulation and Ethics Core of the National Institute on Aging Imbedded Pragmatic Alzheimer's disease (AD) and AD-related dementias (AD/ADRD) Clinical Trials (IMPACT) Collaboratory discusses key ethical and regulatory challenges for ePCTs in PLWD. A central thesis is that researchers should strive to anticipate and address these challenges early in the design of their ePCTs as a means of both ensuring compliance and advancing science. J Am Geriatr Soc 68:S37-S42, 2020.

Cluster over individual randomization: are study design choices appropriately justified? Review of a random sample of trials.

BACKGROUND: Novel rationales for randomizing clusters rather than individuals appear to be emerging from the push for more pragmatic trials, for example, to facilitate trial recruitment, reduce the costs of research, and improve external validity. Such rationales may be driven by a mistaken perception that choosing cluster randomization lessens the need for informed consent. We reviewed a random sample of published cluster randomized trials involving only individual-level health care interventions to determine (a) the prevalence of reporting a rationale for the choice of cluster randomization; (b) the types of explicit, or if absent, apparent rationales for the use of cluster randomization; (c) the prevalence of reporting patient informed consent for study interventions; and (d) the types of justifications provided for waivers of consent. We considered cluster randomized trials for evaluating exclusively the individual-level health care interventions to focus on clinical trials where individual randomization is only theoretically possible and where there is a general expectation of informed consent. METHODS: A random sample of 40 cluster randomized trials were identified by implementing a validated electronic search filter in two electronic databases (Ovid MEDLINE and Embase), with two reviewers independently extracting information from each trial. Inclusion criteria were the following: primary report of a cluster randomized trial, evaluating exclusively an individual-level health care intervention, published between 2007 and 2016, and conducted in Canada, the United States, European Union, Australia, or low- and middle-income country settings. RESULTS: Twenty-five trials (62.5%, 95% confidence interval = 47.5%-77.5%) reported an explicit rationale for the use of cluster randomization. The most commonly reported rationales were those with logistical or administrative convenience (15 trials, 60%) and those that need to avoid contamination (13 trials, 52%); five trials (20%) were cited rationales related to the push for more pragmatic trials. Twenty-one trials (52.5%, 95% confidence interval = 37%-68%) reported written informed consent for the intervention, two (5%) reported verbal consent, and eight (20%) reported waivers of consent, while in nine trials (22.5%) consent was unclear or not mentioned. Reported justifications for waivers of consent included that study interventions were already used in clinical practice, patients were not randomized individually, and the need to facilitate the pragmatic nature of the trial. Only one trial reported an explicit and appropriate justification for waiver of consent based on minimum criteria in international research ethics guidelines, namely, infeasibility and minimal risk. CONCLUSION: Rationales for adopting cluster over individual randomization and for adopting consent waivers are emerging, related to the need to facilitate pragmatic trials. Greater attention to clear reporting of study design rationales, informed consent procedures, as well as justification for waivers is needed to ensure that such trials meet appropriate ethical standards.

The importance of decision intent within descriptions of pragmatic trials.

OBJECTIVE: It is now more than 50 years since the concepts of explanatory and pragmatic attitudes toward trials were first discussed by Schwartz and Lellouch in their influential 1967 paper. Since then, there has been increasing focus on design aspects that may be consistent with more pragmatic attitudes within clinical trials, and a number of tools developed to assist investigators prospectively think about their trial design. Researchers have subsequently expressed interest in using these tools retrospectively to characterize trials as pragmatic or explanatory. RESULTS: We suggest that recent attempts to retrospectively dichotomize trials solely on the basis of quantitative scoring of trial design features are flawed. Instead, we argue that there is a need to consider both the intent and design when assessing the degree of pragmatism within a trial. CONCLUSION: The practical implication of our suggestion for trial reporting is that investigators should explicitly state the intent of the trial through a clear articulation of the decision that they hope will be informed by the trial results. This should be coupled with a completed PRagmatic-Explanatory Continuum Indicator Summary 2 assessment (or similar) with an explanation of study design choices to appropriately assess whether the study design is consistent with the study intent. We believe this will assist reviewers and knowledge users in making assessments of trials.

The evidence landscape in precision medicine.

Precision medicine is beginning to make an impact on the treatment of different diseases, but there are still challenges that must be overcome, such as the complexity of interventions, the need for marker validation, and the level of evidence necessary to demonstrate effectiveness. In this Perspective, we describe how evidence landscapes can help to address these challenges.

A Systematic Review and Meta-Analysis of Bevacizumab in First-Line Metastatic Breast Cancer: Lessons for Research and Regulatory Enterprises.

BACKGROUND: The US Food and Drug Administration's accelerated approval and later withdrawal of bevacizumab in patients with metastatic breast cancer (mBC) is a seminal case for ongoing debates about the validity of using progression-free survival (PFS) as a surrogate measure for overall survival (OS) in cancer drug approvals. We systematically reviewed and meta-analyzed the evidence around bevacizumab's regulatory approval and withdrawal in mBC. METHODS: We searched for all published phase II or III clinical trials testing bevacizumab as a first-line therapy for patients with mBC. Data were extracted on trial demographics, interventions, and outcomes. Descriptive analysis was stratified by whether the trial was initiated before, during, or after the accelerated approval. We used a cumulative random-effects meta-analysis to assess the evolution of evidence of the effect of bevacizumab on PFS and OS. We estimated the association between the trial-level PFS and OS effect using a nonlinear mixed-regression model. RESULTS: Fifty-two studies were included. Trial activity dramatically dropped after the accelerated approval was withdrawn. Eight clinical trials reported hazard ratios (hazard ratios) and were meta-analyzed. The cumulative hazard ratio for PFS was 0.72 (95% CI = 0.65 to 0.79), and the cumulative hazard ratio for OS was 0.90 (95% CI = 0.80 to 1.01). The regression model showed a statistically nonsignificant association between PFS benefit and OS benefit (ß = 0.43, SE = 0.81). CONCLUSION: The US Food and Drug Administration's decision-making in this case was consistent with the evolving state of evidence. However, the fact that seven clinical trials are insufficient to conclude validity (or lack thereof) for a trial-level surrogate suggests that it would be more efficient to conduct trials using the more clinically meaningful endpoints.

Why High Drug Pricing Is A Problem for Research Ethics.

The high price of drugs is receiving due consideration from ethicists, policymakers, and legislators. However, much of this attention has focused on the difference between the cost of drug development and company profits and the possible laws and regulations that could limit a drug's price once it reaches market. By contrast, little attention has been paid to the ethical implications of high drug prices for the research subjects whose bodies were essential to the drug's development. Indeed, the future price of a drug is routinely ignored and treated as unknowable during the ethical evaluation of the clinical trials that support its development. In this paper, I will argue that ignoring the future price of a drug during the research process is in tension with all three of the major principles of research ethics: it fails to show respect for the research participants, undermines the quality of risk/benefit judgements made by ethical review committees, and makes it impossible to judge future patient access and assess justice.

US Food and Drug Administration Recommendations on the Use of Surrogate Measures as End Points in New Anti-infective Drug Approvals.

Importance: Regulatory and scientific guidelines stipulate that indirect, surrogate measures of patient benefit, such as a change in microbial culture status, should be used as primary end points only in pivotal trials of chronic conditions that are serious or life threatening and when the experimental therapy is expected to offer substantial benefit compared with available therapy. However, many recent US Food and Drug Administration (FDA) anti-infective drug approvals for acute and/or non-life-threatening diseases have been based on pivotal trials using surrogate measures as primary end points rather than clinical outcomes, such as symptom resolution or survival. Objectives: To review FDA recommendations for primary end points in pivotal trials of new anti-infective drugs and assess the concordance of those recommendations with the regulatory and scientific conditions for the appropriate use of surrogate measures as primary trial outcomes. Evidence Review: All guidance documents for antimicrobial drug development hosted on the FDA website were searched in November 2017; the search was updated in June 2018. For each document, 2 reviewers independently extracted data on the recommended primary end points for a pivotal or phase 3 trial. Findings: Twenty-two FDA guidance documents met the inclusion criteria, which included recommendations for primary end points in pivotal clinical trials in 27 infectious disease indications. Twenty-one of 27 indications recommended surrogate outcomes as either the sole primary end point or as components of composite end points. None of the recommendations for the use of surrogate measures matched the regulatory and scientific conditions favoring indirect outcomes in place of clinical outcomes. Conclusions and Relevance: The FDA guidance documents for developing new anti-infective agents frequently recommend indirect measures of patient benefit, rather than direct measures of patient benefit, as sole primary end points or components of primary end points. Existing guidance documents should be updated and revised to recommend appropriate clinical outcomes consistent with general scientific and regulatory parameters.

Heuristics and Explanation in Translational Medicine.

The reigning paradigm of rational drug discovery in translational medicine attempts to exploit biological theories and pathophysiological explanations to identify novel drug targets and therapeutic strategies. Yet because many theories in medicine are either incomplete (at best) or false (at worst), relying on theoretical explanations can have some puzzling and troubling consequences. New drugs may be shown to be effective in clinical trials and receive regulatory approval despite a faulty explanation for why they are effective. If physicians rely on this explanation to make treatment decisions, it can lead to systematic misdiagnoses and patient harm. For research programs, underdetermination may shield faulty biomedical explanations, and this can result in wasted research resources and avoidable burdens on human subjects. These problematic features of biomedical explanations can be resolved by reconceiving the epistemology of translational medicine in terms of heuristics.

Community-engaged Evidence Synthesis to Inform Public Health Policy and Clinical Practice: A Case Study.

BACKGROUND: This case study documents the work of the Rhode Island Arts and Health Advisory Group, which convened in 2016 to develop a set of policy, clinical practice, and research recommendations for implementation by the Rhode Island Department of Health, The Rhode Island State Council on the Arts, and partners. Comprised of artists, clinicians, community members, and patients, the group partnered with researchers to complete an evidence synthesis project of arts-based health care interventions. METHODS: The group took a community-engaged approach to evidence synthesis, featuring the use of online, and in-person training materials to facilitate the codesign and coexecution of the evidence synthesis protocol. The final evidence map was translated into an online evidence map to facilitate analysis and discussion on arts-based interventions in health care. RESULTS: The evidence map informed the development of recommendations for advancing the integration of arts and health in the state. The project evaluation indicated that our community-engaged approach to evidence synthesis promoted engagement as defined by the PCORI Engagement Strategy Rubric (ie, reciprocal relationships, partnership, colearning, transparency, honesty, and trust). Participation also improved community research partners confidence in engaging with the health care system, developed greater empathy and understanding of others in the community, and increased interest in using science or research in advocacy efforts. CONCLUSIONS: Engaging community partners in evidence synthesis promotes community dialogue and engagement in research, specifically towards: (1) elucidating outcomes of import to patients and communities that are not represented in the medical literature; and (2) identifying comparisons among interventions that resonate with patients and communities.

Challenges and Opportunities for Biomarker Validation.

Biomarkers can be powerful tools to guide diagnosis, treatment, and research. However, prudent use of bio-markers requires formal validation efforts. Although the data needed for biomarker validation has traditionally been hard to access, new research initiatives can ease this process.

Surrogate Endpoints and Drug Regulation: What Is Needed to Clarify the Evidence.

The FDA's new table of surrogate endpoints used for drug approvals is an important step forward for overseeing the use of biomarkers in clinical trials. Nevertheless, we present several ways in which the table can be improved.