Flying Blind: How Thorough are IRBs when Assessing Scientific Value?

Background: Institutional Review Boards (IRBs) in the United States play a crucial role in ensuring the ethical conduct of clinical trials, including assessing the scientific merit of studies to justify the risks to participants. However, prior research suggests that many IRBs do not systematically evaluate scientific merit, raising concerns about the approval of low-quality trials.

Objective: To investigate whether IRBs provide adequate guidance on assessing scientific merit in their Standard Operating Procedures (SOPs) and other relevant materials.

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.

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.

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.

An analysis of published trials found that current use of pragmatic trial labels is uninformative.

Objectives: Randomized trials labelled as "pragmatic" are attractive to funders, patients, and clinicians as the label implies that the results are directly applicable to clinical care. We examined how authors justify use of the label (e.g.

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).

Principal investigators over-optimistically forecast scientific and operational outcomes for clinical trials.

Objective: To assess the accuracy of principal investigators' (PIs) predictions about three events for their own clinical trials: positivity on trial primary outcomes, successful recruitment and timely trial completion.

Study Design And Setting: A short, electronic survey was used to elicit subjective probabilities within seven months of trial registration. When trial results became available, prediction skill was calculated using Brier scores (BS) and compared against uninformative prediction (i.

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.

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.

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.

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 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.

A search filter to identify pragmatic trials in MEDLINE was highly specific but lacked sensitivity.

Objectives: Identifying pragmatic trials from among all randomized trials is challenging because of inconsistent reporting. Our objective was to develop and validate a search filter to identify reports of pragmatic trials from Ovid MEDLINE.

Study Design And Setting: Two sets of known and probable pragmatic trial records were analyzed using text mining to generate candidate terms.

Evaluating the evidence behind the surrogate measures included in the FDA's table of surrogate endpoints as supporting approval of cancer drugs.

Background: In July 2018, the FDA first published a table listing all surrogate measures that it has used, and may accept for future use, in regulatory approval. However, the strength of surrogacy for those measures was not formally assessed. Using the case example of breast cancer, we aimed to evaluate the strength of correlation of surrogate measures listed in the FDA's Table with overall survival.

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.

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.

The ethical challenges raised in the design and conduct of pragmatic trials: an interview study with key stakeholders.

Background: There is a concern that the apparent effectiveness of interventions tested in clinical trials may not be an accurate reflection of their actual effectiveness in usual practice. Pragmatic randomized controlled trials (RCTs) are designed with the intent of addressing this discrepancy. While pragmatic RCTs may increase the relevance of research findings to practice they may also raise new ethical concerns (even while reducing others).

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.

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.

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.

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.