Benjamin S. Wilfond, Investigator, Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute; Professor, Division of Bioethics and Palliative Care, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA

Devan M. Duenas, Coordinator, Research Bioethics Consultation Service, Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, WA, USA

Liza-Marie Johnson, Investigator, Bioethics Consultant, and Associate Member (Professor), Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA

Holly A. Taylor, Research Bioethicist, Department of Bioethics, Clinical Center, National Institute of Health Bethesda, MD, USA

Foreword

Introduction

A Framework for Research Ethics. Principles of Research Ethics. Topics in Research Ethics . Values of Research Ethics.

Section 1. Collaborative Partnership

Introduction

Case 1.1 Supporting Community-Academic Research Partnerships: Reflections from the Ground

Commentary 1.1.1: Community Partnered Participatory Research in Southeast Louisiana Communities Threatened by Climate Change: The C-LEARN EXPERIENCE. Commentary 1.1.2: Leveraging Academic Institutional Structures to Support Asian American Community Organizations' Engagement in Research: The Korean Community Service Center. Commentary 1.1.3: Engaging the Sickle Cell Community in Participatory Research. Commentary 1.1.4: Being in Good Community: Engagement in Support of Indigenous Sovereignty.

Case 1.2 Protecting Research Subject Welfare in Preventative Trials for Autosomal Dominant Alzheimer's Disease

Commentary 1.2.1: When There Are Only Two Who Can Tango: Ethical Concerns at the Juncture of Highly Novel Interventions and Precisely Targeted Research Populations. Commentary 1.2.2: Conceptualization and Assessment of Vulnerability in a Complex International Alzheimer's Research Study. Commentary 1.2.3: Barriers and Facilitators to the Consent Process in a Study of ComplexGenetic Factors.

Case 1.3 Studying the Role of Financial Incentives to Promote Hepatitis B Vaccination in a Community Clinic

Commentary 1.3.1: Treatment Incentives and the Nature of the Doctor-Patient Relationship. Commentary 1.3.2: The Ethics of Studying Financial Incentives in Public Health Implementation: Study Design Challenges. Commentary 1.3.3: You Can Lead a Horse to Water, But Can You Pay to Make Him Drink? An Ethical Analysis of Research on Using Incentives to Promote Patient Health.

Case 1.4 A Cluster Randomized Trial to Screen for Abusive Head Trauma in the Paediatric Intensive Care Unit--How to Manage Site-Specific Evidence of Racial/Ethnic Disparity

Commentary 1.4.1: Issues of Justice and Risk: Setting Stopping Criteria in Cluster-Randomized Trials. Commentary 1.4.2: Clinical Trials Not Causing Harm with Potential for Realizing Benefit Should Continue. Commentary 1.4.3: Responding to Implicit Bias in Abusive Head Trauma Evaluations and Reporting in the PICU: Ethical Consideration During a Clinical Trial.

Case 1.5 When a Clinical Trial Is the Only Option

Commentary 1.5.1: "Respect for Persons," Not "Respect for Citizens". Commentary 1.5.2: The Potentially High Cost of a Free Clinical Trial. Commentary 1.5.3: Contextualizing "Choice" for Undocumented Immigrants in U.S. Clinical Trials Research.

Case 1.6 A Randomized Trial of Rapamycin to Increase Longevity and Healthspan in Companion Animals: Navigating the Boundary Between Protections for Animal Research and Human Subjects Research

Commentary 1.6.1: Rapamycin: Risking Harm for Canine Longevity. Commentary 1.6.2: Companion Animal Studies: Slipping Through a Research Oversight Gap. Commentary 1.6.3: Research to Promote Longevity and Health Span in Companion Dogs: A Paediatric Perspective.

Section 2. Respect for Participants

Introduction.

Case 2.1 Ethical Considerations for Unblinding a Participant's Assignment to Interpret a Resolved Adverse Event

Commentary 2.1.1: Considerations for Unblinding in Biopharmaceutical Industry

Sponsored Trials. Commentary 2.1.2: Blinds and Research Risks. Commentary 2.1.3: The Scientific and Social Implications of Unblinding a Study Subject.

Case 2.2 Should Research Participants Be Notified About Results of Currently Unknown by Potential Significance?

Commentary 2.2.1: The Need for National Guidance Around Informed Consent About GBCA Safety. Commentary 2.2.2: Returning Individual Research Results Regarding Gadolinium Deposition in the Brain Is the Preferable Choice. Commentary 2.2.3: Research Participants Should Have the Option to Be Notified of Results of Unknown but Potential Significance.

Case 2.3 The Ethics of Contacting Family Members of a Subject in a Genetic Research Study to Return Results for an Autosomal Dominant Syndrome

Commentary 2.3.1: What Does the Duty to Warn Require?Commentary 2.3.2: Should Researchers Disclose Results to Descendants?Commentary 2.3.3: Relationships Matter: Ethical Considerations for Returning Results to Family Members of Deceased Subjects.

Case 2.4 Ethics of Continuing to Provide a Drug on an Open-Label Extension Study for an "Unapproved Indication"

Commentary 2.4.1: When Should Open-Label Extension Studies Be Stopped? Commentary 2.4.2: The Role of Clinical Equipoise and Practical Considerations in Deciding Whether to Continue to Provide a Drug on an Open-Label Extension Study for an "Unapproved Indication". Commentary 2.4.3: Open-Label Extension Studies: Are They Really Research?

Case 2.5 Supporting Investigators in Challenging Cases: Unease in the Face of an Ethically Appropriate Action

Commentary 2.5.1: Researchers Experience Moral Distress Too!Commentary 2.5.2: Relieving Investigator Angst After an Appropriate but Concerning Ethics Consultation. Commentary 2.5.3: Acknowledging Angst: Research Ethics Consultation in Disclosing Experimental Research Results of Uncertain Benefit.

Case 2.6 Recontact and Recruitment of Young Adults Previously Enrolled in Neonatal Herpes Simplex Virus Research

Commentary 2.6.1: Research Recruitment of Adult Survivors of Neonatal Infections: Is There a Role for Parental Consent?Commentary 2.6.2: A Knotty Problem of Intertwined Rights. Commentary 2.6.3: Consent Is the Cornerstone of Ethically Valid Research: Ethical Issues in Recontacting Subjects Who Enrolled in Research as a Minor.

Case 2.7 Genotype-Driven Recruitment in Population-Based Biomedical Research

Commentary 2.7.1: Genotype-Driven Recruitment Without Deception. Commentary 2.7.2: Harms of Deception in FMR1 Premutation Genotype-Driven Recruitment. Commentary 2.7.3: Genotype-Driven Recruitment and the Disclosure of Individual Research Results.

Section 3. Fair Participant Selection

Introduction.

Case 3.1 Is It Ethical to Enrol Cognitively Impaired Adults in Research that is More than Minimal Risk with No Prospect of Benefit?

Commentary 3.1.1: Inconsistent Approaches to Research Involving Cognitively Impaired Adults: Why the Broad View of Substituted Judgment Is Our Best Guide. Commentary 3.1.2: Ethical and Regulatory Considerations Regarding Enrolment of Incompetent Adults in More Than Minimal Risk Research as Compared with Children. Commentary 3.1.3: Acceptable Approaches to Enrolling Adults Who Cannot Consent in More Than Minimal Risk Research.

Case 3.2 Should Patients Be Required to Undergo Standard Chemotherapy Before Being Eligible for Novel Phase I Immunotherapy Clinical Trials?

Commentary 3.2.1: A Rationale for Relaxing the Requirement to Undergo a Noncurative Chemotherapy for Advanced Cancer in a Phase I Immunotherapy Trial. Commentary 3.2.2: Participation of Citizen Scientists in Clinical Research and Access to Research Ethics Consultation. Commentary 3.2.3: Forgoing Conventional Therapy in Phase I Oncology Research: Don't Forget About the Children.

Case 3.3 Involving Pregnant Women in Research: What Should We Recommend When the Regulations Seem Ethically Problematic?

Commentary 3.3.1: Conflicts Between Regulations and Ethical Principles: Resolving Ambiguity in Favour of the Ethically Preferable Outcome. Commentary 3.3.2: When to Avoid Giving Advice on the Ethical Conduct of Research. Commentary 3.3.3: When Research Regulations and Ethics Conflict.

Case 3.4 Regulatory, Legal, Ethical, and Practical Challenges of Enrolling Wards of the State in Research

Commentary 3.4.1: Fuzzy Logic: How the Practicalities of State Involvement Shape the Most Ethically Supportable Way Forward. Commentary 3.4.2: Enrolling Foster Youth in Clinical Trials: Avoiding the Harm of Exclusion. Commentary 3.4.3: No Justification to Exclude State Ward from Paediatric Transplant Research. Commentary 3.4.4: Life-Saving Experimental Treatment for a Teenage Ward of the State.

Case 3.5 Selecting Children for an Autism Spectrum Disorder Study: Justice and Geography

Commentary 3.5.1: Fair Participant Selection: A Negative Obligation Not to Exclude. Commentary 3.5.2: Unequal Individual Risk and Potential Benefit Balanced by Benefits to the Population at Large in Autism Clinical Trials? Commentary 3.5.3: Justice in Selecting Participants for a Study in Phelan-McDermid Syndrome.

Section 4. Favourable Risk-Benefit Ratio

Introduction.

Case 4.1 Obligations to Act on Patient Reported Outcomes in Electronic Health Records

Commentary 4.1.1: Informed Consent for PROs in EHR Research: Are Additional Requirements Necessary? Commentary 4.1.2: Patient Reported Outcomes at the Crossroads of Clinical Research and Informatics. Commentary 4.1.3: PROs in the Balance: Ethical Implications of Collecting Patient Reported Outcome Measures in the Electronic Health Record.

Case 4.2 A Trial to Test a Novel Approach to Diabetes Prevention

Commentary 4.2.1: Is It Ethically Acceptable to Screen Patients for Obstructive Sleep Apnea and Not Offer Them Positive Air Pressure Therapy in a Clinical Trial? Commentary 4.2.2: Can We...