The ethical value of consulting community members in non-emergency trials conducted with waivers of informed consent for research.

There is growing interest in using embedded research methods, particularly pragmatic clinical trials, to address well-known evidentiary shortcomings afflicting the health care system. Reviews of pragmatic clinical trials published between 2014 and 2019 found that 8.8% were conducted with waivers of informed consent; furthermore, the number of trials where consent is not obtained is increasing with time. From a regulatory perspective, waivers of informed consent are permissible when certain conditions are met, including that the study involves no more than minimal risk, that it could not practicably be carried out without a waiver, and that waiving consent does not violate participants' rights and welfare. Nevertheless, when research is conducted with a waiver of consent, several ethical challenges arise. We must consider how to: address empirical evidence showing that patients and members of the public generally prefer prospective consent, demonstrate respect for persons using tools other than consent, promote public trust and investigator integrity, and ensure an adequate level of participant protections. In this article, we use examples drawn from real pragmatic clinical trials to argue that prospective consultation with representatives of the target study population can address, or at least mitigate, many of the ethical challenges posed by waivers of informed consent. We also consider what consultation might involve to illustrate its feasibility and address potential objections.

Enhancing social value considerations in prioritising publicly funded biomedical research: the vital role of peer review.

The main goal of publicly funded biomedical research is to generate social value through the creation and application of knowledge that can improve the well-being of current and future people. Prioritising research with the greatest potential social value is crucial for good stewardship of limited public resources and ensuring ethical involvement of research participants. At the National Institutes of Health (NIH), peer reviewers hold the expertise and responsibility for social value assessment and resulting prioritisation at the project level. However, previous research has shown that peer reviewers place more emphasis on a study's methods ('Approach') than on its potential social value (best approximated by the criterion of 'Significance'). Lower weighting of Significance may be due to reviewers' views on the relative importance of social value, their belief that social value is evaluated at other stages of the research priority-setting process or the lack of guidance on how to approach the challenging task of assessing expected social value. The NIH is currently revising its review criteria and how these criteria contribute to overall scores. To elevate the role of social value in priority setting, the agency should support empirical research on how peer reviewers approach the assessment of social value, provide more specific guidance for reviewing social value and experiment with alternative reviewer assignment strategies. These recommendations would help ensure that funding priorities align with the NIH's mission and the obligation of taxpayer-funded research to contribute to the public good.

Establishing a global regulatory floor for children's decisions about participation in clinical research.

BACKGROUND: Enrolling children in clinical trials typically requires parental or guardian permission and, when appropriate, child assent. Aligning requirements across jurisdictions would facilitate multisite pediatric trials. Guidance from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is the best candidate for a global standard but would benefit from additional specification. METHODS: Ethical analysis of ICH guidance for permission and assent for pediatric trials, with recommendations for clarification. RESULTS: ICH guidance regarding permission and assent would be enhanced by additional detail in the following areas: (1) what information should be provided to parents, guardians, and children considering a trial, and how that information should be provided; (2) the definition of "assent," the criteria for when assent should be required, and the need to include children in discussions even when assent is not mandated; (3) criteria for requiring children's signatures indicating agreement; (4) greater specificity regarding children's right to decline or withdraw; and (5) clarification of when children's wish to decline or withdraw from participation may be overridden and of what the overriding process should entail. CONCLUSION: ICH guidance provides a global standard for decision making regarding children's participation in trials. Several clarifications would facilitate the conduct of multinational pediatric research. IMPACT: Enrolling children in clinical trials requires the permission of a parent/guardian ± the assent of the minor. Differing global regulatory requirements for enrolling children complicate the conduct of multicenter and multinational trials. The authors identify points of ambiguity and/or contradiction in the International Council for Harmonization guidelines and offer recommendations for a common ethical platform for conducting global pediatric research.

Ethical Responsibilities for Companies That Process Personal Data.

It has become increasingly difficult for individuals to exercise meaningful control over the personal data they disclose to companies or to understand and track the ways in which that data is exchanged and used. These developments have led to an emerging consensus that existing privacy and data protection laws offer individuals insufficient protections against harms stemming from current data practices. However, an effective and ethically justified way forward remains elusive. To inform policy in this area, we propose the Ethical Data Practices framework. The framework outlines six principles relevant to the collection and use of personal data-minimizing harm, fairly distributing benefits and burdens, respecting autonomy, transparency, accountability, and inclusion-and translates these principles into action-guiding practical imperatives for companies that process personal data. In addition to informing policy, the practical imperatives can be voluntarily adopted by companies to promote ethical data practices.

Data and Safety Monitoring of COVID-19 Vaccine Clinical Trials.

To speed the development of vaccines against SARS-CoV-2, the United States Federal Government has funded multiple phase 3 trials of candidate vaccines. A single 11-member data and safety monitoring board (DSMB) monitors all government-funded trials to ensure coordinated oversight, promote harmonized designs, and allow shared insights related to safety across trials. DSMB reviews encompass 3 domains: (1) the conduct of trials, including overall and subgroup accrual and data quality and completeness; (2) safety, including individual events of concern and comparisons by randomized group; and (3) interim analyses of efficacy when event-driven milestones are met. Challenges have included the scale and pace of the trials, the frequency of safety events related to the combined enrollment of over 100 000 participants, many of whom are older adults or have comorbid conditions that place them at independent risk of serious health events, and the politicized environment in which the trials have taken place.

An ethics framework for consolidating and prioritizing COVID-19 clinical trials.

Given the dearth of established safe and effective interventions to respond to COVID-19, there is an urgent ethical imperative to conduct meaningful clinical research. The good news is that interventions to be tested are not in short supply. Unfortunately, the human and material resources needed to conduct these trials are finite. It is essential that trials be robust and meet enrollment targets and that lower-quality studies not be permitted to displace higher-quality studies, delaying answers to critical questions. Yet, with few exceptions, existing research review bodies and processes are not designed to ensure these conditions are satisfied. To meet this challenge, we offer guidance for research institutions about how to ethically consolidate and prioritize COVID-19 clinical trials, while recognizing that consolidation and prioritization should also take place upstream (among manufacturers and funders) and at a higher level (e.g. nationally). In our proposed three-stage process, trials must first meet threshold criteria. Those that do are evaluated in a second stage to determine whether the institution has sufficient capacity to support all proposed trials. If it does not, the third stage entails evaluating studies against two additional sets of comparative prioritization criteria: those specific to the study and those that aim to advance diversification of an institution's research portfolio. To implement these criteria fairly, we propose that research institutions form COVID-19 research prioritization committees. We briefly discuss some important attributes of these committees, drawing on the authors' experiences at our respective institutions. Although we focus on clinical trials of COVID-19 therapeutics, our guidance should prove useful for other kinds of COVID-19 research, as well as non-pandemic research, which can raise similar challenges due to the scarcity of research resources.

Allocating scarce life-saving resources: the proper role of age.

The COVID-19 pandemic has forced clinicians, policy-makers and the public to wrestle with stark choices about who should receive potentially life-saving interventions such as ventilators, ICU beds and dialysis machines if demand overwhelms capacity. Many allocation schemes face the question of whether to consider age. We offer two underdiscussed arguments for prioritising younger patients in allocation policies, which are grounded in prudence and fairness rather than purely in maximising benefits: prioritising one's younger self for lifesaving treatments is prudent from an individual perspective, and prioritising younger patients works to narrow health disparities by giving priority to patients at risk of dying earlier in life, who are more likely to be subject to systemic disadvantage. We then identify some confusions in recent arguments against considering age.

Pediatric reporting of genomic results study (PROGRESS): a mixed-methods, longitudinal, observational cohort study protocol to explore disclosure of actionable adult- and pediatric-onset genomic variants to minors and their parents.

BACKGROUND: Exome and genome sequencing are routinely used in clinical care and research. These technologies allow for the detection of pathogenic/likely pathogenic variants in clinically actionable genes. However, fueled in part by a lack of empirical evidence, controversy surrounds the provision of genetic results for adult-onset conditions to minors and their parents. We have designed a mixed-methods, longitudinal cohort study to collect empirical evidence to advance this debate. METHODS: Pediatric participants in the Geisinger MyCode® Community Health Initiative with available exome sequence data will have their variant files assessed for pathogenic/likely pathogenic variants in 60 genes designated as actionable by MyCode. Eight of these genes are associated with adult-onset conditions (Hereditary Breast and Ovarian Cancer Syndrome (HBOC), Lynch syndrome, MUTYH-associated polyposis, HFE-Associated Hereditary Hemochromatosis), while the remaining genes have pediatric onset. Prior to clinical confirmation of results, pediatric MyCode participants and their parents/legal guardians will be categorized into three study groups: 1) those with an apparent pathogenic/likely pathogenic variant in a gene associated with adult-onset disease, 2) those with an apparent pathogenic/likely pathogenic variant in a gene associated with pediatric-onset disease or with risk reduction interventions that begin in childhood, and 3) those with no apparent genomic result who are sex- and age-matched to Groups 1 and 2. Validated and published quantitative measures, semi-structured interviews, and a review of electronic health record data conducted over a 12-month period following disclosure of results will allow for comparison of psychosocial and behavioral outcomes among parents of minors (ages 0-17) and adolescents (ages 11-17) in each group. DISCUSSION: These data will provide guidance about the risks and benefits of informing minors and their family members about clinically actionable, adult-onset genetic conditions and, in turn, help to ensure these patients receive care that promotes physical and psychosocial health. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03832985. Registered 6 February 2019.

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine.

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.

Ethical considerations in genomic testing for hematologic disorders.

As our technological capacities improve, genomic testing is increasingly integrating into patient care. The field of clinical hematology is no exception. Genomic testing carries great promise, but several ethical issues must be considered whenever such testing is performed. This review addresses these ethical considerations, including issues surrounding informed consent and the uncertainty of the results of genomic testing; the challenge of incidental findings; and possible inequities in access to and benefit from such testing. Genomic testing is likely to transform the practice of both benign and malignant hematology, but clinicians must carefully consider these core ethical issues in order to make the most of this exciting and evolving technology.

When Is It Ethical for Physician-Investigators to Seek Consent From Their Own Patients?

Classic statements of research ethics advise against permitting physician-investigators to obtain consent for research participation from patients with whom they have preexisting treatment relationships. Reluctance about "dual-role" consent reflects the view that distinct normative commitments govern physician-patient and investigator-participant relationships, and that blurring the research-care boundary could lead to ethical transgressions. However, several features of contemporary research demand reconsideration of the ethics of dual-role consent. Here, we examine three arguments advanced against dual-role consent: that it creates role conflict for the physician-investigator; that it can compromise the voluntariness of the patient-participant's consent; and that it promotes therapeutic misconceptions. Although these concerns have merit in some circumstances, they are not dispositive in all cases. Rather, their force-and the ethical acceptability of dual-role consent-varies with features of the particular study. As research participation more closely approximates usual care, it becomes increasingly acceptable, or even preferable, for physicians to seek consent for research from their own patients. It is time for a more nuanced approach to dual-role consent.

The Multidimensional Illness Severity Questionnaire: Preliminary evaluation of a brief parent-reported measure of illness severity.

AIM: This study describes the reliability and concurrent validity of the Multidimensional Illness Severity Questionnaire (MISQ), a five-item measure for capturing parents' reports of their child's illness severity. METHODS: We conducted a cross-sectional survey of parents of children participating in a paediatric research study (n = 20). We assessed parents' perceptions of illness severity using five measures: (i) the MISQ, (ii) the Lansky Play Performance scale, (iii) the Severity of Illness Scale, (iv) subscales of the Parent Experience of Child Illness and (v) general health. We calculated the internal reliability of the MISQ using Cronbach's alpha and assessed concurrent validity through correlations between scores on the MISQ and other measures. RESULTS: MISQ scores ranged from 6/21 to 17/21 (mean = 11.5). The MISQ had adequate internal consistency (Cronbach's α = 0.76) and correlated strongly with other measures. CONCLUSION: Preliminary evaluation suggests that the MISQ is an easy-to-administer and internally consistent multidimensional assessment of parent-reported illness severity.

Easy-to-Read Informed Consent Form for Hematopoietic Cell Transplantation Clinical Trials: Results from the Blood and Marrow Transplant Clinical Trials Network 1205 Study.

Because of the complexity of hematopoietic cell transplant trial treatments, informed consent forms are often long and difficult to read. We evaluated a 2-column easy-to-read informed consent (ETRIC) form that incorporates elements of health literacy and readability in participants and centers participating in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) clinical trials. In a randomized study 198 adult patients from 25 centers potentially eligible to participate in 4 BMT CTN interventional trials were randomized to the ETRIC form or a standard consent form for that trial. Both forms were written at no more than an eighth-grade reading level. The primary endpoint was objective comprehension score on the Quality of Informed Consent, part A (QuIC-A) instrument. In a parallel evaluation study, 2 moderators conducted semistructured interviews of 49 investigators, research staff, and institutional review board (IRB) members at 9 BMT CTN trial sites. The mean QuIC-A scores were comparable in 152 patients (77%) assessable for the primary endpoint (ETRIC form, 80.5; standard form, 81.8; P = .37). In regression analysis there was no significant association between the consent type and QuIC-A score. In the evaluation study dominant themes identified on qualitative analyses included general comfort and willingness to use the ETRIC template and that its formatting and layout enhancements would offer additional value to research participants, investigators, and IRBs. IRB language preferences and requirements, length, and prior experience with alternative consent formats were perceived as barriers. Among patients considering participation in BMT CTN clinical trials, the formatting enhancements of the ETRIC form did not alter comprehension of the trial. Despite local challenges to implementation, trial sites generally viewed the ETRIC form favorably and expressed willingness to use it over standard consent form.

Will my child do better if she enrolls in a clinical trial?

The question of whether children with cancer who enroll in clinical trials have superior outcomes compared with those who do not participate has been pursued for more than 4 decades, and recent studies have provided conflicting answers. Whether clinical trial participation influences outcome has important implications for how clinicians should present trial participation to patients and families. Methodological challenges limit generalizations about the impact of clinical trial participation on outcome compared with nonparticipation. Oncologists should inform patients and families that clinical trials are the engine for future progress because they identify more effective therapies and that clinical trial participation is a reasonable option to consider for children with cancer. However, as noted in by Truong and colleagues in this issue, the rationale for trial enrollment should not include an expectation of better outcomes compared with nonenrollment.

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.

The benefit sharing vision of H3Africa.

One of the central ethical tenets of research in developing countries is the sponsor's obligation to benefit host participants and communities. Two known models of benefits provision dominate the ethical discourse of research in developing countries. The first model, known as the "reasonable availability," endorses the obligation to provide interventions proven to be effective at the end of a study. This contrasts with the second model, known as "fair benefits," which endorses other forms of benefits that host communities may deem as fair beyond those derived directly from the study's findings. This paper explores a third benefit model consistent with the writings of the Human Hereditary and Health in Africa (H3Africa) research initiative. The H3Africa-a North-South collaborative initiative predicated by U.S. National Institutes of Health, the Wellcome Trust and the African Society of Human Genetics upholds a benefit model that endorses capacity building as the primary obligation of its research agenda. This is evident by the endorsement of mechanisms to strengthen capacity building in its research projects. While capacity building remains a plausible means of improving the expertise, quality and independence of research in Africa, sustainable measures are needed to realizing the full potential for African-led research on the continent.

Biomarker-Defined Subsets of Common Diseases: Policy and Economic Implications of Orphan Drug Act Coverage.

Aaron Kesselheim and colleagues examine orphan-designated drugs approved between 2009 and 2015 in the United States.