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.

The Genomics Research and Innovation Network: creating an interoperable, federated, genomics learning system.

PURPOSE: Clinicians and researchers must contextualize a patient's genetic variants against population-based references with detailed phenotyping. We sought to establish globally scalable technology, policy, and procedures for sharing biosamples and associated genomic and phenotypic data on broadly consented cohorts, across sites of care. METHODS: Three of the nation's leading children's hospitals launched the Genomic Research and Innovation Network (GRIN), with federated information technology infrastructure, harmonized biobanking protocols, and material transfer agreements. Pilot studies in epilepsy and short stature were completed to design and test the collaboration model. RESULTS: Harmonized, broadly consented institutional review board (IRB) protocols were approved and used for biobank enrollment, creating ever-expanding, compatible biobanks. An open source federated query infrastructure was established over genotype-phenotype databases at the three hospitals. Investigators securely access the GRIN platform for prep to research queries, receiving aggregate counts of patients with particular phenotypes or genotypes in each biobank. With proper approvals, de-identified data is exported to a shared analytic workspace. Investigators at all sites enthusiastically collaborated on the pilot studies, resulting in multiple publications. Investigators have also begun to successfully utilize the infrastructure for grant applications. CONCLUSIONS: The GRIN collaboration establishes the technology, policy, and procedures for a scalable genomic research network.

Correction: The Genomics Research and Innovation Network: creating an interoperable, federated, genomics learning system.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Guidelines for return of research results from pediatric genomic studies: deliberations of the Boston Children's Hospital Gene Partnership Informed Cohort Oversight Board.

PURPOSE: Approaches to return individual results to participants in genomic research variably focus on actionability, duty to share, or participants' preferences. Our group at Boston Children's Hospital has prioritized participants' preferences by implementing the Gene Partnership, a genomic research repository, based on the "Informed Cohort" model that offers return of results in accordance with participant preferences. Recognizing that ethical oversight is essential, the Gene Partnership Informed Cohort Oversight Board was convened in 2009. METHODS: Over 3 years, the Informed Cohort Oversight Board developed guidelines for the return of individual genomic research results. RESULTS: The Informed Cohort Oversight Board defined its guiding principles as follows: to respect the developing autonomy of pediatric participants and parental decision-making authority by returning results consistent with participants' preferences and to protect participants from harm. Potential harms and strategies to eliminate harm were identified. Guidelines were developed for participant preferences that consider the child's development and family dynamics. The Informed Cohort Oversight Board agreed that to prevent harm, including harms related to interfering with a child's future autonomy, there will be results that should not be returned regardless of participant preferences. CONCLUSION: The Informed Cohort Oversight Board developed guidelines for the return of results that respect the preferences of parents, children, and adult participants while seeking to protect against harm.

Establishing a Pediatric Health Equity, Diversity, and Inclusion Research Review Process.

Equity, diversity, and inclusion (EDI) research is increasing, and there is a need for a more standardized approach for methodological and ethical review of this research. A supplemental review process for EDI-related human subject research protocols was developed and implemented at a pediatric academic medical center (AMC). The goal was to ensure that current EDI research principles are consistently used and that the research aligns with the AMC's declaration on EDI. The EDI Research Review Committee, established in January 2022, reviewed EDI protocols and provided recommendations and requirements for addressing EDI-related components of research studies. To evaluate this review process, the number and type of research protocols were reviewed, and the types of recommendations given to research teams were examined. In total, 78 research protocols were referred for EDI review during the 20-month implementation period from departments and divisions across the AMC. Of these, 67 were given requirements or recommendations to improve the EDI-related aspects of the project, and 11 had already considered a health equity framework and implemented EDI principles. Requirements or recommendations made applied to 1 or more stages of the research process, including design, execution, analysis, and dissemination. An EDI review of human subject research protocols can provide an opportunity to constructively examine and provide feedback on EDI research to ensure that a standardized approach is used based on current literature and practice.

Children's rare disease cohorts: an integrative research and clinical genomics initiative.

While genomic data is frequently collected under distinct research protocols and disparate clinical and research regimes, there is a benefit in streamlining sequencing strategies to create harmonized databases, particularly in the area of pediatric rare disease. Research hospitals seeking to implement unified genomics workflows for research and clinical practice face numerous challenges, as they need to address the unique requirements and goals of the distinct environments and many stakeholders, including clinicians, researchers and sequencing providers. Here, we present outcomes of the first phase of the Children's Rare Disease Cohorts initiative (CRDC) that was completed at Boston Children's Hospital (BCH). We have developed a broadly sharable database of 2441 exomes from 15 pediatric rare disease cohorts, with major contributions from early onset epilepsy and early onset inflammatory bowel disease. All sequencing data is integrated and combined with phenotypic and research data in a genomics learning system (GLS). Phenotypes were both manually annotated and pulled automatically from patient medical records. Deployment of a genomically-ordered relational database allowed us to provide a modular and robust platform for centralized storage and analysis of research and clinical data, currently totaling 8516 exomes and 112 genomes. The GLS integrates analytical systems, including machine learning algorithms for automated variant classification and prioritization, as well as phenotype extraction via natural language processing (NLP) of clinical notes. This GLS is extensible to additional analytic systems and growing research and clinical collections of genomic and other types of data.

Determining risk in pediatric research with no prospect of direct benefit: time for a national consensus on the interpretation of federal regulations.

United States federal regulations for pediatric research with no prospect of direct benefit restrict institutional review board (IRB) approval to procedures presenting: 1) no more than "minimal risk" ( section sign 45CFR46.404); or 2) no more than a "minor increase over minimal risk" if the research is commensurate with the subjects' previous or expected experiences and intended to gain vitally important information about the child's disorder or condition ( section sign 45CFR46.406) (DHHS 2001). During the 25 years since their adoption, these regulations have helped IRBs balance subject protections with the pursuit of scientific knowledge to advance children's welfare. At the same time, inconsistency in IRB application of these regulations to pediatric protocols has been widespread, in part because of the ambiguity of the regulatory language. During the past decade, three federally-charged committees have addressed these ambiguities: 1) the National Human Research Protections Advisory Committee (NHRPAC) (Washington, DC), 2) the Institute of Medicine (IOM) Committee on the Ethical Conduct of Clinical Research Involving Children (Washington, DC); and 3) the United States Department of Health and Human Services Secretary's Advisory Committee for Human Research Protections (SACHRP) (Washington, DC). The committees have reached similar conclusions on interpretation of language within regulations section sign section sign 45CFR46.404 and 406; these conclusions are remarkably consistent with recent international recommendations and those of the original National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1977) report from which current regulations are based. Drawing on the committees' public reports, this article identifies the ethical issues posed by ambiguities in regulatory language, summarizes the committees' deliberations, and calls for a national consensus on recommended criteria.

Development of the Precision Link Biobank at Boston Children's Hospital: Challenges and Opportunities.

Increasingly, biobanks are being developed to support organized collections of biological specimens and associated clinical information on broadly consented, diverse patient populations. We describe the implementation of a pediatric biobank, comprised of a fully-informed patient cohort linking specimens to phenotypic data derived from electronic health records (EHR). The Biobank was launched after multiple stakeholders' input and implemented initially in a pilot phase before hospital-wide expansion in 2016. In-person informed consent is obtained from all participants enrolling in the Biobank and provides permission to: (1) access EHR data for research; (2) collect and use residual specimens produced as by-products of routine care; and (3) share de-identified data and specimens outside of the institution. Participants are recruited throughout the hospital, across diverse clinical settings. We have enrolled 4900 patients to date, and 41% of these have an associated blood sample for DNA processing. Current efforts are focused on aligning the Biobank with other ongoing research efforts at our institution and extending our electronic consenting system to support remote enrollment. A number of pediatric-specific challenges and opportunities is reviewed, including the need to re-consent patients when they reach 18 years of age, the ability to enroll family members accompanying patients and alignment with disease-specific research efforts at our institution and other pediatric centers to increase cohort sizes, particularly for rare diseases.

Ethics of Placebo Control in Trials for Idiopathic Sudden Sensorineural Hearing Loss.

Idiopathic sudden sensorineural hearing loss (ISSHL) involves sudden loss of hearing from cochlear or retrocochlear origin of unknown cause. Systemic corticosteroids may be considered in the management of ISSNHL. However, an updated Cochrane systematic review concludes that "the value of steroids in the treatment of idiopathic sudden sensorineural hearing loss remains unclear since the evidence obtained from randomized controlled trials is contradictory in outcome." Therefore, a new clinical trial that addresses this question is mandatory. A first step in its design is to determine if placebo control would be ethically acceptable. We conclude that there is equipoise (uncertainty) about the use of corticosteroids for ISSHL. A new trial is justified-but with the inclusion of interim analyses to detect early imbalances on efficacy or safety and with the ability to stop the trial if needed.

Engaging Institutional Review Boards in Developing a Brief, Community-Responsive Human Subjects Training for Community Partners.

BACKGROUND: Engaging community partners as co-investigators in community-based participatory research (CBPR) requires certification in the rules, ethics, and principles governing research. Despite developments in making human research protection trainings more convenient and standardized (eg, self-paced Internet modules), time constraints and the structure of the content (which may favor academic audiences) may hinder the training of community partners. OBJECTIVES: This paper is motivated by a case example in which academic and community partners, and stakeholders of a community-based organization actively engaged the leadership of a pediatric hospital-based institutional review board (IRB) in implementing a brief, community-responsive human subjects training session. METHODS: A 2-hour, discussion-based human subjects training was developed via collaborations between the IRB and the community and academic partners. Interviews with trainees and facilitators after the training were used to evaluate its acceptability and possible future applications. CONCLUSIONS: Local IRBs have the potential to assist community partners in building sufficient knowledge of human subjects research protections to engage in specific projects, thereby expediting the progress of vital research to address community needs. We propose the need for developing truncated human subjects education materials to train and certify community partners, and creating formally organized entities within academic and medical institutions that specialize in community-based research to guide the development and implementation of alternative human subjects training certification opportunities for community partners.