Vasiliki Rahimzadeh

Genetics and primary care: where are we headed?

Since first sequencing the human genome in 2003, emerging genetic/genomic technologies have ushered in a revolutionary era of medicine that purports to bridge molecular biology and clinical care. The field of translational medicine is charged with mediating this revolution. Sequencing innovations are far outpacing guidelines intended to ease their practice-based applications, including in primary care. As a result, genomic medicine’s full integration in primary care settings especially, has been slow to materialize. Researchers and clinicians alike face substantial challenges in navigating contentious ethical issues raised in translation and implementation, namely preserving the spirit of whole-person approaches to care; maintaining respect for persons and communities; and translating genetic risk into clinical actionability. This commentary therefore explores practical barriers to, and ethical implications of, incorporating genomic technologies in the primary care sector. These ethical challenges are both philosophical and infrastructural. From a primary care perspective, the commentary further reviews the ethical, legal and social implications of the Center for Disease Control’s proposed model for assessing the validity and utility of genomic testing and family health history applications. Lastly, the authors provide recommendations for future translational initiatives that aim to maximize the capacities of genomic medicine, without compromising primary care philosophies and foundations of practice.

To disclose, or not to disclose? Context matters

Progress in understanding childhood disease using next-generation sequencing (NGS) portends vast improvements in the nature and quality of patient care. However, ethical questions surrounding the disclosure of incidental findings (IFs) persist, as NGS and other novel genomic technologies become the preferred tool for clinical genetic testing. Thus, the need for comprehensive management plans and multidisciplinary discussion on the return of IFs in pediatric research has never been more immediate. The aim of this study is to explore the views of investigators concerning the return of IFs in the pediatric oncology research context. Our findings reveal at least four contextual themes underlying the ethics of when, and how, IFs could be disclosed to participants and their families: clinical significance of the result, respect for individual, scope of professional responsibilities, and implications for the healthcare/research system. Moreover, the study proposes two action items toward anticipatory governance of IF in genetic research with children. The need to recognize the multiplicity of contextual factors in determining IF disclosure practices, particularly as NGS increasingly becomes a centerpiece in genetic research broadly, is heightened when children are involved. Sober thought should be given to the possibility of discovering IF, and to proactive discussions about disclosure considering the realities of young participants, their families, and the investigators who recruit them.

Statement of principles on the return of research results and incidental findings in paediatric research: a multi-site consultative process.

This paper proposes a set of recommendations for the return of research results and incidental findings in paediatrics. The Network of Applied Genetic Medicine of Quebec spearheaded the initiative to develop the Statement of Principles on the Return of Research Results and Incidental Findings, which was the result of a consultation process with clinical and research experts in the field. To formulate the Statement of Principles, the authors (i) reviewed empirical and grey literature on the return of research results and incidental findings in Europe and Canada, (ii) conducted a qualitative study of stakeholder groups, (iii) developed, and (iv) validated the recommendations through consultations with the stakeholder groups. The Statement of Principles provides a useful disclosure tool for deciding when, and under what circumstances to return research results and incidental findings. It addresses the issue of return of results in genetic research generally, and has also specific principles for various research contexts, including paediatric research. It delineates ethical issues unique to paediatric research, and provides a framework to guide research ethics committees as well as the research community in addressing these issues.

Promoting an ethic of engagement in pediatric palliative care research.

BackgroundThis paper defends the ethical and empirical significance of direct engagement with terminally ill children and adolescents in PPC research on health-related quality of life. Clinical trials and other forms of health research have resulted in tremendous progress for improving clinical outcomes among children and adolescents diagnosed with a life-threatening illness. Less attention has been paid, however, to engaging this patient population directly in studies aimed at optimizing health-related quality of life in PPC. Though not restricted to care at the end of life, PPC—and by extension PPC research—is in part dependent on recognizing the social complexities of death and dying and where health-related quality of life is a fundamental element. To explore these complexities in depth requires partnership with terminally ill children and adolescents, and acknowledgement of their active social and moral agency in research.DiscussionPrinciples of pediatric research ethics, theoretical tenets of the “new sociology of the child(hood),” and human rights codified in the United Nations Convention on the Rights of the Child (UNCRC) underpin the position that a more engagement-centered approach is needed in PPC research. The ethics, sociologies and human rights of engagement will each be discussed as they relate to research with terminally ill children and adolescents in PPC. Qualitative method(ologies) presented in this paper, such as deliberative stakeholder consultations and phenomenology of practice can serve as meaningful vehicles for achieving i) participation among terminally ill children and adolescents; ii) evidence-bases for PPC best practices; and iii) fulfillment of research ethics principles.ConclusionPPC research based on direct engagement with PPC patients better reflects their unique expertise and social epistemologies of terminal illness. Such an approach to research would strengthen both the ethical and methodological soundness of HRQoL inquiry in PPC.

Uncertainty and innovation: Understanding the role of cell-based manufacturing facilities in shaping regulatory and commercialization environments

The purpose of this qualitative study is to elucidate stakeholder perceptions of, and institutional practices related to cell-based therapies and products (CTP) regulation and commercialization in Canada. The development of reproducible, safe and effective CTPs is predicated on regulatory and commercialization environments that enable innovation. Manufacturing processes constitute a critical step for CTP development in this regard. The road from CTP manufacturing to translation in the clinic, however, has yet to be paved. This study aims to fill an empirical gap in the literature by exploring how CTP manufacturing facilities navigate Canadian regulatory and commercialization environments, which together drive the translation of novel CTPs from bench to bedside. Using the multi-level model of practice-driven institutional change proposed by Smets et al., we demonstrate how CTP manufacturing practices are governed by established standards, yet meaningfully shape higher-order regulatory and commercial norms in CTP research and development. We identify four key themes that undergird such processes of innovation: 1) managing regulatory uncertainty, which stems from an inability to classify CTPs within existing regulatory categories for approval and commercialization purposes; 2) building a ‘business case’ whereby a CTPs market potential is determined in large part by proving its safety and effectiveness; 3) standardizing manufacturing procedures that mobilize CTPs from a research and development phase to a commercialization one; and 4) networking between researchers and regulators to develop responsible commercialization processes that reflect the uniqueness of CTPs as distinct from other biologics and medical devices.

Streamlining review of research involving humans: Canadian models

Biomedical research post sequencing of the first human genome is increasingly eroding a traditional ecology of individualist science. It is, furthermore, normalising collective innovation and shared scientific discovery.1 ,2 Achieving sound statistical power in a genome-wide association study, for example, can often be well beyond the scope of any one researchers capacity. For this reason and others, the scientific imperative of research collaboration can be more pronounced in the ‘omics’ disciplines,3 where millions of data points are needed to make global inferences about links between the human genome and disease.4 From the scientific necessity to adequately power a study through research collaborations is also born an ethical imperative to do so. That is, the anticipated benefits and harms of a particular study are justified based on the researchers’ sound predictions about potential outcomes and contributions to knowledge. Either underestimating or overestimating translational possibilities can disturb the benefit–harm balance due largely to insufficient statistical power.5 Two important milestones, therefore, rest on this bench-to-bedside continuum for ‘omics’ research, and are essential for any clinical translation endeavour: research ethics and data-access reviews. The former ensures appropriate ongoing ethical oversight and participant protections, while the latter enables research collaboration by providing researchers with access to data. Debates surrounding traditional issues facing such reviews are ubiquitous in the literature, yet little attention has been paid to how these issues are exacerbated when studies span across multiple jurisdictions. This is particularly true for research typified in the ‘omics’ disciplines, where international collaboration is the norm rather than the exception. Here, a distinction between multi-site and multi-jurisdictional research should be emphasised. While multi-site research implies that the project takes place across many individual sites, multi-jurisdictional research involves sites in different legal jurisdictions. Multi-jurisdictional research along with the ethics review processes required to …

Key Implications of Data Sharing in Pediatric Genomics

Accurate clinical interpretation of children’s whole-genome and whole-exome sequences relies on comparing the patient’s linked genomic and phenotypic data with variant reference databases of both healthy and affected patients. The robustness of such comparisons, in turn, is made possible by sharing pediatric genomic and associated clinical data. Despite this, sparse ethical-legal policy attention has been paid to making such sharing routine in practice. The interdisciplinary Paediatric Task Team of the Global Alliance for Genomics and Health considered in detail the current ethical, legal, and social implications of sharing genomic and associated clinical data involving children. An initial set of points to consider was presented at a meeting of the Paediatric Task Team at the 4th Plenary of the Global Alliance for Genomics and Health. The Key Implications for Data Sharing (KIDS) framework for pediatric genomics was developed based on feedback from this group and was supplemented by findings from a critical appraisal of the data-sharing literature. The final points to consider that comprise the KIDS framework are categorized into the following 4 primary themes: children’s involvement, parental consent, balancing benefits and risks, and data protection and release requirements.

How mutually recognizable is mutual recognition? An international terminology index of research ethics review policies in the USA, Canada, UK and Australia

Could this Shakespearean adage be true of the policy terms used to describe research ethics review processes based on the principle of mutual recognition? Today, biomedical research is contingent on sharing research data [1–3] often across international borders [4]. This is because of the size of datasets necessary to make scientifically sound links between the human genome and underlying determinants of disease [5]. The degree of collaboration between researchers/research institutions typified in genomics and related ‘omics disciplines’ can therefore pose significant challenges for research ethics review where approval is sought on an institution-byinstitution basis [6]. Policy initiatives and legislation adopted to streamline research ethics review in North America, Europe and Australia are unified in their motivation and philosophy [7–9]. The motivation is that research ethics review processes must complement the collaborative and data-centric nature of biomedical research if they are to enable clinical innovation [10]. The philosophy is the principle of mutual recognition, generally understood to describe an arrangement whereby one research ethics review committee (REC) accepts the processes used to come to decisions of other institutional RECs. The plurality of terms used for policies and models of research ethics review that activate the principle of mutual recognition is the focus of this paper. An index of the terms equivalence, reciprocity, centralization and mutual acceptance from the USA, Canada, UK and Australia, respectively, will be compared. In addition to differences in nomenclature, policies that operationalize mutual recognition between RECs also vary in their degree of legislative formality. Although some policies pursuant to mutual recognition are legislated, not all can be centrally enforced. This is particularly true of countries with federated health systems such as Canada and Australia. The tediousness of the ethics approval process for principal investigators involved in multisite/jurisdictional projects was the primary motivation for reform in these countries, where memoranda of understanding and interinwstitutional agreements are still used to operationalize mutual recognition (see Figure 1).

P 3 G: Towards an International Policy Platform for Population Genomics

The widening scope of biobanking activities in recent decades necessitates purposeful networking that aggregates international efforts and expertise in population health research. To this end, the Public Population Project in Genomics and Society (P3G) has been able to streamline the process of establishing, operating and supporting the work of international biobanks since 2004. Since its inception, networking has been a central focus in all P3G initiatives. This chapter discusses P3G’s networking experiences and its evolving goals that have allowed for collaborative tool building and innovation in international biobank research. As a direct result of its networking initiatives, P3G (1) facilitates innovation, (2) improves data sharing and accessibility, and (3) continues to expand its service delivery to the international research community. Initially created to meet the increasing demands for an international consortium a decade ago, P3G has since allowed international biobanks to oversee the technical, organizational and infrastructural aspects of their research with confidence that the tools used to build them have been the product of collaboration and leadership in the field.

The sIRB System: A Single Beacon of Progress in the Revised Common Rule?

O’Rourke, P. P. 2017. “The final rule: When the rubber meets the road.” American Journal of Bioethics 17 (7):27–33. Public Comments on the Draft NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research. National Institutes of Health, December 3, 2014 – January 29, 2015. Available at: http://osp.od.nih.gov/sites/default/files/resources/sIRB%200721-2015.pdf (accessed May 30, 2017).