Teri A. Manolio, Robyn Ward & Geoffrey S. Ginsburg (2016): Clinical implementation of genomic medicine: the importance of global collaboration, Expert Review of Precision Medicine and Drug Development.
1. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
2. University of Queensland, Australia
3. Center for Applied Genomics and Precision Medicine, Duke University, Durham, NC
The growing number of genomic advances directly relevant to disease diagnosis, treatment, and prevention as well as the declining cost of detection of genomic variation are leading to the
use of genomic technologies in routine clinical care [1,2]. Among the many challenges to widespread implementation of genomic medicine, one of the most significant is the lack of
evidence of its impact on clinical outcomes . Other barriers include needs for standardization and quality assurance of genomic data produced by clinical laboratories, differences in
interpretation of pathogenicity of variants, clinical informatics infrastructure for managing genomic information, education for health professionals and patients in using the information,
and policies for data sharing that permit ongoing capture and sharing of clinical experience. A host of ongoing efforts worldwide to establish national implementation strategies for
genomic medicine reflects the growing level of discovery and understanding in this area [3,4], but many such efforts are being conducted in relative isolation. Sharing strategies, data, and
standards could minimize wasteful duplication and facilitate pooling of outcomes, to identify genomics-based interventions most likely to improve patient care. Dissemination and
adaptation of successful implementation strategies in an online global genomic medicine “toolbox” would speed adoption of genomics to enhance outcomes for patients and
populations. Given the critical needs to generate clinical evidence, evaluate the impact and cost-effectiveness of genomic medicine interventions, and harness information from
genomically diverse populations to capture the immensity of human genomic variation, international collaborative projects in clinical implementation are an obvious solution.
Areas that could benefit from multinational collaborations in genomic medicine implementation include evidence generation, health information technology, workforce
development, pharmacogenomics, variant interpretation, and policy and regulatory issues including economic evaluation. Recognizing the important differences among countries in
culture, public perceptions, governance structures, health care systems, resources, and infrastructure– and notwithstanding some clear biologic differences in allele frequencies and
prevalent diseases– there is so much to be learned and the potential for unnecessary duplication is so great that some degree of coordination and sharing of results is critical .
Generating evidence of the value of genomics for patients, clinicians, payers, policy makers, and health care systems is among the most expensive of potential international collaborations,
but several ongoing national efforts could form the foundation for such collaborations . Despite differences in health care delivery systems, international collaborations have amply
shown the speed with which multi-national consortia can answer questions that few countries can tackle on their own, as demonstrated for global burdens of disease  and HIV/AIDS .
Identifying countries and health care systems willing to permit access to patient data, within appropriate constraints of policy, privacy, and consent, will be a key step in combining data to
fill evidence gaps. Healthcare providers, payers, and regulators should agree on the evidentiary standards required for implementation of a genomic medicine intervention. As with evidentiary
standards in other areas of medicine, these will likely vary depending on whether genetic information would be used for risk prediction, diagnosis, treatment, or understanding disease
pathogenesis. Standards should also be developed for performance of genetic tests and incorporating genomic information into the electronic medical record. A sufficient body of
evidence, once available, will facilitate development of practice guidelines by professional societies, payers, and regulators that are suitable for a specific setting or country. A framework
for the translation of genomic-based tests from discovery to health care could be modeled on that of Australia’s National Health and Medical Research Council .
Health information technology is a critical component of genomic medicine implementation, given the vast and complex nature of genome sequence data. The rapid
evolution of knowledge about clinically relevant variants and the changing clinical situation of an individual patient requires a dynamic approach for presenting variant information only when
it can potentially make a difference in that individual’s care . In addition, genome sequence data should ideally be retrievable for use later in a patient’s clinical course, and throughout
their lifetime, and should be accessible to other specialists and care systems as needed. Truly global resources for actionable clinical genomic variants are urgently needed and should build
on current efforts such as the Clinical Genome Resource (ClinGen) . Use of available and widely accepted controlled vocabularies (ontologies) for phenotypes and avoidance of
proliferation of local or regional ontologies will be essential to interpretation of variants and sharing of information. The Innovative Medicine Initiative project “eTRIKS,” funded jointly be
the European Union and industry, aims to create and run an open, sustainable research informatics and analytics platform for sharing data and supporting translational research in
personalized medicine . Such platforms would benefit from the use of genomic information to improve disease classification and taxonomy, an important step in linking information and
assessing outcomes systematically, as recommended in the U.S. Institute of Medicine’s Toward Precision Medicine report .
An educated clinical workforce will be critical to effective implementation, given the dearth of such expertise world-wide. Competencies for health care professionals at multiple levels
within a given system will need to be defined and appropriate educational programs developed . Integration of genomics into health professional curricula will become increasingly
necessary. As materials developed in one part of the world are shared globally, translation for language and cultural appropriateness will be needed, but these efforts will be worthwhile if
effective training paradigms and practices can be identified and shared rather than invented (or re-invented) de novo. Relying increasingly on distance learning and other online tools  will
facilitate rapid implementation and global spread. The importance of genomic counselling to patients and clinicians cannot be overstated, both in anticipating the potential risks and
benefits of genomic information prior to testing, and in making rational and informed decisionmaking once results are available. The need for such counselling has already exceeded the
availability of qualified genetic counselors in many developed countries, to say nothing of resource-limited settings, and expansion of this workforce should be a high priority for genomic
Pharmacogenomics represents a probable “early win” ripe for trans-national sharing of best practices and lessons learned, given the multiple pharmacogenomic applications that have
already been widely implemented in the U.S. and elsewhere [1,15]. Effective international collaborations have been formed to study the genomics of adverse drug reactions [16, 17], but
actual implementation efforts have been more isolated. Guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC ), which provides recommendations on drug selection and dosing based on an individual’s genotypic data, are a notable exception and are increasingly used clinically. Application of whole-genome sequencing in
pharmacogenomics could eventually define fully an individual’s personalized pharmacogenomics profile, allowing the evidence supporting a whole genome strategy to be
assessed. Customizing such an approach in a targeted sequencing effort of the several hundred pharmacogenes involved in drug metabolism and transport, or the smaller subset of clinically
actionable pharmacogenes, would reduce costs and make this application more immediately affordable than more comprehensive sequencing efforts.
Variant interpretation is becoming increasingly challenging as genomic sequencing efforts identify additional never-before seen variants with every genome sequenced. Such efforts also
hold the key to interpretation of these variants, however, to the degree that the findings are widely shared to pool phenotypic information on multiple carriers of rare variants .
Policy recommendations to facilitate data sharing in genomic research are the subject of multiple international initiatives, particularly the Canadian-led Public Population Project in
Genomics (P3G) , the International Cancer Genome Project , and the Global Alliance for Genomics and Health (GA4GH) . The 100,000 genomes to be sequenced in the Genomics
England project , and the one million or more participants anticipated for the U.S. Precision Medicine Initiative  will also add valuable data and policy developments. Such efforts are
quite relevant to genomic medicine implementation and, as with the evidence realm, an assessment of current activities along with a gap analysis would be important initial steps.
Harmonizing national ethical guidelines and regulatory frameworks as feasible is essential for successful international collaborations, as will a more complete understanding of regional laws
relevant to genomics governing research, privacy, and confidentiality. In evaluating costs, risks, and benefits of genomic interventions, identifying conditions for which genomic tools could
have the greatest impact on patient and population outcomes– such as cancer, metabolic disorders, HIV therapy, or cystic fibrosis– would be a useful first step. By integrating economic
assessments into translational research, not only can the utility of genomic interventions be determined, but the relative value of such interventions can also be assessed to inform health
care decision-makers. Expanding single-country studies of cost-effectiveness to multiple health care systems may help identify key underpinning structural components that promote
favorable cost-benefit ratios . Multi-national collaborations may be particularly valuable for examining different systems and models, such as those with one or a few centralized payers
that can provide a more unified and systematic examination of the decision-making process.
In summary, numerous genomic medicine programs are being effectively implemented around the globe, demonstrating the potential for genomic medicine to improve our ability to individualize and deliver health care . Widespread adoption of these approaches will require demonstrating their impact on outcomes in diverse clinical settings in multiple countries. To facilitate such collaborations we initiated the Global Genomic Medicine Collaborative (G2MC) hosted by the U.S. National Academy of Medicine as part of its Genomic Medicine Roundtable . Goals of the G2MC are to serve as a nexus for genomic medicine activities globally, develop opportunities for genomic medicine implementation and outcomes research, and capture and disseminate best practices for genomic medicine implementation worldwide. It grew from a gathering of 90 leaders in genomic medicine from the U.S. and 25 other countries in January 2014 . A second meeting of the group in November 2015 demonstrated growing opportunities for pilot partnerships in the areas of policy, information technology, and genomic sequencing and variant interpretation.
As we work toward realizing our common interests in the appropriate implementation of genomic medicine, efforts to combine forces in generating and assessing evidence of its impact
and in disseminating best practices for effective implementation, will enhance the use of genomics to improve clinical care worldwide.