Challenges in cardiovascular pharmacogenomics implementation: a viewpoint from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy Free

Abstract

Challenges in clinical implementation

Across Europe, there have been multiple government-funded initiatives to embed genomics into healthcare. These have largely focused on cancer and rare diseases, but many also include pharmacogenomics (PGx).¹ Aside from the technical aspect of testing, common barriers to implementation are differing healthcare delivery across European populations, workforce capacity and capability, the development of digital infrastructure and clinical systems to interpret and integrate data, and limited evidence of clinical benefit and/or cost-effectiveness.² The Ubiquitous Pharmacogenomics Consortium, funded by the H2020 programme, is currently evaluating the use of a multi-gene panel in a cluster design, across seven countries, for clinically relevant endpoints and cost-effectiveness.

Differences in delivery of European healthcare

Only European Union (EU) member states are subject to EU guidelines related to use of medicines. Even among member states, adoption of guidelines related to healthcare and education is not uniform, often relying on local policy. Additionally, across Europe there are differences in the level of healthcare expenditure and approach to funding. Finally, populations across Europe vary significantly in terms of ethnicity, and cultural and religious beliefs.

Workforce capacity and capability

Clinical geneticists are experts in understanding genetic variation but are a limited resource, with numbers of clinical genetics consultants varying from 1 per 150 000 to 1 per 1 136 666 people across Europe.³ Furthermore, they may be less familiar with other diagnostics and complex prescribing encompassed by PGx. Thus, in order to facilitate the implementation of PGx, the wider workforce needs to be upskilled. This needs to involve at least enough basic genetic literacy to use clinical decision support tools, which will need to be developed to support translation of data to clinical action.

At present, PGx rarely features in European higher specialty medical training programmes, undergraduate medical education, and pharmacy or nursing programmes across Europe, and it is vital that this is addressed for the successful implementation of PGx. There is some encouraging evidence of increased curricular inclusion as compared with 15 years ago.⁴ However, the amount of time dedicated to PGx training is often minimal and the quantity of actionable PGx information is likely to increase over time, presenting further challenges.

Short courses on advanced training in genomics in medicine are available for healthcare professionals through the European School of Genetic Medicine. In England, the Genomics Education Programme supports a postgraduate Master's degree in Genomic Medicine. The impact of these programmes is yet to be determined. Although these bespoke programmes will increase training of a minority of individuals, they are unlikely to impact the majority of the workforce where training as part of continual professional development is needed.

Systems and infrastructure

Across Europe, most healthcare information technology systems are poorly equipped to deal with the volume and complexity of genetic data; therefore, expanding digital infrastructure across the healthcare sector is key. To support clinicians with limited knowledge in PGx, clinical decision support software is particularly important and may be facilitated by electronic healthcare systems.

Due to geographical variation in provision of genetic services, countries such as France and the UK have created regional hubs in centres of excellence to ensure standardized testing, data collection, and equitable access to services for patients.

Clinical outcomes and cost-effectiveness

One of the major barriers to the implementation of PGx has been the paucity of evidence demonstrating improved efficacy, safety, or cost-effectiveness. Examples of where there is evidence are included in the accompanying position paper, and this evidence base is growing. Thus far, the majority of studies support PGx as cost-effective.⁵ Longer-term data demonstrating positive clinical outcomes and cost-effectiveness are vital to gain support from governmental policymakers.

There are currently recommendations for more than 80 drugs (https://cpicpgx.org/); PharmGKB curates a database of pharmacogenetic variants (https://www.pharmgkb.org/). Most are based on genetic studies done in Caucasian European ancestry populations. Interpretation, and any necessary reclassification, of variants of unknown significance (VUS) may be a challenge given the spectrum of ancestries across Europe and admixing of populations.

Importance of collaborative networks

Many of the challenges related to the implementation of PGx across Europe have begun to be addressed by the development of national and international collaborative networks between healthcare professionals, academic researchers, industry, and regulatory bodies. This enables sharing of clinical and research data from differing populations and educational resources, and begins to address the legal, social, and ethical concerns arising across Europe. These collaborations will enable rapid expansion of knowledge, improving the care for patients and minimizing resource waste and duplication. Governmental, academic, and regulatory cooperation will be required, and such a unified approach will make possible data-sharing opportunities, which will in turn require infrastructure to be built.

Ethical, legal, and cultural considerations

Legal and regulatory framework

Legislation: European laws relating to the use of genetic testing in healthcare systems, applicable to but not specific to PGx testing, are heterogeneous and designed for diagnostic purposes rather than PGx. The framework for diagnostic genetic testing may be inappropriately stringent in a PGx setting and pose an unnecessary barrier to PGx implementation.⁶

European Medicines Agency (EMA) stance on PGx: The EMA endorses best practice in genetic testing analysis and actionability of results: product information includes up-to-date PGx data.⁷ Currently, individual medications contain PGx data as endorsed by EMA licensure rather than an enveloping EMA comment on PGx panel testing. Fifteen per cent of all EMA licensed pharmaceutical agents contain PGx information in the summary of product characteristics.⁸ As PGx testing and intervention move to an integrated panel approach, concurrent evolution in regulatory guidance is likely to be needed.

Direct-to-consumer (DTC) genetic tests’ regulation: A description of the regulatory framework in Europe from experts across the EU showed that while some nations restrict genetic testing to the purview of medical practitioners, other nations allow DTC testing, while a third model exists with provision to refuse license for tests that are not scientifically sound.⁹ Legislation is often not specific to DTC.¹⁰ In the current context of intra-European movement, it may thus be prudent to standardize access to PGx test results and interface with national health service access.

The in vitro diagnostic framework applies to commercial diagnostic devices, via the Communauté Européenne (CE) mark. The role of the CE label, which denotes that the commercial product ‘has been assessed by the manufacturer and deemed to meet EU safety, health and environmental protection requirements’, should be clarified; it may be misconstrued as a quality standard from a scientific or medical perspective.¹¹

Ethical concerns and implications

Confidentiality and genetic data: Individuals and relationships are increasingly identifiable from increased coverage in genetic panels and sequencing. This is particularly relevant with PGx as testing would likely be polymorphism or gene panel based rather than based on an individual single nucleotide polymorphism test. Police investigations have made use of genetic data processed by DTC companies. This raises questions about the extent to which forensic access to genomic databases stored in clinical systems may be broached in the future (presumably under court order).

Privacy and data protection: PGx testing is likely to generate an enormous quantity of data. How will these data be managed and who can have access under what circumstances? If someone dies, can these data be accessed by clinicians or shared with next of kin in case of clinically actionable and genetically transmissible variant identifications? Existing consensus is to treat any genetic data like all other sensitive data contained within electronic health records from an information governance perspective, though some have queried a need for extended legislative protection for genetic data.¹²

Informed consent with imperfect information: Informed consent (IC) is a cornerstone of ethical clinical practice. In the context of incomplete and evolving information regarding variant classification and actionability in prescribing, participants may be consenting to treatment based on a rapidly evolving interpretation of the information base. Current consent practices vary and should be standardized at a minimum content level.¹³ IC for ongoing research from PGx data mining should be addressed separately.

Transparency and provisions to action an evolving knowledge base: The uncertainty around VUS and emerging PGx variants and the rapid evolution of genetic knowledge make transparency paramount and necessitate viable plans to keep patients appraised of changes in variant classification. The European Society of Human Genetics framework for next-generation sequencing recommends that the laboratory is responsible for re-issuing reports and contacting referring clinicians when a variant changes categories.¹⁴

Responsibility: Clinical decision-making with limited gold standard randomized controlled trial evidence and an enormous number of variables may open up clinicians to criticism in case of an adverse event and retrospective cherry-picking of data. How will responsibility in PGx decisions be shared between government, healthcare organizations, clinical practitioners, and patients? Further clarity is needed. This should include consultation with all stakeholders to assess acceptability. There are clearly legal implications in terms of prescriber liability if any standard practice PGx is not integrated.

Distributional justice: PGx will have to prove worthy of the substantial investment to justify propelling PGx forward at the opportunity cost of other public healthcare initiatives.

Social justice: As touched on earlier, most genetic studies do not include representation from a full cross-section of society, limiting variant detection, clinical validity, and PGx applicability. Worldwide ancestry-based research should therefore be encouraged. Furthermore, relations of the mainstream research community and medical establishment with several ethnic minority groups, such as indigenous people, have been fraught with mistrust.¹⁵ There is therefore a concern raised as the most historically privileged ethnic group, Caucasian Europeans, will be even more privileged as personalized medicine advances care tailored to this group. This is an example of the Matthew effect, a phrase taken from the biblical adage describing an age-old rich get richer phenomenon of perpetuated privilege and inequality. The social justice implications of this pattern must be made explicit and rectified by initiatives encouraging expansion in this area of research.

In summary, differences in healthcare delivery across Europe, as well as workforce and infrastructure shortfalls, represent barriers to implementation of evidence-based cardiovascular PGx within the EU. Collaboration and adequate consideration of ethical issues can help PGx to advance cardiovascular care for all strata of society, across the EU.

Acknowledgements

M.J.C. is an NIHR Senior Investigator and this work forms part of the research portfolio of the NIHR Biomedical Research Centre at Barts. M.P. is an Emeritus NIHR Senior Investigator, and wishes to thank the MRC Centre for Drug Safety Science and Wolfson Centre for Personalised Medicine for infrastructure support.

Conflict of interest: M.J.C. is seconded to Genomics England as Chief Scientist and part of his salary is funded by Genomics England Ltd, a wholly owned Department of Health and Social Care company. M.P. receives research funding from various organizations, including the MRC, NIHR, EU Commission, HDR UK, and Health Education England. He has also received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (co-funded by MRC and Roche, UCB, Eli Lilly, and Novartis); a PhD studentship jointly funded by EPSRC and Astra Zeneca; and grant funding from VistaGen Therapeutics. He has also unrestricted educational grant support for the UK Pharmacogenetics and Stratified Medicine Network from Bristol Myers Squibb and UCB. He has developed an HLA genotyping panel with MC Diagnostics, but does not benefit financially from this. He is also a member of the IMI Consortium ARDAT (www.ardat.org). None of the funding declared here has been directly used for the current review paper. S.A. has received speaker fees and advisory board fees from Boehringer Ingelheim, Daiichi Sankyo, Bayer, and Thermo Fisher. A.G.S. has received speaker honoraria and/or consulting fees from Sanofi, AbbVie, Novartis, Bayer, and Lilly. G.S. reports grants and personal fees from Vifor, grants and non-financial support from Boehringer Ingelheim, personal fees from Società Prodotti Antibiotici, grants and personal fees from AstraZeneca, personal fees from Roche, personal fees from Servier, grants from Novartis, personal fees from GENESIS, personal fees from Cytokinetics, personal fees from Medtronic, and grants from Boston Scientific, outside the submitted work. P.S. reports grants from Daiichi Sankyo, and grants and personal fees from Boehringer Ingelheim, outside the submitted work.

References

Author notes