Policy Guidance for Direct-to-Consumer Genetic Testing Services: Framework Development Study.

BACKGROUND: The online offer of commercial genetic tests, also called direct-to-consumer genetic tests (DTC-GTs), enables citizens to gain insight into their health and disease risk based on their genetic profiles. DTC-GT offers often consist of a combination of services or aspects, including advertisements, information, DNA analysis, and medical or lifestyle advice. The risks and benefits of DTC-GT services have been debated and studied extensively, but instruments that assess DTC-GT services and aid policy are lacking. This leads to uncertainty among policy makers, law enforcers, and regulators on how to ensure and balance both public safety and autonomy and about the responsibilities these 3 parties have toward the public. OBJECTIVE: This study aimed to develop a framework that outlines aspects of DTC-GTs that lead to policy issues and to help provide policy guidance regarding DTC-GT services. METHODS: We performed 3 steps: (1) an integrative literature review to identify risks and benefits of DTC-GT services for consumers and society in Embase and Medline (January 2014-June 2022), (2) structuring benefits and risks in different steps of the consumer journey, and (3) development of a checklist for policy guidance. RESULTS: Potential risks and benefits of DTC-GT services were mapped from 134 papers and structured into 6 phases. In summary, these phases were called the consumer journey: (1) exposure, (2) pretest information, (3) DNA analysis, (4) data management, (5) posttest information, and (6) individual and societal impact. The checklist for evaluation of DTC-GT services consisted of 8 themes, covering 38 items that may raise policy issues in DTC-GT services. The themes included the following aspects: general service content, validity and quality assurance, potential data and privacy risks, scientific evidence and robustness, and quality of the provided information. CONCLUSIONS: Both the consumer journey and the checklist break the DTC-GT offer down into key aspects that may impact and compromise individual and public health, safety, and autonomy. This framework helps policy makers, regulators, and law enforcers develop methods to interpret, assess, and act in the DTC-GT service market.

Stakeholder perspectives on the implementation of genetic carrier screening in a changing landscape.

BACKGROUND: In most countries, genetic carrier screening is neither offered, nor embedded in mainstream healthcare. Technological developments have triggered a two-fold transition in carrier screening: the expansion from screening one single disorder to many disorders simultaneously, and offering screening universally, regardless of ancestry. This study aims to identify general and population-specific barriers and needs reflected by stakeholders regarding the implementation of carrier screening in a changing landscape. METHODS: Seventeen semi-structured interviews were conducted with Dutch key stakeholders working in the practical and scientific field of carrier screening. The constellation approach was used to categorise barriers and needs into three levels: culture, structure and practice. RESULTS: Barriers on a cultural level include: undecidedness about the desirability of carrier screening, and a lack of priority of screening in mainstream healthcare. On a structural level barriers included: need for organisational structures in healthcare for embedding carrier screening, need for guidelines, financial structures, practical tools for overcoming challenges during counselling, and a need for training and education of both professionals and the public. A lack of demand for screening by the public, and a need for a division of responsibilities were barriers on a practical level. CONCLUSION: The absence of a collective sense of urgency for genetic carrier screening, a lack of organisational structures, and uncertainty or even disagreement about the responsibilities seem to be important barriers in the implementation of carrier screening. Stakeholders therefore suggest that change agents should be formally acknowledged to strategically plan broadening of current initiatives and attune different stakeholders.

Challenges and opportunities for ELSI early career researchers.

BACKGROUND: Over the past 25 years, there has been growing recognition of the importance of studying the Ethical, Legal and Social Implications (ELSI) of genetic and genomic research. A large investment into ELSI research from the National Institutes of Health (NIH) Human Genomic Project budget in 1990 stimulated the growth of this emerging field; ELSI research has continued to develop and is starting to emerge as a field in its own right. The evolving subject matter of ELSI research continues to raise new research questions as well as prompt re-evaluation of earlier work and a growing number of scholars working in this area now identify themselves as ELSI scholars rather than with a particular discipline. MAIN TEXT: Due to the international and interdisciplinary nature of ELSI research, scholars can often find themselves isolated from disciplinary or regionally situated support structures. We conducted a workshop with Early Career Researchers (ECRs) in Oxford, UK, and this paper discusses some of the particular challenges that were highlighted. While ELSI ECRs may face many of the universal challenges faced by ECRs, we argue that a number of challenges are either unique or exacerbated in the case of ELSI ECRs and discuss some of the reasons as to why this may be the case. We identify some of the most pressing issues for ELSI ECRs as: interdisciplinary angst and expertise, isolation from traditional support structures, limited resources and funding opportunities, and uncertainty regarding how research contributions will be measured. We discuss the potential opportunity to use web 2.0 technologies to transform academic support structures and address some of the challenges faced by ELSI ECRs, by helping to facilitate mentoring and support, access to resources and new accreditation metrics. CONCLUSION: As our field develops it is crucial for the ELSI community to continue looking forward to identify how emerging digital solutions can be used to facilitate the international and interdisciplinary research we perform, and to offer support for those embarking on, progressing through, and transitioning into an ELSI research career.

Newborn screening for pompe disease? a qualitative study exploring professional views.

BACKGROUND: Developments in enzyme replacement therapy have kindled discussions on adding Pompe disease, characterized by progressive muscle weakness and wasting, to neonatal screening. Pompe disease does not fit traditional screening criteria as it is a broad-spectrum phenotype disorder that may occur in lethal form in early infancy or manifest in less severe forms from infancy to late adulthood. Current screening tests cannot differentiate between these forms. Normally, expanding screening is discussed among experts in advisory bodies. While advisory reports usually mention the procedures and outcome of deliberations, little is known of the importance attached to different arguments and the actual weighing processes involved. In this research we aim to explore the views of a wide range of relevant professionals to gain more insight into the process of weighing pros and cons of neonatal screening for Pompe disease, as an example of the dilemmas involved in screening for broad-spectrum phenotype disorders. METHODS: We conducted 24 semi-structured interviews with medical, lab, insurance and screening professionals, and executive staff of patient organisations. They were asked about their first reaction to neonatal screening for Pompe disease, after which benefits and harms and requirements for screening were explored in more detail. RESULTS: Advantages included health gain by timely intervention, avoiding a diagnostic quest, having a reproductive choice and gaining more knowledge about the natural course and treatment. Being prepared was mentioned as an advantage for the later manifesting cases. Disadvantages included treatment costs and uncertainties about its effect, the timing of treatment in later manifesting cases, the psychological burden for the patient-in-waiting and the family. Also the downsides of having prior knowledge as well as having to consider a reproductive option were mentioned as disadvantages. CONCLUSION: When weighing pros and cons, interviewees attach different importance to different arguments, based on personal and professional views. Professionals expect benefits from neonatal screening for Pompe disease, especially for early-onset cases. Some interviewees valued screening in later manifesting cases as well, while stressing the need for adequate support of pre-symptomatic patients and their families. Others considered the psychological burden and uncertainties regarding treatment as reasons not to screen.

[Direct-to-consumer genetic tests in the Netherlands: impact on consumers and clinical practice]. / 'Direct-to-consumer' genetische tests in Nederland.

Over the last 75 years, the field of Human Genetics has developed enormously. One of the recent developments involves health-related direct-to-consumer genetic tests (DTC-GTs), through which consumers gain insight in their genetic information and personal health risks without involvement of a health care professional. The DTC-GT market is diverse and dynamic, testing for continuously changing combinations of traits and DNA-variants that can affect personal health and disease. DTC-GTs can have positive and negative consequences for individuals, health care, society, and science. Notably, consumers are presently not optimally empowered for informed decision making regarding health-related DTC-GT usage. It is important to protect them from negative impact, given the present lack of actionable legislation. Insight in which citizens buy these tests, and why they do so, will help to properly inform and empower consumers to make informed decisions both before and after purchasing health-related DTC-GTs. Projects answering these questions are ongoing.

Genetic Screening-Emerging Issues.

In many countries, some form of genetic screening is offered to all or part of the population, either in the form of well-organized screening programs or in a less formalized way. Screening can be offered at different phases of life, such as preconception, prenatal, neonatal and later in life. Screening should only be offered if the advantages outweigh the disadvantages. Technical innovations in testing and treatment are driving changes in the field of prenatal and neonatal screening, where many jurisdictions have organized population-based screening programs. As a result, a greater number and wider range of conditions are being added to the programs, which can benefit couples' reproductive autonomy (preconception and prenatal screening) and improve early diagnosis to prevent irreversible health damage in children (neonatal screening) and in adults (cancer and cascade screening). While many developments in screening are technology-driven, citizens may also express a demand for innovation in screening, as was the case with non-invasive prenatal testing. Relatively new emerging issues for genetic screening, especially if testing is performed using DNA sequencing, relate to organization, data storage and interpretation, benefit-harm ratio and distributive justice, information provision and follow-up, all connected to acceptability in current healthcare systems.

Information Provision Regarding Health-Related Direct-to-Consumer Genetic Testing for Dutch Consumers: An in-Depth Content Analysis of Sellers' Websites.

Background: Previous studies have suggested that information offered by sellers of health-related direct-to-consumer genetic tests (DTC-GTs) is often incomplete, unbalanced, or too difficult to understand. The extent to which this is the case for sellers accessible to Dutch consumers has not previously been studied. Methods and Goals: The present study aimed to assess the completeness, balance, readability, and findability of informational content on a selection of websites from several health-related DTC-GT sellers accessible to Dutch consumers. An in-depth content analysis was performed based on a recently published checklist outlining key items for policy guidance regarding DTC-GT services. Results: The information provided by sellers did not equally cover all aspects relevant to health-related DTC-GT service provision. The provided information was slightly unbalanced, with benefits of health-related DTC-GT usage being overemphasized compared to its risks and limitations. The readability of the provided information was low, on average requiring college education for proper understanding. A findability analysis showed that information concerning all themes is overall relatively evenly distributed across analyzed sellers' websites. Conclusions: Information provision by assessed health-related DTC-GT sellers is suboptimal regarding completeness, balance, and readability. To better empower potential consumers to make an informed decision regarding health-related DTC-GT usage, we advocate industry-wide enhancement of information provision.

Reflecting on earlier experiences with unsolicited findings: points to consider for next-generation sequencing and informed consent in diagnostics.

High-throughput nucleotide sequencing (often referred to as next-generation sequencing; NGS) is increasingly being chosen as a diagnostic tool for cases of expected but unresolved genetic origin. When exploring a higher number of genetic variants, there is a higher chance of detecting unsolicited findings. The consequential increased need for decisions on disclosure of these unsolicited findings poses a challenge for the informed consent procedure. This article discusses the ethical and practical dilemmas encountered when contemplating informed consent for NGS in diagnostics from a multidisciplinary point of view. By exploring recent similar experiences with unsolicited findings in other settings, an attempt is made to describe what can be learned so far for implementing NGS in standard genetic diagnostics. The article concludes with a set of points to consider in order to guide decision-making on the extent of return of results in relation to the mode of informed consent. We hereby aim to provide a sound basis for developing guidelines for optimizing the informed consent procedure.

Predictive Value of SLCO1B1 c.521T>C Polymorphism on Observed Changes in the Treatment of 1136 Statin-Users.

Pharmacogenomic testing is a method to prevent adverse drug reactions. Pharmacogenomics could be relevant to optimize statin treatment, by identifying patients at high risk for adverse drug reactions. We aim to investigate the clinical validity and utility of pre-emptive pharmacogenomics screening in primary care, with SLCO1B1 c.521T>C as a risk factor for statin-induced adverse drug reactions. The focus was on changes in therapy as a proxy for adverse drug reactions observed in statin-users in a population-based Dutch cohort. In total, 1136 statin users were retrospectively genotyped for the SLCO1B1 c.521T>C polymorphism (rs4149056) and information on their statin dispensing was evaluated as cross-sectional research. Approximately half of the included participants discontinued or switched their statin treatment within three years. In our analyses, we could not confirm an association between the SLCO1B1 c.521T>C genotype and any change in statin therapy or arriving at a stable dose sooner in primary care. To be able to evaluate the predictive values of SLCO1B1 c.521T>C genotype on adverse drug reactions from statins, prospective data collection of actual adverse drug reactions and reasons to change statin treatment should be facilitated.

Severely impaired health status at diagnosis of Pompe disease: a cross-sectional analysis to explore the potential utility of neonatal screening.

Since the introduction of enzyme replacement therapy for Pompe disease, awareness and early diagnosis have gained importance. Because the therapy is most effective when started early and methods for dried bloodspot screening for Pompe disease are currently being explored, neonatal screening is getting increased attention. The objective of this study was to investigate the gains that might be achieved with earlier diagnosis by neonatal screening. For this purpose we analyzed the health and functional status of non-screened patients with Pompe disease at the time of diagnosis. Previously collected clinical data and results of an international patient-reported questionnaire were used. Cross-sectional data of 53 patients with Pompe disease diagnosed between 1999 and 2009 (aged 0-64 years) were analyzed. According to the World Health Organization's International Classification of Functioning, Disability and Health the following domains are described: body function, activity, participation and contextual factors. In all patients with classic infantile Pompe disease cardiac function, hearing, muscle strength and motor development were considerably impaired at the time of clinical diagnosis. The use of oxygen and/or nasogastric tube-feeding was reported in more than 70% of these cases. Most children, adolescents and adults had advanced muscle weakness and impaired respiratory function at the time of their diagnosis, causing varying degrees of handicap. About 12% of them used a walking device and/or respiratory support at the time of diagnosis. The severely impaired health status reported here provides a strong argument for earlier diagnosis and to further explore the potential of neonatal screening for Pompe disease.

Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 1. From blood spot to screening result.

In many European countries neonatal screening has been introduced over the last 50 years as an important public health programme. Depending on health care structure, available funds, local politics, input from professional groups, parent groups, and the general public this introduction has led to different approaches in the way the screening programmes have been set up, financed and governed. To get some insight about the current situation, in 2009 the European Union, via its EAHC agency, put out a call for a tender that was acquired by our project group. An online survey was compiled in which the whole screening programme was covered by a questionnaire. This survey covered the EU member states, (potential) candidate member states and EFTA countries, in total 40 countries. Results showed little consensus concerning 1. information of parents including informed consent; 2. which conditions are screened for, ranging from 1 to around 30 conditions; 3. sampling time post partum; 4. screening methodology including cut-offs values even between screening laboratories within countries.; 5. storage of residual specimens, varying from 3 months to 1000 years. In addition, confirmatory diagnostics and follow-up also show large discrepancies (Burgard et al. http://www.iss.it/cnmr/prog/cont.php?id=1621&lang=1&tipo=64 2011). In addition to the current practices report an expert opinion document has been produced with recommendations to the EU Commission for future improvements, e.g. in parallel to the way the USA has harmonized its practices based on recommendations by the American College of Medical Genetics (Watson et al., Pediatrics 117: S296-S307, 2006).

Newborn screening programmes in Europe; arguments and efforts regarding harmonization. Part 2. From screening laboratory results to treatment, follow-up and quality assurance.

In a survey conducted in 2010/2011 data from the 28 EU member states, four EU candidate states (Croatia, FYROM, Iceland, Turkey), three potential EU candidate states (Bosnia Herzegovina, Montenegro, Serbia), and two EFTA states (Norway and Switzerland) were collected. The status and function of newborn screening (NBS) programmes were investigated from the information to prospective parents and the public via confirmation of a positive screening result up to decisions on treatment. This article summarises the results from screening laboratory findings to start of treatment. In addition we asked about the existence of feedback loops reporting the conclusions of confirmation of screening results to the screening laboratory and communication of long-term outcome to diagnostic units and possibly existing central registries. Parallel to the description of actual practices of where, how and by whom the different steps of the programmes are executed, we also asked for the existence of guidelines or directives regulating the screening programmes, material to support information of parents about diagnoses and treatment and training facilities for professionals involved in the programmes. This survey gives a first comprehensive overview of the steps following a positive screening result in European NBS programmes. The 37 data sets reveal substantial variation of national screening panels, but also a lot of similarities. Analysis across all countries revealed that actual practice is often organised but not regulated by guidelines. Material to inform patients is available more often for explaining treatment (69 %) than explaining the necessity of confirmatory diagnostics (41 %). Training of professionals is rarely regulated by a guideline (2 %), but is offered for paediatricians (40 %) and dieticians (29 %) and only rarely for other professions (e.g. geneticists, clinical nurse specialists, psychologists). Registry-based evaluation of long-term outcome is as yet almost nonexistent (3 %).

Pursuing Public Health Benefit Within National Genomic Initiatives: Learning From Different Policies.

Introduction: Population-based genomic research is expected to deliver substantial public health benefits. National genomics initiatives are widespread, with large-scale collection and research of human genomic data. To date, little is known about the actual public health benefit that is yielded from such initiatives. In this study, we explore how public health benefit is being pursued in a selection of national genomics initiatives. Methods: A mixed-method study was carried out, consisting of a literature-based comparison of 11 purposively sampled national genomics initiatives (Belgium, Denmark, Estonia, Finland, Germany, Iceland, Qatar, Saudi Arabia, Taiwan, United Kingdom (UK), and United States (USA)), and five semi-structured interviews with experts (Denmark, Estonia, Finland, UK, USA). It was analyzed to what extent and how public health benefit was pursued and then operationalized in each phase of an adapted public health policy cycle: agenda setting, governance, (research) strategy towards health benefit, implementation, evaluation. Results: Public health benefit within national genomics initiatives was pursued in all initiatives and also operationalized in all phases of the public health policy cycle. The inclusion of public health benefit in genomics initiatives seemed dependent on the outcomes of agenda setting, such as the aims and values, as well as design of governance, for example involved actors and funding. Some initiatives focus on a research-based strategy to contribute to public health, while others focus on research translation into healthcare, or a combination of both. Evaluation of public health benefits could be performed qualitatively, such as assessing improved public trust, and/or quantitatively, e.g. research output or number of new diagnoses. However, the created health benefit for the general public, both short- and long-term, appears to be difficult to determine. Conclusion: Genomics initiatives hold the potential to deliver health promises of population-based genomics. Yet, universal tools to measure public health benefit and clarity in roles and responsibilities of collaborating stakeholders are lacking. Advancements in both aspects will help to facilitate and achieve the expected impact of genomics initiatives and enable effective research translation, implementation, and ultimately improved public health.

Dynamics of reproductive genetic technologies: Perspectives of professional stakeholders.

Reproductive and genetic medicine are evolving rapidly, and new technologies are already impacting current practices. This includes technologies that can identify a couples' risk of having a child with a genetic disorder. Responsible implementation of new technologies requires evaluation of safety and ethics. Valuable insights for shaping governance processes are provided by various stakeholders involved, including healthcare professionals. Their willingness to adopt these technologies and guide the necessary systemic changes is required for the successful implementation of these technologies. In this study, twenty-one semi-structured interviews were conducted with professionals from different disciplines in the field of reproductive and genetic healthcare in the Netherlands. Three emerging technologies were discussed: expanded carrier screening (ECS), non-invasive prenatal diagnosis (NIPD) and germline genome editing (GGE). By probing stakeholders' views, we explored how culture, structure and practice in healthcare is being shaped by innovations and changing dynamics in genetic and reproductive medicine. The general consensus was that the implementation of reproductive genetic technologies nationwide is a slow process in Dutch healthcare. A "typical Dutch approach" emerged that is characterized by restrictive legislation, broad support for people living with disabilities, values of an egalitarian society and limited commercialisation. Different scenarios for embedding ECS in future practice were envisioned, while implementation of NIPD in clinical practice was considered obvious. Views on GGE varied among stakeholders. Previous implementation examples in the Netherlands suggest introduction of new technology involves an organized collective learning process, with pilot studies and stepwise implementation. In addition, introducing and scaling up new technologies is complex due to perceived barriers from the legislative framework and the complex relationship between the government and stakeholders in this area. This paper describes how the international trends and advances of technologies are expected to manifest itself in a national setting.

Moving somatic gene editing to the clinic: routes to market access and reimbursement in Europe.

Somatic gene editing (SGE) holds great promise for making genetic therapy possible for many monogenic conditions very soon. Is our current system of European market authorization and reimbursement ready for the expected tsunami of gene therapies? At a recent workshop of the Netherlands ZonMw consortium on ethical, legal, and social implications of personalized medicine, we discussed the current possibilities for bringing new gene therapies to the clinic. In Europe, it is not yet clear whether the route via the European medicines agency as an advanced therapy medicinal product is the most appropriate for evaluation of highly personalized SGE applications, although this may optimally guarantee safety and effectiveness. Compassionate use may ensure faster access than the centralized procedure but does not stimulate the commercial development of products. Prescription to named patients may only provide adequate access for single patients. Temporary authorization of use may allow access to medication half a year before formal market authorization has been granted, but may also have large budget impacts. Magistral compounding under a hospital exemption may be an attractive solution for rare, tailor-made applications at an acceptable price. To approve local experimental use of a therapy on a case-by-case basis may be fast, but does not guarantee optimal safety, effectiveness, and broad implementation. We argue that alternative routes should be considered for products developed for a market of large groups of patients versus unique personalized treatments. A balance between scientific evidence for safety and effectiveness, affordability, and fast access may demand a range of alternative solutions.

Neonatal and carrier screening for rare diseases: how innovation challenges screening criteria worldwide.

Screening for rare diseases first began more than 50 years ago with neonatal bloodspot screening (NBS) for phenylketonuria, and carrier screening for Tay-Sachs disease, sickle cell anaemia and ß-thalassaemia. NBS's primary aim is health gain for children, while carrier screening enables autonomous reproductive choice. While screening can be beneficial, it also has the potential to cause harm and thus decisions are needed on whether a specific screening is worthwhile. These decisions are usually based on screening principles and criteria. Technological developments, both treatment driven and test driven, have led to expansions in neonatal screening and carrier screening. This article demonstrates how the dynamics and expansions in NBS and carrier screening have challenged four well-known screening criteria (treatment, test, target population and programme evaluation), and the decision-making based on them. We show that shifting perspectives on screening criteria for NBS as well as carrier screening lead to converging debates in these separate fields. For example, the child is traditionally considered to be the beneficiary in NBS, but the family and society can also benefit. Vice versa, carrier screening may be driven by disease prevention, rather than reproductive autonomy, raising cross-disciplinary questions regarding potential beneficiaries and which diseases to include. In addition, the stakeholders from these separate fields vary: Globally NBS is often governed as a public health programme while carrier screening is usually available via medical professionals. The article concludes with a call for an exchange of vision and knowledge among all stakeholders of both fields to attune the dynamics of screening.

Towards a Responsible Transition to Learning Healthcare Systems in Precision Medicine: Ethical Points to Consider.

Learning healthcare systems have recently emerged as a strategy to continuously use experiences and outcomes of clinical care for research purposes in precision medicine. Although it is known that learning healthcare transitions in general raise important ethical challenges, the ethical ramifications of such transitions in the specific context of precision medicine have not extensively been discussed. Here, we describe three levers that institutions can pull to advance learning healthcare systems in precision medicine: (1) changing testing of individual variability (such as genes); (2) changing prescription of treatments on the basis of (genomic) test results; and/or (3) changing the handling of data that link variability and treatment to clinical outcomes. Subsequently, we evaluate how patients can be affected if one of these levers are pulled: (1) patients are tested for different or more factors than before the transformation, (2) patients receive different treatments than before the transformation and/or (3) patients' data obtained through clinical care are used, or used more extensively, for research purposes. Based on an analysis of the aforementioned mechanisms and how these potentially affect patients, we analyze why learning healthcare systems in precision medicine need a different ethical approach and discuss crucial points to consider regarding this approach.

Implementation of Pharmacogenetics in Primary Care: A Multi-Stakeholder Perspective.

INTRODUCTION: Aberrant pharmacogenetic variants occur in a high proportion of people and might be relevant for the prescription of over 26 drugs in primary care. Early identification of patients who metabolize these drugs more rapidly or slowly than average could predict therapeutic effectivity and safety. Yet implementation of pharmacogenetics is progressing slowly. A high public health impact can potentially be achieved by increasing the proportion of people tested, when and where eligible according to clinical validity and utility. METHODS: In this study we defined actions, roles, and responsibilities for implementation of pharmacogenetics in primary care in consultation with stakeholder groups, by using a three-step mixed-methods approach. First, to define barriers and facilitators, public pharmacists (n = 24), primary care physicians (n = 8), and patients (n = 21) participated in focus groups and face-to-face interviews. Second, a multidisciplinary expert meeting (n = 16) was organized to define desired actions, roles, and responsibilities. Third, an online Delphi Study (n = 18) was conducted to prioritize the designated actions. RESULTS: For the integration of pharmacogenetics in primary care guidelines and practice, lack of evidence for clinical utility was mentioned as a main barrier. Furthermore, reimbursement, and facilitation of data registration and sharing were considered as key elements for future routine application of pharmacogenetic testing. Moreover, the division of roles and responsibilities, especially between general practitioners and pharmacists, is currently perceived as unclear. Sixteen actions in these four areas (clinical utility, reimbursement, data registration and sharing, and roles and responsibilities) were formulated and assigned to specific actors during the expert meeting. After ranking these 16 actions in the Delphi Study, nine actions remained pertinent, covering the four areas with at least one action. However, participants showed low agreement on the prioritization of the different actions, illustrating their different perspectives and the need to attune between them. DISCUSSION: Stakeholders together were able to formulate required actions to achieve true integration of pharmacogenetics in primary care, but no consensus could be achieved on the prioritization of the actions. Coordination of the current independent initiatives by the different stakeholders could facilitate effective and efficient implementation of useful pharmacogenetics in primary care.

DPD Testing Before Treatment With Fluoropyrimidines in the Amsterdam UMCs: An Evaluation of Current Pharmacogenetic Practice.

INTRODUCTION: The fluoropyrimidines (FP) (5-Fluorouracil, capecitabine, and tegafur) are commonly used anti-cancer drugs, but lead to moderate to severe toxicity in about 10-40% of patients. DPD testing [either the enzyme activity of dihydropyrimidine dehydrogenase (DPD) or the DPYD genotype] identifies patients at higher risk for toxicity who may be treated more safely with a lower drug dose. The Netherland's National guideline for colon carcinoma was updated in 2017 to recommend DPYD genotyping before treatment with FP. Pretreatment DPYD genotyping identifies approximately 50% of the patients that will develop severe FP toxicity. The aim of the study was to assess the uptake of DPD testing in the Amsterdam University Medical Centers over time and to evaluate stakeholder experiences to indicate barriers and facilitators of implementation in routine clinical care. MATERIALS AND METHODS: We used a mixed-method approach involving electronic patient records of 753 unique patients and pharmacy information systems analyses and fifteen semi-structured interviews with oncologists, pharmacists, and patients. The constellation perspective was used to identify barriers and facilitators at the level of practice, culture and structure. The proportion of FP users who were DPD tested pretreatment showed an increase from 1% (1/86) in Q2-2017 up to 87% (73/84) in Q4-2018. Unlike a landmark paper published in 2015, the National guideline for colorectal carcinoma followed by meetings to achieve local consensus led to this steep increase in the proportion of patients tested. RESULTS: Facilitating factors for stakeholders to implement testing included the existence of clear protocols, (anecdotal) evidence of the utility, being aware that peers are adhering to standard practice and clear and simple procedures for ordering and reporting. Main barriers included the lack of clear divisions of responsibilities, the lack of consensus on a test approach, long turn-around times and non-user-friendly IT-infrastructures. More professional education on the utility and limitations of pharmacogenetic testing was desired by most stakeholders. CONCLUSION: While the evidence for DPD testing was sufficient, only after the update of a National guideline and local consensus meetings the proportion of FP users that were DPD tested pretreatment rose to 87%. The implementation of personalized medicine requires stakeholders involved to attune practice, culture and structure.

[Pharmacogenetics in primary health care: implementation and future expectations]. / Farmacogenetica in de eerstelijnszorg: toepassing en toekomstverwachtingen.

Personalised medicine is a targeted approach to the prevention, diagnosis and treatment of disorders on the basis of the specific genetic profile of the patient. Pharmacogenetics research shows that differences in the genetic profile of patients explain the interindividual differences in efficacy and side effects of medicines. Although there are high expectations of personalised medicine and pharmacogenetics in healthcare, both are only used to a limited extent to date. Pharmacogenetics seems particularly important in diseases with a poor prognosis and treatments with potentially serious side effects. Pharmacogenetics testing is reimbursed in the case of serious side effects or unexpected ineffectiveness. 95% of patients in the Netherlands have at least one abnormality in the panel of genes for which guidance is available. The KNMP (Royal Dutch Pharmacists' Association) provides dosing advice based on genotype for 80 medicines, 27 of which are regularly prescribed in primary health care.