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.
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 ...β-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.
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.
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.
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.
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.
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.
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.
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
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
genotyping before treatment with FP. Pretreatment
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.
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.
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.
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.
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.
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.
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.
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.
Genetic Screening-Emerging Issues Cornel, Martina C; van der Meij, Karuna R M; van El, Carla G ...
Genes,
05/2024, Letnik:
15, Številka:
5
Journal Article
Recenzirano
Odprti dostop
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.
The European Union (EU) Council Recommendation on rare diseases urged the member states to implement national and EU collaborative actions to improve the health care of rare disease patients. ...Following this recommendation, the European Commission launched a tender on newborn screening (NBS) to report on current practices of laboratory testing, form a network of experts and provide guidance on how to further implement NBS screening in a responsible way, the latter of which was provided in an Expert Opinion document. After consultation of experts from EU member states, (potential) candidate member states and European Free Trade Association countries, in a consensus meeting in June 2011, 70 expert opinions were finalized. They included the need to develop case definitions for all disorders screened for to facilitate assessment and international outcome studies. Decision whether a screening program should be performed can be based on screening criteria updated from the traditional Wilson and Jungner (1968) criteria, relating to disease, treatment, test and cost. The interest of the child should be central in the assessment of pros and cons. A European NBS body should assess evidence on (new) screening candidate disorders. For rare conditions, best level evidence should be used. The health system should ensure treatment to cases diagnosed by screening, controlled and revised by follow-up outcome studies. Screening methodology should aim to avoid unintended findings, such as mild forms and carrier status information, as much as possible. Activities to improve NBS in Europe, such as training and scientific evaluation, could benefit from collaboration at EU level and beyond.
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
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
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
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
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.
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