Application of the community dialogues method to identify ethical values and priorities related to pharmacogenomics.

Given the expansion of genetics in medicine, there is a growing need to develop approaches to engage patients in understanding how genetics affects their health. Various qualitative methods have been applied to gain a deeper understanding of patient perspectives in topics related to genetics. Community dialogues (CD) are a bi-directional research method that invites community members to discuss a pertinent, challenging topic over the course of a multi-week period and the community members openly discuss their positions on the topic. Authors discuss the first application of the CD method to the topic of pharmacogenetics testing. Additional CD are needed to engage diverse participant populations on this topic to improve genetics literacy, enhance physician engagement and drive policy change.

Why African Americans say "No": A Study of Pharmacogenomic Research Participation.

Objective: To identify reasons for nonparticipation by African Americans in cardiovascular pharmacogenomic research. Design: Prospective, open-ended, qualitative survey. Setting: Research staff approached patients eligible for the Discovery Project of The African American Cardiovascular pharmacogenomics CONsorTium in the inpatient or outpatient setting at four different institutions during September and October 2018. Participants: Potential Discovery Project participants self-identified as African American, aged >18 years, were on one of five cardiovascular drugs of interest, and declined enrollment in the Discovery Project. Main Outcome Measures: Reasons for nonparticipation. Methods: After declining participation in the Discovery Project, patients were asked, "What are your reasons for not participating?" We analyzed their responses using a directed content analytic approach. Ultimately, responses were coded into one of nine categories and analyzed using descriptive statistics. Results: Of the 194 people approached for the Discovery Project during an eight-week period, 82 declined participation and provided information for this study. The most common reason for refusal was concern about the amount of blood drawn (19.5%). The next most common reasons for refusal to participate included concerns about genetic testing (14.6%) and mistrust of research (12.2%). Across study sites, significantly more patients enrolled in the inpatient than outpatient setting (P<.001). Significantly more women and younger individuals declined participation due to concerns about genetic testing and too little compensation (P<.05). Conclusions: Collection of blood samples and concerns about genetic testing are obstacles for the recruitment of African Americans to pharmacogenomics studies. Efforts to overcome these barriers to participation are needed to improve representation of minorities in pharmacogenomic research. Enrolling participants from inpatient populations may be a solution to bolster recruitment efforts.

Pharmacogenetic Testing: The Ethics of Implementing in Clinical Practice for Chronic Pain Patients.

Chronic pain is a common and costly healthcare problem where standard of care often involves the use of opioids and patient response varies widely. Designing a treatment plan based upon an individual's genetic signature provides an individualized patient-centered care approach that can improve functional status, quality of life, and reduce adverse drug events (ADEs). This paper will discuss the ethical implications of pharmacogenetic (PGx) testing using the principlism framework of the four moral principles: beneficence, non-maleficence, autonomy, and justice. Beneficence involves balancing the benefits and risks associated with PGx testing. Non-maleficence is the directive to do no harm to the patient in the delivery or use of PGx test results. Autonomy encompasses self-determination; the patient's right to select PGx testing. Justice is concerned with distributing benefits and burdens of PGx testing access and costs. Maximizing patient autonomy and beneficence during treatment promotes patient-centered care. Principlism supports PGx testing for patients experiencing chronic pain. Integrating PGx testing impact treatment plans and may improve the outlook for patients with chronic pain.

Variantes alélicas *3, *4, *5 y *6 del gen CYP2D6 en una muestra de pacientes cubanos con esquizofrenia / Aallelic variants *3, *4, *5 and *6 of gene CYP2D6 in a sample of Cuban patients with schizophrenia

Introducción: El gen CYP2D6 codifica la proteína de igual nombre, enzima principal del complejo de citocromos P-450 en la fase I del metabolismo de muchos medicamentos ampliamente usados en la práctica clínica, entre los que se encuentran los neurolépticos. Las variantes alélicas que implican una función nula de esta enzima: *3, *4, *5, y *6, predicen entre el 93-97,5(percent) de los posibles fenotipos metabolizadores lentos, que implican acumulación de concentraciones tóxicas y, por consiguiente, mayor riesgo de reacciones adversas. Por otro lado, hay estudios que reportan una baja frecuencia de metabolizadores lentos en pacientes con esquizofrenia. Objetivo: Evaluar la asociación entre las variantes no funcionales del gen CYP2D6 con la esquizofrenia en pacientes cubanos. Métodos: Se realizó un estudio de casos y controles. En el grupo de los casos se incluyeron 212 pacientes con esquizofrenia, y en los controles 326 voluntarios sanos. Resultados: Las frecuencias de los alelos CYP2D6 con actividad enzimática nula fueron similares entre los casos y los controles. No se detectó una diferencia estadísticamente significativa de metabolizadores lentos entre los pacientes con esquizofrenia ni en los voluntarios sanos…(AU)

Issues and Ethical Considerations in Pharmaco-oncogenomics.

The rapid advancements of treatment modalities and vast amounts of information being generated through novel technologies, paint the picture of a very promising future, one that will allow for a more efficient and precise DNA sequencing and potentially more tailored cancer therapies for patients. However, with all these advances we must address the ethical and legal considerations each one of these technologies will raise. This is a necessity in order for advancement, not to stand in the way of science and development, but as a safeguard in protecting humanity and our personal genetic information.

The Ethical, Legal and Regulatory Issues Associated with Pharmacogenomics: Systematically Quantifying the Literature.

Since the human genome was successfully mapped much academic attention has been given to ethical, legal and regulatory issues associated with the integration and application of genomics in health care. In line with the recent political commitment to promoting precision medicine that relies heavily on omic knowledge, it is timely to review the issues that this body of literature has addressed. Focusing on pharmacogenomics, this review quantifies the issues identified in this body of academic work. It reveals that, after nearly two decades, interest in the regulatory and legal issues associated with pharmacogenomics continues to generate significant attention. The ethical issues, while not as predominant, also persist. The analyses highlights that there is a dearth of empirical research exploring the impact that these issues have had.

Teaching students in clinical programs about pharmacogenomics: do they understand drug-drug interactions?

Teaching the clinical implementation of pharmacogenomics to students in clinical programs first requires careful consideration of their aptitude in basic clinical pharmacologic concepts. Prior to developing training exercises on drug-gene interactions, educators must first assess student competency in identifying and managing drug-drug interactions given the similarities in identifying and managing these sources of medication error.

Pharmacogenetics in Pain Treatment.

Pain is an unpleasant feeling usually resulting from tissue damage that can persist along weeks, months, or even years after the injury, turning into pathological chronic pain, the leading cause of disability. Currently, pharmacology interventions are usually the first-line therapy but there is a highly variable analgesic drug response. Pharmacogenetics (PGx) offers a means to identify genetic biomarkers that can predict individual analgesic response opening doors to precision medicine. PGx analyze the way in which the presence of variations in the DNA sequence (single-nucleotide polymorphisms, SNPs) could be responsible for portions of the population reaching different levels of pain relief (phenotype) due to gene interference in the drug mechanism of action (pharmacodynamics) and/or its concentration at the place of action (pharmacokinetics). SNPs in the cytochrome P450 enzymes genes (CYP2D6) influence metabolism of codeine, tramadol, hydrocodone, oxycodone, and tricyclic antidepressants. Blood concentrations of some NSAIDs depend on CYP2C9 and/or CYP2C8 activity. Additional candidate genes encode for opioid receptors, transporters, and other molecules important for pharmacotherapy in pain management. However, PGx studies are often contradictory, slowing the uptake of this information. This is likely due, in large part, to a lack of robust evidence demonstrating clinical utility and to its polygenic response modulated by other exogenous or epigenetics factors. Novel therapies, including targeting of epigenetic changes and gene therapy-based approaches, broaden future options to improve understanding of pain and the treatment of people who suffer it.

Personalized Medicine in the Paediatric Population: The Balance Between Pharmacogenetic Progress and Bioethics.

Personalized medicine (PM) is becoming increasingly important in contemporary clinical and research scenarios. In the context of PM, pharmacogenomics and pharmacogenetics are aimed at the genetic personalization of drug response. Extrinsic and intrinsic factors may explain interindividual variability in drug response. Among such factors, age seems to specifically intervene to modulate drug response since normal developmental changes may influence the exposure-response relation. Consequently, the potential benefit of pharmacogenomics (PGx) in the paediatric population is considerable. However, many challenges still exist in incorporating PGx into clinical practice. In fact, drug prescribing in the paediatric population is often based on extrapolation from clinical trials conducted on adults as there is often a lack of paediatric data. Children are not just 'small adults', as they have their own pharmacological characteristics in terms of drug metabolism and efficacy, adverse drug reactions and toxicity. Although children might potentially benefit from such research, many ethical concerns arise at the intersection of the spheres of drug development and genetic testing. Children require particular attention because of their vulnerability both in research and the clinical applications of PGx; furthermore, children range from preterm newborns and neonates to infants and toddlers and to adolescents, thus forming a further heterogeneous target group. In this paper, we focus on some ethically relevant concerns (i.e., informed consent, stigmatization, ancillary information) that might arise as a result of the possible application of PGx tests in both paediatric practice and research.

Pharmacogenomics inventions in Ukraine and Europe: the issue of patentability and the perspective to create personalized weapon for bioterrorism

Since the researcher in pharmacogenomics has been given the promise to create personalized treatment and drugs for patients suffering from many common diseases, particularly those with multiple treatment modalities, the issue about the legal status of inventions in the field of pharmacogenomics and criteria of patentability for them becomes as one of the most important to solved on the beginning of pharmacogenomics era. The prospect of acquiring exclusive rights for inventions, which are based on the establishment of certain medicines to treat a wide range of health problems, which are provided by patent protection is a strong incentive for pharmaceutical companies to develop research in pharmacogenomic. Patent availability nowadays in a one hand is the main instrument for protecting investments, and guaranteed earnings for pharmaceutical companies what provides the investments to new researches. Although, on the other hand, patents in the pharmaceutical and pharmacogenomics areas are legal instrument for manipulate categories such a health and sickness, life or death depending of the material wealth individuals. The question of compliance with the conditions of patentability to inventions in pharmacogenomic including general questions of the patentability of the inventions, additionally correlates the possibility of obtaining a patent for an invention that uses human genes, the issues of morality and public order, and concerns the use of the results of pharmacogenomic as weapons of bioterrorism. This article analyzes the patentability of inventions pharmacogenomic from the point of view of industrial property rights under the laws of Ukraine and the EU. In addition, this article aims to discuss the issues associated with the new modern object for patent law, which are the results of the study pharmacogenomics; the determination of criteria of patentability of pharmacogenomics in accordance with the legislation of Ukraine and to compare them with the criteria according to EU. Also in this article described the problem of possible appearance personalized bioterrorism, which would considered depends on the genotype of the human. For the end article examines the impact of patent policy on the development of new and innovative medicines and the possibility of using patent protection as an additional instrument for the prevention of bioterrorism

Habida cuenta de que el investigador en farmacogenómica ha prometido crear un tratamiento personalizado y medicamentos para los pacientes que sufren de muchas enfermedades comunes, en particular aquellos con múltiples modalidades de tratamiento, la cuestión de la situación jurídica de las invenciones en el campo de la farmacogenómica y los criterios de patentabilidad para ellos se convierte en uno de los asuntos más importantes a resolver en el inicio de la era de la farmacogenómica. La perspectiva de adquirir derechos exclusivos para las invenciones, que se basan en el establecimiento de ciertos medicamentos para tratar una amplia gama de problemas de salud, que son proporcionados por la protección de patentes, es un fuerte incentivo para que las empresas farmacéuticas desarrollen investigación en farmacogenómica. La disponibilidad de patentes hoy en día, por un lado, es el principal instrumento para proteger las inversiones y garantizar los ingresos para las empresas farmacéuticas proporcionen inversiones a nuevas investigaciones. Aunque, por otro lado, las patentes en las áreas farmacéutica y farmacogenómica son instrumentos legales para manipular categorías tales como salud y enfermedad, vida o muerte dependiendo de la riqueza material de los individuos. La cuestión del cumplimiento de las condiciones de patentabilidad de las invenciones farmacogenómicas, incluidas las cuestiones generales de la patentabilidad de las invenciones, correlaciona adicionalmente la posibilidad de obtener una patente para una invención que utiliza genes humanos, cuestiones de moralidad y orden público, y se refiere al uso de los resultados de la farmacogenómica como armas de bioterrorismo. Este artículo analiza la patentabilidad de las invenciones farmacogenómicas desde el punto de vista de los derechos de propiedad industrial bajo la normativa en Ucrania y en la UE. Además, este artículo pretende discutir las cuestiones asociadas con el nuevo objeto moderno para el derecho de patentes, que son los resultados del estudio de la farmacogenómica; la determinación de criterios de patentabilidad de farmacogenómica de conformidad con la legislación de Ucrania y compararlos con los criterios de la UE. También en este artículo se describe el problema de la posible aparición del bioterrorismo personalizado, que se consideraría dependiente del genotipo del humano. Para terminar, el artículo examina el impacto de la política de patentes en el desarrollo de medicamentos nuevos e innovadores y la posibilidad de utilizar la protección de la patente como instrumento adicional para la prevención del bioterrorismo

Addressing ethical challenges at the intersection of pharmacogenomics and primary care using deliberative consultations.

AIM: Primary care physicians will play a central role in the successful implementation of pharmacogenomics (PGx); however, important challenges remain. We explored the perspectives of stakeholders on key challenges of the PGx translation process in primary care using deliberative consultations. METHODS: Primary care physicians, patients and policy-makers attended deliberations, where they discussed four ethical questions raised by PGx research and implementation in the primary care context. RESULTS: Stakeholders voiced skepticism regarding PGx funding, commercialization, regulation, maintenance of an equal access healthcare system and restructuring of health research incentives and priorities in the public sector. CONCLUSION: Deliberants developed governing principles for a PGx-specific charter of ethics, aiming to protect the interests of patients, and outlined recommendations for the future of PGx in primary care.

Aspectos bioéticos de la farmacogenómica en la fase clínica de desarrollo de medicamentos / Bioethical aspects of pharmacogenomics in the clinical phase of drug development

La fase clínica de desarrollo de medicamentos para el tratamiento de enfermedades multifactoriales es larga y costosa. La farmacogenómica ayuda ese proceso mediante un mejor diseño de los ensayos clínicos y la selección de los pacientes con mayor probabilidad de responder con efectividad y menos reacciones adversas a los candidatos terapéuticos. Los objetivo de la presente revisión bibliográfica es exponer las ventajas de las pruebas farmacogenómicas en los ensayos clínicos de desarrollo de medicamentos, explicar las consecuencias éticas, legales y psicosociales de su aplicación y proponer algunas medidas para contrarrestar los riesgos psicosociales. Las pruebas farmacogenómicas fueron evaluada de manera simple, múltiple y combinada y cumplieron varios objetivos y funciones en las diferentes de fases de los ensayos clínicos de medicamentos. La realización del consentimiento informado de los sujetos participantes en los ensayos clínicos y su evaluación por los Comité de Ética y Revisión, las acciones de las autoridades regulatorias nacionales, el cumplimiento de las regulaciones ministeriales en salud pública, la aplicación de los principios bioéticos internacionales y el análisis de cada dilema ético según sus particularidades, son medidas que buscaron favorecer el respeto a la dignidad, la autonomía e intimidad de los sujetos de investigación y facilitar la aplicación de la farmacogenómica en los ensayos clínicos de medicamentos(AU)

The clinical phase in the development of drugs for the treatment of multifactorial diseases is both lengthy and costly. Pharmacogenomics aids this process by providing a better design of clinical trials as well as a selection of patients with a greater probability to effectively respond and fewer adverse reactions to therapeutic candidates. The present bibliographic review is intended to reveal the advantages of pharmacogenomic tests in clinical trials for drug development, explain the ethical, legal and psychosocial consequences of their application, and propose some measures to counteract psychosocial risks. Pharmacogenomic tests were evaluated in a simple, multiple and combined manner, and fulfilled several objectives and functions at the various phases of clinical trials of drugs. Informed consent from the subjects participating in the clinical trials and their evaluation by the Ethical Review Board, actions taken by national regulatory authorities, compliance with public health ministerial regulations, application of international bioethical principles, and analysis of each ethical dilemma according to its specific characteristics, are all measures aimed at enhancing respect for dignity, autonomy and privacy of research subjects and facilitating the application of pharmacogenomics to clinical trials of drugs(AU)

Aspectos bioéticos de la farmacogenómica en la fase clínica de desarrollo de medicamentos / Bioethical aspects of pharmacogenomics in the clinical phase of drug development

La fase clínica de desarrollo de medicamentos para el tratamiento de enfermedades multifactoriales es larga y costosa. La farmacogenómica ayuda ese proceso mediante un mejor diseño de los ensayos clínicos y la selección de los pacientes con mayor probabilidad de responder con efectividad y menos reacciones adversas a los candidatos terapéuticos. Los objetivo de la presente revisión bibliográfica es exponer las ventajas de las pruebas farmacogenómicas en los ensayos clínicos de desarrollo de medicamentos, explicar las consecuencias éticas, legales y psicosociales de su aplicación y proponer algunas medidas para contrarrestar los riesgos psicosociales. Las pruebas farmacogenómicas fueron evaluada de manera simple, múltiple y combinada y cumplieron varios objetivos y funciones en las diferentes de fases de los ensayos clínicos de medicamentos. La realización del consentimiento informado de los sujetos participantes en los ensayos clínicos y su evaluación por los Comité de Ética y Revisión, las acciones de las autoridades regulatorias nacionales, el cumplimiento de las regulaciones ministeriales en salud pública, la aplicación de los principios bioéticos internacionales y el análisis de cada dilema ético según sus particularidades, son medidas que buscaron favorecer el respeto a la dignidad, la autonomía e intimidad de los sujetos de investigación y facilitar la aplicación de la farmacogenómica en los ensayos clínicos de medicamentos.

The clinical phase in the development of drugs for the treatment of multifactorial diseases is both lengthy and costly. Pharmacogenomics aids this process by providing a better design of clinical trials as well as a selection of patients with a greater probability to effectively respond and fewer adverse reactions to therapeutic candidates. The present bibliographic review is intended to reveal the advantages of pharmacogenomic tests in clinical trials for drug development, explain the ethical, legal and psychosocial consequences of their application, and propose some measures to counteract psychosocial risks. Pharmacogenomic tests were evaluated in a simple, multiple and combined manner, and fulfilled several objectives and functions at the various phases of clinical trials of drugs. Informed consent from the subjects participating in the clinical trials and their evaluation by the Ethical Review Board, actions taken by national regulatory authorities, compliance with public health ministerial regulations, application of international bioethical principles, and analysis of each ethical dilemma according to its specific characteristics, are all measures aimed at enhancing respect for dignity, autonomy and privacy of research subjects and facilitating the application of pharmacogenomics to clinical trials of drugs.

The 3-I framework: a framework for developing public policies regarding pharmacogenomics (PGx) testing in Canada.

The 3-I framework of analyzing the ideas, interests, and institutions around a topic has been used by political scientists to guide public policy development. In Canada, there is a lack of policy governing pharmacogenomics (PGx) testing compared to other developed nations. The goal of this study was to use the 3-I framework, a policy development tool, and apply it to PGx testing to identify and analyze areas where current policy is limited and challenges exist in bringing PGx testing into wide-spread clinical practice in Canada. A scoping review of the literature was conducted to determine the extent and challenges of PGx policy implementation at federal and provincial levels. Based on the 3-I analysis, contentious ideas related to PGx are (i) genetic discrimination, (ii) informed consent, (iii) the lack of knowledge about PGx in health care, (iv) the value of PGx testing, (v) the roles of health care workers in the coordination of PGx services, and (vi) confidentiality and privacy. The 3-I framework is a useful tool for policy makers, and applying it to PGx policy development is a new approach in Canadian genomics. Policy makers at every organizational level can use this analysis to help develop targeted PGx policies.

[ETHICS, MORALS AND SOCIETY IN PERSONALIZED MEDICINE].

Following the completion of the human genome project, genomic medicine including personalized medicine, widely based on pharmacogenetics and pharmacogenomics, is rapidly developing. This breakthrough should benefit humankind thanks to tailoring the most appropriate prevention, interventions and therapies to each individual, minimizing adverse side effects, based on inter-personal genetic variety and polymorphism. Yet wide spectrum ethical, legal and social issues carry significant implications regarding individuals, families, society and public health. The main issues concern genomic information and autonomy, justice and equity, resources allocation and solidarity, challenging the traditional role of medicine and dealing with unlimited boundaries of knowledge. Those issues are not new nor exceptional to genomic medicine, yet their wide unlimited scope and implications on many aspects of life renders them crucial. These aspects will be discussed in light of Beauchamp and Childress' four principles: non-maleficence, beneficence, autonomy and justice, and main moral philosophies, Kant's autonomy, Utilitarianism which promotes the common good, and Rawls' Theory of Justice.

Pharmacogenomics--how close/far are we to practising individualized medicine for children?

The translation of pharmacogenomics into clinical practice is a key approach for practising individualized medicine, which aims to maximize drug efficacy and minimize drug toxicity. Since the completion of both the Human Genome Project and the International HapMap project, the development of pharmacogenomics has been greatly facilitated. However, progress in translating pharmacogenomics into clinical practice, especially in paediatric medicine, is unexpectedly slow. Many challenges from different areas remain. This paper discusses the existing applications and the limitations to the implementation of paediatric pharmacogenomics, as well as possible solutions for overcoming these limitations and challenges.

Calidad y legibilidad de la hoja de información al paciente en estudios con análisis farmacogenético / Quality and legibility of written informed consent form in pahrmacogenetic research

Fundamento y objetivo: Los estudios de farmacogenética se han convertido en una práctica habitual en el desarrollo de nuevos medicamentos, surgiendo la necesidad de evaluar las Hojas de Información al Paciente (HIP). Los objetivos de este estudio son evaluar el grado de adecuación a las recomendaciones establecidas por la legislación y grupos de expertos de la información contenida en las HIP de estudios que incluyan análisis del material genético y analizar su legibilidad. Material y métodos: Se analizó el contenido de las HIP que recibieron los participantes en los estudios farmacogenéticos presentados al Comité Ético entre abril de 2011 y abril de 2013 en un hospital de tercer nivel. Para evaluar la calidad de la HIP se elaboró un cuestionario con 42 preguntas con los elementos que debe contener la información que reciben los sujetos. La facilidad de lectura fue evaluada aplicando distintos índices de legibilidad. Resultados: El 31,5% de las 92 HIP presentaron más del 75% de los apartados considerados en el cuestionario. Las secciones con menor grado de cumplimiento fueron las relativas a los riesgos y beneficios (41,7%) y a las compensaciones derivadas del estudio (56,1%). Ninguna de las HIP cumplió con menos del 50% del global del cuestionario. El 90% de las HIP mostraron un grado adecuado de legibilidad. Conclusiones: Se han encontrado deficiencias en algunos puntos de la información contenida en las HIP evaluadas. El grado de legibilidad es elevado, siendo necesario futuros estudios para establecer el grado de entendimiento real de los pacientes

Background and objective: Pharmacogenetic studies have become in recent years a common practice in the development of new drugs, with the need to evaluate the information and readability of Informed Consent Forms (ICFs) to ensure compliance with the recommendations set by current legislation and expert groups. Materials and methods: Retrospective observational study that analyzes the content of ICFs received by participants of pharmacogenetic studies approved in a tertiary hospital. To evaluate the quality of the ICFs, a questionnaire of 42 questions was prepared (Table 1) with the elements that must contain the information given to subjects, while readability was assessed using different readability indices. Results: The 31.5% of the 92 ICFs analyzed showed more than 75% of sections considered in the questionnaire. Sections with lower compliance were relative to risks and benefits (41.7%) and compensation for study participation (56.1%). None of the ICFs fulfilled with less than 50% of overall sections. Regarding legibility, about 90%, have a suitable degree for the most of population based on indexes used. Conclusions: Deficiencies were found in some parts of the information contained in ICFs, while the degree of legibility was high, being necessary for future studies to establish the degree of real understanding of patients