Human genome project: pharmacogenomics and drug development

Now that all 30,000 or so genes that make up the human genome have been deciphered, pharmaceutical industries are emerging to capitalize the custom based drug treatment. Understanding human genetic variation promises to have a great impact on our ability to uncover the cause of individual variation in response to therapeutics. The study of association between genetics and drug response is called pharmacogenomics. The potential implication of genomics and pharmacogenomics in clinical research and clinical medicine is that disease could be treated according to the interindividual differences in drug disposition and effects, thereby enhancing the drug discovery and providing a stronger scientific basis of each patient's genetic constitution. Sequence information derived from the genomes of many individuals is leading to the rapid discovery of single nucleotide polymorphisms or SNPs. Detection of these human polymorphisms will fuel the discipline of pharmacogenomics by developing more personalized drug therapies. A greater understanding of the way in which individuals with a particular genotype respond to a drug allows manufacturers to identify population subgroups that will benefit most from a particular drug. The increasing emphasis on pharmacogenomics is likely to raise ethical and legal questions regarding, among other things, the design of research studies, the construction of clinical trials and the pricing of drugs.     

Ethical and legal aspects of oncogenomics

The discovery of the genes and cellular pathways that play fundamental roles in several diseases, and the understanding of many diseases at a molecular level due to the advances in the field of genomics, have revolutionized the diagnosis, therapy and prevention of human diseases. Application of genetic testing in numerous medical fields, including pharmacogenomics and oncogenomics, raised numerous ethical questions and introduced legal instruments that are aimed at ensuring the appropriate protection of human research participants. For the effective development of human genomics and translation of novel, validated biomarkers into potentially useful clinical applications in personalized medicine, there is a need for clear ethical standards and principles in all phases of clinical research.     

WHOSE GENOME PROJECT?

The human genome project is a multinational project aimed at obtaining a detailed map and a complete DNA sequence of the human genome. It will have many scientific, medical, economic, ethical, legal, and social implications. A fundamental question to ask is "Whose genome project is it?" We can answer this question from different perspectives, and this aids our thinking about the issues that arise from the project. We can think of who proposed the idea, who should fund the research, who should perform the research, whose genome is mapped and sequenced, who should own the data, who should benefit from the results, and who should make these decisions. We can also compare the answers to these ethical questions with what is occurring in practice.     

A critique of race-based and genomic medicine

Now that a composite human genome has been sequenced (HGP), research has accelerated to discover precise genetic bases of several chronic health issues, particularly in the realms of cancer and cardiovascular disease. It is anticipated that in the future it will be possible and cost effective to regularly sequence individual genomes, and thereby produce a DNA profile that potentially can be used to assess the health risks for each person with respect to certain genetically predisposed conditions. Coupled with that enormous diagnostic power, it will then depend upon equally rapid research efforts to develop personalized courses of treatment, including that of pharmaceutical therapy. Initial treatment attempts have been made to match drug efficacy and safety to individuals of assigned or self-identified groups according to their genetic ancestry or presumed race. A prime example is that of BiDil, which was the first drug approved by the US FDA for the explicit treatment of heart patients of African American ancestry. This race-based approach to medicine has been met with justifiable criticism, notably on ethical grounds that have long plagued historical applications and misuses of human race classification, and also on questionable science. This paper will assess race-based medical research and practice in light of a more thorough understanding of human genetic variability. Additional concerns will be expressed with regard to the rapidly developing area of pharmacogenomics, promoted to be the future of personalized medicine. Genomic epidemiology will be discussed with several examples of on-going research that hopefully will provide a solid scientific grounding for personalized medicine to build upon.     

The need for systematic reviews of reasons

There are many ethical decisions in the practice of health research and care, and in the creation of policy and guidelines. We argue that those charged with making such decisions need a new genre of review. The new genre is an application of the systematic review, which was developed over decades to inform medical decision-makers about what the totality of studies that investigate links between smoking and cancer, for example, implies about whether smoking causes cancer. We argue that there is a need for similarly inclusive and rigorous reviews of reason-based bioethics, which uses reasoning to address ethical questions. After presenting a brief history of the systematic review, we reject the only existing model for writing a systematic review of reason-based bioethics, which holds that such a review should address an ethical question. We argue that such a systematic review may mislead decision-makers when a literature is incomplete, or when there are mutually incompatible but individually reasonable answers to the ethical question. Furthermore, such a review can be written without identifying all the reasons given when the ethical questions are discussed, their alleged implications for the ethical question, and the attitudes taken to the reasons. The reviews we propose address instead the empirical question of which reasons have been given when addressing a specified ethical question, and present such detailed information on the reasons. We argue that this information is likely to improve decision-making, both directly and indirectly, and also the academic literature. We explain the limitations of our alternative model for systematic reviews.     

Pharmacogenomics and personalized medicine: wicked problems, ragged edges and ethical precipices

In the age of genomic medicine we can often now do the genetic testing that will permit more accurate personal tailoring of medications to obtain the best therapeutic results. This is certainly a medically and morally desirable result. However, in other areas of medicine pharmacogenomics is generating consequences that are much less ethically benign and much less amenable to a satisfactory ethical resolution. More specifically, we will often find ourselves left with 'wicked problems,' 'ragged edges,' and well-disguised ethical precipices. This will be especially true with regard to these extraordinarily expensive cancer drugs that generally yield only extra weeks or extra months of life. Our key ethical question is this: Does every individual faced with cancer have a just claim to receive treatment with one of more of these targeted cancer therapies at social expense? If any of these drugs literally made the difference between an unlimited life expectancy (a cure) and a premature death, that would be a powerful moral consideration in favor of saying that such individuals had a strong just claim to that drug. However, what we are beginning to discover is that different individuals with different genotypes respond more or less positively to these targeted drugs with some in a cohort gaining a couple extra years of life while others gain only extra weeks or months. Should only the strongest responders have a just claim to these drugs at social expense when there is no bright line that separates strong responders from modest responders from marginal responders? This is the key ethical issue we address. We argue that no ethical theory yields a satisfactory answer to this question, that we need instead fair and respectful processes of rational democratic deliberation.     

Research versus practice: The dilemmas of research ethics in the era of learning health‐care systems

In this article we attempt to answer the question of how the ethical and conceptual framework (ECF) for a learning health‐care system (LHS) affects some of the main controversies in research ethics by addressing five key problems of research ethics: (a) What is the difference between practice and research? (b) What is the relationship between research ethics and clinical ethics? (c) What is the ethical relevance of the principle of clinical equipoise? (d) Does participation in research require a higher standard of informed consent than the practice of medicine? and (e) What ethical principle should take precedence in medicine? These questions allow us to construct two opposite idealized positions on the distinction between research and practice: the integration model and the segregation model of research and practice. We then compare the ECF for an LHS with these two idealized positions. We argue that the ECF for a LHS does not, in fact, solve these problems, but that it is a third, separate position in the relationship between research ethics and clinical ethics. Moreover, we suggest that the ECF for a LHS raises new ethical problems that require additional ethical analysis and justification. Our article contributes to the discussion on the relationship between research ethics and clinical ethics, revealing that although a learning health‐care system may significantly change the landscape of health care, some ethical dilemmas still require resolving on both theoretical and policy‐making levels.     

Ethical and legal implications of pharmacogenomics

Pharmacogenomics is the application of genomics technology to the discovery and development of drugs. A greater understanding of the way in which individuals with a particular genotype respond to a drug allows manufacturers to identify population subgroups that will benefit most from a particular drug. The increasing emphasis on pharmacogenomics is likely to raise ethical and legal questions regarding, among other things, the design of research studies, the construction of clinical trials and the pricing of drugs.     

The triad of success in personalised medicine: pharmacogenomics, biotechnology and regulatory issues from a Central European perspective

The population of the world has recently passed the 7 billion milestone and as the cost of human genome sequencing is rapidly declining, sequence data of billions of people should be accessible much sooner than anyone would have predicted 10years ago. This will form the basis of personalised medicine. However it is still not clear, even in principle, whether these data, combined with data of the expression of one's genome in various cells and tissues relevant to different diseases, could be used effectively in clinical medicine and healthcare, or in predicting responses to different therapies. Therefore this is an important issue which needs to be addressed before more resources are wasted on less than informative studies and surveys simply because technologies exist. As a typical example, we have selected and summarise here key studies from the biomedical literature that focus on gene expression profiling of the response to biologic therapies in peripheral blood and biopsy samples in autoimmune diseases such as rheumatoid arthritis, spondylarthropathy, inflammatory bowel diseases and psoriasis. We also present the state of the biotechnology market from a European perspective, discuss how spin-offs leverage the power of genomic technologies and describe how they might contribute to personalised medicine. As ethical, legal and social issues are essential in the area of genomics, we analysed these aspects and present here the European situation with a special focus on Hungary. We propose that the synergy of these three issues: pharmacogenomics, biotechnology and regulatory issues should be considered a triad necessary to succeed in personalised medicine.     

Developing the ethics of implementation research in health

Implementation research (IR) is growing in recognition as an important generator of practical knowledge that can be translated into health policy. With its aim to answer questions about how to improve access to interventions that have been shown to work but have not reached many of the people who could benefit from them, IR involves a range of particular ethical considerations that have not yet been comprehensively covered in international guidelines on health research ethics. The fundamental ethical principles governing clinical research apply equally in IR, but the application of these principles may differ depending on the IR question, context, and the nature of the proposed intervention. IR questions cover a broad range of topics that focus on improving health system functioning and improving equitable and just access to effective health care interventions. As such, IR designs are flexible and often innovative, and ethical principles cannot simply be extrapolated from their applications in clinical research. Meaningful engagement with all stakeholders including communities and research participants is a fundamental ethical requirement that cuts across all study phases of IR and links most ethical concerns. Careful modification of the informed consent process may be required in IR to permit study of a needed intervention. The risks associated with IR may be difficult to anticipate and may be very context-specific. The benefits of IR may not accrue to the same groups who participate in the research, therefore justifying the risks versus benefits of IR may be ethically challenging. The expectation that knowledge generated through IR should be rapidly translated into health policy and practice necessitates up-front commitments from decision-makers to sustainability and scalability of effective interventions. Greater awareness of the particular ethical implications of the features of IR is urgently needed to facilitate optimal ethical conduct of IR and uniform ethical review.     

Research Ethics: Beyond the Guidelines

There is international recognition of the need for sustainable research ethics committees to provide ethical review of human subjects research in developing countries, but many developing countries do not have such committees (often called 'IRBs'). Theoretical and practical uncertainties encountered by an IRB on the Caribbean island of Grenada offer insight into ethical review of research in developing countries. Theoretical uncertainties include questions about whether means of ensuring confidentiality and obtaining informed consent will be effective in local settings, and whether deviations from Western norms are justifiable. International guidelines are helpful in addressing these concerns, but are subject to interpretation. Guidelines are less helpful in practical areas like selecting members or chairs. They do not address what sort of procedures and paperwork will work in a developing country, or IRBs' relationships to governments that have no mandate for them. Experiences presented here show that IRBs in developing countries can sustainably adhere to international standards. Sustainability requires knowledge, personal commitment, and an official mandate to uphold international standards. Capacity building must therefore focus on educational programs to make developing country leaders knowledgeable about the value of international guidelines to their nations. Such knowledge is needed before people will become motivated to promote, implement, and uphold the guidelines. People in developing countries must help design bridges to help their nations put international standards into practice. The structure of such bridges may, of necessity, vary in different settings.     

Ethics committees. Research ethics: beyond the guidelines

There is international recognition of the need for sustainable research ethics committees to provide ethical review of human subjects research in developing countries, but many developing countries do not have such committees (often called 'IRBs'). Theoretical and practical uncertainties encountered by an IRB on the Caribbean island of Grenada offer insight into ethical review of research in developing countries. Theoretical uncertainties include questions about whether means of ensuring confidentiality and obtaining informed consent will be effective in local settings, and whether deviations from Western norms are justifiable. International guidelines are helpful in addressing these concerns, but are subject to interpretation. Guidelines are less helpful in practical areas like selecting members or chairs. They do not address what sort of procedures and paperwork will work in a developing country, or IRBs' relationships to governments that have no mandate for them. Experiences presented here show that IRBs in developing countries can sustainably adhere to international standards. Sustainability requires knowledge, personal commitment, and an official mandate to uphold international standards. Capacity building must therefore focus on educational programs to make developing country leaders knowledgeable about the value of international guidelines to their nations. Such knowledge is needed before people will become motivated to promote, implement, and uphold their guidelines. People in developing countries must help design bridges to help their nations put international standards into practice. The structure of such bridges may, of necessity, very in different settings.     

EMPIRICAL ETHICS AS DIALOGICAL PRACTICE

In this article, we present a dialogical approach to empirical ethics, based upon hermeneutic ethics and responsive evaluation. Hermeneutic ethics regards experience as the concrete source of moral wisdom. In order to gain a good understanding of moral issues, concrete detailed experiences and perspectives need to be exchanged. Within hermeneutic ethics dialogue is seen as a vehicle for moral learning and developing normative conclusions. Dialogue stands for a specific view on moral epistemology and methodological criteria for moral inquiry. Responsive evaluation involves a structured way of setting up dialogical learning processes, by eliciting stories of participants, exchanging experiences in (homogeneous and heterogeneous) groups and drawing normative conclusions for practice. By combining these traditions we develop both a theoretical and a practical approach to empirical ethics, in which ethical issues are addressed and shaped together with stakeholders in practice. Stakeholders' experiences are not only used as a source for reflection by the ethicist; stakeholders are involved in the process of reflection and analysis, which takes place in a dialogue between participants in practice, facilitated by the ethicist. This dialogical approach to empirical ethics may give rise to questions such as: What contribution does the ethicist make? What role does ethical theory play? What is the relationship between empirical research and ethical theory in the dialogical process? In this article, these questions will be addressed by reflecting upon a project in empirical ethics that was set up in a dialogical way. The aim of this project was to develop and implement normative guidelines with and within practice, in order to improve the practice concerning coercion and compulsion in psychiatry.     

Deciphering next-generation pharmacogenomics: an information technology perspective

In the post-genomic era, the rapid evolution of high-throughput genotyping technologies and the increased pace of production of genetic research data are continually prompting the development of appropriate informatics tools, systems and databases as we attempt to cope with the flood of incoming genetic information. Alongside new technologies that serve to enhance data connectivity, emerging information systems should contribute to the creation of a powerful knowledge environment for genotype-to-phenotype information in the context of translational medicine. In the area of pharmacogenomics and personalized medicine, it has become evident that database applications providing important information on the occurrence and consequences of gene variants involved in pharmacokinetics, pharmacodynamics, drug efficacy and drug toxicity will become an integral tool for researchers and medical practitioners alike. At the same time, two fundamental issues are inextricably linked to current developments, namely data sharing and data protection. Here, we discuss high-throughput and next-generation sequencing technology and its impact on pharmacogenomics research. In addition, we present advances and challenges in the field of pharmacogenomics information systems which have in turn triggered the development of an integrated electronic ‘pharmacogenomics assistant’. The system is designed to provide personalized drug recommendations based on linked genotype-to-phenotype pharmacogenomics data, as well as to support biomedical researchers in the identification of pharmacogenomics-related gene variants. The provisioned services are tuned in the framework of a single-access pharmacogenomics portal.     

转化医学：现代医学发展的动力

Translational medicine is a class of medicalresearch that proposes a two-way interaction betweenlaboratory and clinical research[1].Elias A.Zerhouni,the director of the National Institutes of Health(NIH),     

Cybrid human embryos--warranting opportunities to augment embryonic stem cell research

The recent vote in the British Parliament allows scientists in principle to create hybrid embryos by transferring human somatic cell nuclei into animal oocytes. This vote opens a fascinating new area of research with the central aim of generating interspecific lines of embryonic stem cells (ESCs) that could potentially be used to understand development, differentiation, gene expression and genomic compatibility. It will also promote human cell therapies, as well as the pharmaceutical industry's search for new drug targets. If this approach is to be successful, many biological questions need to be answered and, in addition, some moral and ethical aspects must be taken into account.     

MicroRNA pharmacogenomics: post-transcriptional regulation of drug response

The field of pharmacogenomics aims to predict which drugs will be most effective and safe for a particular individual based on their genome sequence or expression profile, thereby allowing personalized treatment. The bulk of pharmacogenomic research has focused on the role of single nucleotide polymorphisms, copy number variations or differences in gene expression levels of drug metabolizing or transporting genes and drug targets. In this review paper, we focus instead on microRNAs (miRNAs): small noncoding RNAs, prevalent in metazoans, that negatively regulate gene expression in many cellular processes. We discuss how miRNAs, by regulating the expression of pharmacogenomic-related genes, can play a pivotal role in drug efficacy and toxicity and have potential clinical implications for personalized medicine.     

Community engagement in global health research that advances health equity

Community engagement is gaining prominence in global health research. So far, a philosophical rationale for why researchers should perform community engagement during such research has not been provided by ethics scholars. Its absence means that conducting community engagement is still often viewed as no more than a ‘good idea’ or ‘good practice’ rather than ethically required. In this article, we argue that shared health governance can establish grounds for requiring the engagement of low‐ and middle‐income country (LMIC) community members in global health research, where such research aims to help reduce health disparities. This philosophical basis has important implications for the ethical goals ascribed to engagement and the approach adopted to undertake it. We suggest the ethical goals of engagement in equity‐oriented global health research should include: (a) generating research topics and questions that reflect the key problems disadvantaged groups face in accessing healthcare, services and broader social determinants of health and (b) promoting the translation of research findings into policy and practice in ways that benefit the health of disadvantaged groups. We propose engagement practice should have the following features: deliberation with LMIC community members to make a range of project decisions, beginning with setting research topics and questions; inclusion of members of disadvantaged groups and those with the power to change policy and practice to benefit them; and purposeful structuring of deliberations to minimize the impact of power disparities between LMIC community members. Finally, we reflect on how these features differ from those typical of much current community engagement practice in LMICs.     

Neuroethics and fMRI: mapping a fledgling relationship

Human functional magnetic resonance imaging (fMRI) informs the understanding of the neural basis of mental function and is a key domain of ethical enquiry. It raises questions about the practice and implications of research, and reflexively informs ethics through the empirical investigation of moral judgments. It is at the centre of debate surrounding the importance of neuroscience findings for concepts such as personhood and free will, and the extent of their practical consequences. Here, we map the landscape of fMRI and neuroethics, using citation analysis to uncover salient topics. We find that this landscape is sparsely populated: despite previous calls for debate, there are few articles that discuss both fMRI and ethical, legal, or social implications (ELSI), and even fewer direct citations between the two literatures. Recognizing that practical barriers exist to integrating ELSI discussion into the research literature, we argue nonetheless that the ethical challenges of fMRI, and controversy over its conceptual and practical implications, make this essential.