No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
Ethical, Social and Legal Implications of Pharmacogenomics: A Critical Review
Abstract
My aim was to examine the ethical, social and legal implications of pharmacogenomics.
I performed a critical review of the literature. The primary focal point is the bioethical principle discussed. The second outcome measure is the perspective of the discussion.
This review documents that the pharmacogenomics issues of concern are comparable to issues concerning other genetic developments in general. However, two main issues are particular to the case of pharmacogenomics. Firstly, this review reveals that society, industry, groups and individuals appreciate the prospect of pharmacogenomics very differently. Secondly, there is a lack of research into the post-marketing implications of pharmacogenomics.
An extensive focus on the ethical, social and legal implications of pharmacogenomics, in terms of both pre- as well as post-marketing issues, is essential. Also, a multidisciplinary approach which includes individual and group opinions in an upfront manner in the research and development process is essential. Otherwise, there is a substantial risk that the positive prospects of pharmacogenomics will not survive due to fear and a lack of acceptance and understanding on the part of the general public.
... In essentie houden beide zich bezig met de studie van de interactie tussen genetische varianten en de werking van geneesmiddelen. In de Verenigde Staten alleen zouden 100 000 mensen per jaar sterven door een verkeerde of niet-optimale reactie op toegediende medicijnen (Moldrup, 2001). Het grote voordeel voor de patiënt is dan ook dat hij een betere behandeling krijgt doordat de geneesmiddelen die worden voorgeschreven beter bij zijn of haar genetisch profiel aansluiten, dat nevenwerkingen worden geminimaliseerd, de veiligheid van de geneesmiddelen verhoogd en algemeen gesproken de kostprijs voor de behandeling verlaagt. ...
... -De mogelijkheid bestaat dat de verschillende partijen in deze ontwikkeling, zijnde de farmaceutische industrie, de gemeenschap, de verzekeringen en de individuele patiënten verschillende en zelfs tegenstrijdige belangen hebben (Moldrup, 2001). Zo kan de eis van de verzekeringen om inzage te krijgen in genetische informatie de opkomst van de tests tegenwerken, wat dan weer tegen de belangen van de industrie ingaat. ...
Inleiding Genetische tests vormen reeds geruime tijd een onderdeel van de gezondheidszorg. Voor de duidelijkheid starten we met enkele definities van de verschillende soorten tests. Dit is niet eenvoudig aangezien de auteurs en commissies verschillende definities hanteren. Vaak zijn er trouwens overlappingen mogelijk. De volgende formuleringen moeten als werkdefinities worden gezien: -Diagnostische tests worden uitgevoerd om de aanwezigheid van een gendefect te bevestigen dat een bepaalde symptomatologie veroorzaakt. -Predictieve tests kunnen in drie categorieën worden onderverdeeld: -Tests voor presymptomatische diagnose worden uitgevoerd om het genotype te bepalen van een persoon die geen symptomen vertoont. Deze tests vinden plaats bij personen uit een familie waarin een bepaalde genetische aandoening voorkomt. Wanneer een persoon drager is van de mutatie van een bepaald gen, dan zal die aandoening met zekerheid tot uiting komen in het latere leven van die persoon. Het klassieke voorbeeld hier is de ziekte van Huntington. -Predispositietests worden eveneens uitgevoerd in een context waarin er een familiegeschiedenis is van een aandoening maar in deze gevallen is er sprake van een sterk verhoogde kans op de aandoening maar geen zekerheid (aandoeningen met een grote penetrantie, hoog-risico gen). De voorbeelden zijn erfelijke borst-en ovariumkanker. -Susceptibiliteitstests worden uitgevoerd om na te gaan of de mutatie van een bepaald gen die een verhoogde kans geeft op het ontwikkelen van een aandoening aanwezig is (laag-risico gen). De toepassing is niet gebonden aan een familiegeschiedenis. De tests worden uitgevoerd bij multifactoriële aandoeningen die tot stand komen door de werking van meerdere genen, omgevingsfactoren en de interactie tussen beide. Wanneer we het over grootschalige toepassingen hebben, betreft het meestal dit soort tests. Voorbeelden hier zijn hart-en vaataandoeningen en diabetes type 1.
... They should also be aware of the potential impact that knowledge of their own genetic make up could have on their self-image, particularly if the test results are "negative" (i.e. suggest that the individual is unlikely to respond to therapy) [31,32,33]. This concern may be particularly important in relation to psychiatric disorders; patients may be confronted not only with the burden of suffering from a stigmatised condition but also being told that they cannot be effectively treated for it. ...
... The use of racial or ethnic categorisation in pharmacogenetic research may lead to the use of these categories in the analysis of study results, drug marketing and drug prescription [32,48]. As a result individuals from some ethnic groups may be denied access to certain medical treatments. ...
Current pharmacotherapies for psychiatric disorders are generally incompletely effective. Many patients do not respond well or suffer adverse reactions to these drugs, which can result in poor patient compliance and poor treatment outcome. Adverse drug reactions and non-response are likely to be influenced by genetic polymorphisms. Pharmacogenetics holds some promise for improving the treatment of mood disorders by utilising information about genetic polymorphisms to match patients to the drug therapy that is the most effective with the fewest side effects. Pharmacogenomics promises to facilitate the development of new drugs for treatment. However, these technologies raise many ethical, economic and regulatory issues that need to be addressed before they can be integrated into psychiatry, and medicine more generally. We discuss ethical and policy issues arising from pharmacogenetic testing and pharmacogenomics research, such as informed consent, privacy and confidentiality, research on vulnerable persons and discrimination; and economic viability of pharmacogenetics and pharmacogenomics. We conclude with recommendations for the regulation and distribution of pharmacogenetic testing services and pharmacogenomic drugs.
... 5,6 Obviously, the move towards pharmacotherapy decisions, based to a great deal on the patient's individual genome, expression profiling, or proteome data, would dramatically affect the way that medicine is practiced, posing substantial moral concerns. [17][18][19][20][21][22][23][24][25] Discussions are well under way regarding medical, ethical, societal, and regulatory aspects of pharmacogenomics and its expected implementation into the clinic. [17][18][19][20][21][22][23][24][25] Entire public conferences have been devoted to bioethics and societal aspects of pharmacogenomics, including special working parties such as those set by the Nuffield Council on Bioethics 26 and the European Commission. ...
... [17][18][19][20][21][22][23][24][25] Discussions are well under way regarding medical, ethical, societal, and regulatory aspects of pharmacogenomics and its expected implementation into the clinic. [17][18][19][20][21][22][23][24][25] Entire public conferences have been devoted to bioethics and societal aspects of pharmacogenomics, including special working parties such as those set by the Nuffield Council on Bioethics 26 and the European Commission. 27 In contrast to the extensive on-going interest of leaders of the medical community in bioethics and societal aspects of pharmacogenomics, expressed in debates and publications, 17-25 there appears to be a relative lack of initiatives concerning the educational aspects of pharmacogenomics, both for professionals and for the community. ...
Pharmacogenomics would be instrumental for the realization of personalized medicine in coming decades. Efforts are evident to clarify the potential bioethical, societal, and legal implications of key pharmacogenomics-based technologies projected to be soon introduced into the core practice of medicine. In sharp contrast, a lack of sufficient attention to educational aspects of pharmacogenomics, both for professionals and for society at large, is evident. In order to contribute to this discussion, a 'Pharmacogenomics Education Forum' was held on October 2, 2004 during the 3rd Annual Meeting of the International Society of Pharmacogenomics (ISP) at Santorini, Greece. The participants, members of the ISP Pharmacogenomics Education Forum, after deliberate discussions, proposed a document of 'Background Statement' and 'Recommendations and Call for Action' addressed to Deans of Education at Medical, Pharmaceutical, and Health Schools globally. This document has been considered by the education committee of the International Society of Pharmacogenomics and the result is presented here. We hope that this call would be listened to, and soon followed by beneficial action, ultimately leading to enhanced implementation of personalized medicine into core medical education and practice.
... Finding the genes responsible for common diseases is replacing research on monogenic diseases. These widespread illnesses are heritable, meaning that more than one gene is involved in their multifactorial pathogenesis, and they are of multiple factors, dependent on complex interactions between numerous environmental factors and various alternative forms (alleles) of genes called disease susceptibility genes (Møldrup 2001). Databases abound for the selection of candidate gene for diseases, and a considerable quantity of genomic data products from the pathogen. ...
Recent breakthroughs in the feld of medicine and physiology have come through the application of bioinformatics and computational biology in experimental designs and in silico analyses. Genomics and proteomics-based strategies are currently used for data presentation, sequence analysis and alignment, primer designs, mapping and annotation of the entire human genome. This advancement has made it possible to identify the roles of specifc genes and proteins, understand their
physiological functions, as well as pathophysiology during mutation, malformation and diseased conditions. This review describes the available proteomic databases; essential proteins used as markers of fertility in male, annotation techniques and
data projects on male reproductive physiology. The materials used in this descriptive review were searched using PubMed and Google scholar databases. The following terms and phrases were reviewed: 'genomics', 'proteomics', Interrelationship between bioinformatics and Life sciences', 'bioinformatics tools for analyzing male reproductive system', 'Male reproductive system functions', infertility', and 'Application of bioinformatics in male reproductive physiology research'. Analyses in proteomics and genomics have further expanded the understanding of male reproductive physiology research through different bioinformatics tools and databases. A better understanding of the mechanisms behind spermatogenesis, testicular gene expression, protein involvement in male reproduction, the discovery of cancer genes in reproductive organs, and possible markers to identify infertility in males have evolved. There is, therefore, a need for further application of bioinformatics in the study of male reproductive system with the introduction of more databases, better identification of cancer genes in male reproductive organs and male infertility's possible biomarkers.
... Finding the genes responsible for common diseases is replacing research on monogenic diseases. These widespread illnesses are heritable, meaning that more than one gene is involved in their multifactorial pathogenesis, and they are of multiple factors, dependent on complex interactions between numerous environmental factors and various alternative forms (alleles) of genes called disease susceptibility genes (Møldrup 2001). Databases abound for the selection of candidate gene for diseases, and a considerable quantity of genomic data products from the pathogen. ...
Recent breakthroughs in the field of medicine and physiology have come through the application of bioinformatics and computational biology in experimental designs and in silico analyses. Genomics and proteomics-based strategies are currently used for data presentation, sequence analysis and alignment, primer designs, mapping and annotation of the entire human genome. This advancement has made it possible to identify the roles of specific genes and proteins, understand their physiological functions, as well as pathophysiology during mutation, malformation and diseased conditions. This review describes the available proteomic databases; essential proteins used as markers of fertility in male, annotation techniques and data projects on male reproductive physiology. The materials used in this descriptive review were searched using PubMed and Google scholar databases. The following terms and phrases were reviewed: 'genomics', 'proteomics', 'Interrelationship between bioinformatics and Life sciences', 'bioinformatics tools for analyzing male reproductive system', 'Male reproductive system functions', 'infertility', and 'Application of bioinformatics in male reproductive physiology research'. Analyses in proteomics and genomics have further expanded the understanding of male reproductive physiology research through different bioinformatics tools and databases. A better understanding of the mechanisms behind spermatogenesis, testicular gene expression, protein involvement in male reproduction, the discovery of cancer genes in reproductive organs, and possible markers to identify infertility in males have evolved. There is, therefore, a need for further application of bioinformatics in the study of male reproductive system with the introduction of more databases, better identification of cancer genes in male reproductive organs and male infertility's possible biomarkers.
... To address these challenges, efforts should be made to increase awareness through training programs, educational campaigns, and community outreach initiatives. It is also crucial to involve African researchers and clinicians in the development and implementation of pharmacogenomics initiatives to ensure that they are culturally appropriate and effective [107][108][109][110]. Thirdly, research ethics can be complex, and the research process may take longer than expected as it requires consideration of the diverse cultural and religious beliefs of the people and ensuring that the research is conducted with respect and ethical principles. ...
Background: Pharmacogenomic studies on psychiatric drugs have slowly identified genetic variations that influence drug metabolism and treatment effectiveness in patients with mental illness. Because most of these studies predominantly centered on people of European descent, there remains a substantial knowledge gap on the clinical implications of current pharmacogenomic evidence in multi-ancestry populations such as Africans. Thus, whether pharmacogenomic (PGx) genetic testing implemented in European populations would be valid for a population of African origin is unknown. The objective of this review was to appraise previous psychiatric pharmacogenomic studies in Africa and highlight challenges and opportunities to initiate PGx testing in the region.
Methods: A systematic literature search was conducted on PubMed, Scopus, and Web of Science to identify studies published in the English language from inception up to February 06, 2023. The primary outcomes were treatment response, remission, side effects, and drug metabolism in African psychiatric patients.
Results: The review included 42 pharmacogenomic studies that explored the genetic profiles of psychiatric patients in Africa. Despite the limited number of studies, our review found strong evidence of pharmacogenomic diversity within the African populations, highlighting the importance of pharmacogenomic research in this population. A high degree of variability and differences in the frequencies of cytochrome P450 (CYPs) genotypes have been reported within the African population. It is estimated that 28% of North Africans and Ethiopians are ultrarapid metabolizers of several medications, mainly attributed to the increased activity of the CYP2D6 enzyme. This is significantly higher than the prevalence among Caucasians (10%), or Hispanics, Chinese, or Japanese populations (1%). Due to the defective CYP2C19*2 allele (at a frequency of 14%) and CYP2C19*3 allele (2% frequency), 5.2% of Ethiopians were identified as poor metabolizers of S-mephenytoin, a probe substrate used to assess the activity of the cytochrome P450 enzyme. In Tunisian patients with schizophrenia, genotyping the CYP1A2 gene and using therapeutic drug monitoring (TDM) improved the effectiveness and safety of clozapine. Among South African patients with schizophrenia, antipsychotic treatment response was associated with two gene variants (rs13025959 in the MYO7B gene with the C allele and rs10380 in the MTRR gene with the T allele).
Conclusion: The review has identified evidence of pharmacogenomic diversity in African populations and recommended expanding pharmacogenomic studies while introducing PGx testing in this population. For the few characterized genes, Africans showed qualitative and quantitative differences in the profile of pharmacogenetic variants when compared to other ethnic groups. Limited research funding, inadequate infrastructure, and a shortage of skilled human resources might be a challenge, but by building upon local successes and through collaborations with international partners, it is possible to establish pharmacogenomic biobanks and leverage global genetic resources to initiate personalized treatment approaches in Africa.
Keywords: Pharmacogenomics, Personalized medicine, Psychiatric disorders, Africa, Genetic variants, depression, schizophrenia
... Pharmacokinetics is the study of individual genetic differences (polymorphisms) in drug absorption, metabolism, distribution, and excretion. Pharmacogenomics has been defined as the study of variability in drug response due to sets of variants within an individual or across a population (Vogel 1959;Andersson et al. 1992;Møldrup 2002). ...
Although predicting the effects of variants near intron-exon boundaries is relatively straightforward, predicting the functional Exon Splicing Enhancers (ESEs) and the possible effects of variants within ESEs remains a challenge. Considering the essential role of CYP2D6/CYP2C19 genes in drug metabolism, we attempted to identify variants that are most likely to disrupt splicing through their effect on these ESEs. ESEs were predicted in these two genes using ESEfinder 3.0, incorporating a series of filters (increased threshold and evolutionary conservation). Finally, reported mutations were evaluated for their potential to disrupt splicing by affecting these ESEs. Initially, 169 and 243 ESEs were predicted for CYP2C19/CYP2D6, respectively. However, applying the filters, the number of predicted ESEs was reduced to 26 and 19 in CYP2C19/CYP2D6, respectively. Comparing prioritized predicted ESEs with known sequence variants in CYP2C19/CYP2D6 genes highlights 18 variations within conserved ESEs for each gene. We found good agreement in cases where such predictions could be compared to experimental evidence. In total, we prioritized a subset of mutational changes in CYP2C19/CYP2D6 genes that may affect the function of these genes and lead to altered drug responses. Clinical studies and functional analysis for investigating detailed functional consequences of the mentioned mutations and their phenotypic outcomes is mostly recommended.
... Genomic testing per se may lead to conflicts in a family. In addition, the results of premedication genetic testing may affect access to health insurance, leading some patients to refuse such testing (65,80,113). Health care professionals, including clinicians, pharmacists, and genetic counselors, should complement each other and utilize pharmacogenomics knowledge for optimal disease management and patient stratification. ...
The Global Genomic Medicine Collaborative, a multinational coalition of genomic and policy experts working to implement genomics in clinical care, considers pharmacogenomics to be among the first areas in genomic medicine that can provide guidance in routine clinical practice, by linking genetic variation and drug response. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe life-threatening reactions to medications with a high incidence worldwide. Genomic screening prior to drug administration is a key opportunity and potential paradigm for using genomic medicine to reduce morbidity and mortality and ultimately eliminate one of the most devastating adverse drug reactions. This review focuses on the current understanding of the surveillance, pathogenesis, and treatment of SJS/TEN, including the role of genomics and pharmacogenomics in the etiology, treatment, and eradication of preventable causes of drug-induced SJS/TEN. Gaps, unmet needs, and priorities for future research have been identified for the optimal management of drug-induced SJS/TEN in various ethnic populations. Pharmacogenomics holds great promise for optimal patient stratification and theranostics, yet its clinical implementation needs to be cost-effective and sustainable. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 19 is August 31, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... In general, the impact appears to be minimal even for diseases without clinical interventions such as Alzheimer disease [2][3][4] and even when testing for multiple conditions through panel or array-based testing [5][6][7]. In contrast, PGx testing is believed to raise even fewer risks of psychological harms and stigmatization or discrimination compared to genetic testing for disease [8][9][10]; however, no evidence supports this presumption. It is possible that these risks have been underestimated when considering the challenges of effectively communicating results, particularly given the language used to report PGx test results and the potential long-term and recurring use of PGx test results. ...
... Most entities refute the 'genetic exceptionalism' concept and argue that data resulting from genetic testing in general and PGx testing in particular are qualitatively the same as other medical information; nevertheless, the nature of the generated information may lead to unintended ethical dilemmas such as breaches of privacy and confidentiality that may affect insurability and family dynamics [49]. Therefore, the same fundamental ethical issues as everywhere else in medicine, mainly autonomy, beneficence, nonmaleficence and justice, are applicable [50]. More importantly, one should be aware of the risk of 'reverse genetic exceptionalism', defined by Evans et al. as using the limitations inherent to the specific nature of genomic or PGx research as an excuse to avoid presenting rigorous evidence of improved health outcomes (i.e., clinical utility) when it comes to care and prevention of diseases, as a more significant block to the promise of PGx [51]. ...
Theranostics represents a broadening in the scope of personalized medicine to include companion diagnostics for health interventions ranging from drugs to vaccines, as well as individual susceptibility to disease. Surprisingly, in the course of this broadening of personalized medicine discourse, relatively little attention has been paid to primary care (as compared with tertiary healthcare settings) despite its vast patient population and being a crucial entry point to health services. Recent advances in pharmacogenomics (PGx), a classical theranostics application whereby genotyping and/or gene expression-based tests are used for targeted or optimal therapy, revealed new opportunities to characterize more precisely human genomic variation and the ways in which it contributes to person-to-person and population variations in drug response. In the immediate foreseeable future, the primary-care physicians are expected to play an ever increasing crucial role in PGx-based prescribing in order to reduce the rates of adverse drug events and improve drug efficacy, yet PGx testing in primary care remains limited. In this article, the authors review the advances in PGx applications, the barriers for their adoption in the clinic from a primary care point of view and the efforts that are being undertaken to move PGx forward in this hitherto neglected application context of theranostic medicine. Finally, the authors propose several salient recommendations, including a 5-year forecast, to accelerate the current convergence between PGx and primary care.
... Comme d'autres technologies basées sur la génétique ou la génomique, l'outil décisionnel thérapeutique que constituent les tests analysant le GEP des tumeurs est encore peu connu du public [17]. Or, la littérature montre que les attitudes profanes des patients, leurs perceptions de ces nouvelles technologies, sont importantes pour l'acceptation de ces innovations et leur intégration en clinique [22]. Dans les différentes études, la plupart des femmes interrogées reconnaissaient n'avoir jamais entendu parler de ces techniques auparavant, ou en avaient une compréhension relativement sommaire [19,20]. ...
The purpose of this review of the literature is to document how breast cancer patients perceive the use of tumor gene profiling approaches to better adapt treatments, and to identify the features of these approaches that may impact their clinical application. In general, the use of tumor genomic analysis was perceived by patients as an approach facilitating personalized medicine and received considerable support. Nevertheless, a number of confusions and worries about these practices were also identified. Improving the quality of provider/patient communications should enable patients to play a more active part in the decision-making about their treatment. This will ensure that those who agree to their tumor gene analysis have realistic expectations and sound deductions of the final result disclosure process.
© 2012 médecine/sciences – Inserm / SRMS.
... It is clear that there are ethical and social issues that arise owing to DTC genetic t esting [9] (regardless of the type of tests sold), as well as owing to PGx testing [12,13] (regardless of the Direct-to-consumer (DTC) genetic testing involves the offer and/or the advertising of genetic tests directly to the public. Over the last couple of years, many commercial companies, the majority of which are based in the USA, have been advertising and offering DTC genetic testing services outside of the established healthcare system, and often without the involvement of healthcare professionals. ...
... Dans chacun de ces secteurs, différents acteurs se côtoient. Ils seront appelés à interagir tout en ayant des objectifs et des valeurs propres qui, inévitablement, représenteront des bénéfices pour les uns et des risques pour d'autres (Moldrup, 2001). Ce sont les chercheurs, les décideurs, les professionnels de la santé, les groupes de patients et d'individus qui décideront de l'orientation et de la place que prendront la génétique et la génomique au sein de la société contemporaine. ...
... Groups of patients characterized by less-profitable genotypes are at risk of becoming therapeutic 'orphans' [11]. Ethical problems concerning minorities that carry certain biomarkers or have a particular ethnic background may emerge [12,13], and regulations may be necessary to maintain equity and privacy protection141516. Nevertheless, in certain areas personalized medicine is already an established fact. ...
Personalized medicine: is it hype or revolution? In any case, there is not only real demand for it, but it also has a history. As it is, the personal aspects of health care have been partly neglected in the current era of evidence-based, scientific medicine. We now know that a 'one fits all' type of treatment has its limits. Medicine needs to be (re-)personalized. The time is right: the post-genomic era provides the necessary molecular tools, but does it provide for the risks involved? Privacy, protection of minorities, and prevention of discrimination are at stake. Regulations are required. The health-care process needs redesigning to render personalized medicine effective. Information and communication management is challenged to handle the wealth of personal information and link to global medical knowledge. But the goal is magnificent: personal health planning, early diagnosis, the right drug for the right patient, and predictable side effects.
... Conversely, premiums for groups being at greater risk will rise and insurance might potentially be denied to those whose genes predict extended or expensive medical treatment. The public acceptance of pharmacogenomics, which studies genetic polymorphisms underlying the variations in drug response between individuals and individual populations, is, therefore, high because it promises individualized safe and effective treatment at lower cost [3]. Therefore, pharmacogenomics not only has an impact on the individual, but also affects whole population groups and the pharmaceutical industry. ...
Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.
... Many of the issues discussed here have been the subject of careful, foreward-thinking analysis by scientists, industry and academia alike, and their views form the basis of the start of a wider discussion encompassing the ethical, political, social and technological aspects of the use of pharmacogenomics. [6][7][8][9][10][11][12][13] Genotyping of a whole nation, as was envisioned and currently ongoing in Iceland. 14 for the entire population of 290 000, has political risks. ...
Every presentation at a pharmaceutical company of a drug development project, and, in the past 10 years, every grant application for public funds in the area of biomedical sciences, starts with a litany of diseases that may be treated if the proposed projects are supported and successful. In most, if not all, of these proposals the genetics of the affected population and the pharmacology of current and prospective treatment is a major component for consideration. In this sense, pharmacogenomics has always been part of decision-making and project selection in drug development. The practice of complementing epidemiologic, diagnostic and treatment-rate data with pharmacogenetics data was introduced in the 1950s, and the term pharmacogenetics was coined by Motulsky in 1957.1 Motulsky wrote, 'Genetically controlled drug reactions not only are of practical significance, but may be considered pertinent models for demonstrating the interaction of heredity and environment in the pathogenesis of disease,' much in tune with Vogel's article in 19592 and Haldane's classic book: The Biochemistry of Genetics.3
... field Council on Bioethics, [35] and in numerous publications.3637383940 The PMC has no intention of duplicating such efforts, but rather will serve as a clearinghouse of information from various sources. ...
The concept of personalized medicine — that medical care can be tailored to the genomic and molecular profile of the individual — has repercussions that extend far beyond the technology that makes it possible. The adoption of personalized medicine will require changes in healthcare infrastructure, diagnostics and therapeutics business models, reimbursement policy from government and private payers, and a different approach to regulatory oversight. Personalized medicine will shift medical practices upstream from the reactive treatment of disease, to proactive healthcare management including screening, early treatment, and prevention, and will alter the roles of both physician and patient. It will create a greater reliance on electronic medical records and decision support systems in an industry that has a long history of resistance to information technology.
Personalized medicine requires a systems approach to implementation. But in a healthcare economy that is highly decentralized and market driven, it is incumbent upon the stakeholders themselves to advocate for a consistent set of policies and legislation that pave the way for the adoption of personalized medicine. To address this need, the Personalized Medicine Coalition (PMC) was formed as a nonprofit umbrella organization of pharmaceutical, biotechnology, diagnostic, and information technology companies, healthcare providers and payers, patient advocacy groups, industry policy organizations, major academic institutions, and government agencies. The PMC provides a structure for achieving consensus positions among these stakeholders on crucial public policy issues, a role which will be vital to translating personalized medicine into widespread clinical practice.
In this article, we outline the goals of the PMC, and the strategies it will take to foster communication, debate, and consensus on issues such as genetic discrimination, the reimbursement structures for pharmacogenomic drugs and diagnostics, regulation, physician training and medical school curricula, and public education.
Pharmacogenomics (PGx), an expanding area of precision medicine, focuses on identifying biomarkers of drug response variability to maximize the safety and efficacy of drug treatment based on patient's genetic make-up. While advances in omics technologies have provided the ability to simultaneously process thousands and thousands of samples, the large amount of output data has generated several ethical, legal, and social issues in PGx research concerning privacy and discrimination. Therefore, PGx research involving humans must be designed with respect for the bioethical principles of beneficence, non-maleficence, autonomy, and justice. Sensitive data, including secondary information outside the objectives of the research study, can be disclosed and shared with third parties representing a potential source of stigma, so the need to ensure the confidentiality of research participants should be a high priority. On the other hand, the classification as “at risk” for adverse drug reactions or “non-responders,” the differences between geographically well-defined groups as well as the inclusion in a vulnerable group can be reasons for discrimination. All these issues must be explained and included in the informed consent process provided to research participants. In addition to these aspects, in this book, clinical trial design, biomarker validation and drug development studies are also discussed. All these topics should be carefully evaluated in the aim to overcome barriers for pharmacogenomics implementation as part of routine healthcare in the general vision of precision medicine guidelines harmonized.
Artiklen undersøger unge studerendes (18-25 år) narrativer om trivsel og håndtering af præstationskrav i forbindelse med at være under uddannelse. Unges brug af receptpligtig medicin til ikke-medicinske formål som at trives eller præstere bedre diskuteres i lyset af et øgende præstations- og effektivitetspres i det danske uddannelsessystem. Analysen viser, at de unge bruger medicin ud fra meget forskellige logikker og forbehold. Nogle unge normaliserer egen brug og ser den som en legitim måde at håndtere oplevet pres på og som en mulighed for at differentiere sig. Andre mener, at de burde kunne klare sig uden. Disse unge fortæller om etiske dilemmaer og om en følelse af at snyde og at bevæge sig væk fra et ’autentisk’ selv. Mange unge fortæller om en følelse af utilstrækkelighed og om stor ambivalens over for de samfundsmæssige krav, de oplever. Artiklen diskuterer, hvorvidt den øgende individualisering i samfundet, både når det gælder valg og ansvar, måske kræver for meget af unge under uddannelse.
Pharmacogenomics explores the contribution of genetics to drug safety and specifically examines the single gene interactions with drugs. It also makes use of genetic tests to distinguish among patients whose genetic characteristics predispose them to respond in certain ways to certain medicines. An understanding of the genetic variables that influence drug response could also help pharmaceutical companies design new, more effective therapies.
Pharmacogenetics helps us understand the relationship between an individual’s genetic make-up and the way medicines work for each person. This book reviews the use of pharmacogenetics across all stages of the health innovation cycle from research through to uptake by doctors and patients. It focuses on how to optimise the use of pharmacogenetics to deliver effective innovations for public health, and design policies that enhance their economic and social benefits. The book argues for large-scale studies to validate the biomarkers that underpin pharmacogenetics and policies to share the cost and risk of using pharmacogenetics to improve the use of existing medicines. Governments and others need to align regulatory, reimbursement and other incentives and work with industry to measure better the impacts of pharmacogenetics. Health systems need to take positive steps to adapt to the use of pharmacogenetics and ensure that health professionals receive adequate training.
Nanotechnology represents an emerging technology with varied application areas. It has been identified as the next scientific breakthrough with potential for positive impacts for society. The development and application of emerging technologies has been shown to be contingent upon societal responses to those technologies and their applications. Socio-psychological factors will potentially influence societal responses to nanotechnology, and play an important role in its development and commercialisation. The views of both experts and the general public regarding societal preferences for innovations in nanotechnology will be important in identifying which applications will be commercialised. If expert views regarding the determinants of societal acceptability do not align with those held by the general public, applications that consumers will reject may be introduced early in the commercialisation trajectory and focus public opinion on the negative aspects of nanotechnology. Conversely, applications which are acceptable to consumers may never be commercialised if experts perceive that consumers are likely to reject them. This thesis identifies and describes factors influencing societal response to nanotechnology by incorporating views from experts and the general public. Three research approaches were utilised. The first focused on reviewing previous scientific research into the socio-psychological factors that influence public acceptance of new technologies. The second focused on identifying and quantifying expert views on the factors that will influence societal acceptance or rejection of nanotechnology. The third tested whether the different factors do, in fact, drive public opinion.
There is increasing discussion in public and academic forums about the anticipated benefits of pharmacogenomics, as well as the attendant social and ethical implications of this research. Yet there is often an implicit assumption that the benefits of pharmacogenomics are ‘just around the corner’ and will significantly outweigh the costs. Furthermore, it is argued that the associated ethical issues are not as profound as those that emerge in other areas of genetics, and that experience gained wrestling with these other issues provides ample ethical and regulatory tools to deal with any problems arising with pharmacogenomics.
We contend that this vision of ethical and social issues associated with pharmacogenomics is not so clear-cut. The scientific evidence is more complex and contested than the public, academics, and policy makers, have been led to believe, and while there may be real clinical benefits from this research, they are not likely to arrive in the near future. Pharmacogenomics research is also occurring in a terrain occupied by a multitude of different and powerful actors, with diverse and often competing interests. It is therefore essential to investigate the broader social and political context, unravel the various interests pressuring for early implementation, and deconstruct the hype in order to appreciate a fuller range of ethical and social consequences associated with the current developments of pharmacogenomics.
The lay-attitude to pharmacogenomics is crucial to successful implementation. The intention of the present literature review is to delineate the considerations, expectations, fears, and so on, described in the literature regarding pharmacogenomics; seen from a lay perspective. The literature review was conducted in Medline and EMBASE in March 2005. The combined search in databases, reference lists, and so on, produced a total of 30 relevant articles, of which seven are included in the literature review. Other literature reviews on this issue are included in the discussion. This review documents that, at this time, very little information is available regarding the public's attitude to pharmacogenetic testing and the use of pharmacogenomics in therapy. Thus, studies of lay attitudes to and expectations of pharmacogenomics are highly relevant. Research is increasingly being conducted in the area, and studies have shown that education, income, age, ethnicity and nationality seems to influence lay attitudes. Based on this, it is concluded that knowledge of the relation between national/ cross-national cultural and subcultural settings, and attitudes toward pharmacogenomics seem to be important to a successful pharmacogenomics implementation in healthcare.
The first and crucial step in sensory processing, the transduction of stimuli, such as odor, light and sound, into a cellular response, are all regulated by genetic pathways. The past years have provided a significant increase in our understanding of some of these pathways, due in large part to the genes found to be associated with inherited hearing loss (HL).
From the perspective of current and future patients, the development of the field of pharmacogenetics is of immense interest. The encouraging vision that is now being established is that we may move from trial and error therapies to evidence-based personalized medicine in clinical practice. However, research and the application of pharmacogenetics to clinical practice are believed to raise a host of controversial ethical issues. Some of these are related to the research process, for example, confidentiality and informed consent in association with human tissue sampling. Other issues arise on a societal level, for example, issues regarding justice and the use of race or ethnicity as proxies for genotyping. In this perspective, I comment on this debate and also suggest what we may learn from previous discussions regarding DNA testing and gene transfer methods. Arguably, the most important ethical perspective in medical research and drug development is related to the interests of patients wanting medical treatment that is both effective and carries low risks of adverse effects. Risk:benefit ratios must always be compared with existing alternatives, and while the risk of adverse effects may be tolerable for some individuals, owing to genetic reasons, this may not be relevant for others. This will have consequences for regulatory policies regarding drug development. In the future, personalized medicine will also need to take epigenetic and environmental factors into consideration.
Purpose: Since public acceptance of pharmacogenetic testing will largely influence their implementation in routine medical care, common implications of pharmacogenetic testing from pa- tients', physicians' and scientists' perspective are reviewed. Methods: Broad literature review (MEDLINE; MeSH terms: Phar- macogenetics, Delivery of Health Care, Ethics, Attitude, Patient Acceptance of Health Care) of empirical and theoretical studies describing psychological, family-related, social, and ethical con- sequences of pharmacogenetic testing to describe relevant as- pects for further empirical studies. Results: Apart from antici- pated benefit, acceptance of pharmacogenetic testing might be influenced by the following: Expectation of negative psychoso- cial consequences, fear of discrimination or violation of privacy. Due to its great complexity, understanding of test results and ex- planation of their impact pose new challenges for physician-pa- tient relations. Since most studies are conceptual, empirical stu- dies exploring attitudes of patients/physicians and determining medical as well as economic value of pharmacogenetic testing are imperative.
This study adopts a prospective approach in order to explore and define the perceived risks of future drugs from a citizen perspective. More precisely, we attempt to characterise how citizens anticipate future drugs and their associated risks, the risk focus, risk acceptance and scepticism. The prospective Delphi method was used with a total of 462 (round 1) and 377 (round 2) Danish citizens participating. This study reports that despite the fact that respondents acknowledge the emergence of societal, economic and ethical consequences as a part of the risk profile of future drugs, they tend to evaluate risk taking on an individual level. The results also illustrate a high level of scepticism and low level of risk acceptance in the future. This study concludes, in accordance with the theory of Risk Society, that risks of future drug technologies are anticipated to expand and develop beyond our existing perception and control mechanisms. But at the same time individuals themselves do not feel or see the new societal, economic or ethical consequences of drug utilisation; it is second-hand non-experience based on judgements by experts. Nevertheless, the inclusion of citizens early in the drug research and development process may prove to be an essential and necessary approach in order to legitimise new medical technologies within the biotechnology and genomic areas.
The purpose of the present survey is to describe the Danish perspective on pharmacogenetics and public willingness to adopt and utilize it as part of drug treatment. An Internet-based quantitative survey of a representative segment of the Danish population from ages 18 to 70 was conducted in March 2005. A total of 3,000 participated in the survey, with a response rate of 59%. Only 14.1% of respondents indicated they had heard of pharmacogenetics, while 79% said they had not. However, 81% indicated that they would choose pharmacogenetic drugs rather than ordinary drugs, while 6% would choose the drugs currently available. In addition, 89% indicated willingness to receive pharmacogenetic treatment in future. The population in general has a low level of knowledge about pharmacogenetics, and certain aspects are seen as disadvantageous: the lack of drug treatment for everyone, for example. Nonetheless, the attitude towards the use of pharmacogenetics is generally positive, and pharmacogenetic treatment is considered better than the treatment available at present.
Definition of the problem The ideal of a truly predictive medicine vested with effective causal strategies of prevention down to the molecular level is far from being reality. However, we have to appreciate the fact that the concepts of health negotiated at the intersection of medicine and society are becoming increasingly directed towards a prediction of future health and the notion of prevention. This paper investigates whether novel concepts of a predictive–preventive medicine—especially public health genetics or public health genomics—are likely to promote the social achievability of health. Arguments The analysis presented is based on an assessment of the role of fundamental social values for the function of medicine in society, on the one hand, and on the role of the key concepts of medicine—health and disease—at the interface of medicine and society, on the other. Conclusion We observe a transition of medicine toward increasingly more predictive concepts of disease. With this shift, the normative characteristics of the key concepts of health and disease shared between medicine, individuals, and society are also subject to profound changes. This is a challenge to social values in their function as pillars of health care systems, particularly the social value of justice and its societal perceptions in the realm of health.
The aim of this study was to document how breast cancer patients perceive their prognosis and a tailored treatment based on tumour gene expression analysis, and to identify the features of this approach that may impact its clinical application. In-depth interviews were conducted at three French cancer centres with 37 women (35-69 years of age) with node-positive breast cancer undergoing an adjuvant chemotherapy regimen defined on the basis of the genomic signature predicting the outcome after chemotherapy. Several concerns were identified. First, some misconceptions about these methods were identified due to semantic confusions between the terms 'genomic' and 'genetic', which generated anxiety and uncertainty about the future. Second, the 'not done' and 'not interpretable' signatures were misinterpreted by the women and associated with highly negative connotations. However, the use of tumour genomic analysis to adapt the treatment to each patient received most of the patients' approval because it was perceived as an approach facilitating personalised medicine. In conclusion, improving the quality of provider/patient communications should enable patients to play a more active part in the decision making about their treatment. This will ensure that those who agree to have tumour gene analysis have realistic expectations and sound deductions about the final result disclosure process.
The vision of personalized medicine, the practice of medicine where each patient receives the most appropriate medical treatments and the most fitting dosage and combination of drugs based on his or her genetic make-up, seems to become more realistic as our knowledge about the human genome rapidly expands. We already know the reason for many types of adverse drug reactions, which are often related to polymorphic gene alleles of drug metabolizing enzymes. Moreover, insight into reasons for poor drug efficacy, often related to single nucleotide polymorphisms or larger polymorphisms in genes encoding drug target proteins, has been gained. There is a growing need to incorporate this increasingly complex body of knowledge to the standard curriculum of medical schools, so that the forthcoming generation of clinicians and researchers will be familiar with the latest developments in pharmacogenomics and medical bioinformatics, and will be capable of providing patients with the expected benefits of personalized medicine.
There is increasing discussion in public and academic forums about the anticipated benefits of pharmacogenomics, as well as the attendant social and ethical implications of this research. Yet there is often an implicit assumption that the benefits of pharmacogenomics are 'just around the corner' and will significantly outweigh the costs. Furthermore, it is argued that the associated ethical issues are not as profound as those that emerge in other areas of genetics, and that experience gained wrestling with these other issues provides ample ethical and regulatory tools to deal with any problems arising with pharmacogenomics. We contend that this vision of ethical and social issues associated with pharmacogenomics is not so clear-cut. The scientific evidence is more complex and contested than the public, academics, and policy makers, have been led to believe, and while there may be real clinical benefits from this research, they are not likely to arrive in the near future. Pharmacogenomics research is also occurring in a terrain occupied by a multitude of different and powerful actors, with diverse and often competing interests. It is therefore essential to investigate the broader social and political context, unravel the various interests pressuring for early implementation, and deconstruct the hype in order to appreciate a fuller range of ethical and social consequences associated with the current developments of pharmacogenomics.
The field of pharmacogenetics will soon celebrate its 50th anniversary. Although science has delivered an impressive amount of information in these 50 years, pharmacogenetics has suffered from lack of integration into clinical practice. There are several reasons for this, including the unmet need for education at medical schools and the lack of awareness about the impact of genetic medicine on healthcare in the community. Recently, the FDA announced that it considers pharmacogenomics one of three major opportunities on the critical path to new medical products. This notion by the FDA is filling the regulatory void that existed between drug developers and drug users. However, in order to bring pharmacogenetic testing to the prescription pad successfully, healthcare professionals and policy makers, as well as patients, need to have the necessary background knowledge for making educated treatment decisions. To effectively move pharmacogenetics into everyday medicine, it is therefore imperative for scientists and teachers in the field to take on the challenge of disseminating pharmacogenetic insights to a broader audience.
In September this year the Nuffield Council on Bioethics held a meeting to disclose and discuss the main findings of their newly published report on the ethical issues associated with developments in pharmacogenetics research. The basics of pharmacogenetics science is briefly outlined, and then the extent to which the report was successful in addressing (or at least highlighting) the attendant social, ethical, and policy implications of pharmacogenetics research is evaluated.
Research on the interaction of genes and the environment is revealing that many human diseases have both genetic and environmental components. Even traditional "environmental" diseases, such as infections, appear to interact with genetic components in the human host. Environmental genetics research will inevitably increase understanding of individual susceptibilities to toxic exposures in the environment and harmful side effects of medications; therefore, it has great promise for improving the prevention and treatment of human diseases. However, realizing the benefits of this research requires careful attention to ethical issues that are particularly relevant in this context. This article reviews some of the most pressing issues related to research design and methods, as well as from the application of research results (e.g., workplace genetic screening and legal toxic torts, personal medical responsibility, and the relationship between genetics and public health measures).
Since public acceptance of pharmacogenetic testing will largely influence their implementation in routine medical care, common implications of pharmacogenetic testing from patients', physicians' and scientists' perspective are reviewed.
Broad literature review (MEDLINE; MeSH terms: Pharmacogenetics, Delivery of Health Care, Ethics, Attitude, Patient Acceptance of Health Care) of empirical and theoretical studies describing psychological, family-related, social, and ethical consequences of pharmacogenetic testing to describe relevant aspects for further empirical studies.
Apart from anticipated benefit, acceptance of pharmacogenetic testing might be influenced by the following: Expectation of negative psychosocial consequences, fear of discrimination or violation of privacy. Due to its great complexity, understanding of test results and explanation of their impact pose new challenges for physician-patient relations. Since most studies are conceptual, empirical studies exploring attitudes of patients/physicians and determining medical as well as economic value of pharmacogenetic testing are imperative.
Sociological investigation of informed consent has generated rich and complex descriptions of the clinical encounter, often challenging the straightforward picture painted by medical ethicists. This paper builds on this work, drawing on ideas from the Sociology of Science and Technology, to explore informed consent issues surrounding the use of the drug Herceptin, widely cited as an example of a novel approach to drug development called pharmacogenetics. Drawing on qualitative semi-structured interviews with 25 UK-based breast cancer specialists, this paper explores Herceptin's disputed epistemological status, as an example of pharmacogenetics or as something out of the ordinary in terms of clinical practice. It considers how, in turn, this impacts on the way in which informed consent is sought and influenced by clinicians' desire to protect patients from possibly distressing test results. It highlights the flexible, contingent and context dependent nature of informed consent in the clinical setting.
The progressively aging population in the western world, rising socioeconomic expenditure and increasing costs for the treatment of adverse drug reactions, lead to increasing pressure on public spending. The public acceptance of pharmacogenomics is high, therefore, because it promises individualized safe and effective treatment at lower cost. Pharmacogenomics studies the genetic polymorphisms that underlie the variability in drug response between individuals. Despite the great benefits being awaited from this new field, a number of ethical, social and legal concerns arise, which demand rapid strict international regulations in order to prevent discrimination or harm of any kind from society, industry, groups or individuals.
A series of qualitatively new properties of the complex polygenic systems are transforming the dominant, genome-centric approach of pharmacogenomics towards a more integrative, holistic paradigm. The recent concepts of interposition of regulatory networks between genotype and phenotype, and the emergence of epigenotype as the locus of integration of genetic background with nutritional and lifestyle influences, render problematic any prediction of the consequences of individual gene alterations. In addition, the redefinition of the traditional boundaries of clinical phenotypes, with the promotion of the endophenotypes as methodological strategy, and the initiative of the phenome elucidation, reshape both the research, as well as the application, of pharmacogenomics. These concepts and developments can explain some of the complexity, and the multifactorial nature, of most drug responses and imply another understanding of education in the field, which aims at stimulating a critical reflection on these major shifts prior to a practical training on the immediate application of pharmacogenomics.
The integration of pharmacogenetic testing into routine care will, in part, depend upon the patients' and physicians' acceptance of these tests. Empirical data regarding patients' and physicians' views on pharmacogenetic testing are lacking.
To explore patients' and physicians' perspectives on the potential implications of pharmacogenetic testing, particularly focusing on asthma, and to analyze the possible determinants of their expectations, hopes and fears.
We conducted telephone interviews with patients with asthma or chronic obstructive pulmonary disease taking part in a larger pharmacogenetic study, in addition to general practitioners (GPs) from a different region in Germany. A total of 328 patients and 378 GPs were invited to participate. Determinants of their attitudes toward pharmacogenetic testing were assessed using logistic regression analysis.
Informed consent to participate in this study was given by 196 patients (60%) and 106 GPs (28%). Most patients (96%) and physicians (52%) appreciated the availability of pharmacogenetic tests for a disease such as asthma. Approximately a third of the patients worried about potential unfavorable test results (35%) and violation of privacy (36%). Female patients were more likely to have a fearful attitude (odds ratio [OR]=2.85; 95% confidence interval [CI]=1.58-5.12). Younger patients were generally more likely to be hopeful about the usefulness of pharmacogenetic testing (OR=2.12; CI=1.01-4.46). The GPs' concerns were mainly related to the possibility that patients might either be put under pressure to be tested (72%) or be disadvantaged at private health insurance agencies (61%). The nature of the responsible institution, the clarity of the research aim and explicit informed consent from patients influenced a physicians' decision regarding whether to support a pharmacogenetic study.
The concerns of patients and GPs differ somewhat with respect to negative psychosocial consequences, discrimination or violation of privacy. Development of information for physicians and patients would be helpful in preventing unrealistic fears or hopes.
Major depression is a debilitating and recurrent disorder with a substantial lifetime risk and a high social cost. Depressed patients generally display co-morbid symptoms, and depression frequently accompanies other serious disorders. Currently available drugs display limited efficacy and a pronounced delay to onset of action, and all provoke distressing side effects. Cloning of the human genome has fuelled expectations that symptomatic treatment may soon become more rapid and effective, and that depressive states may ultimately be "prevented" or "cured". In pursuing these objectives, in particular for genome-derived, non-monoaminergic targets, "specificity" of drug actions is often emphasized. That is, priority is afforded to agents that interact exclusively with a single site hypothesized as critically involved in the pathogenesis and/or control of depression. Certain highly selective drugs may prove effective, and they remain indispensable in the experimental (and clinical) evaluation of the significance of novel mechanisms. However, by analogy to other multifactorial disorders, "multi-target" agents may be better adapted to the improved treatment of depressive states. Support for this contention is garnered from a broad palette of observations, ranging from mechanisms of action of adjunctive drug combinations and electroconvulsive therapy to "network theory" analysis of the etiology and management of depressive states. The review also outlines opportunities to be exploited, and challenges to be addressed, in the discovery and characterization of drugs recognizing multiple targets. Finally, a diversity of multi-target strategies is proposed for the more efficacious and rapid control of core and co-morbid symptoms of depression, together with improved tolerance relative to currently available agents.
Uncertainty for policy makers is not new but the pressure to make decisions under conditions of uncertainty is perhaps greater than ever. The arrival of new scientific developments such as pharmacogenetics offers potentially great benefits (as well as significant risks). They have passionate supporters as well as doubters. The evidence is often extensive but unclear and policy makers may find themselves under pressure to make decisions before they feel that the evidence is compelling. The UK is particularly well placed to play a leading role in the development of pharmacogenetics and is equally well placed to derive the benefits to both health and wealth that could flow from this. However, the uncertainties threaten to overwhelm the capacity of policy makers to act effectively. The uncertainties are both about the context within which the science and delivery of pharmacogenetics is being developed and about the interests that could be served. This paper maps these uncertainties and concludes with some suggestions, drawing on deliberative democracy and futures thinking, as to how policy makers might manage the tensions and dilemmas they face by moving from an unstable, emergent policy arena to a more stable one.
Pharmacogenomics has the potential to not only revolutionize drug discovery and development, but it also has the potential to affect the may drugs are prescribed in the future. Genetics-based analyses will accelerate our understanding of disease mechanisms and will cause fundamental changes in the diagnosis, classification, and pharmacotherapy of disease. Uncovering genetic associations and gene functions may uncover more unknown related diseases and disease mechanisms, which can potentially widen therapeutic options. Unraveling the heterogeneity of disease mechanisms will lead to a better understanding of disease heterogeneity and patient variability in disease severity or disease progression. This knowledge will allow a better understanding of variation in response to pharmacotherapy and in the future, identification of new and potentially disease-modifying drug targets. This approach mill place a larger burden on education within the healthcare profession. Patients will have additional information and options about health and disease; they will have to make decisions now about therapy and life-style choices for future disease risks. Healthcare providers will be faced with new diagnostic standards, disease classifications, methods of choosing pharmacotherapy and providing counseling on pharmacogenetics, These new horizons in medicine will open new ethical and legal considerations that will significantly impact healthcare providers, patients, and payers.
Molecular genetic parameters are not only important in medical diagnostics but they are also the basic element of pharmacogenetics and of great importance for a personalized drug therapy. The development of an individualized therapeutic strategy for each patient will become an exciting challenge. Genetic polymorphisms are responsible for distinct individual differences in sensitivity to and elemination of many drugs. The isozymes of the cytochrome P450 superfamily play a central role in drug metabolism. They are part of the metabolism and elimination pathways of most endo- and xenobiotic substances and drugs. Metabolic interaction of drugs by competition for the same metabolic pathways is one cause of severe adverse drug reactions. Metabolic deficiencies due to genetic polymorphisms of such enzymes are the other reason for severe side effects becoming dramatic for metabolic limiting enzymes. Consequently drug plasma level are highly increasing. In Germany the actual number of severe adverse drug reactions can only roughly be estimated. It is beyond doubt that adverse drug reactions based either on genetic polymorphisms or metabolic competition are of great clinical as well as economic importance. New diagnostic and therapeutic strategies are urgently needed and the use of DNA microarrays in diagnostics and drug development will be one of the key technologies to reach successfully the goal ora new individualized drug therapy.
Although few companies are currently applying genetic tests or using genetic data, further developments in genetics will likely increase the role of genetics in the workplace. This article discusses the complex ethical issues raised by the variety of genetic tests that could become available and proposes guidelines for dealing with genetics in the workplace. It discusses how the results of genetic testing could be used for employment purposes, and argues that the existence of unequal bargaining power in the workplace limits the validity of consent as a basis for policymaking. Instead, two specific justifications for genetic testing in the workplace are proposed: the protection of health and the avoidance of harm to others. The author suggests that genetic testing should be permitted only in exceptional circumstances and that every genetic test should be evaluated on its scientific validity and submitted to rigorous review. Existing antidiscrimination law proves to be a useful model for examining the rationality and proportionality of genetic testing in the workplace.
Conventional drug development involves a series of clinical trials comprising relatively heterogeneous patient populations coupled with the measurement of registrable endpoints. These endpoints are often long-term clinical outcomes. However, an alternative and complementary strategy based upon the new technologies of genomics and proteomics is now emerging, which will permit smaller, continuously monitored and faster trials. Genetic subtyping of patients is central to this new approach. It has been apparent for many years that the efficacy and toxicity of drug action can vary genetically according to a variety of pharmacokinetic and pharmacodynamic parameters, as well differences in the pathophysiology of disease processes. Such differences are now being systematically screened within the new discipline of pharmacogenomics, in which the leading methodology involves the construction of a genome-wide map of single-nucleotide polymorphisms (SNPs). However, although genetic-level analysis has great potential in identifying disease susceptibility and in predicting therapeutic outcomes, it is not directly effective in diagnosing diseases and monitoring responses. Pharmacogenomic approaches based on mRNA expression analysis, and especially pharmacoproteomic techniques based on protein analysis are highly effective in these areas, providing accurate indicators of clinical response as well as having the ability, like pharmacogenomics, to subtype patients on a predictive basis. By combining pharmacogenomics and pharmacoproteomics, it will be possible to define smaller, more rapidly responsive trial populations and to monitor drug responses more effectively, leading to reductions in the time and cost of drug development. As a result of these developments, pharmacological therapy is likely to become increasingly tailored to the genetic and molecular profiles of specific patient subgroups.
In the not-so-distant future, patients may be able to walk into a doctor's office and have a simple test to decode all of their genetic information. Doctors would be able to use that information to tell patients not only what diseases they currently have, but to predict what diseases they might get, even many years down the road. The implications for health care are extremely promising. Many experts say increased knowledge of the genetic basis of disease will lead to the development of specially targeted drug treatments and better preventive care. Such a scenario is becoming a reality because of the rapid progress of the Human Genome Project, the 15-year effort to completely characterize the 100,000 or so genes that form the blueprint for a human being. Since its inception in 1990, however, the $3 billion Human Genome Project, which is funded in the U.S. by the National Institutes of Health and the Department of ...
Individual variation in response to drugs is a substantial clinical problem. Such variation ranges from failure to respond to a drug to adverse drug reactions and drug-drug interactions when several drugs are taken concomitantly. The clinical consequences range from patient discomfort through serious clinical illness to the occasional fatality. One UK study has suggested that about 1 in 15 hospital admissions are due to adverse drug reactions,1 and a recent US study estimated that 106 000 patients die and 2.2 million are injured each year by adverse reactions to prescribed drugs.2It is now clear that much individuality in drug response is inherited: this genetically determined variability in drug response defines the research area known as pharmacogenetics.3 This article discusses the potential of pharmacogenetic testing to improve both the efficacy and safety of drug prescribing.Methods
We compiled the article from the published literature, information presented at scientific meetings, our own published research work, and information gained from working with the pharmaceutical industry on drugs in development.
Over the next 3–5 years pharmacogenetics will provide opportunities to enhance the efficacy and tolerability of medicines, accelerated by the ongoing rapid development of a high-density map of single-nucleotide polymorphisms (SNP) and of high-throughput SNP scoring technologies. It is important that this application of genetic technology is clearly differentiated from genetic tests for monogenic and complex diseases, which are associated with a number of ethical, legal and social implications. The ethical, legal and social issues associated with pharmacogenetics need to be identified and clearly differentiated from those associated with gene-specific tests for disease.
In view of the fact that for-profit enterprise exceeds public expenditures on genetic research and that benefits from the Human Genome Project may accrue only to rich people in rich nations, the HUGO Ethics Committee discussed the necessity of benefit-sharing. Discussions involved case examples ranging from single-gene to multifactorial disorders and included the difficulties of defining community, especially when multifactorial diseases are involved. The Committee discussed arguments for benefit-sharing, including common heritage, the genome as a common resource, and three types of justice: compensatory, procedural, and distributive. The Committee also discussed the importance of community participation in defining benefit, agreed that companies involved in health have special obligations beyond paying taxes, and recommended they devote 1–3% of net profits to healthcare infrastructure or humanitarian efforts.
A dusty, old field called “pharmacogenetics,” which attempts to understand why drugs affect different people differently, may revolutionize the way drugs are prescribed in the future.
Pharmacogenomics is an emerging field in drug development and clinical medicine. The advent of single nucleotide polymorphisms (SNPs) and genetic maps of these markers have made the potential for broad applications of this field possible. Drug development and therapeutic success of a compound may be affected by genetic factors that contribute to safety, efficacy, and economics. Pharmacogenomics has the potential for important applications and contributions to help identify and/or minimize adverse events of therapeutic compounds. Some of this knowledge is being applied currently, and as more genetic contributions to drug safety are identified, the applications will increase. Pharmacogenomics may provide opportunities to improve clinical development outcomes, reduce costs of development, increase efficacy and reduce adverse events for specific patients, and develop diagnostic and/or prognostic tests that impact therapeutic decisions.
A research program on the ethical, legal, and social implications of genome studies, launched as an “afterthought” to the
Human Genome Project, is now the world's biggest bioethics program. Experts are divided, however, on how effective the program
has been in helping develop policies to guide the genetics revolution.
The genomics revolution has produced a vast amount of information about genes, their functions, and their polymorphisms and has, in turn, dramatically changed the way that drugs are discovered and developed. These newly found capabilities within the pharmaceutical and biotechnology industries have created both optimism and strain for the healthcare market beneficiaries of these new products, particularly in the area of pharmacogenomics. Pharmacogenomics, the integration of pharmacogenetics with the new technologies of genomics, has created the potential for developing new drugs for genetically subdivided markets. While these new pharmacogenomic technologies are providing us with the possibility for customizing drug therapies for patients, they are also creating financial and marketing uncertainties within the healthcare industry and causing conflict between the interests of drug manufacturers, healthcare payers, healthcare providers, and healthcare consumers. Current cost-containment pressures on the healthcare system would seem to favor the adoption of pharmacogenomically targeted drugs. However, the pharmaceutical companies' concern for losing market share and the patients' concern for loss of privacy appear to be formidable stallers of the adoption process. Government intervention or even the threat of government intervention could be the trigger that accelerates the pharmacogenomics revolution. If that occurs, reallocations of financial risk-sharing between the payers, the healthcare providers, the pharmaceutical companies, and the patients are to be expected. However, the public's concerns about privacy and the healthcare system's need for more data will also have to be addressed before we will witness the new era of personalized medicine. Drug Dev. Res. 49:17–21, 2000. © 2000 Wiley-Liss, Inc.
Adverse drug reactions, due at least in part to interindividual variability in drug response, rank between the 4th and 6th leading causes of death in the USA. The field of ‘pharmacogenetics’, which is ‘the study of variability in drug response due to heredity’, should help in reducing drug-caused morbidity and mortality. The recently coined term ‘pharmacogenomics’ usually refers to ‘the field of new drug development based on our rapidly increasing knowledge of all genes in the human genome’. However, the two terms – pharmacogenetics and pharmacogenomics – are often used interchangeably. A classification of more than five dozen pharmacogenetic differences is presented here. Most of these variations occur in drug-metabolizing enzyme (DME) genes, with some presumed to exist in the DME receptor and drug transporter genes, and others have not yet been explained on a molecular basis. A method for unequivocally defining a quantitative phenotype (drug efficacy, toxicity, etc.) is proposed; this is where help from the clinical geneticist can be especially important. Our current appreciation of the degree of variability (including single-nucleotide polymorphisms, SNPs) in the human genome is described, with emphasis on the need to prove that a particular genotype is indeed the cause of a specific phenotype; this topic has been termed ‘functional genomics’. Furthermore, the current amount of admixture amongst almost all ethnic groups will obviously make studies of gene–drug interactions more complicated, as will the withholding of ethnic information about DNA samples during any molecular epidemiologic study. DME genes and DME receptor and drug transporter genes can be regarded as ‘modifier genes’, because they influence disorders as diverse as risk of cancer, bone marrow toxicity resulting from occupational exposure, and Parkinson's disease; for this reason, the clinical geneticist, as well as the medical genetics counselor, should be knowledgeable in the rapidly expanding fields of pharmacogenetics and pharmacogenomics.
Pharmacogenetics is moving rapidly to assemble a large set of polymorphisms that define the influence of genetic diversity on human drug response. Scientific and technological advances of the last 10 years have led to new approaches to the discovery of genetic drug susceptibility loci, the development of high-tech analytical strategies for drug susceptibility profiling, and a flood of new gene discoveries in the area of receptors and receptor polymorphisms. Extension and refinement of our knowledge of human genetic diversity is essential to the use of drugs in more of an individualized manner and to the discovery of better therapies, but knowledge of the functional consequences of this diversity, the next great challenge in pharmacogenetics, provides the best chance to profit from this diversity. Environ. Mol. Mutagen. 37:179–184,2001. © 2001 Wiley-Liss, Inc.
New technologies in both combinatorial chemistry and combinatorial biology promise to unlock new opportunities for drug discovery and lead optimisation. Using such genome-based technologies to measure the dynamic properties of pharmacological systems, pharmacogenomics can now provide an objective measure of a drug's biological efficacy, including its potential adverse effects.
The Pharmacogenetics and Pharmacogenomics Euroconference was held at the Pasteur Institute in Paris on 12–13 October 2000.
Following the publication of the first draft of the human genome, this is a good time to re-analyse the potential contribution of genomics to drug development. Pharma, biotech and academia are already queuing up to deliver novel data impinging on every aspect of medicine and we can foresee a five-year scenario in which every new drug with a known mode of action will have a target gene sequence in the public domain. As such, current development strategies must ultimately be capable of anticipating and addressing genetic issues. This article attempts to position recent developments in genomics from an industrial perspective.
Pharmacogenetics holds great promise for the optimization of new drug development and the individualization of clinical therapeutics in the 21st century. In this brief review, we trace the historical roots of pharmacogenetics, discuss its rapidly evolving processes and paradigms, and look towards future applications of pharmacogenetics in enhancing the efficiency of the drug development pipeline and in improving patient care.
Genomics research and the use of genetic information will transform performance in the health service and the pharmaceutical industry. Since cost benefit implications for health care and health gain will be complex, pilot work is needed to explore options. Current mechanisms for translating research advances into improved health care need radical review. Education of all healthcare professionals and greater awareness of users' perspectives are needed in order to capitalise on the results of genomics research. If the supply of new products and services is to be rational rather than rationed, a strategic public-private partnership is essential.
* A position paper prepared for the Committee on Ethics of the American Heart Association. Research was supported in part by a grant from the National Heart and Lung Institute (HL-06350).
1. The American obsession with basketball has had an unexpected result of interest to geneticists and cardiologists. High public interest has led to the establishment of many college scholarships for tall, skinny boys with long fingers who can reach above the rim of the basket without jumping and drop the ball through the hoop. Some of them have been found in retrospect to have Marfan's syndrome, and aortic medial necrosis has led to at least one recent death from aortic rupture. Readers of the sports section of newspapers who are aware of the Marfan phenotype sometimes find themselves making this diagnosis on 7-foot "pivot men" whose recruitment is being announced by pleased coaches.
2. J. L. Glick points out [17] that certain key experiments were done many years ago.
Since Galton introduced the twin method in 1875 to study the nature-nurture problem (Galton, 1875), the use of twins to identify the relative contributions of genetic and environmental factors to phenotypic variation among human beings has experienced marked shifts in popularity as a genetic instrument or tool. The initial successes of the twin technique in providing answers to questions concerning the role of genetic factors in the maintenance of large phenotypic variations, as well as the accessibility of twins and the ease of analyzing them rapidly for many traits, led to indiscriminate applications of the twin method. In the 1940’s this misuse caused population geneticists, such as Neel and Schull (1954), to condemn the twin approach entirely. Neel and Schull pointed to erroneous conclusions drawn from ill-conceived twin studies on Down’s syndrome and spina bifida, which indicated mainly genetic control of these disorders. Such mistakes arose due to ascertainment bias, i. e., preferential reporting in the medical literature of concordant rather than discordant twins. Furthermore, the advent of molecular biology in the late 1940’s produced our current theories on regulation of gene expression and these ideas seem to run counter to the underlying tenets of the twin method. Such theories require intimate participation by the cytoplasm or environment both in transcription, where, repressors derived from the cytoplasm regulate the rate of structural gene activity, and in translation of genetic information on the ribosome, where amino acid availability in the cytoplasm modulates rates of nascent polypeptide chain formation and release.
KIE
The prospect of tests to detect susceptibility to genetic diseases that will develop later in life or under certain environmental conditions raises many ethical concerns. Among these are the experimental nature of these tests, the age at which they should be offered to individuals, and the repercussions of disclosing test results to patients, employers, and insurance companies. At present, research is most advanced on the marker for Huntington's disease, and Massachusetts General Hospital and Johns Hopkins University Hospital soon will become the first institutions to offer screening for this disorder. Although Johns Hopkins plans to treat the results as confidential research data, many investigators acknowledge that it will be difficult in the future to keep the information from third parties. Kolata warns that now is the time to develop policies for handling data, before widespread genetic testing becomes a reality.
Drug research developed around a purpose: the cure of diseases. This intent to cure, however, offered no clue to the understanding of diseases and to their treatment. Instead such guidance had to come from scientific disciplines which laid the foundations for drug research and offered specific opportunities for the solution of therapeutic problems. In the sequence of their appearance, these scientific disciplines were: chemistry, pharmacology/physiology, microbiology, biochemistry and molecular biology. It can be shown that new therapeutic classes of drugs like muscle relaxants, diuretics, L-dopa, antibiotics, recombinant proteins, monoclonal antibodies and others were generated on the basis of scientific opportunities rather than therapeutic need. All of these drugs were created within the confines of a chemical paradigm of medicine and drug therapy. We are now witnessing the entry of a new informational paradigm into medicine which is most prominently represented by genomic sciences. This paradigm will bring two important changes to the therapy of diseases. First, molecular biology has matured to such a degree that it can now study complex genomes and their functionality in complex organisms such as humans. Therefore, results from these studies no longer have to be translated into the context of medicine: they are already within this context. Secondly, drug therapy which used to be largely symptomatic, will now aim at targets which are closer to the causes of diseases than previously. Therapeutic progress, which used to be indirect, conjectural and coincidental, is about to become more directed, definitive and intentional. At least from the limited and utilitarian perspective of medicine, drug discovery will be more often based on intent rather than coincidence. But industry and, for that matter, society as a whole should not forget that this situation has come about through the evolution of science which was not, and can never be, predictable.
Clinical Pharmacology & Therapeutics (1995) 58, 1–14; doi: 10.1016/0009-9236(95)90066-7
Rapid advances in our ability to test persons presymptomatically for genetic diseases have generated increasing concern that genetic information will be abused by insurance companies. Reasoning that the insurance companies may have the strongest interest in using genetic data and that the medical directors of those companies with responsibility for rating applicants would be a good source of information on the use of such data, we conducted a large survey of medical directors of North American life insurance companies. We received responses from 27 medical directors. Our results suggest that (1) few insurers perform genetic tests on applicants, but most are interested in accessing genetic test information about applicants that already exists; (2) the degree of insurers' interest in using genetic test results may depend on the face amount of the policy applied for and on the specificity and sensitivity of the test; (3) many companies employ underwriting guidelines with respect to certain genetic conditions but may not always have specific actuarial data in house to support their rating decisions; (4) a considerable degree of subjectivity is involved in most insurers' rating decisions; and (5) some of the medical directors who responded to our survey are not fully informed about certain basic principles of medical genetics.
We may create a catch-22 so that only people who are unlikely to need health insurance can afford it.... Genetic risk testing is important because it exposes the logic of a system that provides access to health insurance to those least likely to need it.
The union of genomics and computational information retrieval raises a number of ethical issues, including data sharing, database accuracy, group and subgroup stigma, and privacy and confidentiality. These issues are introduced and assigned a preliminary analysis which, it is hoped, may be of use in more sustained efforts to identify issues, solutions and potential guidelines, to stimulate education, and to strike the most appropriate balance between the rights of individuals and the needs of researchers and society.
In a study of the perceptions of 332 members of genetic support groups with one or more of 101 different genetic disorders
in the family, it was found that as a result of a genetic disorder 25 percent of the respondents or affected family members
believed they were refused life insurance, 22 percent believed they were refused health insurance, and 13 percent believed
they were denied or let go from a job. Fear of genetic discrimination resulted in 9 percent of respondents or family members
refusing to be tested for genetic conditions, 18 percent not revealing genetic information to insurers, and 17 percent not
revealing information to employers. The level of perceived discrimination points to the need for more information to determine
the extent and scope of the problem.
Economic evaluation of pharmaceutical products, or pharmacoeconomics, is a rapidly growing area of research. Pharmacoeconomic evaluation is important in helping clinicians and managers make choices about new pharmaceutical products and in helping patients obtain access to new medications. Over the last few years, the scientific rigor of this field has increased greatly. At the same time, new types of analysis, based on prospective data collection, have been developed. This article reviews the basic concept of pharmacoeconomics, the types of data available for economic evaluation, and the "state of the art" in pharmacoeconomics as reported in the medical literature.
Pharmacogenomics will help explain why drugs work better in some patients than in others. These tools should be used as early in the drug development process as possible.
Common diseases are currently defined by their clinical appearance, with little reference to mechanism. Molecular genetics may provide the tools necessary to define diseases by their mechanisms. This is likely to have profound effects on clinical decisions such as choice of treatment and on our ability to characterise more clearly the course of disease and contributory environmental factors. This information also raises the possibility that new therapeutic interventions can be obtained rationally, based on a clear understanding of pathogenesis. Most of these genetic factors will act as “risk factors” and should be managed ethically and practically, as would other risk factors (in hypertension or hypercholesterolaemia, for example). The rapid advances in human molecular genetics seen over the past five years indicate that within the next decade genetic testing will be used widely for predictive testing in healthy people and for diagnosis and management of patients.
Guidelines for submitting commentsPolicy: Comments that contribute to the discussion of the article will be posted within approximately three business days. We do not accept anonymous comments. Please include your email address; the address will not be displayed in the posted comment. Cell Press Editors will screen the comments to ensure that they are relevant and appropriate but comments will not be edited. The ultimate decision on publication of an online comment is at the Editors' discretion. Formatting: Please include a title for the comment and your affiliation. Note that symbols (e.g. Greek letters) may not transmit properly in this form due to potential software compatibility issues. Please spell out the words in place of the symbols (e.g. replace “α” with “alpha”). Comments should be no more than 8,000 characters (including spaces ) in length. References may be included when necessary but should be kept to a minimum. Be careful if copying and pasting from a Word document. Smart quotes can cause problems in the form. If you experience difficulties, please convert to a plain text file and then copy and paste into the form.