Ethical Scenario Presentation

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Taking the patient's side: the ethics of pharmacogenetics Author: Mats G Hansson Date: Jan. 2010 From: Personalized Medicine(Vol. 7, Issue 1) Publisher: Future Medicine Ltd. Document Type: Report Length: 8,129 words DOI: http://dx.doi.org/10.2217/pme.09.47

Full Text: Author(s): Mats G Hansson 1

KEYWORDS

:

bioethics; ethics; hype; informed consent; justice; personalized medicine; pharmacogenetics; race; risk management

Developments within pharmacogenetics have received a great deal of attention from ethicists, lawyers and social scientists (for some recent examples, see [1-6] ). One may get the impression that truly new and urgent ethical problems have arisen that need to be sorted out before any large-scale introduction of pharmacogenetics into clinical practice; however, this appears not to be the case. The ethical issues that are suggested to capture our interest are the same ones that have been focused on and debated since the early days of gene transfer and genetic diagnosis. Other issues, such as the casting of roles between scientists, industry and government, have been thoroughly discussed within moral philosophy for centuries. Of course, these ethical issues may still be of relevance to pharmacogenetics but one should keep earlier discussions in mind. This perspective will provide a critical overview of some of the major themes of the ethics debate that are of relevance to pharmacogenetics.

One group of ethical issues discussed is related to the handling of genetic information of individuals in association with genotyping for treatment efficacy and the avoidance of adverse reactions to drugs. Here, the old questions concerning third-party access to genetic information are revisited again. Questions regarding privacy are asked, which is also believed to be at stake during the research process when human tissue samples are used together with medical and personal data in order to detect genetic and environmental vulnerabilities. Another group of issues is related to the stratification of patients according to genotype with concerns regarding individuals whose genetic responses to common drugs fall outside the range. As suggested by Dorothy Wertz, "the cost of drug development raises questions of government, industry and insurance company responsibilities to individuals whose pharmacogenetic responses are in a minority" [1] . I will not go into these issues in any detail, but will point out some of the solutions and consensus views that have emerged over the years. Instead, I will use the major part of this article to elaborate on some of the themes in discussion with regard to the framing of the ethical discussion of pharmacogenetics.

A lasting impression when reading the ethico-social literature on pharmacogenetics is that ethical concerns are often only indirectly related to the health and well-being of current and future patients. Concern has been expressed regarding the role of the pharmaceutical industry, commercialization, justice and the meaning and role of race in association with genotyping [7-10] . I do not regard these issues as uncontroversial and I will comment on some of them, but it seems to me that this framing of the ethics debate may risk losing the arguably most important ethical perspective in medical research and drug development - the perspective of current and future patients wanting medical treatment that is both effective and carries low risks of adverse effects. The 'social' framing of the ethics discussion is well illustrated in a comprehensive paper by Adam Hedgecoe and Paul Martin [11] . They claim that:

"By creating a more complete picture of the process of technical change in biotechnology, as well as carrying out empirical research on the ethical, legal and social issues raised by emerging genetic technologies, social scientists such as ourselves are also helping - construct and shape the future" [11] .

This is an important remark; there are no neutral accounts. Hedgecoe and Martin recurrently state that the area of pharmacogenetics is 'highly controversial' and that it raises 'controversial ethical issues'. However, unfortunately, they neither explain what it is that makes this kind of biotechnology controversial, nor do they make any suggestion as to how the alleged ethical controversies should be understood. The 'controversies' seem to be taken for granted, belonging to a necessary framing of the issues that are needed in

order to proceed with a sociological analysis. In any case, they are honest about their normative interests and this is good. Sociologists feed on controversy, real or imaginary. In this perspective, I will also take a normative stance. Ethicists feed on conflicting interests and the task of balancing interests that are at stake for different parties. I will discuss the ethics of pharmacogenetics from the perspective of current and future patients' interests in sufficiently safe medicines. According to this view, the patients are the primary stakeholders.

Drug efficacy:safety ratio is decisive from the patient's perspective

Hedgecoe and Martin invest a great deal of energy in imposing a superficial structure on the technological development within pharmacogenetics. They claim that there are two 'visions' guiding the field:

"In the first vision, pharmacogenetic variations are focused on drug metabolism and are independent of disease-causing genes. Here the emphasis is on the safety of the drug. In the second, the introduction of pharmacogenetics is centered on the genes associated with disease and will lead to changes in how common diseases are classified. Here the emphasis is on drug efficacy" [11] .

There is certainly room for many different focal points in pharmaceutical science and genetics research. However, any vision regarding increased efficacy that does not take potential adverse effects into account is doomed to fail. The ambition of all drug- development projects is to find a favorable balance between efficacy and safety for targeted patient groups, and this is also the concern of the regulatory authorities. I will come back to the issue of setting the balance later. More important is that, from the patient's perspective, this sociotechnical framing is entirely superficial and of little interest. Any medication, with or without pharmacogenetics, has the purpose of providing a benefit to the patient with as little risk of negative side effects as possible. There is, to my knowledge, no drug that has only beneficial effects with no risk of adverse reactions. Before pharmacogenetics, the doctor tried to master the efficacy:safety ratio for the individual patient with the help of rather blunt instruments, often only adjusting the dosage on a trial and error basis. In some instances a higher risk may be justified, for example, in life-threatening situations when no alternative treatment is available. In other cases, safer drugs may be available, but any drug involves some kind of risk-taking on the part of the patient. The important point is that, from the patient's perspective, keeping efficacy and safety concerns together is absolutely essential. The encouraging vision that is now being established in pharmacogenetics is that we may move from trial and error to evidence-based personalized medicine in clinical practice.

I will not review the current status of pharmacogenetic research and its clinical significance in different areas of medicine. Several recent reviews from the field of pharmacogenetics point at significant possibilities for treatment, even though there is an indicated need for more research [12-14] . Instead, I will give a concrete example of what pharmacogenetics can achieve for patients in clinical practice.

Abacavir

The antiviral drug abacavir (Ziagen® , GlaxoSmithKline, London, UK ) is a nucleoside reverse transcriptase inhibitor that is used in HIV treatment. It has demonstrated efficacy, few drug interactions and a favorable long-term toxicity profile [15] . However, many doctors hesitate to prescribe this drug owing to the risk of hypersensitivity reactions. These immunologically-mediated reactions affect 5-8% of patients, with skin rash, fever, gastrointestinal and respiratory symptoms occuring during the first 6 weeks of treatment. As described by Simon Mallal et al. , the symptoms of these reactions to abacavir are nonspecific and are difficult to distinguish from concomitant infection, a reaction to other drugs or inflammatory disease [15] . This implies that the doctor may hesitate to prescribe the drug or discontinue an effective treatment in cases where the symptoms have nothing to do with the antiviral drug.

In 2002, it was found that the hypersensitivity reactions were strongly associated with the presence of the HLA-B*5701 allele [16,17] . Several retrospective and prospective studies were carried out, but overall, the evidence was not sufficient for introducing the screening of patients into clinical practice. Besides methodological limitations, Mallal et al. refer to clinical overdiagnosis that "has led to a substantial overestimation of the prevalence of hypersensitivity reaction over the true prevalence of immunologically mediated hypersensitivity reaction. This is particularly true in racial groups with a low carriage frequency of HLA-B*5701 , in which false positive clinical diagnosis has resulted in the erroneous conclusion that the test lacks sensitivity" [15] . A prospective, randomized, multicenter, double-blind study (Prospective Randomized Evaluation of DNA Screening in a Clinical Trial [PREDICT-1]) has now provided evidence that screening for the HLA-B*5701 allele before treatment with abacavir will significantly reduce the incidence of hypersensitivity reactions [15] . It was found that in predominantly white populations, 94% of patients do not carry this allele. Therefore, a pharmacogenetic test can prevent these toxic effects and patients need not stop taking a beneficial drug if their symptoms are not truly due to hypersensitivity. For now, this is one of the clearest examples of the effect of pharmacogenetics on evidence-based clinical practice and, again, it is a reminder that benefit and safety concerns must be kept together. Whether or not this scientific evidence implies a 'bipolarization' of race and is, for this reason, ethically problematic is a theme I will return to [18] . It should definitely have consequences for the regulation of drugs and risk assessment. I will address these questions in turn, but first, I want to highlight a recurrent theme in the bioethical, legal and social science literature on genetic medicine - the question of hype.

Is there hype & who is the 'hypist'?

Exaggerations and unsubstantiated claims in medical science should not be taken lightly. Vital patient interests are at stake and the promotion of these kinds of accounts may further give nourishment to false ideas regarding drugs that are free of risks or adverse effects. The example of abacavir provides evidence of what we may realistically expect in pharmacogenetics and thus, a description that is not fit to be labeled 'hype'. Hyperbole in this context is a description that exaggerates the potentiality of cure with unsubstantiated claims of treatment effect while downplaying the risks and the significance of adverse reactions. Oonagh Corrigan seems confident that there is hype in pharmacogenetics. In a critical account of the Nuffield report on ethics and pharmacogenetics, she concludes that the report fails to "analyze the political and economic context surrounding the much publicized hype surrounding pharmacogenetics research and development" [7] . However, it is not clear who is the author of the 'publicized hype' - the biomedical

scientists or their social counterparts, or both.

It is an important and legitimate part of science to try to promote ideas, but if the promotion is exaggerated, it is believed to undermine public trust and financial support in the long run [19,20] . Michael McDonald and Bryn Williams-Jones have argued that this is what happened to gene therapy:

"When legitimate promotion became hype, followed by very public failures of clinical trials venture capital and government sponsors withdrew from the field. The result was that scientific research suffered, and the public and other stakeholders were left holding an empty bag of promises" [21] .

According to the witnesses in social science, enthusiasts within the academic and business fields of genetic medicine are guilty of too much speculation and unsubstantiated claims [22] . The sociological analyses of these expectations have focused on how key actors communicate visions regarding the future prospects of a new technology in the media [11] . The key actors represent several different interests, for example, industry, government, the medical profession and patient groups, and visions are seen as co-constructions whereby each actor is actively helping to shape the trajectory of an emerging promising technology [23] . Even bioethics is suggested as a helpmate, actively recruited by pharmaceutical companies and the biotechnology scientific community in order to serve as a 'political broker' [24] . A basic message in these sociological analyses is that industry, the medical profession and patient groups are responsible, not only for providing hope, but also for producing hype.

An investigation of the social aspects of new medical technologies is vital, in the sense that it is not enough to increase understanding of the scientific rationale and applicability of a technology; one must also understand more about the society in which this technology is to be applied. However, as can be seen from the sociological accounts presented in this perspective, there are no neutral accounts of the use of new medical technologies. As Mary Dixon-Woods et al. have recently argued, the ethical, legal and sociological accounts of medical research that influence the debate describe this research as operating in opposition to the norms and interests of the general public [25] . Dixon-Woods et al. studied the use of human tissue in biomedical science and conclude that "in much recent social science, anthropological and sociolegal studies, the use of human tissue for research is deeply troubling" [25] . They argue, using several examples [26-28] , that a large body of the academic literature has been activist in its commentary on biomedical research and genetic medicine. An account of 'social unease' in biomedical research is given, arguing for the existence of a public crisis of confidence. One example given in the legal accounts is a perception of the general population as individuals "who feel disenfranchised from, and disempowered by, the modern machinery of research-" [29] . As suggested by Dixon-Woods et al. , some of this 'social unease' work seems to be more consistent with a 'horror' genre than with social science [26] .

Accordingly, one may suspect that it is not only scientists and industry that are producing hype rather than well-informed hope. Bioethicists as well as anthropologists, social scientists and lawyers, among the sceptics, may be equally guilty. Without sound arguments, they define genetic medicine as deeply controversial and provide unsubstantiated claims about public perceptions and attitudes. One characteristic feature of the sociological accounts seems to be that the patient completely falls outside the picture, something that, in accordance with my declared normative interest, is ethically problematic. The patient's perspective disappears when the broader picture of political and social theory is painted. One example is a description of the endeavors of pharmacogenetic research in the following terms:

"The legitimacy of such projects has been linked to national prestige and images of the nation, the purity of scientific Endeavour, the entrepreneurial spirit, medical progress and the public health" [8] .

Nowhere in this description is there a hint of the possibility that a driving motive in pharmacogenetic research is the need to develop treatments that try to optimize the efficacy:safety ratio for groups of patients with a specific genotype.

I am not claiming that the scientists are not guilty of exaggerations and unsubstantiated visions but, in terms of the publicized hype, social scientists may be equally guilty. More realistic accounts are preferable and it is not unlikely that the extra public attention incurred by the 'hypists' will lead to the overregulation and premature withdrawal of new drugs from the market. One illustrative example of this may be the recent gene therapy trial involving ten children suffering from X-linked severe combined immunodeficiency syndrome (SCID-X1) in France [30] . It is conceivable that, owing to a great deal of publicity regarding gene transfer and unrealistic hopes of cure without adverse effects, the study was discontinued after it was learned that two children had developed leukemia as a side effect. However, the treatment had beneficial effects on the childrens' immune systems and some of the children and their parents wanted to continue the trial. It is not difficult to imagine that life in plastic bubble tents with an extremely poor prognosis may be regarded as a worse scenario than the cancer risk. For those SCID-X1 patients who do not have a HLA-identical sibling or an unrelated fully HLA-matched donor, the efficacy of gene therapy may be superior to other available treatments [31] . Risk:benefit ratios should always be compared with existing alternatives. Regarding gene transfer for SCID diseases, it has been suggested that the immunodeficiencies of the patients need to be molecularly characterized in order to guide treatment [32] . Here, as in pharmacogenetics, it is a matter of finding the right patients where a favorable balance of benefits against risks may be attained. I will now elaborate on the consequences of this for the regulation of pharmaceutical products.

Need for a life-cycle approach in the risk management of drugs

The antiviral drug abacavir is a good example of the realism of pharmacogenetics and the new possibilities of defining genetic subpopulations with an optimal benefit:risk balance. This may accelerate the drug-discovery process and provide early market access of new drugs that fit these specifically defined groups of patients.

One implication of this development is that the drug is only tested on a small and genetically homogenous group of patients. As pointed out by Kathinka Evers, a consequence of this is that drugs may be marketed with less premarketing exposure and less information regarding adverse reactions for other populations, for example, the risk of nonprescribed use [33] .

However, from the perspective of the patients who may benefit from the drug, a solution that requires an overall assessment of adverse reactions before marketing is not preferable, particularly if the drug responds to a great medical need. Hans-Georg Eichler et al. recently proposed a better solution [34] . They recognize a mounting challenge for the regulatory authorities in the need to balance early market access to new drugs with the need for comprehensive data on the efficacy and safety of the drugs. This problem is general and does not only concern pharmacogenetics. As they point out, all regulatory decisions are taken under conditions of uncertainty and, as I discussed earlier, there is no drug that carries no risk of adverse effects. Raising the bar will exclude patients from beneficial treatment, and lowering it may imply inflicting unknown risks on patients. The solution that Eichler et al. suggest is that the regulatory authorities start applying a life-cycle approach to risk management by which benefit:risk data are also collected and monitored following post-market decisions and presumably during the entire lifetime of the drug. Rare drug adverse reactions will almost always be identified after broad use. Such a reaction should not automatically result in the drug's withdrawal, but in balancing the judgment of the risks versus the benefits.

Eichler et al. point to the need for regulatory authorities to further develop post-marketing risk management systems. They hope that this "proactive approach will inform more 'learning-confirming' cycles throughout the drug's life-cycle and into the post-marketing phase. This in turn is expected to allow regulators who are faced with an increasingly risk-averse environment to continue granting early (limited) approval by conducting repetitive benefit/risk assessments" [34] . It is likely that developments in pharmacogenetics will force the pace of this change in regulatory approach. Clinical trials will include a hypothesis for overall treatment as well as a hypothesis concerning the effect in a genetic subpopulation. This will not solve the problem associated with nonprescribed use; however, this problem is not unique to pharmacogenetics. Arguably, patients also need to assume some responsibility for taking the advice of doctors and reading the packaging information.

Tailoring does not imply individualizing

The metaphor 'tailoring' is frequently used by both scientists and in sociological criticism when describing the visions of pharmacogenetics. Corrigan states that "developments in this field will eventually move away from a 'one-size-fits-all' approach - to the tailoring of new medicines to an individual's genetic profile" [7] .

There is room for a misconception here, since genotyping is only one limited route for specifying the phenotype of an individual. There are many polymorphisms, epigenetic factors and environmental conditions that must also be understood and mastered before the characteristic metabolic reactions of an individual can be accurately predicted. Even biological chance may play a significant role, particularly concerning late-onset conditions and diseases. Caleb Finch and Tom Kirkwood presented a strong argument on this by mating brothers and sisters of the nematode Caenorhabditis elegans for 100 generations, acquiring nearly identical genotypes [35] . Despite strictly controlled environmental conditions, for example, humidity, temperature and nourishment, the result was great variation regarding late-onset diseases (after reproductive ages) and death.

In my view, personalized medicine does not necessarily imply a unique drug profile for each individual. To continue the metaphor, as in fashion, few individuals can afford their own individual tailor. However, this does not imply that one needs to settle with 'one-size- fits-all'. An individual can still select in accordance with a personal profile of taste, a selection that in practice may fit several others. The great challenge for personalized medicine is to understand not only the biological variations (genotype, epigenetic factors or biological chance) but also the role of gene-environment interactions and how different environmental conditions and lifestyle factors influence health - that is, both the efficacy of a drug and its adverse reactions.

Mastering gene-environment interactions: the great challenge for personalized medicine

In order to fit the profile of individual patients, the approach to health-related risk information needs to be multidimensional. An individual who has suffered from an acute myocardial infarction carries the greatest risk of suffering a new infarction. As described earlier, for some diseases and drugs there is a known genetic risk that is communicated to a patient on the basis of a genetic test. Risk information may also be based on the measurement of protein or lipid levels, for example, serum cholesterol and apolipoproteins, or the measurement of blood pressure. Other risk factors are related to lifestyle, for example, smoking, physical activity, dietary patterns and psychosocial factors such as depression, a sense of control or perceived stress. The absolute risk faced by an individual is a combination of genetic and environmental factors as well as individual psychosocial factors.

There is a growing body of information regarding the modifiable risk factors related to lifestyle. According to the INTER-HEART study (a prospective, randomized, double-blind and powered study, designed to evaluate the clinical utility of HLA-B*5701 screening in the management of abacavir), nine modifiable risk factors account for 90% of the population-attributable risk, for example, smoking, apolipoproteins and psychosocial factors [36] . A total of 85% of all cancers are not hereditary, but rather bear strong associations with lifestyle factors. For Type 2 diabetes, almost the entire absolute risk is related to lifestyle. The variation can be described with the help of Figure 1. For group I, treatment may be available, but the individual can do very little to control his or her risks. Research on the psychological effects of genetic risk information is still important, as is the development of counseling and care. However, from both an individual and a public health perspective, it is now urgent to also direct the research attention to epigenetic and environmental factors, to psychosocial factors and to what affects health-related behavior. In group IV, individuals can control their risk by changing specific behaviors, for example, quitting smoking, drastically reducing sun exposure or losing weight. For groups II and III, there are now well-known modifiable risk factors that, if controlled, may reduce the relative risk to the individual.

In groups II-IV, one finds diseases with a high frequency among all populations, for example, cardiovascular diseases, various forms of cancer and Type 2 diabetes. Adverse lifestyle characteristics and modifiable risk factors are now well understood for these diseases. However, one should keep in mind that even if both the genetic and environmental risk factors are known, it is also well known that a change in behavior is not directly correlated to information regarding health risks. Health promotion activities present a substantial unrealized potential, since individuals at risk do not change their lifestyle or health-related behavior as a result of risk

information, for example, changing diet, starting to exercise, limiting sun exposure, quitting smoking or taking prescribed medicine. A major challenge for personalized medicine from the perspective of patients' health and well-being is to understand why currently known modifiable risk factors develop in some individuals and to identify approaches for preventing or reducing their development.

Ethical problems related to the research process: biobank ethics

Pharmacogenetic research uses population-based blood/tissue sampling for the study of genetic variation, and gene-environment interaction studies require large biobanks and access to medical and personal data. One example is the use of archived pathology biobanks for the evaluation of genetic polymorphisms in order to determine whether there is a genotype-phenotype correlation [37] . Selection of informed consent procedures is believed to constitute a special ethical problem that is intrinsic to pharmacogenetic research [38,39] . However, a great deal of ethics research has been conducted on the specific problems related to informed consent and the confidentiality of personal information, the two main questions in the ethics of biobanking. In a recent review of this research, it was concluded that, regarding these themes, different arguments have been proposed and challenged in the literature to the extent that it is now possible to see the beginning of a concordance and some emerging trends related to the central issues [40] . For previously collected human biological material, no consent is needed, provided that the material and data are safely coded, securely stored and only accessible to authorized individuals, and that the original donors have not explicitly said 'no' to future use [41] . For new collections of samples and data, the current and generally preferred solution is to obtain broad or general consent for future research, again provided that the material and data are coded and securely stored and that there is a viable option for the donor/participant to withdraw from the study [42] . Regarding nomenclature in coding, the European Medicines Agency (EMEA) proposal has now become the authoritative nomenclature version in Europe, with agreement from the USA and Japan [40] . The question regarding whether and how to return information, research results or incidental findings to donors of tissue material is still the focus of intensive discussion, and a couple of helpful analyses and suggestions have recently been published [43,44] .

Ethnicity/race may serve as a proxy but elaboration is needed in pharmacogenetics

As previously mentioned, abacavir was demonstrated to have an effect without causing any hypersensitivity reactions in 94% of a predominantly white population who did not carry the HLA-B*5701 allele. Perhaps more famous, regarding the potential link between pharmacogenetics and ethnicity/race, is the heart failure drug BiDil ® (NitroMed Inc., NC, USA), which was approved by the US FDA in 2005 for use in a self-identified black population. The original study did not demonstrate any significant efficacy for the general population, but when the data were re-examined, it was found that the efficacy was better in a subsample of African-Americans [45] . This led to a new trial being conducted with 1050 self-identified black patients with severe heart failure who had already received the best available treatment. Patients on BiDil experienced a 43% reduction in death and a 39% decrease in hospitalization for heart failure compared with those who were given a placebo, as well as a decrease in their symptoms of heart failure [101] .

In a critical remark on this move towards a 'medicalization of race', Troy Duster argues that if one wants to categorize patients in clinical trials according to race, this would require the researcher to make a clear specification of the boundaries of the relevant population [46] . Without such a design, one does not truly know if the drug has a greater effect on African-Americans than on white populations. Duster believes that the approval of BiDil promotes the view that racial differences in health are owing to biological differences and that the significance of environmental factors, for example, employment, housing conditions and psychosocial stress, is underestimated. Søren Holm is also critical of the approval of BiDil on these grounds, asserting that race is a poor proxy of pharmacogenetic knowledge. His argument is also related to the definition of race and the reliance on self-definition. He states that:

"Various estimates for the average percentage of non-African genetic material in African-Americans range from 16-26% and - the amount of non-African genetic material in a person self-identifying as African-American may range from 0-80%" [47] .

The reason for this is the continuous migration of human populations over time and the increasing mixing of genetic material and cultural traditions.

Thus, race and ethnicity are critical and rather loose concepts. However, from the patient's perspective, the evidence is rather appealing. The possibility of prescribing abacavir without risk of reactions of hypersensitivity represents a clear benefit for a large group of patients. A 43% reduction of death and a 39% decrease in hospitalization for black patients with heart failure and with no alternative therapy available is clearly of great ethical significance. These figures contradict Holm's assertion that race is not a good proxy for pharmacogenetic knowledge. More evidence exists that points in the direction of using race or ethnicity as good proxies. One further example is the anticoagulant Exanta® (melagratan/ximelagatran, AstraZeneca, London, UK), which was withdrawn from the market by AstraZeneca in 2006. The withdrawal was triggered by an adverse event report of serious liver injury, but there were no previous clinical signs that indicated this effect. Long-term treatment with this oral direct thrombin inhibitor resulted in elevated levels of serum alanine aminotransferase in some patients, but there is now evidence that these adverse reactions and the serious liver injury did not affect all populations. The presence of a certain allele has a geographic distribution with a carrier frequency of approximately 11% in Scandinavia versus 0.3% in Japan [48] . On this basis, at least a preliminary conclusion may be that the decision to withdraw the drug was premature; an Asian population would presumably have benefited from Exanta. As a Scandinavian, I would not feel discriminated against on these grounds.

Ethnicity and race may accordingly serve as good proxies in pharmacogenetics, but more work needs to be carried out in order to describe different at-risk populations based on genotypes. One also needs to take cultural differences and environmental effects into consideration. An individual's coping capacity in situations of stress is a good example for the need of a broad approach. The ability to cope with stress is essential for health and failure in this capacity may increase one's susceptibility to psychopathology. It has recently been demonstrated that early epigenetic events in the stress-coping machinery may influence the capacity to cope with stressful events later in life [49] . In rats, maternal deprivation through the separation of mother and pups for 24 h during the first weeks of life has been demonstrated to have long-lasting consequences on the stress-coping system of the pups [50] . Recently, Bastiaan Heijmans et al. presented the first data that show empirical support for the hypothesis that epigenetic changes caused by

environmental conditions early in human life can have effects throughout life [51] . Individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944-1945 following a food embargo imposed by the Germans had, six decades later, less DNA methylation of an imprinted gene compared with unexposed same-sex siblings. One can expect genetic epidemiology to uncover more of these gene-environment interactions, and subsequently, an increasing challenge in pharmacogenetics is to define, not only different genotypes, but also the effect of epigenetic changes earlier in an individual patient's history.

Leave questions about justice to the authorities & politicians

Questions concerning justice are a legitimate ethical concern from the perspective of disadvantaged individuals. As described at the beginning of this article, Dorothy Wertz suggested that "the cost of drug development raises questions of government, industry, and insurance company responsibilities to individuals whose pharmacogenetic responses are in a minority" [1] . Questions regarding global justice and the distribution of limited healthcare resources have been recurrent themes in the ethics literature focusing on pharmacogenetics (e.g., [3,6,9,33] ). Holm asks if the development of pharmacogenetics will benefit low- and middle-income countries [47] . These questions are of great importance, but it is of equal importance to address them to the right audience. In my view, it is wrong to ask the scientists or the pharmaceutical companies to answer these questions. It is not their task, and neither is it their task to be concerned about societal implications regarding scientifically-based definitions of genotypes and 'epigenotypes'. Individual scientists and company executives may feel a moral duty to contribute to a just world and to help those who have been disadvantaged owing to earlier injustice from the rich and powerful in particular. Sentiments like these are commendable but are entirely private concerns and nothing that can be imposed on these individuals by society. The reason for this casting of roles has been described in detail by John Rawls in his theory of justice as fairness [52] .

Rawls' idea is that specific moral duties for individuals require specific kinds of moral bonds, such as the relationships between a wife and husband and mother and child, as well as between siblings, friends or colleagues. He also acknowledges altruistic feelings reaching fellow humans across long distances in time and geography. However, these kinds of individual moralities are not transferable to the duties we have as institutions, universities, companies and so on. The chief interest of a university is to provide scientific evidence based on sound research. In addition to this, pharmaceutical companies must also deliver drugs with favorable efficacy:safety ratios, and in order to do so they must also make money in competition with others. Rawls' question is: how would we like to organize a just society if we were ignorant of our positions and our specific interests? His fundamental answer to this question is that without knowing anything about our own or others' needs and interests, we would go for a society with just institutions that distribute resources to the advantage of all, and that unequal distribution is only acceptable - as it may sometimes be unavoidable - if the worst placed members of society reap a benefit.

Justice is then a question of organizing just institutions, for example, for patenting, drug approval, the licensing of drugs, the ethical review of research projects, supervising health delivery, giving aid to the poor and so on. As individuals we have a moral duty to promote the organizing of such institutions in society. Pharmaceutical companies have no moral duty to subsidize certain drugs or to treat certain groups of patients more favorably than others. The obvious reason for this is that we do not want these decisions to be taken into the secret boardrooms of large multinational companies. We want them to be taken by governments, parliaments and public authorities, institutions that are accountable and transparent and where the individuals can be cast out of office at the public's will if they do not do what is expected of them.

Sweden has provided a good example of this casting of roles regarding the use of genetic information by different parties, one of the much debated ethical issues in association with genetic medicine. A Swedish Parliamentary Commission reasoned that an essential part of the public trust in medical research using genetic and other kinds of sensitive medical information depends on patients and research subjects being aware that third parties are prohibited by law to request or inquire about genetic or medical information from an individual, with the exception of in specified medical situations [53] . The Commission's proposal is now incorporated into a law on genetic integrity [102] . The law states that no-one may stipulate, as a condition for entering into an agreement, that another party should undergo a genetic examination or submit genetic information about themselves. There is also a general prohibition that without support in law, genetic information may not be sought or used by anyone other than the person the information is about. This even applies if the individual in question has given their consent to such an investigation for its use, but not if they themselves have requested it. According to this law, there cannot be any legitimate area of application in the general field of genetic information, apart from the medical field, the judicature and other areas that are subject to special regulation, including the use of genetic information by insurance companies. This prohibition is not applicable to genetic information that is sought for medical purposes, for scientific or genealogical research or in order to obtain evidence in legal proceedings. For criminal investigations and insurance purposes, other regulations are in place.

Illegitimate requests for, or use of, information may still be a problem, but this risk is minimized since according to the law, such actions constitute criminal offences. The prohibitions are enforced by a scale of penalties that include fines or a term of imprisonment not exceeding 6 months. From a patient's perspective, the law is of great significance. With these strict requirements regulating potential misuse by third parties, cumbersome restrictions on genetic research may be lifted, creating a more favorable climate for medical research that may benefit current and future patients. The Swedish law on genetic integrity is a good example of how social roles may be cast in pharmacogenetics.

Conclusion

Pharmacogenetics has started to deliver promising results that have decisive influence on the possibility of doctors prescribing drugs with more beneficial efficacy:safety ratios for patients. Exaggerations of results and unsubstantiated claims should be avoided by both scientists and their ethical and social examiners. The developments within pharmacogenetics will call for a more rapid movement among regulatory authorities to adopt a life-cycle approach in the risk assessment and benefit:risk monitoring of new and old drugs. Although controversial, race, ethnicity and cultural conditions can be good proxies for the assessment of efficacy and the risk of adverse reactions to drugs, but pharmacogenetics needs to develop more finely-tuned instruments for genotyping and epigenotyping.

In order to serve as personalized, medicine also needs to take into account the health-associated risks that are modifiable through changed lifestyle. Questions regarding informed consent and the confidentiality of data in association with pharmacogenetic research are approaching consensus within the scholarly literature. Questions about global justice and access to new and more efficient drugs are central for the societal institutions to handle with thoughtful legislation that will not hinder research that may benefit current and future patients.

Future perspective

Pharmacogenetics promises realistic improvements in tailoring efficacy/safety concerns in medical treatment to the needs of groups of individuals with specific genotypes. A challenge in the implementation of a personalized medicine, which should be taken seriously in multidisciplinary settings, is to include research on the role of epigenetic factors and how individuals react to modifiable factors related to health. Concerns about inequalities based on race or ethnicity, as well as concerns about justice, should not be taken lightly, but this is not something that scientists should focus on. Overall, there is a need for bioethics that is well informed in science and in clinical practice, hopefully remembering that saying 'no' to new developments in medicine and biotechnology is of equal moral significance to saying 'yes'.

Executive summary

* There are no neutral social or ethical accounts of pharmacogenetics.

* The most arguably important ethical perspective is related to the interests of patients wanting medical treatment that is both effective and carries low risks of adverse effects.

* Exaggerations and unsubstantiated claims should be avoided by scientists as well as by sociologists and ethicists.

* Regarding human tissue sampling, an international consensus is emerging concerning information and consent procedures.

* A life-cycle approach in the risk management of drugs is called for.

* Genotyping is essential for a personalized medical approach but so is the assessment of epigenetic and environmental factors.

* Even if controversial, race, ethnicity and cultural conditions can be good proxies for the assessment of efficacy and the risk of adverse reactions to drugs.

* Concerns regarding racial inequalities and justice should be addressed by political and legal authorities, although they are not a primary concern in pharmacogenetics.

CAPTION(S):

Figure 1. Relative importance of genetic and environmental factors affecting an individual's prospect of modifying his or her health risk.

The numeral I at the left of the figure represents diseases in which an individual can do very little to control his or her risk. At the other extreme, IV on the right, we find diseases where almost the entire risk may be managed if the individual changes health-related behavior.

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Author Affiliation(s):

1 Centre for Research Ethics & Bioethics, Department of Public Health and Caring Sciences, Uppsala University, PO Box 564, SE 75122, Uppsala, Sweden. [email protected]

Acknowledgements

The author acknowledges the valuable suggestions from the anonymous reviewers to an earlier draft of this article.

Financial & competing interests disclosure

The work on this paper has been carried out within the format of the author's permanent position as Professor at Uppsala University. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Mats G Hansson

Copyright: COPYRIGHT 2010 Future Medicine Ltd. http://www.futuremedicine.com/loi/pme Source Citation (MLA 9th Edition) Hansson, Mats G. "Taking the patient's side: the ethics of pharmacogenetics." Personalized Medicine, vol. 7, no. 1, Jan. 2010, pp.

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