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Abstract

This entry explores the ethical questions related to pharmacogenomics not only in the clinical practice but also in the ﬁeld of research. Since everyone is the titleholder of their own information, it is essential to obtain their informed consent and provide safeguards concerning both conﬁdentiality of and access to this information at all times. At the same time, it is crucial that these scientiﬁc advances contribute to a global justice and not to increase inequalities among individuals and communities.

Introduction

There is some degree of confusion surrounding the two terms pharmacogenetics and pharmacogenomics because some people use them as synonyms while others to refer to distinct ﬁelds of science. Pharmacogenetics is understood as the science which studies the impact of genetic variation in response to drugs, while pharmacogenomics is concerned with the same objectives but incorporates new tools from the genetic age such as gene expression proﬁling, proteomics, or bioinformatics. The deﬁnition of these two terms endorsed by the International Conference on Harmonization (ICH), the body which comprises the drug regulatory authorities from Europe, the USA, and Japan, coincides only in part with those given above. According to the ICH, pharmacogenetics is “the study of variations in DNA sequence as related to drug response,” while pharmacogenomics is “the study of variations of DNA and RNA characteristics as related to drug response” (ICH 2008, p. 2).

The term pharmacogenetics was coined in the mid-1950s to refer to a new discipline which studies genetically conditioned pharmacological reactions. The term pharmacogenomics, which ﬁrst appeared in scientiﬁc publications in 1997, began to evolve along with the technologies which made possible the sequencing of the human genome and set out a more comprehensive and rigorous view of how a person’s response to drugs relates to their genetic characteristics. Although both terms are still used as synonyms, it is pharmacogenomics which has upstaged pharmacogenetics and is the more commonly used term.

Pharmacogenomics is a very promising ﬁeld of scientiﬁc knowledge, one which poses ethical questions of enormous relevance in terms of clinical practice as well as for research and which affects individual human rights as well as social justice. There are three international regulatory documents sanctioned by UNESCO which set out the legal principles which should act as a guide in these matters: the Universal Declaration on the Human Genome and Human Rights (1997), the International Declaration on Human Genetic Data (2003), and the Universal Declaration on Bioethics and Human Rights (2005). Noteworthy at a European regional level is the regulating role of the Council of Europe through the Convention on Human Rights and Biomedicine (Oviedo Convention 1997) and its Additional Protocol concerning Genetic Testing for Health Purposes (2008). The section which follows concerns the aim and importance of pharmacogenomics and the ethical problems which it raises regarding how it is applied to clinical practice as well as research and social justice issues. It also takes into account the international regulations mentioned above, not only because states are required to follow them to one degree or another, but because they also illustrate an ethical consensus on this matter at a global level.

Aim And Importance Of Pharmacogenomics

Pharmacogenomics provides us with extraordinarily useful information for enhancing medication safety, in that it can anticipate adverse reactions associated with certain genetic characteristics. It likewise increases drug efﬁcacy because it facilitates prescribing those drugs which would be most effective and in the correct dosage on the basis of an individual’s genetic characteristics. Accordingly, we can move toward drug prescriptions which are no longer determined by the “one pill ﬁts all” principle and instead prescribe “the right patient with the right drug at the right dose at the right time” (Marshall 1998, p. 1). The potential opportunities it offers are many: predicting a patient’s response to drugs; developing “customized” prescriptions; minimizing or eliminating adverse events; improving efﬁcacy and patient compliance; improving rational drug development; improving accuracy when determining appropriate dosages of drugs; screening and monitoring certain diseases; developing more powerful, safer vaccines; and allowing improvements in drug R&D and the approval of new drugs (Issa 2002). This all amounts to major savings in healthcare costs because it prevents those with certain pharmacogenetic proﬁles from taking counter-indicated drugs and it reduces hospital care costs in terms of dealing with the iatrogenic effects of certain drugs.

However, the great expectations which pharmacogenomics has generated since the end of the twentieth century, while the human genome was being sequenced, are still a long way from being fulﬁlled. Those drugs whose effects are known depending on a person’s genetic variations are few in number. Furthermore, the knowledge which pharmacogenomics provides itself is not usually sufﬁcient to determine the appropriate pharmaceutical prescription because both pharmacodynamics (the mechanisms of a drug action on the organism) and pharmacokinetics (the processes a drug undergoes from the moment it is administered until it is eliminated by the organism) vary according to many other circumstances and not just an individual’s genetic variation (Tutton 2012). As has likewise happened with the Human Genome Project in general, the move from research to clinical practice in pharmacogenomics has proved to be much slower than initially believed (Godman et al. 2013).

Before tackling the ethical questions related to pharmacogenomics, three factors need to be considered by way of a preliminary. First, our knowledge of pharmacogenomics is mainly based on pharmacogenetic tests on individuals. Genetic tests identify mutations associated with diseases and provide a person with decisive information about their future health or procreative options. However while pharmacogenetic tests provide valuable information, this is not always as crucial as other information, because in principle they only provide information about the genes involved in metabolizing the drug (Roses 2000). For those people identiﬁed as not suited to a given drug, this information comes as a negative, but even in these cases it is positive for them in that it prevents them from being exposed to a drug which could harm rather than cure them. Nevertheless, these differences in the type of information these tests provide are not always so clear-cut because the pharmacogenetic test can also provide information about a person’s state of health or the genetic characteristics of other family members. Given this, when it comes to establishing guarantees which protect the information from one or other tests, we need to begin with the type of information they provide and not simply the type of analysis being carried out.

Second, with the development of the Human Genome Project, a degree of genetic determinism began to hold sway, according to which knowledge about the human genome was going to provide the key to solving health-related problems. The impact of other considerations, such as the importance of the environment and individual lifestyles for taking care of one’s health, lost ground to the protagonism given to an individual’s genetic makeup. However, since knowledge of the genome did not automatically manifest itself in medical practice, this view began to lapse. Given the risks involved in assigning too much importance to genomics and pharmacogenomics, it needs to be stressed that while these sciences provide the ﬁeld of medicine with necessary information, it is far from sufﬁcient.

Third, the great expectations at the end of the twentieth century to develop predictive medicine based on genetic science, and which generated enormous investments by the richest states in the world, are a long way from being fulﬁlled. Meanwhile, millions of people still live without an acceptable level of healthcare, and there has been a brake on assigning resources for less spectacular research projects, but which could have given short-term beneﬁts in clinical practice. It is imperative that resources in the ﬁeld of biomedical research and healthcare are distributed in accordance with criteria of justice and opportunity and not vested interests at any given moment.

Ethical Questions In Pharmacogenomics

The aim of pharmacogenomics is to obtain information about an individual which is highly valuable but also very sensitive. Since everyone is the titleholder of their own information, it is essential to obtain their informed consent and provide safeguards concerning both conﬁdentiality of and access to this information at all times. The international regulations concerning genetics are unanimous about the individual’s right to self-determination in such matters, embodied in the right to informed consent and conﬁdentiality of information, and to access to their genetic information (Romeo-Malanda and Nicol 2008).

Informed Consent

The aim of a pharmacogenetic test is to assess the capacity to metabolize a given drug according to one’s genotype. This information comes as a negative if it reveals that a person cannot beneﬁt from a drug suited to curing a disease they are suffering from. There are times when pharmacogenetic tests can provide information about genetic diseases or the risk of suffering from them because, sometimes, the genetic mutations which affect drug response can cause, or mean that a person is predisposed to, a disease (Buchanan et al. 2002). Therefore, pharmacogenetic tests can also reveal information which can have consequences at a personal, medical, family, or social level, so those who undergo these tests must be duly informed beforehand about these aspects (Robertson 2001).

Before anyone undergoes a pharmacogenetic test, they should be informed, at the very least, about the following: the exact type of information that will be obtained with the DNA sample; the risks and beneﬁts regarding the information the test is searching for, including psychological and social considerations; where the DNA sample will be sent (if it will be stored and under what conditions or whether it will be later destroyed); how privacy will be guaranteed concerning both the sample and the information obtained; and the ﬁnal destination and future uses of the DNA samples and of the information obtained.

Informed consent in genetic analyses about diseases poses many problems, some of which are common to pharmacogenetic tests. Firstly, genetic information tends to be difﬁcult to understand and handle for test subjects, so it may well happen that they do not exactly know what they are giving their informed consent for. Secondly, we are dealing with sensitive information: it transcends time (since it does not only refer to a single moment in time) and the subjects themselves (because it frequently affects their family, a given community, or racial group). Thirdly, this information says a lot about the subject and could end up having an impact on how they see themselves (Chadwick 2004). To guarantee that consent to pharmacogenetic tests is free and the result of a truly informed decision, it is essential for the subjects to be given appropriate pharmacogenetic counseling, not only after obtaining the test results but also prior to giving consent (Bellver 2002).

Direct-to-consumer pharmacogenetic tests pose speciﬁc problems. Given the nature of the information, it seems reasonable that informed consent should also be required and that it should be accompanied by genetic counseling. But in these tests, it is far more difﬁcult to fulﬁll these guarantees. In any event, the Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Genetic Testing for Health Purposes (2008), requires that “a genetic test for health purposes may only be performed under individualized medical supervision” (art. 7.1).

Confidentiality

Although in principle the information from pharmacogenetic analyses is not of such a transcendental nature as that provided by genetic analyses on disease, it should also be conﬁdential. Pharmacogenetic analyses reveal which patients do not respond adequately to certain drugs.

Except when there is a feasible alternative treatment, these patients generate considerable healthcare costs, since it is more difﬁcult to deal with their disease (Buchanan et al. 2002). For this and other reasons, breach of conﬁdentiality can easily lead to social stigmatization or discrimination. Guarantees concerning the protection of conﬁdentiality must be sufﬁcient enough so that people do not refuse to take part in these tests for fear of a possible future breach of conﬁdentiality.

A dilemma which doctors can be faced with when prescribing a pharmacogenetic test is whether they should inform family members of the results of the subject’s test when it provides information which could also prove valuable for them. In principle, it is the test subject who is the titleholder of this information, and it should be he/she who gives consent to share this information (Ellul 2015).

On occasions, drug response variability is associated with some genetic variations which are not exclusive to an individual but rather to a group or community to which the individual belongs. In these cases anyone could be informed about the genetic problems of the members of these groups without having to carry out a pharmacogenetic analysis. When such situations crop up, it is common to resort to the protection of communities against risk of discrimination principle (Weijer 1999).

The question has been posed as to whether the community should be informed when the test on an individual could provide information which would affect an entire community. While it may seem reasonable to consult with the corresponding community authorities, we should not lose sight of the fact that the prime moral subject of consideration should always be the person himself/herself (Anderlik and Rothsein 2001).

Pharmacogenetic Research

We are still a long way from these tests being incorporated into habitual clinical practice on a major scale basis. For the time being, pharmacogenomics is mainly being developed at the research level and should be subject to generally accepted ethical principles for such research which are set out in the Helsinki Declaration (1964, last amended in 2013). The following paragraphs only set out some of the most relevant ethical issues regarding pharmacogenomic research.

As is the case in clinical practice, pharmacogenomic research must be carried out with full respect for individual rights. The main mission of the Research Ethics Committees is to guarantee both formal and real respect for these rights. These committees take on even greater importance when the decision is made to disassociate the names of people from their biological samples, since in these cases extreme caution and supervision must be exercised regarding what is done with these samples (Erice Declaration 2002).

There are times when researchers want to make use of these biological samples in further research. This is only possible if the sample subject has given her or his sufﬁciently broad consent which allows for these new research projects. Although this necessarily involves having broad consent, it is essential that this is not vague and gives the subject an approximate idea of future uses that his/her sample could be used for (Ellul 2015). If not, then we are not talking about real consent.

Pharmacogenetic information means that the number of people participating in clinical trials can be reduced since it can rule out those subjects who would not respond well to the drug. Consequently it can protect the health of people and also lower the costs of developing new drugs. Furthermore, it makes it possible to develop new drugs that had previously been ruled out because they were unsafe for many subjects. However, when it comes to recruiting test subjects, we also need to allow for the fact that excluding subjects with certain genetic variations prevents us from obtaining further information about the drug that could prove valuable when it comes to prescribing it.

Justice Issues In Pharmacogenomics

There are a number of justice issues posed by pharmacogenomics, and the following paragraphs refer to three: (1) relationships between the pharmaceutical industry, healthcare suppliers, and patients; (2) fair distribution of resources within a given society and worldwide; and (3) new training and behavior standards required of doctors and pharmacists.

Relationships between the pharmaceutical industry, healthcare suppliers, and patients. It can happen that pharmaceutical companies link sales of their products to acquiring the corresponding pharmacogenetic tests for these products. Should we consider this practice acceptable or not? The pharmaceutical industry can provide two solid arguments. First, performing a pharmacogenetic test prior to dispensing the drug guarantees drug efﬁcacy and additionally prevents unwanted effects. Second, if the drug is used by subjects who are not ideal from a pharmacogenetic perspective, this can have detrimental effects on the health of the individual in question and healthcare costs and is prejudicial to the company’s product/brand image. Given this situation for the pharmaceutical industry, the best option is for them to be governed by drug regulation agencies such as the FDA (USA) or the EMA (European Union), who can determine whether it is necessary, advisable, or irrelevant to perform a pharmacogenetic test before deciding whether or not a drug can be prescribed.

It can be the case that it is the healthcare provider that wishes to perform a pharmacogenetic test before making the drug available. What in principle is a cautionary measure can sometimes become nothing more than a defense mechanism against possible future liability. Once again, the solution is for drug regulation bodies to establish clear guidelines.

Fair distribution of resources within a society and worldwide. Pharmacogenomics allows us to discover which individuals or groups have genetic variations that prevent them from beneﬁting from a given drug. From the perspective of proﬁtability, the tendency would seem to be in favor of developing drugs which ideally suit majority groups and to overlook the research of drugs which would prove particularly beneﬁcial for minority groups. If the minority group in question has sufﬁcient ﬁnancial resources, then almost certainly the necessary research would be ﬁnanced until a suitable drug is obtained. If however the group is an economically disadvantaged racial or social minority, they are in risk of being overlooked.

However, it does not have to be like this. First of all, pharmacogenetic analyses only forecast what would be discovered as soon as patients with a genotype which is not apt for this drug began the treatment. Therefore, pharmacogenomics in principle does not discriminate but rather is limited to warning of the risks that a drug represents for an individual or group. Secondly, the cost of developing new drugs can be considerably reduced by incorporating pharmacogenetic analyses, making research into orphan diseases more feasible, and as a result the development of orphan drugs which are suited to those who, because of their genotype, cannot use the common drugs (Olivier and Williams-Jones 2011). Finally, governments would have to take steps to provide incentives to developing research whose costs could not be recovered under normal market conditions and, at the same time, ensure through funding that the price of drugs designed for minority groups is not exorbitant.

New training and behavior standards required of doctors and pharmacists. It is likely that in the not too far distant future, pharmacogenetic tests will become a common tool when prescribing drugs for patients. At that moment, doctors will need to have the necessary competence to incorporate pharmacogenomics into their daily clinical practice. On the other hand, as pharmacotherapies are going to be increasingly linked to a patient’s genetic characteristics, pharmacists will also need to have access to this knowledge. Moreover doctors and pharmacists will need to be adequately trained to explain to patients all the necessary information so that they can give their truly free and informed consent to pharmacogenetic tests. They also will need to be trained to be able to give appropriate genetic counseling. Given this immediate future need, it is only reasonable to expect pharmacogenomics to be incorporated into university training of these future healthcare professionals (Gurwitz et al. 2005).

Conclusion

Pharmacogenomics is a science in its early stages which studies the impact of drugs on individuals according to their genetic characteristics. With this knowledge, the aim is to develop the most effective drugs and dosages tailored to the individual. The advent of pharmacogenomics toward the end of the last century generated great expectations; however, transferring the results of advances in pharmacogenomics to clinical practice has been somewhat slow. In part, this is because the variability in drug response does not depend exclusively on individual genetic variation.

Although they contribute different types of information, it has not been possible to establish a qualitative difference between disease-related genetic tests and pharmacogenetic tests. The self-determination of the subject has to be assured in each and embodied in informed consent, data conﬁdentiality and privacy, and genetic counseling. The requirements of informed consent, conﬁdentiality, and privacy must also be fulﬁlled when pharmacogenetic tests are research oriented.

It is important for pharmacogenomics to contribute to improving the healthcare of everyone and not to increasing the gap between the rich and the poor. For this to happen, public authorities must motivate the pharmaceutical industry to develop orphan drugs and make pharmacogenetic tests available for everyone. Finally, there is an urgent need to improve training for healthcare professionals in relation to pharmacogenomics so that they can offer a professionally irreproachable service.

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