The Ethics of Pharmacogenomics & Pharmacogenetics

 

By Babur Khalique, Drexel University

 

         

During the last several decades, the advances in medicine based on new, increasingly smaller-scale technologies have heralded the advent of molecular medicine. Normally, this approach to medicine is confined to research laboratories due to the difficulties in transforming the in vitro techniques pioneered in these labs into in vivo diagnostic or therapeutic techniques that can be used in a clinical situation. Recently, however, the field of pharmacogenomics has gained prominence in both the public eye and scientific eye as perhaps the greatest achievement in therapeutic molecular medicine, because it is one that can easily be moved into clinical settings (Paul 2003).

Pharmacogenomics is a field that aims to use data contained within the genotype of individual patients and data gleaned from genotypic variation within the population to produce drugs that will cause the fewest adverse drug responses (ADRs) and deliver the drug best suited to each individual’s genotype to patients. Technically, two distinct terms should be used here: pharmacogenomics and pharmacogenetics. Pharmacogenetics studies differences between individuals with regard to responses to drugs in a clinical setting, while pharmacogenomics adopts a broader scope and deals with the study of the whole genome and of which genomes may determine drug response. The goals of the two fields are thus different; pharmacogenetics attempts to find the best medicine for the best patient in a clinical setting, while pharmacogenomics attempts to help researchers in the pharmaceutical industry find the best drug candidate from a set of compounds that they are testing. This distinction, however, is sometimes arbitrary and the terms have not yet reached stable use, so they are often used interchangeably (as I will do here) (Sutrop 2004).

Despite the recent buzz around the developing field, pharmacogenomics actually had its modern genesis in the 1950’s, when scientists began to document their clinical observations of inherited differences in drug response. Friedrich Vogel first used the term pharmacogenetics in 1959 (Sutrop 2004), but he likely could not have predicted what the field has become today with advances in genome sequencing technologies. These technologies, like most new medical technologies, have caused a controversy in scientific and medical communities that are attempting to identify and address the ethical issues created by pharmacogenomics in the last decade.

Many of the experts agree that pharmacogenomics does not actually create new ethical issues for the Bioethics community to address, but reproduces old issues in new guises (Breckenridge 2004). This may be the case, but pharmacogenomics does not simply repackage old issues and allow us the luxury of dealing with them in the same way we have done for the past 50 years; it creates new subtleties and complexities by connecting ethical issues already present in disparate fields of bioethics. Ethical issues from the areas of pharmaceutical research & development, clinical practice, healthcare, genetics, genetic databases, insurance and other all become relevant to the issue of pharmacogenomics. The ethical analysis of this field is still in its infancy, and many of the issues raised are based on the possible benefits and possible risks without any definite knowledge that either the risks or benefits will ever be realized or what direction pharmacogenomics will take in the future (Sutrop 2004).

Some may claim that ethical analysis at this point is a waste of resources because it is science fiction until more commercial products that use pharmacogenomics techniques are available and the field is more established (Breckenridge 2004). I believe, however, that is the responsibility of the ethics community to use analytical thinking to determine the possible outcomes of pharmacogenomics and identify the problems before they occur. If this had been done in the past, many of the unfortunate consequences of medicine could have been avoided. It is the duty of the bioethics community to use hypothetical thinking to determine potential problems and put in place guidelines and regulations for the field before harm is done to patients.

Of the three legal approaches to ethics (deontological, utilitarian, casuistry), the deontological approach and the utilitarian approach play the biggest role in the debate about pharmacogenomics. The casuist approach is a factor, but the major problem with resolving the ethical issues around this topic involve taking the established principles of Bioethics in all the fields that contribute to pharmacogenomic issues and developing one consistent approach out of them when, on the surface, many of the traditional legal approach conflict with each other. All the information about the legal traditions of the contributing fields comes from casuistry, but deontology and utilitarianism must be used in deciding how to combine this information into one approach or policy directive for pharmacogenomics.

Several, often conflicting duties dominate the deontological view of the ethical concerns with pharmacogenomics. First among these is the duty upon which many western nations, especially the United States, were founded: the duty to uphold the principles of egalitarianism and equality. In the field of medicine, this dictates that all members of society must have some access to effective treatments/medications, and that no particular group within society be excluded from having access to effective treatments. Justice is another deontological ideal that must be addressed; that is, those who are equal in all morally relevant way must be treated equally, and those who are unequal in some morally relevant way must be treated unequally (Smart 2004). Personal sovereignty and privacy must be reasonably maintained in all uses of pharmacogenomics. Also, among the most basic duties that the deontological view considers are the duties to protect the health of individuals and not to endanger them. Each of these issues is encountered in the analysis of the ethical issues surrounding pharmacogenomics that will follow.

Utilitarianism is fundamentally a cost-benefit analysis of the positive and negative ethical consequences of a particular course of action. In the case of pharmacogenomics, those who take the utilitarian view generally are greatly in favor of further use of pharmacogenomic techniques. The argument is that by using genotypic analysis of patients and genotype-specific drugs, doctors can reduce ADRs and increase the effectiveness of treatment. Increased cost associated with drugs targeted at a smaller group will be offset, at the level of society as a whole, by reduced hospitalization costs due to greater efficacy in treatment and fewer hospitalizations due to ADRs. Drug costs, utilitarians argue, are only a small percentage of total healthcare costs; hospitalizations and procedure costs constitute the vast majority of overall healthcare expenditures (Breckenridge, Alasdair 2004). If the pharmaceutical companies do not develop drugs for some genotypes, these groups will be relatively small and will be no worse off than they were previously—they will still have access to the drugs they currently use. In addition, the overall savings to society provided by pharmacogenomic treatments will free up more money for further investment in healthcare that could be used to treat the groups for whom drugs are not developed or for Medicare/Medicaid. A basic accounting approach to the situation, however, does not do justice to the complexities of the issues raised by pharmacogenomics.

Among the most widely recognized ethical issues involved in pharmacogenomics is the danger of patient stratification, possibly along ethnic, racial, or socioeconomic lines. One of the primary dangers is the creation of so-called “orphan populations.” Orphan populations already exist in the form of groups that have a very rare disease for which there is little economic incentive for pharmaceutical companies to develop treatments; currently, legislation in both the US and Europe provides incentives for treatment of these groups (Smart 2004). New orphan populations could be created by pharmacogenomics in various ways. During the drug development process, some groups may be excluded either because they have a “bad” genotype that it proves more difficult to develop drugs for, or because their genotype is too small for it to be economically attractive to develop treatments for them.

In clinical trials, genotypic bias might cause pharmaceutical companies to exclude certain groups identified as “bad responders” – this would be particularly the case when the type of metabolic enzyme a patient possesses determines the responder status, and this enzyme metabolizes a wide spectrum of drug compounds (Smart 2004). For example, the human gene NAT2 gene (hepatic arylamine N-acetyltransferase-2) has several alleles, some encoding for fast acetylation and others for slow acetylation. Many drugs are metabolized by acetylation reaction, and the group who has the slow acetylation gene may be excluded from many clinical trials (Netzer 2004). These non-responder groups have the potential to become orphan populations, without access to a wide variety of drugs. Here, the principle of equality must be considered; the orphan groups are not receiving equal treatment in terms of drug development and are broadly ignored in the clinical trial process.

          Connected to the idea of orphan populations and stratification in clinical trial is the idea of risk distribution. Groups that are largely left out of clinical trials may not have their responder profile well identified. If clinicians use pharmacogenomic drugs for off-label uses or make a prescription mistake and give the drug to someone whose genotype was excluded from the trials, these individuals could be in serious danger (Smart 2004). Risk is thus unevenly distributed across the genotypic spectrum, compromising the deontological duty we have to protect a patient’s safety.

          Another consequence of stratification due to pharmacogenomic testing is social stigmatism. Those who are categorized as bad responders, in general, may have a very difficult time getting access to healthcare, as they will be difficult to care for and more expensive. In the United States, a nation without a national healthcare system, these individuals would likely be forced to pay extremely high insurance premiums, significantly decreasing their ability to support themselves while maintaining good health. In addition, these patients may suffer psychological consequences because they see themselves or are seen by others to be “untreatable” (Smart 2004).

          Perhaps the most dangerous consequence of pharmacogenomics due to stratification is the reinforcement of existing social stratifications. Because the markets of pharmacogenomic drugs are so small, it is very likely that their prices will be significantly higher than current medications. Expensive, highly tailored drugs may then become the province of the affluent; in nations that have national healthcare, such as the UK, the national healthcare systems will likely not be able to pay for these expensive treatments. Those that are wealthier, or even just better educated may thus have increased access to superior treatments. Extending this situation globally, it is extremely unlikely that most of the poorer nations in the world will have any access to these treatments. In addition to the requirement for drugs to be developed for the genotypic profiles of these nations (unlikely, given their overall lack of ability to afford them), the nations must be able to foot the cost of not only the drugs themselves, but the sophisticated testing and information infrastructure required to use them (Smart 2004). Here, the issue of justice arises. The less affluent people of the world may be denied access to effective medical treatment, despite the fact that affluence is not a morally relevant difference when discussing health.

          Another danger of pharmacogenomics interacting with existing social stratifications is its affect on the concept of race. Many clinicians argue that a patient’s race often has important significance to that individual’s genotype (Smart 2004). ADRs or non-response profiles could be linked to certain racial profiles, reinforcing the popular notion of “race” and the discrimination often linked to it. There is a fundamental danger in using racial composition for any medical purpose, as medicine occurs always against the backdrop of wider social patterns. This may lead to entrenchment of traditional ideas about race or even the creation of new social stigmas in connection with a particular ethnic background. Recently, the Food and Drug Administration approved a drug called BiDil for use in the United States only for African Americans. After this announcement, there was a great deal of controversy over the issue in the medical community, but the social consequences of this move remain to be seen (“US approves first ‘ethnic drug.’” 2005).

          Some experts have made the argument, however, that ethical issues of stratification should not be a problem with pharmacogenomics (Lindpaintner 2003). These people argue that much of the progress in medicine in the previous century has been due to increased patient and disease stratification, often through effective classification of subtypes of a disease based on molecular biology. Though they concede that pharmacogenomics may lead to a change in degree of stratification, it is not a “change in kind” (Lindpaintner 2003). They claim that genetic stratification for more effective treatment is simply an extension of the steps taken towards stratification in previous eras of medicine, leading to more targeted and thus better treatment.

          Other ethical issues arise in pharmacogenomics based on secondary information gained from tests for drug efficacy. Some authors have made the claim that pharmacogenomic tests do not reveal any other information to those performing the test, but as our understand of molecular biology has increased, this has proven not to be the case (Netzer 2004). A test for the NAT2 gene described earlier, for example, also may reveal various other information to a knowledgeable physician; possession of the alleles for slow acetylation has recently been associated with incidence of environmentally induced cancers (Netzer 2004). Other examples can also be given. For example, mutations in the gene RYR1 (a ryanodine receptor gene) can be used as a pharmacogenomic test to determine if a patient will have an ADR to certain anesthetics. However, mutations in this gene are also heavily associated with occurrence of malignant hypothermia and central core disease (Netzer 2004). Issues of privacy arise when all this data is available to the relatively large number of people involved in the clinical care of a patient. To maximize the efficacy of medical care for a patient, a number of individuals must have access to pharmacogenomic tests, including the lab technicians who perform the tests, the attending physicians, nurses who may have to administer medications, and administrative staff. As I have just demonstrated, though, access to pharmacogenomic data may give all these individuals information regarding the patient’s susceptibility to various conditions. The question of the balance between the patient’s right to privacy and the necessity of various individuals having access to pharmacogenomic information for effective treatment must be answered. One solution may involve having people who do not deal with the patient evaluate a test that is not linked with a specific individual, and give only the results to the physicians and other staff.

          All the secondary information produced in a pharmacogenomic test also forces us to address the issue of informed consent. Before a test is administered, the patient must be given a complete explanation of the purpose of the test, and the possible results it will yield, including primary information about drug efficacy and any secondary information. All medical terms must be defined, and the significance of the results will have to be discussed (Netzer 2004). Simply stating that the test will look for mutations in such-and-such enzyme, which affects the efficacy of such-and-such drugs will not suffice. Patients must be made aware of the broader significance in terms of what the results may mean for their lifestyle, their treatment choices in the future, and their risks for other, possibly unrelated conditions. Furthermore, to preserve personal autonomy, the patient must be given the choice of what information they would like to hear after the test has been completed (Netzer 2004). This choice is important to maintaining personal freedom for the patient; he may choose to learn only about the drugs which will be effective for him, about disease for which he is at risk and for which there are effective treatments, or about all secondary information, and both the clinician and the laboratory technicians must comply with this request. Once secondary information is learned, however, further ethical issues arise.

          Much of pharmacogenetic testing is germ-line testing—that is, it tests for genetic mutations and allele distributions that are inheritable. Once a patient has gained knowledge about his own genotype, this may also give him knowledge about his relatives. Relatives may not want to know about their risk for a particular condition or about the effectiveness of a treatment for them (Van Delden 2004). Indeed, a relative has the right not to know these things about their genotype. This raises a difficult issue, as it is impossible to legally regulate the distribution of this information once it has been given to a patient.

          The desire to not want knowledge of one’s own genotype carries additional problems. Because of the risk of receiving a non-responder profile to many drugs, and the associated increase in insurance costs and other problems outlined above, a patient may not want to be genotyped (Van Delden 2004). Without a pharmacogenomic profile, they do not have to worry about being in a disadvantageous position. Physicians are put in a difficult position when this situation arises. By giving the patient in question the bulk drug, he is in fact providing inferior treatment and exposing the patient to possible ADRs, because he has not been tested. Similarly, if the physician gives the patient a genotype-specific drug, there is risk of ADRs because it is unknown whether the patient matches the genetic profile of those for whom the drug was designed. If ADRs do arise, even in the situation of the bulk drug, there is the question of responsibility (Van Delden 2004). Should the physician be held responsible, or should the responsibility lie on the shoulders of the patient? These issues could cause subtle changes in the doctor-patient relationship.

          Pharmacogenomics is a technology that spans nearly all fields of medicine, from drug development to clinical treatment. As a result, it incorporates ethical issues present in each of these fields, taking the subtleties and nuances of these issues and adding further layers of complexity by relating them to each other. The depth and breadth of all the ethical concerns involved are far too great to fully discuss here, but I have presented a broad outline of the most important ethical problems to bear in mind as pharmacogenomics advances into the future. Two important points must be made before I can complete this analysis of the ethical implications of pharmacogenomics. First, we must avoid the dangers of the slippery slope arguments that lead to visions of science fiction worlds like that in the movie, Gattaca. Realism and critical analysis must be exercised rigorously before any conclusions can be drawn or extrapolations made. Second, it is important to re-analyze and re-evaluate every argument and perspective frequently, as the field of pharmacogenomics evolves. It is a new, rapidly developing technology that is likely to change drastically as it establishes itself. Once its direction and usefulness have been more firmly established, many of the arguments presented here may no longer be an issue or may not be relevant at all.

In the final analysis, several points become clear. First, pharmacogenomics is not so new and groundbreaking that it requires a whole new kind of bioethics, as some have suggested. Second, these new advances will require strict regulation and oversight of any market economies where it is used. In this case, the market economy will use the technology to the tremendous advantage of many people, but will likely do so by casually disregarding many more—a situation which neither Utilitarianism nor Respect for Persons, as ethical tools, would allow. Third, pharmacogenomic technology is a tremendous advance in medicine and we cannot over regulate it or apply to strict a standard on individuals or organizations that employ the technology, for if we do that we may be hindering the development of a plethora of fantastic new treatments that will change the lives of many. At last, we must keep in mind that ethical analysis of biotechnology in this Brave New World~esque age requires a dynamic approach that is never constrained and always willing to re-examine old philosophies and overturn old ideas.◦

© Babur Khalique, 2006

 

 

 

 

 

References

 

 

Breckenridge, Alasdair, et al. "Pharmacogenetics: Ethical Problems and Solutions." Nature 5 (2004): 676-80.

 

Lindpaintner, Klaus ER -. "Pharmacogenetics and the Future of Medical Practice." Journal of Molecular Medicine 81.3 (2003): 141-53. <http://www.springerlink.com/openurl.asp?genre=article&id=doi:10.1007/s00109-002-0416-5>.

 

Meisel, Christian, et al. "Implications of Pharmacogenetics for Individualizing Drug Treatment and for Study Design." Journal of Molecular Medicine 81.3 (2003): 154-67. <http://www.springerlink.com/openurl.asp?genre=article&id=doi:10.1007/s00109-002-0417-4>.

 

Netzer, Christian, and Nikola Biller-Andorno. “Pharmacogenetic Testing, Informed Consent and the Problem of Secondary Information.” Vol. 18., 2004. <http://www.blackwell-synergy.com/loi/biot ER ->.

 

Paul, Norbert W., and Allen D. ER -. Roses. "Pharmacogenetics and Pharmacogenomics: Recent Developments, their Clinical Relevance and some Ethical, Social, and Legal Implications." Journal of Molecular Medicine 81.3 (2003): 135-40. <http://www.springerlink.com/openurl.asp?genre=article&id=doi:10.1007/s00109-002-0415-6>.

 

Schubert, Lilian. “Ethical Implications of Pharmacogenetics - do Slippery Slope Arguments Matter?.” Vol. 18., 2004. <http://www.blackwell-synergy.com/loi/biot ER ->.

 

Smart, Andrew, Paul Martin, and Michael Parker. “Tailored Medicine: Whom Will it Fit? the Ethics of Patient and Disease Stratification.” Vol. 18., 2004. <http://www.blackwell-synergy.com/loi/biot ER ->.

 

Sutrop, Margit. “From the Guest Editor.” Vol. 18., 2004. <http://www.blackwell-synergy.com/loi/biot ER ->.

 

————————- “US Approves First 'Ethnic Drug'.” BBC News Friday, 24 June, 2005, sec. Health.

 

Van Delden, Johannes, et al. “Tailor-made Pharmacotherapy: Future Developments and Ethical Challenges in the Field of Pharmacogenomics.” Vol. 18., 2004. <http://www.blackwell-synergy.com/loi/biot ER ->.