Ethical Issues in Pharmacogenomics

Pharmacogenomics is defined as the study of how genetic variation in drug-metabolizing enzymes, receptors, transporters, and targets contribute to phenotypic variation in drug response, such as toxicity or decreased effectiveness.¹ The clinical implementation of pharmacogenomics is an exciting area that is showing promise of enhancing the quality of patient care. As this field of study becomes more widespread, pharmacists are also increasingly being recognized as leaders in this field and are positioned to assume responsibilities that include interpreting pharmacogenomic test results and advising patients and other health care professionals regarding their clinical use.² Nonetheless, there are ethical implications associated with pharmacogenomics that warrant discussion, including genetic discrimination and the use of genetic information in pharmacogenomic research. Genetic discrimination is especially significant because of legislation that has been passed to prevent its occurrence. Moreover, there is uncertainty about how to best obtain informed consent from research participants when their genetic information is required. It is therefore important that pharmacists understand the principles of pharmacogenomics and consider the ethical dilemmas that may arise with its increased use.

Background

There are 3 general ways in which pharmacogenomics is clinically applied: using drugs to treat diseases that are genetically inherited, using genetic information to determine the safety and efficacy of drugs in certain individuals (risk assessment), and designing a drug regimen based on a patient’s metabolic enzyme activity.^3,4 Much of the current focus of pharmacogenomics, and perhaps most of the future, is on the third application. Many drugs are hepatically metabolized by the cytochrome P450 (CYP) family of enzymes. In some patients, these enzymes are encoded by genetic variants, the most common being single nucleotide polymorphisms.¹ These are single DNA base pair changes that may produce phenotypic variation, often causing drugs to be metabolized too slowly or too rapidly and to remain in the body for too long or not long enough, respectively, as a result. Patients, therefore, could be put at risk of experiencing drug toxicity or subtherapeutic effects.

CYP2C19 and Clopidogrel

Most of the medications for which pharmacogenomic implications exist are used for a variety of conditions and preventive measures in areas such as cardiology, infectious disease, psychiatry, and oncology. One example is the antiplatelet drug clopidogrel, a prodrug that requires hepatic biotransformation by CYP2C19 to its active metabolite, which is responsible for the drug’s anticlotting effect.⁴ Most people are genetically classified as “extensive metabolizers” for CYP2C19, which is considered normal physiology. The establishment of safe and effective dosing for clopidogrel during the drug development process was based on the metabolic action of extensive metabolizers. However, individuals who have loss-of-function CYP2C19 polymorphisms, or genes that code for less functional versions of the CYP2C19 enzyme, experience impaired formation of the active metabolite of clopidogrel.⁴ This results in a reduced antiplatelet effect.

A recent publication describes the results of a pilot project conducted by Owusu-obeng et al at the University of Florida Health Personalized Medicine Program involving clopidogrel genotype—guided antiplatelet therapy for patients undergoing percutaneous coronary intervention and stent placement.⁵ This initiative demonstrates the benefit of clinical pharmacogenomics and identifies the elements that are necessary for its implementation. Moreover, the article describes pharmacists as being uniquely qualified to play essential roles in areas such as pharmacy informatics, medication safety, drug information, logistical issues in genetic testing, and ethical issues. The project, which was led by a pharmacist, also defines the education, training, and resources needed to support such programs. As pharmacists become more involved in pharmacogenomic patient care programs, they need to be aware of the ethical implications.

Genetic Discrimination

Individuals who undergo pharmacogenomic testing may be vulnerable to genetic discrimination, which refers to one being treated differently on the basis of genetic information. In a survey to health care professionals regarding different ways genetic information could be used by health insurers for genetic discrimination, the following items were suggested: (1) justify a refusal of therapy for pharmacoeconomic reasons, (2) create treatment guidelines, (3) set co-pay amounts for coverage, and (4) determine premiums.⁶

One of the first cases to indicate that genetic discrimination is a concern comes from the 1970s when African Americans were required by some state governments to undergo genetic testing for sickle cell anemia.⁷ Knowledge of who were carriers and who suffered from the disease resulted in discrimination from health insurers and employers. This was addressed by Congress in the 1972 National Sickle Cell Anemia Control Act, which withheld federal funding from states that required sickle cell testing.⁸

The Genetic Information Nondiscrimination Act of 2008

The Genetic Information Nondiscrimination Act (GINA) was passed by Congress to protect Americans from genetic discrimination. This law has important components that health care professionals and patients should know about as pharmacogenomics moves closer to widespread implementation. GINA focuses on preventing discrimination in the contexts of health insurance and employment; its major provisions include making it illegal to require the purchase of genetic tests; prohibiting insurance companies from using genetic information to adjust premiums, deny coverage, or impose restrictions that relate to preexisting conditions; and barring companies with 15 employees or more from requiring or using genetic information, which includes asking for a medical history, for the purpose of employment.⁷

GINA does not apply to life, disability, or long-term care insurance, nor care provided through the military, Veterans Administration, or Indian Health Service.⁹ It also does not prohibit health insurers from determining a premium rate for an individual based on the manifestation of a disease in that person.⁹ It should be noted, however, that the Patient Protection and Affordable Care Act (PPACA) of 2010 contains provisions that complement GINA.¹⁰ Although the PPACA does not directly reference GINA’s requirements, the 2 laws may interact in some situations. The PPACA allows health insurers to adjust premiums based only on the following: whether coverage is for self or family, geographic area, age, and tobacco use.¹⁰ Therefore, whereas GINA does not prohibit a premium adjustment based on a manifested disease, the PPACA does.

GINA is partly enforced by the Equal Employment Opportunity Commission (EEOC), and as of December 2013, more than 1000 charges have been filed against GINA.¹¹ The first lawsuit for a GINA violation was settled in 2013 (EEOC v Fabricut Inc),¹² while a similar lawsuit was settled in January 2014 (EEOC v Founders Pavilion Inc).¹³ While it is clear that some evidence of genetic discrimination exists, data are still somewhat limited for documented cases.⁷ This could be due to pharmacogenomics having been slow to translate into clinical practice. However, as this field expands, it is important to be aware of how discrimination can occur, including an individual being treated differently as a result of knowledge that he or she is a poor or ultrarapid metabolizer. It has been shown that stigmatization can occur when people are described in such ways, which can lead to discrimination.¹⁴ Additionally, individuals can be exposed to discrimination if they are discovered to be at an increased risk for a disease because of pharmacogenomic testing.

Consider also the following example involving cystic fibrosis (CF) and ivacaftor (Kalydeco). Cystic fibrosis is a genetic disorder that results from an abnormality in the gene coding for CF transmembrane conductance regulator (CFTR), a protein channel responsible for the transport of chloride ions; the root cause of pathology is considered to be decreased chloride transport.³ Ivacaftor is the first drug in its class and is indicated for CF patients with certain genetic polymorphisms in the CFTR gene, and acts directly on the CFTR channel.³ As far as progress in CF treatment, ivacaftor may shift the treatment paradigm; however, considering that can cost more than $300,000 per year,¹⁵ is it unethical for a patient’s insurance premium to increase due to a genetic test result and subsequent treatment with this expensive new drug? Scenarios like this already occur.^16,17 Some might call it unethical only if the costs outweigh the benefits of having such drugs. When would the costs outweigh the benefits? These may be difficult questions to answer, but they are important to consider if genotype-guided drugs continue to be developed and health insurers have access to pharmacogenomic information.

The Pharmacist’s Role in Patient Education

Education is essential when exercising your rights regarding genetic information and being aware that its use in clinical practice presents the potential for genetic discrimination; the benefits of this law are only as good as the general knowledge of its provisions. Pharmacists, as recognized drug experts and leaders in clinical pharmacogenomics, can play an important role in educating patients about genetics in drug therapy, how that knowledge can benefit them, and the laws in place to protect them.

Informed Consent in Pharmacogenomic Research

Informed consent for pharmacogenomic research is another area where ethical dilemmas may arise. A major factor that makes informed consent difficult to obtain in pharmacogenomic research is a lack of standardization for dealing with disclosure of the use of genetic information. Whether a study is designed to assess specific polymorphisms or entire genomes, the DNA sample that patients would need to provide includes all of their genetic information. Therefore, researchers would probably receive more information from patients than they actually require. Thus, there is a need to ensure that complete disclosure is provided about what and how information from genetic testing will be used. Additionally, obtaining informed consent may be more difficult when dealing with pediatric patients due to a lack of understanding of the benefits and risks of providing genetic information.¹⁸

The courts currently recognize 2 competing standards as governing the general disclosure of information in research studies: the professional practice standard holds that a professional community’s customary practices must reveal the information that is disclosed, and the reasonable person standard states that the type and amount of information disclosed is determined by reference to a hypothetical reasonable person.¹⁹ Beauchamp and Childress, however, suggest that a third standard be applied, the subjective standard, which refers to information provided being dependent on an individual’s informational needs.¹⁹

Disclosure can best be provided using the strengths of each standard. An investigator who knows what needs to be disclosed should consider what a reasonable person needs to know and then, perhaps most importantly, what a specific individual would need to know, taking into consideration his or her level of understanding. We must assume that subjects who choose to participate in a study are regular people with families, jobs, struggles, and different walks of life just like everyone else and that patient care must be upheld in the research setting. This includes showing empathy and respecting patient autonomy.

Resources for Researchers

Resources are available for clinical investigators, institutional review boards, and sponsors to provide guidance on conducting research involving genetic information, such as the creation of consent documents that include language regarding genetics.^20,21 Such resources should be used not only to ensure that the informed consent process is ethically sound, but also to ensure compliance with GINA.

Conclusion

Pharmacogenomics is proving to be an exciting discipline with a promising future, especially for pharmacy, that has the potential to increase the effectiveness of drug therapy and minimize toxicities. Nonetheless, ethical issues may arise with pharmacogenomics as it continues to expand, and such issues need to be continuously explored to ensure that patients are not fearful of nor harmed by the misuse of their genetic information.

References

• Crews KR, Hicks JK, Pui CH, Relling MV, Evans WE. Pharmacogenomics and individualized medicine: translating science into practice. Clin Pharmacol Ther. 2012;92(4):467-475. doi: 10.1038/clpt.2012.120.
• Crews KR, Cross SJ, McCormick JN, et al. Development and implementation of a pharmacist-managed clinical pharmacogenetics service. Am J Health Syst Pharm. 2011;68(2):143-150. doi: 10.2146/ajhp100113.
• Clancy JP, Johnson SG, Yee SW, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for ivacaftor therapy in the context of CFTR genotype. Clin Pharmacol Ther. 2014;95(6):592-597. doi: 10.1038/clpt.2014.54.
• Scott SA, Sangkuhl K, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94(3):317-323. doi: 10.1038/clpt.2013.105.
• Owusu-Obeng A, Weitzel KW, Hatton RC, et al. Emerging roles for pharmacists in clinical implementation of pharmacogenomics. Pharmacotherapy. 2014;34(10):1102-1112. doi: 10.1002/phar.1481.
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• Feldman EA. The Genetic Information Nondiscrimination Act (GINA): public policy and medical practice in the age of personalized medicine. J Gen Intern Med. 2012;27(6):743-746. doi: 10.1007/s11606-012-1988-6.
• Kaufmann MB. Genetic discrimination in the workplace: an overview of existing protections. Loyola Univ Chicago Law J. 1999;30(3):402-03.
• Department of Health and Human Services. The Genetic Information Nondiscrimination Act of 2008: information for researchers and health care professionals. National Human Genome Research Institute website. www.genome.gov/Pages/PolicyEthics/GeneticDiscrimination/GINAInfoDoc.pdf. Published April 6, 2009. Accessed December 10, 2014.
• Sarata AK, DeBergh JV, Staman J; Congressional Research Service. The Genetic Information Nondiscrimination Act of 2008 and the Patient Protection and Affordable Care Act of 2010: overview and legal analysis of potential interactions. National Human Genome Research Institute website. www.genome.gov/Pages/PolicyEthics/GeneticDiscrimination/CRS_GINA_and_ACA.pdf. Published December 21, 2011. Accessed December 23, 2014.
• Genetic Information Non-Discrimination Act Charges (includes concurrent charges with Title VII, ADEA, ADA, and EPA), FY 2010 - 2014. U.S. Equal Employment Opportunity Commission website. www.eeoc.gov/eeoc/statistics/enforcement/genetic.cfm. Accessed December 30, 2014.
• Fabricut to pay $50,000 to settle EEOC disability and genetic information discrimination lawsuit [press release]. Tulsa, OK: US Equal Employment Opportunity Commission; May 7, 2013. www.eeoc.gov/eeoc/newsroom/release/5-7-13b.cfm. Accessed December 30, 2014.
• Founders Pavilion will pay $370,000 to settle EEOC genetic information discrimination lawsuit [press release]. New York, NY: US Equal Employment Opportunity Commission; January 13, 2014. www.eeoc.gov/eeoc/newsroom/release/1-13-14.cfm. Accessed December 30, 2014.
• Billings PR, Kohn MA, de Cuevas M, Beckwith J, Alper JS, Natowicz MR. Discrimination as a consequence of genetic testing. Am J Hum Genet. 1992;50(3):476-482.
• Ivacaftor. Lexi-Drugs Online. Lexicomp Website. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/3636103#fee. Accessed December 10, 2014.
• Pear R. Obama administration to investigate insurers for bias against costly conditions. New York Times. December 22, 2014:A19. www.nytimes.com/2014/12/23/us/politics/obama-administration-to-investigate-insurers-for-bias-against-costly-conditions.html. Accessed March 9, 2015.
• Thomas K. Group sues Aetna, claiming discrimination against HIV patients. New York Times. December 22, 2014:B1. www.nytimes.com/2014/12/23/business/group-sues-aetna-claiming-discrimination-against-hiv-patients.html. Accessed March 9, 2015 .
• Brothers KB. Ethical issues in pediatric pharmacogenomics. J Pediatr Pharmacol Ther. 2013;18(3):192-198. doi: 10.5863/1551-6776-18.3.192.
• Beauchamp TL, Childress JF. Respect for autonomy. In: Principles of Biomedical Ethics. 7th ed. New York, NY: Oxford University Press; 2013:125-127.
• Beskow LM, Burke W, Merz JF, et al. Informed consent for population-based research involving genetics. JAMA. 2001;286(18):2315-2321.
• National Human Genome Research Institute. Informed Consent for Genomics Research. http://www.genome.gov/27026588. Updated February 4, 2015. Accessed March 9, 2015