Within 3–5 years, new discoveries in genetics may make it possible to tailor-make drugs for individual genotypes. Population-wide genetic testing for potential adverse reactions to widely used drugs may come into use. The overriding ethical issue associated with these developments is equity of access to possibly expensive treatments, especially for those whose genetic responses to common drugs fall outside the usual range. The cost of drug development raises questions of government, industry, and insurance company responsibilities to individuals whose pharmacogenetic responses are in a minority. Other ethical issues include genetic testing of children for potential future drug reactions, duties to warn about genetically based reactions when advertising pharmaceuticals directly to the public, returning benefits to persons or communities whose genotypes made drug development possible, and treatment of transgenic animals used for ‘pharming’ new drugs. The following addresses each of these issues.
DESIGNER DRUGS AND ECONOMIC EQUITY
The concept of tailor-making drugs for individual genotypes contravenes the conventional model of mass-producing drugs suitable and safe for the widest possible range of people at competitive prices. Designing drugs for individuals is analogous to going back from machine-made, mass-produced goods to a crafts tradition of handmade products, which today are almost always more expensive in industrialized societies and appeal to the affluent. In view of the costs of drug development and the limited market, it is questionable whether major pharmaceutical companies are interested in tailor-making drugs. A spokesperson for Bristol-Myers-Squibb recently stated that ‘individualized treatment doesn't play to our core interests’.1 If industry is not interested, should governments underwrite development of individualized drugs, along the lines of supports currently offered for ‘orphan drugs’? Will countries with national public health insurance be willing to cover the added costs of providing these drugs? In terms of ethics, the answers should be ‘yes,’ but in most health budgets limits of some kind are necessary. Everybody cannot have everything. Health policy-makers may have to draw some lines, while making sure that people whose genetic constitutions require more expensive drugs receive them.
Nations without national health insurance, such as the US, will face special problems, as private insurance companies may refuse to pay for individualized drugs or may refuse to insure people whose genetic tests suggest they need them. In such nations, laws may be necessary to mandate insurance coverage of individually tailored drugs and to prevent insurance companies from excluding people who are ‘pharmacogenetically different.’
Inequalities between the developed and developing world will likely be exacerbated by pharmacogenomics, as they are by most technological medicine, with most benefits going to the affluent.
PREMEDICATION GENETIC TESTING
According to Alan Roses, speaking at the Human Genome Organization (HUGO) meetings in Edinburgh in April 2001, there were 2 216 000 serious drug reactions in 1994 in the US alone, with an estimated 100 000 deaths and a $76 billion cost for drug morbidity and mortality.2 Many of these reactions were based on genetics. ‘Slow metabolizers’ are likely to have adverse reactions. On the other hand, ultrafast metabolizers may have no clinical response to the usual dose of a drug. For example, about 5–10% of Caucasians are slow metabolizers of tricyclic antidepressants and 1% are ultrarapid metabolizers. Early identification of both groups, through a test for DNA variants of cytochrome P450 2D6, could prevent much misery.3
In the future, genetic testing to identify slow and fast metabolizers of a wide range of drugs may be conducted early in life, on a one-time basis, with the information placed on file in an individual's medical record. This could be performed by examining about 200 000 single nucleotide polymorphisms (SNPs) from each person, which now costs between 1 and 10 cents per SNP, but may be as low as one-tenth of a cent per SNP ($200 per person) in a few years.2
Such testing could have many benefits, both for individuals and drug companies. It could identify people who are susceptible to adverse drug reactions, and could also identify those who are unlikely to benefit from a particular drug. It would also make possible the resurrection of some older drugs that are safe and effective for most people, but have been taken off the market because a few people had serious reactions. Companies would be able to reduce the size of clinical trials, creating greater efficiency. (In the absence of genetic testing, longer development or review time does not necessarily remove risk. If the risk for an adverse event is one in 50 000, there may be no such events until after the drug is marketed.)
Although genetic testing for drug responses appears to have many benefits, there are also potential harms. Insurance companies, which have heretofore not expressed an interest in population-wide testing, may be interested in the results of tests for drug reactions in order to exclude or charge higher premiums for those who can only tolerate very expensive drugs. Unlike much of the information currently available from genetic tests, responses to drugs are usually not in the family histories from which insurance companies get their information. Fear of losing health insurance (in countries without national insurance systems) is already a major cause of refusal of genetic testing4 and may lead some people to refuse tests for potential reactions to drugs. Premedication genetic testing, when developed, will be so important to care that it must be part of the medical record; keeping the so-called ‘shadow charts’ to prevent insurers from seeing the information would be highly unethical. The problem is best addressed through laws mandating coverage for those who require unusual or expensive drugs, whether for genetic reasons or otherwise. HMOs may welcome such tests because they could save the billions lost on adverse reactions or ineffective drugs.
When developed, such a one-time test, given early in life, should be part of routine medical care. It should not require a special informed consent or privacy protection beyond that accorded to usual medical tests. Labeling such a test as ‘genetic’ (especially when not associated with a disease) might only serve to frighten people away from optimum medical care. It is close to impossible to specify what constitutes a ‘genetic’ test when so much of human disease has at least a partly genetic foundation. A test with wide ramifications for health should be considered as part of general medical care. Potential benefits justify the genetic testing of children; the test would fall within the ethical guidelines of professional organizations.5,6,7
DUTIES TO WARN
SNP profiling may affect drug labeling, so as to restrict prescriptions only to individuals with the suitable genetic profile. For drugs already approved by the regulatory agencies (eg, Food and Drug Administration in the US), subsequent discoveries that people with particular genetic profiles may have adverse reactions would require addition of this information to the label and a warning that genetic screening is necessary. Based on a ‘failure to warn’ concept, plaintiffs in a class action suit against SmithKline Beecham have argued that about 30% of the population has a genotype that elevates their risk for developing Lyme disease after taking the company's vaccine, Lymerix, and that the company failed to warn of the need for genetic screening.8
Pharmacogenomics may lead to legal requirements for direct disclosure to the public about genetic risks from drugs. In the past, pharmaceutical companies were only required to warn the physician, who acted as a ‘learned intermediary’ in interpreting risks to the patient. Genetic testing may remove some of the uncertainties and make the information more comprehensible to the public. Therefore, in the future, courts may require disclosure of risks associated with certain genetic profiles to patients and also to the public if a drug is marketed directly.
Sometimes community, family or even individual genotypes may make essential contributions to drug development. The drug itself may not benefit the community or individual. A hypothetical example would be an extended family with an osteochondrodysplasia (a group of rare genetic disorders that cause secretion of extra bone) who contributed tissue to research on osteoporosis, lending to a major new drug, which unfortunately does not help the family. Unlike most participants in research, this family had something unique to offer. Are they owed anything? Such cases occur from time to time in genetic research, the best known being the Moore case.9 Regarding one's cells as objects for sale undercuts the basic principle of participation in research, which should be a desire to help others. Yet justice requires that communities or families receive some benefits, not necessarily monetary. Often the group concerned is a genetic support group, which may have made the study possible by locating research participants. Arrangements for benefit-sharing are best agreed upon between researchers and the group participating before the initiation of the research.10
THE ETHICS OF ‘PHARMING’
Using genetically altered animals to produce human drugs (‘pharming’) raises special ethical issues beyond those usually associated with humane care of animals. Pharming will likely use living domestic animals on a scale not previously employed in medicine, and despite the best care and prevention of outright pain, some of these animals may inevitably live a less-than-healthy or even downright miserable life in order to serve humankind, somewhat like the goose with the swollen liver that produces foie gras. In mainstream Western religion, and cultural traditions, human welfare has always been placed above animal welfare, although with some admonitions to avoid unnecessary animal suffering. However, other traditions say that animals and humans are all part of a continuum of life and that all suffering must be taken into account. The 19th-century utilitarian Jeremy Bentham argued that we should not dismiss the pain and suffering we cause to other species, especially those close to humans,11 a few carried forward today by Peter Singer.12 (Few people are greatly concerned about mice and microbes.) Should patients be told that their medications are derived from pharming and also about the condition of the animals? Probably not, because knowing that an animal might be miserable would only serve to make the patient feel more miserable and would not help the patient's health. However, people should have the right to know about the use of animals in producing their medications, if they wish the information. Making this ‘right to know’ a clinic policy, and posting it, recognizes and respects the beliefs of those who support animal rights. Most people will not want to know, just as they prefer ignorance about the conditions under which their food is raised.
Equality of access is the major issue, as with most expensive technologies. North–South inequalities may be exacerbated. There is need for regulations that assure that the benefits of the genetic revolution are accessible to all.
Genetic tests for responses and reactions to drugs should be part of regular health care, not set aside in a special ‘genetic’ category. As with any diagnosis or treatment, people have a right to refuse testing.
Duties to warn of possible adverse reactions and the need for premedication testing may need to be extended to include warning the general public, especially if there is direct advertising to potential patients.
Attention to quality of life for animals used in pharming may increase.
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American Society of Human Genetics Board of Directors and American College of Medical Genetics Board of Directors. Points to consider: ethical, legal and psychosocial implications of genetic testing in children and adolescents. Am J Genet 1995; 57: 1233–1236.
Clinical Genetics Society (UK). Report of a working party of the Clinical Genetics Society. In: Clarke A (ed). The genetic testing of children. Bios Scientific: Oxford, 1998, pp 281–328.
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DUALITY OF INTEREST
Dr. Wertz tragically died on 29 April, 2003 in Cancun, Mexico. She is deeply missed by fellow members of the HUGO Ethics Committee, and her friends and colleagues around the world. This article is dedicated to her memory. Her academic address was: DC Wertz, Shriver Division, University of Massachusetts Medical School, 200 Trapelo Road, Waltham, MA 02452, USA.
Correspondence should be sent to
D Macer, Institute of Biological Sciences, University of Tsukuba, Tsukuba Science City 305-8572, Japan. Tel: +81 29 853 4662; Fax: +81 29 853 6614; E-mail: email@example.com
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Wertz, D. Ethical, social and legal issues in pharmacogenomics. Pharmacogenomics J 3, 194–196 (2003). https://doi.org/10.1038/sj.tpj.6500188
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