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might vary in frequency among differentpopulation subgroups, important socialissues arise in multi-ethnic countries, such asthe United States. Finally, pharmacogenomicswill change the standard of care for pharma-ceutical companies and health professionals,including physicians and pharmacists.

This article provides an overview of someethical and social concerns that arise with theintegration of pharmacogenomics into thediscovery of drugs and the practice of preven-tive and therapeutic medicine. Specifically, thearticle addresses issues associated with thedesign of clinical trials, the relatively highercost of pharmaceuticals developed usingpharmacogenomics, and the allocation ofethical and legal responsibility. The objectiveis to highlight a few of the questions and chal-lenges that will require further attention inthe near future.

A new model of clinical trialsPharmacogenomics promises to reduce thetime and money required to develop a drug.The ability to predict drug efficacy by geno-typing participants during the early stages ofclinical trials for a drug would enableresearchers to recruit for later trials only thosepatients who, according to their genotype, arelikely to benefit from the drug4. As a result,clinical trials could become smaller, cheaperand faster to run.

The prospect of clinical trials that are com-posed of smaller groups with the same poly-morphisms at one or more loci of interestposes some risks, however. A group thatreflects the diversity of the population yieldsinformation on how a drug will behave in agreater number of people. If the clinical trialgroup is smaller, or is less genotypicallydiverse, there is a greater risk that some sideeffects will go undetected. So, the trials willyield a greater quantity and quality of infor-mation, but on a smaller segment of the popu-lation.Whereas the conventional model yield-ed information about harmful side effects in agreater proportion of the population, the con-centration of individuals pre-selected for afavourable response under the newer modelmight not produce the same information.Compared with traditionally designed humanclinical trials, genotype-specific human clini-cal studies might be subject to equal or greaterlimitations in that the relatively short durationof the study, combined with the narrower sub-ject population and smaller size, would hinderthe ability of the studies to identify rare ordelayed adverse reactions or druginteractions5. A drug could reach the marketwith less information about the side effects orrisk of harm from its non-prescribed uses. An

and other technologies to construct clinicaltrial groups that are composed of people mostlikely to benefit from a particular drug. Theability to streamline clinical trials by genotyp-ing will enable researchers to ‘rescue’ drugsthat could not be approved under convention-al models of research trials. In other words,drugs that were previously rejected after givingunacceptable rates of adverse responses in tra-ditionally constructed trials will yield loweradverse-response rates after testing under thenew model, thereby becoming acceptable can-didates for approval. Pharmacogenomics willnot only produce better drugs but also yieldgreater efficiency in the allocation of resourcesin drug development.

Other changes attributable to pharma-cogenomics will be less welcome.Notwithstanding the increasingly efficientresearch and development process, pharma-cogenomic-based drugs will be expensive,because of, for example, the need to recoupthe cost of investment in new technologies.The ability to develop specialized drugs thatare ultimately approved for smaller popula-tions rather than for general use will fragmentthe market for pharmaceuticals. Will a phar-maceutical manufacturer react to this eco-nomic reality in a way that better suits profitmargins than health, and is that sociallyacceptable? The use of groups in clinical trialsthat are increasingly similar genotypicallyraises several important ethical issues regard-ing social inclusion and the adequacy of cur-rent regulatory frameworks. Because poly-morphisms of pharmacological interest

Pharmacogenomics is the application ofgenomics technology to the discovery anddevelopment of drugs. A greaterunderstanding of the way in whichindividuals with a particular genotyperespond to a drug allows manufacturers toidentify population subgroups that willbenefit most from a particular drug. Theincreasing emphasis on pharmacogenomicsis likely to raise ethical and legal questionsregarding, among other things, the design ofresearch studies, the construction of clinicaltrials and the pricing of drugs.

Pharmacogenomics is changing the way thatdrugs are developed, approved, marketed andprescribed. The objective of pharmacoge-nomics is to define the pharmacological sig-nificance of genetic variation among individu-als and to use this information in drugdiscovery, thereby decreasing the number ofadverse drug responses that injure and killthousands each year1. By determining whichgenetic variations are likely to affect a person’sability to metabolize a drug, drug manufactur-ers intend to develop more predictable andeffective therapeutic agents. Towards this end,pharmaceutical companies are investing hugeamounts of capital in the technologies thatwill revolutionize both how researchers identi-fy drug targets and the amount of time neededto move a drug through development andapproval2,3. Pharmacogenomics promises tostreamline the clinical trial phase of drugdevelopment. Researchers hope to use knowl-edge gained from high-throughput screening

Ethical and legal implications of pharmacogenomics

Mark A. Rothstein and Phyllis Griffin Epps

S C I E N C E A N D S O C I E T Y

Box 1 | Ethical principles of human subject research

In the United States, federal regulations that govern human subject research stem from threeethical principles that were identified in the Belmont Report: respect for persons, beneficenceand justice26. As a principle, respect for persons includes two moral requirements:acknowledgement of personal autonomy and protection of individuals with diminishedautonomy. In research that involves human subjects, the proper exercise of autonomy demandsthat research participants agree to enter into research voluntarily and with adequate information.The participant’s informed consent is essential. Beneficence also entails two requirements: do noharm and maximize the possible benefits, while minimizing the possible harms. Justice looks athow to fairly distribute the benefits and burdens of research. In the context of research on humansubjects, questions regarding how and why research participants are selected are important insatisfying the principle of justice27.

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The significance of data that imply a rolefor ethnicity in research has been a source ofconsiderable debate among the researchethics community15. One issue is how toadvise potential research participants aboutthe possibility of social harms from group-based findings even where the research is con-ducted without using the names of partici-pants. Another matter of considerable debatein the literature is whether it is necessary orfeasible to engage in community consultationwhen genetic research focuses on socially orpolitically distinct population subgroups15, 16.

Cost as a barrier to accessPharmacogenomic drugs will be expensive,cheaper clinical trials notwithstanding17.Collectively, the pharmaceutical industry isinvesting huge amounts of time and moneyin the development of new technologies thatwill yield drugs that are more effective thanthose already available2. Without the opportu-nity to recoup their investment, drug compa-nies will not continue their efforts. At thesame time, insurance systems and consumersare struggling to absorb the rising costs ofpharmaceutical products18,19.

Pharmacogenomics is based on the ideathat pharmaceutical consumers will be betterserved by drug therapy once they have beensubdivided by genotype and matched withthe most suitable drug. From the industryperspective, the subdivision of a market intosmaller markets is hardly ideal7. Incentives forpharmaceutical companies to invest time,effort and resources into the development ofdrugs to treat limited populations are fewcompared with the development of drugs totreat more prevalent genotypes in the contextof pharmacogenomics. Most drug companiesmight be expected to direct their resourcestowards the development of drugs to treat themore prevalent genotypes.

Those groups characterized by less-prof-itable genotypes are at risk of becoming thera-peutic ‘orphans’. At present, pharmaceuticalsfor rare diseases are termed ‘orphan drugs’20.The United States and Japan have enacted leg-islation to stimulate research and the develop-ment of orphan drugs through market mecha-nisms, such as tax-based cost incentives andtime-limited monopolies20, with varyingdegrees of governmental intervention. Canada,Sweden, France, the United Kingdom andother countries rely on broader national drugpolicies based on more substantial governmen-tal intervention. The European Union hasentertained initiatives to stimulate legislativeaction on orphan drugs, and the EuropeanAgency for the Evaluation of MedicinalProducts has a provision that exempts drug

unresolved issue is whether the ethical princi-ples of beneficence (BOX 1) and non-malefi-cence (that is, not causing harm to others)would preclude the deliberate inclusion ofanyone who is not likely to respond favourablyto treatment. With the advent of genotype-specific clinical trials, manufacturers and regu-lators must be ready to carefully evaluate post-market data by strengthening the existingguidelines for phase IV, or post-approval, clin-ical trials2,3,5,6–8 (BOX 2).

As in other areas of genetic research thatinvolve human subjects, the likely effect ofpharmacogenomics on clinical trials raisesimportant questions regarding informed con-sent, which might include considerations ofprivacy and confidentiality9. Current ideasregarding patient autonomy and informedconsent require that patients agree to enterinto research on the basis of adequate infor-mation regarding the risks and consequencesof participation. Genotyping that is appropri-ate to pharmacogenomic research might notproduce information regarding susceptibilityto disease or early death, but it might revealevidence of genetic variation that could leadto individuals being classified as ‘difficult totreat’, ‘less profitable to treat’, or ‘more expen-sive to treat’. The fear of being so classifiedcould act as a barrier to the recruitment ofresearch participants.

Fear of stigmatization might prove to be asignificant barrier to participation in clinicaltrials among members of population sub-groups. Genetic variations of pharmacologi-cal significance are known to occur in varyingfrequency in groups categorized by their eth-nicity10,11. For example, different variants ofglucose-6-phosphate dehydrogenase (G6PD— an enzyme critical for NADPH (nicoti-namide-adenine dinucleotide phosphatereduced) generation in mature red bloodcells) are found at a high frequency in African,

Mediterranean and Asiatic populations12,some of which disrupt the function of theenzyme. A deficiency of G6PD can predisposeindividuals from these populations tohaemolytic anaemia, both in individuals withloss-of-function G6PD mutations and in

response to some drugs, such as the malarialdrug primaquine13. Isoniazid is an anti-tuber-culosis drug that is inactivated by acetylation;its impaired metabolism by slow acetylationcauses it to accumulate to toxic levels.Variation in the N-acetyl transferase 2(NAT2) gene accounts for whether individu-als are rapid or slow acetylators of isoniazid,as well as of other therapeutic and carcino-genic compounds14. About 50% of individu-als in many Caucasian populations are geno-typically slow acetylators of isoniazid, butmore than 80% of individuals in certainMiddle Eastern populations and fewer than20% in the Japanese population have the slowacetylator phenotype13.

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The ability to developspecialized drugs … forsmaller populations ratherthan for general use willfragment the market forpharmaceuticals. Will apharmaceuticalmanufacturer react to thiseconomic reality in a waythat better suits profitmargins than health …?

Box 2 | Post-approval monitoring of pharmaceuticals

Despite continuing efforts to harmonize pharmaceutical regulations worldwide, the protectionafforded to populations from the risks attendant to drugs that have been approved, after testing insmaller, less genotypically diverse clinical trial groups, depends on the market, member state orcountry at issue.

United States: In addition to clinical trials, the Food and Drug Administration requiresmanufacturers to maintain records of clinical experience that would be relevant to determiningwhether approval of a drug should be withdrawn, and to submit adverse drug reports.

European Union (EU): For pharmaceuticals that have been approved according to thecentralized approval process administered by the EU, the European Agency for the Evaluationof Medicinal Products and the Commission on Proposed Medicinal Products require thatreports on adverse reactions be submitted every six months for the first two years after approval.Individual member states may have different guidelines in effect that override the guidelines ofthe European Agency.

Japan: Through the Pharmaceuticals Affairs Bureau, the Ministry of Health and Welfarerequires the manufacturer to collect data on adverse drug reactions and to submit products for re-examination and re-evaluation.

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of a drug being effective or causing adversereactions in persons possessing a particulargenetic characteristic, and will certainly yielddrugs that are more likely to be suitable forsmaller, specific groups of individuals. Byincreasing the information available for con-sideration in drug therapy and the importanceof matching the right drug to the right person,pharmacogenomics will raise the standard ofcare applicable to all involved in the safe pre-scription and distribution of pharmaceuticals.

Pharmacists are primarily charged withthe dispensation of prescriptions as admin-istered by physicians, but the scope of theirresponsibilities has expanded over time toinclude ensuring that prescriptions andpatient directions are correct and appropri-ate. Pharmacists also have a duty to warntheir customers of the potential adverseeffects or other problems associated with aprescribed drug therapy. Even if a pharma-cist has dispensed a prescription accordingto a physician’s instructions, some jurisdic-tions have imposed liability on pharmacistsfor the harm that resulted from a drug thatwas properly dispensed in accordance withan improper or harmful prescription24. Asinformation regarding the genotype of anindividual becomes increasingly importantto safe prescription and dosage, pharmacistsmight be charged with greater knowledge oftheir customers’ genetic information thanthey now require. The increased amount ofgenetic information in pharmacies raisesprivacy and confidentiality concerns, espe-cially where pharmacists belong to largepharmacy chains or corporations withwidely accessible, centralized records. Forphysicians and pharmacists, the issue ofcontinuing professional education andrecord maintenance will become moreimportant, not only for improving compe-tence but also for preventing liability.

Pharmacogenomics is likely to increase theburden shared by the pharmaceutical indus-try to provide adequate warnings of the limi-tations and dangers of their products. In theUnited States, for example, pharmaceuticalmanufacturers have a duty to warn physiciansabout any known or knowable risks, or dan-gers, of the use of a manufactured drug. Manystates in the US will impose strict liability on adrug company for harm caused by the failureto adequately warn against the dangerouspropensities of a drug that it has manufac-tured. Unlike negligence theory, the rules ofstrict liability are not concerned with the stan-dard of care nor the reasonableness of themanufacturer’s conduct; and an aggrievedparty need only prove that the manufacturerdid not adequately warn of a particular risk

availability to patients. The issues raised arenot unique to pharmacogenomics but dorequire new applications of ethical principlesand legal doctrine.

In countries where the legal systems arebased on common law (that is, the Englishtradition of law-making based on the courtdecisions of judges), physicians and pharma-cists are subject to liability under theories ofnegligence, which involve the violation of aduty based on a ‘reasonableness’ standard or astandard of reasonable care. The standard ofcare is defined by how a similarly qualifiedpractitioner would act in treating a patientunder the same or similar circumstances. Theliterature, which includes professional schol-arship and guidelines published by profes-sional societies, and clinical experience estab-lish the standard of care. In cases based onnegligence in the form of medical malprac-tice, the standard of care is defined throughthe testimony of witnesses regarding whatconstitutes conventional practice within themedical community.

As pharmacogenomic-based drugs increasein prevalence over the next several years, theuse of genotyping or genetic testing as a diag-nostic tool and the prescription of medicationsbased on genotypic information will becomethe standard of care for physicians. Physiciansand pharmacists might be subject to liability ifthey lack sufficient knowledge of genetics toadequately interpret diagnostic tests, prescribeappropriate pharmacogenomic-based drugtherapy in proper dosages, consider pharma-cogenomic-based drug interactions, or proper-ly dispense pharmacogenomic-based prescrip-tions. With greater knowledge comes greaterresponsibility. Pharmacogenomics might pro-vide greater information about the likelihood

companies from having to pay application feesto develop a drug if it is an orphan drug (seelink to The European Commission’s report onorphan medicinal products). Despite allega-tions of overpricing of orphan drugs under theAmerican model19, nearly all efforts have beenfollowed by a measurable increase in the num-ber of drugs that have been developed andapproved for the treatment of rare diseases21.As clinical trials increasingly consist of geneti-cally non-diverse groups, policy makers willneed to consider whether to expand the con-cepts underlying orphan drug policies to stim-ulate research into and the development ofdrugs for populations who, by virtue of theirgenetic make-up, face inequities in drug devel-opment efforts.

Cost might act as a barrier to access topharmacogenomics in that the cost of partici-pating in clinical trials or of the resulting drugtherapy might be excluded from insurancecoverage. Particularly in the United States,where managed care systems attempt to con-tain costs by rationing medical services, pub-lic and private third-party payers have refusedor been reluctant to pay for treatments thatthey deem ‘experimental’ or not ‘medicallynecessary’22,23. Increasingly, these terms havemore political than legal or medical signifi-cance. There is some evidence that the insur-ers’ disinclination to cover expenses that areassociated with new drug therapies can becountered by high physician or consumerdemand for the new drug21. If consumersmust absorb rising pharmaceutical costs,pharmacogenomics will not introduce newquestions so much as it will intensify existingones about equitable access to medical care.

Professional standards of careAs pharmacogenomic-based drugs enter intothe marketplace, physicians will encounteralternatives to conventional drug therapy andprescription practices. Although the evalua-tion of genetic variation among patients todetermine proper medication and dosageduring the course of treatment is not thestandard of care at present, ethical concerns,economic considerations and the threat ofmalpractice liability are likely to encouragephysicians to begin testing for and prescrib-ing medications designed for use by specific,smaller groups of individuals. Moral and eth-ical proscriptions against causing harmmight require a physician to integrate phar-macogenetics into clinical practice wherenecessary to minimize risk to a patient. Bycontrast, budgetary constraints imposed byinsurers could slow the acceptance of drugsdeveloped through pharmacogenomics bylimiting their use by physicians and their

Genotyping appropriate topharmacogenomic researchmay not produceinformation regardingsusceptibility to disease orearly death, but it mayreveal evidence of geneticvariation that could lead toindividuals being classifiedas … less profitable … or‘more expensive to treat’.

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7. Richmond, M. H. et al. Human Genomics: Prospects forHealth Care and Public Policy (Pharmaceutical Partners forBetter Healthcare, England, 1999).

8. Wood, A. J. J. & Woosley, R. Making medicines safer —the need for an independent drug safety board. N. Engl. J.Med. 339, 1851–1853 (1998).

9. Rothstein, M. A. Genetic privacy and confidentiality: whythey are so hard to protect. J. Law Med. Ethics 26,198–204 (1998).

10. Meyer, U. A. Pharmacogenetics and adverse drugreactions. Lancet 356, 1667–1671 (2000).

11. Evans, W. E. & Relling, M. V. Pharmacogenomics:translating functional genomics into rational therapeutics.Science 286, 487–491 (1999).

12. Beutler, E. G6PD: population genetics and clinicalmanifestations. Blood Rev. 10, 45–52 (1996).

13. Weber, W. W. Pharmacogenetics Vol. 15 (Oxford Univ.Press, New York, 1997).

14. Grant, D. M. et al. Human acetyltransferasepolymorphisms. Mutat Res. 376, 61–70 (1997).

15. Sharp, R. S. & Foster, M. W. Involving study populations inthe review of genetic research. J. Law Med. Ethics 28,41–50 (2000).

16. Juengst, E. T. Commentary: what ‘community review’ canand cannot do. J. Law Med. Ethics 28, 52–54 (2000).

17. Holmer, A. F. Correspondence: the pharmaceuticalindustry — to whom is it accountable? N. Engl. J. Med.343, 1415 (2000).

18. Mrazek, M. F. & Mossialos, E. Increasing demand whiledecreasing costs of generic medicines. Lancet 356,1784–1785 (2000).

19. Angell, M. The pharmaceutical industry — to whom is itaccountable? N. Engl. J. Med. 342, 1902–1904 (2000).

20. Thamer, M. et al. A cross-national comparison of orphandrug policies: implications for the U. S. Orphan Drug Act. J.Hlth Politics Policy Law 23, 265–290 (1998).

21. Pulsinelli, G. A. The orphan drug act: what’s right with it.Santa Clara Computer & High Technology Law J. 15,299–345 (1999).

22. Kuszler, P. C. Financing clinical research and experimentaltherapies: payment due, but from whom? DePaul J. HlthCare Law 3, 441–494 (2000).

23. Schoonmaker, M. M. et al. Factors influencing healthinsurers’ decisions to cover new genetic technologies. IntlJ. Technol. Assess. Hlth Care 16, 178–189 (2000).

24. Horner v. Spalitto, 1 S. W. 3d 519 (Mo. Ct. App. 1999)(reversing grant of summary judgement in favor ofcustomer who died from overdose following accurate fillingof incorrectly prescribed drug by pharmacist). Available athttp://www.mobar.org/bulletin/nov99/bul-bod.htm

25. Cassidy v. Smithkline Beecham, No. 99-10423 (Pa.Chester County Dec. 14, 1999).

26. National Commission for the Protection of HumanSubjects of Biomedical and Behavioral Research, TheBelmont Report (April 18, 1979).

27. Emanuel, E. J., Wendler, D. & Grady, C. What makesclinical research ethical? J. Am. Med. Assoc. 283,2701–2711 (2000).

AcknowledgementsThis work was supported by the National Institutes of Health. Theauthors are grateful to Joseph Wang for his research assistance.

that was knowable in the light of generallyrecognized and prevailing best scientific andmedical knowledge available at the time ofmanufacture and distribution. Pharmaceuticalcompanies must consider the potential for lia-bility if patients are harmed because they wereexcluded from the subgroup for which apharmacogenomic-based drug is deemed safeand efficacious, particularly if the exclusionleads to a failure to yield information on pos-sible side effects or alternative therapies. Notall adverse side effects are predictable, owingto the number of genes relevant to drugresponsiveness, as well as environmental fac-tors8. The question is how to allocate respon-sibility for taking the greatest advantage ofdrugs specialized to suit relatively smaller seg-ments of the population.

In June 2000, four individuals filed a classaction lawsuit against SmithKline Beecham,alleging that the manufacturer of a vaccine forLyme disease knew that some individualswould be susceptible to arthritis on exposureto the vaccine because of their genotype, butfailed to warn about this by labelling25. Thecase is still pending. Similar cases involve mal-practice actions by the patient against the pre-scribing physician, who in turn seeks torecover against the manufacturer for failure toprovide adequate information. Put simply,pharmacogenomics will raise the legal stakesfor all involved whenever a patient suffersadverse reactions from the use of a drug thatmight have been contraindicated based on hisor her genotype.

ConclusionBy lessening the uncertainty associated withthe selection of drug targets and the design ofhuman clinical studies in the development ofnew drugs, pharmacogenomics will result inthe production of safer, more effective drugs

for use in therapeutic medicine. The integra-tion of pharmacogenomic technology intothe drug development process and the prac-tice of medicine will require consideration ofethical, social and legal questions. Answers tothese questions might well determine thelevel of social acceptance and realization ofthe benefits of pharmacogenomic technology.

Mark A. Rothstein is at the Institute for Bioethics,Health Policy and Law, University of Louisville

School of Medicine, 101 West Chestnut, Louisville,Kentucky 40202, USA. Phyllis Griffin Epps is at the

Health Law and Policy Institute , University ofHouston Law Centre, Houston, Texas

77204 -6391, USA.Correspondence to:maroth01@gwise.louisville.edu

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2. Flanagan, A. Screening technologies evolve: innovationsspurred by race to profit from genetic data. Genet. Eng.News 20, 1, 19–20, 71 (September 1, 2000).

3. Barrett, A. The pharma frenzy: in the race for gene-basedtherapies, big drugmakers join forces with upstarts.Business Week 160–161 (June 2000).

4. Roses, A. D. Pharmacogenetics and the practice ofmedicine. Nature 405, 857–865 (2000).

5. Noah, B. A. Adverse drug reactions: harnessingexperiential data to promote patient welfare. Catholic U.Law Rev. 49, 449–504 (2000).

6. Roses, A. D. Pharmacogenetics and future drugdevelopment and delivery. Lancet 355, 1358–1361 (2000).

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Physicians and pharmacistsmight be subject to liabilityif they lack sufficientknowledge of genetics toadequately interpretdiagnostic tests, … , orproperly dispensepharmacogenomic-basedprescriptions. With greaterknowledge comes greaterresponsibility. Links

DATABASE LINKS G6PD | haemolytic anaemia| NAT2 | Lyme diseaseFURTHER INFORMATION European Agency forthe Evaluation of Medicinal Products | TheEuropean Commission’s report on orphanmedicinal products | Belmont Report | Foodand Drug Administration | European Agencyfor the Evaluation of Medicinal Products |Pharmaceuticals Affairs Bureau | Journal ofHealth Politics, Policy and Law | Journal ofInternational Law and Practice | Santa ClaraComputer & High Technology Law Journal |Genetic Engineering News

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