Research Commentary

Pharmacogenomics, Drug Development, and Ethics:Some Points to ConsiderJeantine Lunshof1,3* and Guido de Wert2

1Center of Ethics and Philosophy, VU University Medical Center, Amsterdam, The Netherlands2Department of Biomedical Ethics, Faculty of Medicine, Maastricht University, The Netherlands

3Department of Clinical Genetics and Human Genetics, VU University Medical Center,Amsterdam, The Netherlands

Strategy, Management and Health Policy

Enabling

Technology,

Genomics,

Proteomics

Preclinical

Research

Preclinical Development

Toxicology, Formulation

Drug Delivery,

Pharmacokinetics

Clinical Development

Phases I-III

Regulatory, Quality,

Manufacturing

Postmarketing

Phase IV

ABSTRACT Pharmacogenomics will contribute in the near future to significant changes in drugdelivery and drug development. In both areas, the application of pharmacogenomics gives rise to ethical,legal, and social concerns. These concerns have recently been addressed by various national andinternational working groups. In this article, we will give a concise overview of the ethical issues raised inparticular by the application of pharmacogenomics in the context of drug development. Taking a basicapproach, we will show the cumulative development of ethical issues in clinical research, medicalgenetics, and in pharmacogenomics with special focus on drug development. The relevance of ‘‘geneticexceptionalism’’ will be scrutinized with regard to its impact on questions concerning stratification inparticular. To this end, we will refer to the views expressed in documents by various expert working groupsand to the recent recommendations made by international organizations. We will show which points toconsider arise specifically in the context of pharmacogenomics in addition to the known issues covered bythe established guidelines on ethical, legal, and social aspects of clinical research and genetics. Drug Dev.Res. 62:112–116, 2004. �c 2004 Wiley-Liss, Inc.

Key words: clinical research; ethics; genetic exceptionalism; pharmacogenomics; points to consider; stratification

INTRODUCTION

Even if progress is slower than anticipated[Nebert et al., 2003], pharmacogenomics will contri-bute in the near future to major changes in the way inwhich drugs are developed and used in clinicalpractice. In several areas, the implementation ofpharmacogenomics-guided treatment is already feasi-ble [Kerwin, 2003]. Traditionally, drug developmentand especially clinical research are areas connectedwith serious ethical, legal, and social concerns. In thefollowing, we give an overview of the cumulativedevelopment of ethical issues in clinical research,medical genetics, and pharmacogenomics with a specialfocus on drug development. Several expert groupsworking on behalf of national and internationalorganizations, like the Nuffield Council on Bioethics,the Consortium on Pharmacogenetics, the Consultants

to the World Health Organization, and the EuropeanCommission Expert Group on Genetic Testing haverecently prepared reports and issued statementsconcerning the appropriate dealing with ethical issuesin genetics, including pharmacogenomics. We will referto these views and recommendations. Genetic excep-tionalism is a crucial concept that must be scrutinizedin particular because of its impact on stratification,which is an important feature of clinical research.While pharmacogenomics does not give rise tocompletely new ethical issues, it increases, however,

DDR

nCorrespondence to: Jeantine Lunshof, VU UniversityMedical Center, Van der Boechorststraat 7, 1081 BT Amsterdam,The Netherlands.E-mail: je.lunshof@vumc.nl

Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/ddr.10373

DRUG DEVELOPMENT RESEARCH 62:112–116 (2004)

�c 2004 Wiley-Liss, Inc.

complexity in clinical research and calls for regulatoryand policy adjustments as well as for educating boththe general public and the health professionals.

ETHICAL ISSUES IN CLINICAL RESEARCH

Voluntary consent given without any constraintsand after comprehensive information, and a favorablerisk-benefit ratio for the participant are the coreconditions for the justification of enrolling humansubjects in any kind of research. When the gain ofknowledge is recognized as the primary aim of clinicalresearch and the participants, either patients or healthyprobands, are admitted to be the means to this end inthe first place, the need for regulation and controlbecomes obvious. The guidelines and regulationsconcerning medical research that have been in usefor several decades are founded on rules that wereoriginally formulated in reaction to crimes againsthumanity guised as medical experiments committed byphysicians during the Nazi regime [The NurembergCode, 1949; The Declaration of Helsinki, 1964].

New developments in science and in the scopeand mode of conduct of clinical research as well as theuncovering of various research scandals led to a greatand yet increasing number of regulatory frameworks,the older ones being regularly extended and theirinterpretation revisited [The Belmont Report, 1979;Cassell,2000]. These frameworks contain concreteaction guides adjusted to a particular research contextthat can be as different as drug research, behavioralresearch, or population-wide epidemiological studies.Basically, they always address the core issues ofvoluntary participation, informed consent, and risk-benefit balancing. Issues beyond the individual re-search participants concern the just distribution ofburdens and benefits in a society or particularpopulation, and the criteria for fair subject selection.In the context of pharmacogenomics guided clinicalresearch, the latter issues are of particular importancein view of the stratification involved (these issues arediscussed in depth in ‘‘Stratification’’). Recently,Emanuel et al. [2000] proposed seven universal ethicalrequirements whose fulfillment is claimed by theauthors to be both necessary and sufficient for makingclinical research ethical. These seven requirements are:(1) social or scientific value of research, (2) scientificvalidity, (3) fair subject selection, (4) favorable risk-benefit ratio, (5) independent review, (6) informedconsent, and (7) respect for potential and enrolledsubjects. Future research must show the sustainabilityof the authors’ claim and further clarify the operatio-nalization of these requirements.

ETHICAL ISSUES IN MEDICAL GENETICS

The practice of medical genetics and relatedresearch gives rise to a set of specific ethical questionsthat go beyond the known issues in clinical research ingeneral. Most existing guidelines and regulatory frame-works in medical genetics focus on issues that arise inthe individual patient-physician, namely counselee-counselor, relationship. Consent, which must be bothvoluntary and informed, privacy, and confidentialityare the central issues in this specific context ofdiagnostic or predictive genetic testing on the indivi-dual’s request [WHO, 2003]. The potential socialimplications, however, can be important, as unfavor-able results of genetic testing might put individuals at adisadvantage in attaining employment and health or lifeinsurance. These possible disadvantages are a majorreason for concern about, and the rejection of, genetictesting in the general population, even though there islittle evidence of cases in which the results of genetictesting were the sole cause for social discrimination.Some specific questions arise in the context of geneticscreening and genetic research. Genetic screening hasraised substantial ethical concerns since the early 1980s[Screening and Counseling for Genetic Conditions1983; Nuffield Council, 1993]. In this case the testing isoffered by a third party and not sought by the testsubject. Thus, the relative importance of ensuringvoluntary and informed consent, the right not to knowthe test results, and adequate balancing of risks andbenefits are more substantial than in testing onindividual request for weighty medical and personalreasons. However, the practice of genetic screening hasremained, in general, rather limited and has not causedtoo much societal commotion, contrary to fears andexpectations.

Research in genetics and the collection andstorage of data and samples for scientific purposesraises additional questions concerning the ownership ofhuman tissue and genetic data and the scope andextent of the informed consent. The establishment ofbiobanks raises, among other issues, important ques-tions about the use of data for commercial purposes,third-party interests, and benefit-sharing [Knoppers,2000; Anderlik, 2003]. The report of the EuropeanCommission Expert Group [2004a] points to theimportance of these issues, as they do not only bearupon the interests of individuals but also relate tonational policies in an international context. Obviously,these issues will be equally important in the context ofresearch and development in pharmacogenomics, asthis will require the establishment of huge genetic datacollections after large-scale genotype screening ofpopulations or population sub-groups.

PHARMACOGENOMICS, DRUG DEVELOPMENT, AND ETHICS 113

THE CRUCIAL QUESTION OF GENETICEXCEPTIONALISM

A crucial question in the context of bothindividual genetic testing and genetic screening regards‘‘genetic exceptionalism,’’ namely, ‘‘is genetic informa-tion qualitatively different from other medical informa-tion?’’ [Nuffield Council, 1993; European Commission,2004a]. The answer to this question is definitelyimportant for the application of pharmacogenomics inclinical research and drug development. An affirmativeanswer, for example as given by UNESCO [UNESCO,2003] and the Council of Europe [Council of Europe2003], implies that special regulatory and safetymeasures must be taken to protect any kind of geneticdata. The Nuffield Council on Bioethics and theEuropean Commission’s Expert Group on genetictesting hold contrasting views [Nuffield Council,2003; European Commission, 2004a], as does theConsortium on Pharmacogenetics [Buchanan et al.,2002]. All three groups point to the relevance of theinformation content of medical data: medical data ofany kind with a high information content (e.g., resultsof HIV tests) deserve high standards of confidentialityboth in clinical research and in routine medicalpractice. However, medical data, in general, containinformation that requires high standards of confidenti-ality. Therefore, the European Commission ExpertGroup recommends that ‘‘genetic exceptionalism’’ isnot to be used as a basis for policy and specialregulation, and demands high standards of quality andconfidentiality for all medical data [European Commis-sion, 2004b]. The codification of genetic exceptionalismby law, with the intention to prohibit and prevent‘‘genetic discrimination,’’ may be counterproductive aslong as health status–related discrimination based onnon-genetic data is an accepted practice [Suter, 2001;European Commission, 2004a]. As a rule, adherents ofgenetic exceptionalism will require strict regulation inall areas of genetics and, therefore, also in theapplication of pharmacogenomics. However, thosewho dismiss the concept may also be in favor ofprotective regulatory measures, the criterion being inthis case the ‘‘richness’’ of information content.

ETHICAL ISSUES OF PHARMACOGENOMICS INDRUG DEVELOPMENT

What ethical issues are of importance to pharma-cogenomics, and, moreover, to pharmacogenomics inthe context of clinical research and drug development?A fairly comprehensive answer is given by the ethicsand policy group of the Consortium on Pharmacoge-netics, as they identify the following issues: (1)regulatory oversight, (2) confidentiality and privacy,

(3) informed consent, (4) availability of drugs, (5)access, and (6) clinicians’ changing responsibilities inthe era of pharmacogenetic medicine [Buchanan et al.,2002]. While the Group uses the term ‘‘pharmacoge-netics,’’ they address issues both in pharmacogeneticsand pharmacogenomics. These issues mainly representpoints to consider in the (future) application ofpharmacogenetics in clinical practice. With regard toregulatory oversight the Group discusses the problemregarding the approval and control of genetic tests.They conclude that, as far as the United States isconcerned, current FDA regulation offers safeguardsfor commercial tests, but not for ‘‘home brews’’ that areused on a large scale by many laboratories. However, inclinical practice the specific benefits gained bypharmacogenetic-guided drug therapy mainly rely onthe quality of the initial diagnostic genotyping proce-dure.

According to Buchanan et al. [2002], the generalbenefits of pharmacogenetics for patients and cliniciansare, for example, the improved understanding of drugresponse mechanisms, improved drug safety by usinggenotype data in post-marketing surveillance, and thepossible expediting of clinical research. However,scientific as well as social factors set limits to thedevelopment of pharmacogenetics. Among the socialfactors mentioned by the authors, in particular thefollowing may influence the development of clinicalresearch in pharmacogenomics: (1) the public attitudestowards genetic research and testing, (2) the characterof regulation and oversight, and (3) the willingness ofindustry to invest in the technologies that are needed torealize the potential of the methodology. The crucialimportance of taking public fears with regard to‘‘genetics’’ seriously is dealt with at length both by theEuropean Commission Expert Group and the NuffieldCouncil working group [Europe, 2004a; NuffieldCouncil, 2003]. Public attitudes may be influenced bya careful implementation of the requirements men-tioned above, such as protecting the individual, e.g., bysafeguarding informed consent and confidentiality, andestablishing clear and trustworthy structures forregulatory oversight. All groups emphasize the im-portance both of raising public awareness of changes inmedicine and drug prescription and of integratingpharmacogenomics in the medical curriculum. Up tonow only very few educational concepts addressinghealth professionals have been put into practice[Gurwitz et al., 2003]. The scientific factors that poselimits to a rapid development of pharmacogenomics arerelated to the widely recognized problems of the multi-gene determinants of drug response that require a‘‘polygenic and genome-wide approach’’ [Evans andRelling, 2004].

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STRATIFICATION

The ethical implications of stratification are dealtwith extensively in the report by the Nuffield Councilon Bioethics, to a lesser extent in the report by theEuropean Commission Expert Group, and in acontroversial way in the Food and Drug Adminis-tration’s Guidance on the Collection of Race andEthnicity Data in Clinical Trials [FDA, 2003]. Both thescientific and the normative problems related tovarious forms of stratification, e.g., stratification ofpatients, diseases, genotypes, markets, are very com-plex and so far more problems are being raised thansolutions can be offered.

Stratification is a relevant aspect of: (1) the drugdevelopment process, in particular of the design ofclinical trials including Phase IV post-marketingsurveillance, and (2) the outcome of drug development,as it determines the availability or the non-availabilityof drugs for individuals with particular genotypes. Theintroduction of genotype as an eligibility criterion forparticipation in clinical trials raises various kinds ofmoral concerns, as can be easily shown by applying the‘‘7 universal ethical requirements’’ suggested by Ema-nuel et al. [2000]. For example: how strong must thecase be for genotype-based inclusion, without compro-mising the second requirement of scientific validity?Obviously, only research that is methodologicallyrigorous can be deemed ethically acceptable. In thecase of genotype-based inclusion or exclusion, thismeans that scientifically sound reasons, e.g., based onadequate statistical power and sound hypothesisconcerning causation [Page et al., 2003], must be given.

The third requirement of fair subject selectionaims at the protection of individuals from vulnerableand stigmatized groups: how is genotype-selection tobe weighed against the need for protecting the interestsof these individuals? This implies the need to preventthat vulnerable populations are exposed to particularlyrisky research. Moreover, on the individual level, notmentioned by Emanuel et al. [2000]: how can the riskof harm for the individual be weighed against potentialbenefits for that individual? And, how valid mustgenotype-based exclusion be when participation in atrial is the ‘‘last resort’’ for an individual?

In Phase I clinical trials, prospective genotypingcan be used to ensure a representative initial studypopulation [Norton, 2001]. Genotyping responders andnon-responders during Phase II clinical trials andidentifying the genotypes of participants that sufferedfrom serious adverse effects could reduce the requiredcohort size of Phase III clinical trials. This could meana reduction of clinical trial costs, but might lead tostratification and even fragmentation of prospective

markets. Fragmented drug markets raise the question:how can equity and cost-effectiveness be balanced toguarantee access to orphan drugs for those who needthem? In any case, using stratification from the earliestPhase I to the post-marketing Phase IV of drugdevelopment presupposes the broad use of individualgenotyping both in the context of clinical trials andafter approval in the practice of selective drugprescription. Can consent to genotyping be a justifiablecondition for the participation in a clinical trial and,even more important, for access to novel medicines? Ifindividual genetic testing is declined either to avoid theperceived drawbacks or for economic reasons, theoption of group-based stratification must be consid-ered. In the context of pharmacogenomics, this oftenimplies a race or ethnicity-based stratification. Such anapproach, including self-reported race and/or ethnicitydesignation of trial participants, is favored by the FDAin its draft Guidance for the Collection of Race andEthnicity Data in Clinical Trials [FDA, 2003]. Theserecommendations were, however, fiercely criticizedboth on scientific and normative grounds, and Hagaand Venter [2003] argue convincingly for an individual-oriented approach instead, paying due attention toindividual genotype as well as to other relevantindividual variants [see also Burchard et al., 2003].The Nuffield Council on Bioethics too explicitly statesthat race can never be used as a proxy for a geneticprofile and as a substitute for individual genotyping[Nuffield Council, 2003].

CONCLUSIONS

Points to consider in the ethical evaluation ofpharmacogenomics in drug development and post-marketing surveillance include the established ethicalissues in clinical research and medical genetics as wellas recognized policy issues, such as regulatory over-sight, availability of and access to drugs within thecontext of the health care system, and requirements forprofessional education. The outcome of the applicationof these widely accepted considerations in the contextof pharmacogenomics-guided drug development ispartly determined by the stance taken on the statusof genetic data. Are specific standards needed, whengenetic data are concerned? An affirmative answer mayslow down the implementation of pharmacogenomicsin clinical research and may put too strict limits onindividual genotyping. Obviously, a rejection of geneticexceptionalism does not necessarily result in a laissez-faire approach; if pharmacogenomics-related genotyp-ing yields data of potentially very rich informationcontent, strict protective regulation is required. Stra-tification by using phenotype characteristics to desig-nate individuals to target populations may fail to realize

PHARMACOGENOMICS, DRUG DEVELOPMENT, AND ETHICS 115

the goal of optimal protection of research subjects andwill be ethically unacceptable in most cases.

ACKNOWLEDGMENTS

We thank David Gurwitz for useful suggestionson the manuscript and Magret Pauels for her help inpreparing the final version of the text.

REFERENCES

Anderlik MR. 2003.Commercial biobanks and genetic research. AmJ Pharmacogenomics 3:203–215.

The Belmont Report. 1979. National Commission for the Protectionof Human Subjects in Biomedical and Behavioral Research.Washington, D.C.: DHEW Publications.

Buchanan A, Califano A, Kahn J, McPherson E, Robertson J, BrodyB. 2002. Pharmacogenetics: ethical issues and policy options.Kennedy Inst Ethics J 12:1–15.

Burchard EG, Ziv E, Coyle N, Gomez SL, Tang H, Karter AJ,Mountain JL, Perez-Stable EJ, Sheppard D, Risch N. 2003. Theimportance of race and ethnic background in biomedical researchand clinical practice. N Engl J Med 348:1170–1175.

Cassell EJ. 2000. The principles of the Belmont Report revisited:how have respect for persons, beneficence, and justice beenapplied to clinical medicine? Hastings Center Rep 30:12–21.

Council of Europe. 2003. Council of Europe Working Party onHuman Genetics. Working document on the applications ofgenetics for health purposes. (CDBI-CO-GT4). http://www.coe.int/T/E/Legal_affairs/Legal_co-operation/Bioethics/Ac-tivities/Human_genetics

The Declaration of Helsinki. 1964. World Medical AssociationDeclaration of Helsinki. Edinburgh, 2000.

http://www.wma.net/ethicsunit/helsinki.htm

Emanuel EJ, Wendler D, Grady C. 2000. What makes clinicalresearch ethical? JAMA 283:2701–2711.

European Commission. 2004a. European Commission ExpertGroup. Ethical, legal and social aspects of genetic testing:research, development and clinical applications. Brussels: Eur-opean Commission.

http://europa.eu.int/comm/research/conferences/2004/genetic/re-port_en.htm

European Commission. 2004b. European Commission ExpertGroup. 25 Recommendations on the ethical, legal and socialimplications of genetic testing. Brussels: European Commission.

http://europa.eu.int/comm/research/conferences/2004/genetic/re-commendations_en.htm

Evans WE, Relling MV. 2004. Moving towards individualizedmedicine with pharmacogenomics. Nature 429:464–468.

FDA . 2003. Food and Drug Administration document: Collectionof Race and Ethnicity Data in Clinical Trials; Draft Guidance forIndustry.

http://www.fda.gov./cder/guidance/5054dft.pdf

Gurwitz D, Weizman A, Rehavi M. 2003. Education: teachingpharmacogenomics to prepare future physicians andresearchers for personalized medicine. Trends Pharmacol Sci24:122–125.

Haga SB, Venter CJ. 2003. FDA races in wrong direction. Science301:466.

Kerwin RW. 2003. A perspective on progress in pharmacogenomics.Am J Pharmacogenoms 3:371–373.

Knoppers BM. 2000. Population genetics and benefit sharing.Commun Genet 3:212–214.

Nebert DW, Jorge-Nebert L, Vesell ES. 2003. Pharmacogenomicsand individualized drug therapy: high expectations anddisappointing achievements. Am J Pharmacogenom 3:361–370.

Norton RM. 2001. Clinical pharmacogenomics: applications inpharmaceutical R&D. Drug Discov Today 6:180–185.

Nuffield Council on Bioethics. 1993. Genetic screening: ethicalissues. London.

http://www.nuffieldbioethics.org/geneticscreening/index.asp

Nuffield Council on Bioethics. 2003. Pharmacogenetics: ethicalissues. London.

http://www.nuffieldbioethics.org/pharmacogenetics/latestnews.asp

Nuremberg Code. 1949. Trials of war criminals before theNuremberg Military Tribunals under Control Council Law,1949. Washington, DC: U.S. Government Printing Office.p.181–182.

Page GP, George V, Go RC, Page PZ, Alison DB. 2003. ‘‘Are wethere yet?’’: Deciding when one has demonstrated specific geneticcausation in complex disease and quantitative traits. Am J HumGenet 73:711–719.

Screening and Counseling for Genetic Conditions. 1983. President’sCommission for the Study of Ethical Problems in Medicine andBiomedical and Behavioral Research. Washington, D.C.: U.S.Government Printing Office.

Suter SM. 2001. The allure and peril of genetics exceptionalism: dowe need special genetics legislation? Washington Univ Law Q79:669–748.

UNESCO.2003. International Declaration on Human Genetic Data.Paris: UNESCO.

http://unesdoc.unesco.org/images/0013/001342/134217e.pdf

WHO. 2003. World Health Organization. Wertz DC, Fletcher JC,Berg K, editors. Review of ethical issues in medical genetics.Geneva: WHO

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