The Consortium was created to promote abalanced and informed approach to ethical andregulatory issues in the rapidly developingfield of pharmacogenetics. The guiding ideaof the Consortium was to create a venue inwhich academic bioethicists from Law andPhilosophy with scholarly and public policyexpertise and scientists and policy experts fromthe pharmaceutical and biotechnologyindustries could work together proactively andconstructively. Too often public commissionson bioethical topics fail to utilize as well asthey might the essential expertise of the bestminds from industry, and too oftenrepresentatives from industry find themselvesin the role of reacting defensively to policyproposals that were developed largely withoutthe benefit of their input.

ABOUT THE CONSORTIUMON PHARMACOGENETICS

John A. RobertsonVinson & Elkins Chair in LawThe University of Texas Law School

Allen BuchananProfessor of Law and PhilosophyUniversity of Arizona

Elizabeth McPhersonGenetic Ehtics AdvisorGlaxoSmithKline

Baruch A. BrodyDirector, Center for EthicsBaylor College of Medicine

Jeffrey KahnDirector, Center for Bioethics andProfessor of MedicineUniversity of Minnesota

Andrea CalifanoChief Technology OfficerFirst Genetic Trust, Inc.

Ned McCulloughGovernment ProgramsIBM Corporation

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The initial proposal for forming theConsortium came from discussions between Dr.Allen Roses, Dr. Penelope Manasco, and ElizabethMcPherson, all of GlaxoSmithKline, and AllenBuchanan. GlaxoSmithKline, IBM, and FirstGenetic Trust provided financial support for theConsortium through an unrestricted grantadministered by the University of Arizona. Thethree industry sponsors of the project alsogenerously provided scientific and policy expertsto advise the core research team, which consistedof Baruch A. Brody, Director, Center for Ethics,Baylor College of Medicine; Allen Buchanan(Consortium Director), Professor of Law andPhilosophy, University of Arizona; AndreaCalifano, Chief Technology Officer, First GeneticTrust, Inc.; Jeffrey Kahn, Director, Center forBioethics and Professor of Medicine, Universityof Minnesota; Ned McCulloch, GovernmentalPrograms, IBM Corporation; ElizabethMcPherson, Genetics Ethics Advisor,GlaxoSmithKline; and John A. Robertson,University of Texas-Austin Law School. The coreresearch team convened for a total of sevenmeetings between November, 2000 and October,2001.

The Consortium completed three writtenproducts: this Report, an article entitled“Pharmacogenetics: Ethical Issues and PolicyOptions,” forthcoming in the May 2002 issue ofThe Kennedy Institute of Ethics Journal, and anarticle entitled “Pharmacogenetic Challenges forthe Health Care System,” forthcoming in the July2002 issue of Health Affairs. The three industrysponsors provided experts who supplied valuablecomments on drafts of all three written products,but the core research team exercised full controlover the content.

The development of this Report also benefitedgreatly from the generous comments of thefollowing persons on the penultimate draft: KathyHudson, Director of Policy and Public Affairs,DHHS/NIH, Washington, D.C.; Laura Beskow,Doctoral Candidate, Department of Health Policyand Administration, School of Public Health,University of North Carolina-Chapel Hill; BertSpilker, Senior Vice President of Scientific &Regulatory Affairs of the PharmaceuticalResearch and Manufacturers of America; BarthaKnoppers, Law Professor and Senior Researcherat the Centre for Public Law Research, Universityof Montreal; Susannah Baruch, Director, Legaland Public Policy of the National Partnership forWomen & Families; David Beier of the law firmof Hogan and Hartson, and former Vice Presidentof Government Affairs for Genentech; and DavidFlockhart, Medicine Department, IndianaUniversity. The Consortium endeavored to takethese comments to heart and we are convincedthat in doing so the Report was greatly improved.However, the responsibility for the content of theReport rests solely with the Consortium, andnothing contained in the Report should be seen asbeing endorsed by the reviewers.

The authors of this Report believe that theConsortium on Pharmacogenetics can provide amodel for extensive, sustained collaborativeefforts between industry and academia on a widerange of public policy issues in the pharmaceuticaland biotechnology industries. It is also our hopethat the work of the Consortium will contribute toan environment in which public policy bodiesaddressing bioethical issues will engage moreproactively with experts not only from academiabut from industry as well.

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Table of Contents I. Introduction ......................................................................................................................................................... Page 5

Definitions .............................................................................................................................................................. 5The need for—and risks of—prospective analysis ................................................................................................ 5Potential benefits of PGx........................................................................................................................................ 6

Understanding the genetic bases of drug response mechanisms ............................................................. 6More efficient, safer, and quicker drug-development, through smaller-scale clinical trials ................... 6Safer drug use ........................................................................................................................................... 6Increased drug efficacy ............................................................................................................................. 7Improved post-market surveillance of approved drugs............................................................................ 7Salvaging beneficial drugs ....................................................................................................................... 7

Risks of PGx ........................................................................................................................................................... 7Scientific and social factors that may affect the development of PGx .................................................................. 7

Scientific factors ....................................................................................................................................... 7Social factors ............................................................................................................................................ 8Incentives to develop PGx tests ............................................................................................................... 8Intellectual property .................................................................................................................................. 9

The possible expansion of the methodology beyond medicine ............................................................................. 9Clearing the way for productive ethical analysis ................................................................................................. 10

Ethics, risks, and benefits ....................................................................................................................... 10Avoiding three fallacies regarding things genetic .................................................................................. 10

II. Research ............................................................................................................................................................ Page 11The need to integrate clinical, epidemiological, and research data ..................................................................... 11

Multiple sources of information ............................................................................................................. 11The flow of information ......................................................................................................................... 11

Informed consent .................................................................................................................................................. 11The ethical basis of informed consent in research ................................................................................. 11Scope ....................................................................................................................................................... 12Content .................................................................................................................................................... 13The terminology of informed consent .................................................................................................... 13Group-based harms and the limitations of individual consent ............................................................... 13

The problem of secondary information ................................................................................................................ 15Types of secondary information ............................................................................................................. 15The speculative nature of risks associated with secondary information ................................................ 16

Reducing the risks of secondary information ...................................................................................................... 16Fire-walls versus prohibitions on uses of information ........................................................................... 16Trusted intermediary entities .................................................................................................................. 17

Disclosure of information to research subjects .................................................................................................... 17The responsibility to inform ................................................................................................................... 17The responsibilities of sponsors ............................................................................................................. 18

Alternative models for controlling the flow of information ................................................................................ 18Comparing the models ............................................................................................................................ 19Single- versus double-coding ................................................................................................................. 20

Inclusiveness and diversity ................................................................................................................................... 21The rationale for the requirement of inclusion ....................................................................................... 21Exclusion of racial or ethnic groups ....................................................................................................... 21

The availability of drugs ...................................................................................................................................... 21Orphan genotypes? ................................................................................................................................. 21PGx orphan diseases? ............................................................................................................................. 22Identifying, not creating orphan groups ................................................................................................. 22A different access problem ..................................................................................................................... 22

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III. Clinical Practice ...............................................................................................................................................Page 24The role of regulatory agencies: Oversight of the introduction of PGx into clinical medicine ........................................ 24

Accuracy and safety ............................................................................................................................................. 24Oversight and regulation ...................................................................................................................................... 25

Physician acceptance of PGx testing ................................................................................................................................. 25The key role of the physician ............................................................................................................................... 25The division of labor ............................................................................................................................................ 26

Physicians’ responsibilities regarding the use of PGx testing ........................................................................................... 26The duty to offer a PGx test ................................................................................................................................. 26Informed consent .................................................................................................................................................. 27What sort of consent? ........................................................................................................................................... 27The duty to prescribe according to PGx test results ............................................................................................ 28Off-label and against-label uses of drugs ............................................................................................................. 28

Direct marketing of and direct access to PGx tests ........................................................................................................... 29Beyond medical gate-keeping .............................................................................................................................. 29Self-administered PGx tests ................................................................................................................................. 29The need for safeguards ....................................................................................................................................... 29

Payer-acceptance and access to PGx tests and to “PGx drugs” ........................................................................................ 30Insurance coverage ............................................................................................................................................... 30Policy rationality versus individual patient rationality ........................................................................................ 30The limitations of pharmacoeconomics ............................................................................................................... 31

General Findings and Recommendations .............................................................................................................Page 32Findings and Recommendations Regarding Research ................................................................................................. 33

Regulatory oversight of research ......................................................................................................................... 33Informed consent .................................................................................................................................................. 33Privacy and Confidentiality .................................................................................................................................. 34Disclosure to subject ............................................................................................................................................ 34Controlling the flow of information: Alternative Models ................................................................................... 34Participation in research ....................................................................................................................................... 35The impact of PGx on the research agenda and the availability of drugs ........................................................... 35

Findings and Recommendations Regarding Clinical Application .....................................................................Page 35Regulatory Oversight ........................................................................................................................................... 35Physician acceptance and responsibilities ............................................................................................................ 36Direct marketing of and consumer access to PGx ............................................................................................... 37Payer Acceptance ................................................................................................................................................. 37

Endnotes ...................................................................................................................................................................Page 39

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PHARMACOGENETICS:ETHICAL AND REGULATORY ISSUES INRESEARCH AND CLINICAL PRACTICE

I. INTRODUCTION

For as long as physicians have administereddrugs, they have known that individuals canrespond differently to the same drug and surmisedthat this was at least sometimes due to in-borndifferences among individuals. But only with therecent rapid increase in scientific understandingof the human genome is it becoming possible toidentify the extent to which genetic variationsinfluence drug response. The emergence ofpharmacogenetics (PGx) heralds a new era inwhich drug therapies will be selected in the lightof differences in individuals’genotypes,enhancing drug safety and efficacy.

A. DefinitionsThe terms pharmacogenetics and

pharmacogenomics have yet to achieve a fixedstandard usage. For purposes of this report, wedefine pharmacogenetics as the study of theeffects of genetic variations in the individual ondrug response, including safety and efficacy, anddrug-drug interaction. These genetic variationsare not tissue-specific and constitute a static,global characteristic of the individual.

The second type of variation that influencesdrug response lies in the expression of genes inthe cells of particular tissues. This factor isdynamic, changing in response to endogenous andexogenous stimuli. The study of this secondsource of variations in drug response ispharmacogenomics. The major focus of thisReport is pharmacogenetics, primarily becausethis methodology employs knowledge of anindividual’s stable genotype and thereforegenerally may raise more significant ethical issuesconcerning privacy and confidentiality, includingthe implications of pharmacogenetic test resultsfor biological relatives of the person tested.

Both types of variations in individuals havebeen shown to be strongly correlated with drug

response.1 Once such correlations are established,a pharmacogenetic or pharmacogenomic test canbe devised. Such a test reveals the likelihood ofan individual’s response (regarding safety orefficacy) to a particular drug or class of drugs.

PGx research focuses either on establishingcorrelations between particular genotypes ofindividuals and responses to particular drugs (orrelated groups of drugs) or upon generalmechanisms of drug response, as these areaffected by genetic variations. As PGx advances,the latter, potentially much more efficientapproach, is likely to become dominant.

B. The need for—and risks of—prospectiveanalysis

PGx has the potential to become a large-scalemethodology with profound effects both on drugdevelopment and on clinical medicine. As with othermajor biomedical advances, PGx raises ethical,regulatory, and policy issues. This Report provides asystematic prospective analysis of these issues.

PGx research and the development of PGxtesting are taking place in an era of globalization.As we argue below, harmonization, both at thenational and international levels, is required in thedevelopment of appropriate guidelines andprotections. While there is a recognized need foroversight of genetic research and genetic testing,there has been insufficient appreciation of theparticularities of PGx. Appropriate protectionsand guidelines that take into account theparticularities of PGx should be integrated into acomprehensive framework for the development ofthis methodology that includes provisions forapproval of and reimbursement for PGx tests andof drugs for which there are PGx tests.

The Consortium believes that at the presenttime pharmacogenetics represents a rareopportunity to explore the ethical, regulatory, andpolicy issues of an important new advance inbiomedical science while it is still underdevelopment and before it has come to shape andbe shaped by existing institutions and socialpractices. This prospective analysis shouldcontinue the focus on ethical, legal and social

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implications (ELSI) that has distinguished theHuman Genome Project from its very beginning,along with other efforts such as those of theNational Institute of General Medical Sciences(NIGMS) Pharmacogenetics Research Network.2

The Consortium has taken a first step toward acomprehensive prospective analysis by focusingprimarily on PGx in the United States.

Too often, serious analysis only occurs afterthe fact, as a reaction to ethical problems that arerecognized only after a new biomedical advancehas already become so thoroughly entrenched inconcrete social practices and institutions thatefforts to solve them are futile or at leastextremely difficult. Although it would be naive tothink that all the issues raised by PGx can beforeseen in advance, now is the time to attempt toidentify the most important questions and toarticulate a range of reasonable responses. Theadvantage of prospective analysis is that it maysucceed in identifying potential problems early,when less costly and more effective responses tothem are possible.

Prospective normative analysis is not a risk-free enterprise. One danger is that some of thepotential issues may not be identifiableprospectively. Alternatively, some potentialissues that are identified may never arise. Allbiomedical advances carry risks. Although weattempt to fully identify the issues that may arisefrom PGx, nothing said in what follows should beunderstood as implying that PGx presents risksthat are disproportionate to its potential benefits.

One final limitation on prospective analysisshould be noted. Which ethical, regulatory, andpolicy issues turn out to be most significant willdepend upon the broader social context in whichPGx develops (insurance discrimination,reimbursement decisions, etc.), and this isnotoriously difficult to predict. Nevertheless, webelieve that the risks of prospective analysis areworth taking and that much is to be gained froman attempt to anticipate the most significant socialissues that PGx is likely to raise.

Before the ethical, regulatory, and policyissues can be usefully addressed, it is necessaryto articulate the potential benefits and risks ofthis new methodology, and to understand theconditions under which these potential benefitsand risks may or may not be realized.

C. Potential benefits of PGxThese fall under six main headings.(1)Understanding the genetic bases of drug

response mechanisms. Discovering linksbetween drug response phenotypes andgenotypic variations can contribute to a betterunderstanding of how genes affect drugmetabolism, transport, distribution, excretion,and absorption. For example, it has long beenknown that individuals with one or more specificmutations in the cytochrome P450 family ofenzymes tend to be poor or rapid drugmetabolizers over a wide range of drugs.3 ThisPGx information could be valuable, not only forphysicians and patients, but also for drugdevelopers. It is also information that health carepayers may find valuable for the design of morerational drug use policies.4

(2) More efficient, safer, and quicker drugdevelopment, through smaller-scale clinicaltrials. PGx testing could allow individuals whoare not likely to respond to a candidate drug orwho are likely to experience adverse reactions toit to be identified and excluded fromparticipation in phase III (or possibly phase II)clinical trials. Exclusion on the basis of genotypefrom the participant pool would have threeadvantages: (a) a reduced risk that someparticipants will suffer adverse reactions in thetrial, (b) an increased probability of success indeveloping a drug that will be approved and madeavailable, by reducing the percentage of adversereactions and low- or non-responders, and (c)savings in time and money by facilitating trialswith fewer participants.5

(3) Safer drug use. If reliable correlationsbetween specific genotypes and adverse reactionsto drugs can be identified, existing drugs can beused more safely.6 In some cases this will be a

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matter of using knowledge of genotype tochoose a different drug with a lower-risk ofadverse reactions; in other cases, genotypicinformation will indicate the need to adjust thedosage of a drug.

(4) Increased drug efficacy. PGx tests canbe used to distinguish responders from non-responders or high- from low-responders to aparticular drug or group of drugs. More effectivetreatment in a shorter time frame can then beachieved, by avoiding fruitless or less productivetreatments, by avoiding a trial and error processof modifying dosages, or by selecting alternativedrug therapies.7 8 9 10

(5) Improved post-market surveillance ofapproved drugs. Regrettably, a seriousfrequency of adverse reactions sometimes appearsafter a drug has been approved by FDA and usedfor some considerable period of time. If thegenotypes of those individuals who have adversereactions can be ascertained, it may be possible toidentify correlations between specific genotypesand the risk of adverse reaction. It may then bepossible to identify an adverse reaction problemearlier and to predict more accurately howwidespread the problem is likely to be.11

(6) Salvaging beneficial drugs. Drugs thatare highly beneficial for many individuals maynot be approved or may be withdrawn from themarket after approval because a minority of usersexperience serious adverse reactions. If a PGx testcan identify those who are likely to experienceadverse reactions, the drug could be salvaged forthe many individuals who can benefit from it,with appropriate labeling regulations.

D. Risks of PGxBearing in mind the impossibility of

definitively identifying in advance the risks ofnew biomedical advances, we neverthelessbelieve that the following are risks worthconsidering. Most of the remainder of this Reportelaborates upon these risks and possible strategiesfor addressing them. We also address thequestions as to whether these risks and strategiesfor addressing them are unique to PGx.

In the research area, risks include: use ofbiological samples and health information withoutappropriate consent; harms to families or groupsfrom stigmatizing information; inappropriatedisclosure of information from PGx tests; failureto disclose clinically relevant research results;failure to include diverse groups in research; andnarrowing of the research agenda in ways thatmay create orphan drug groups (populations forwhom it is not sufficiently profitable to developspecial drugs).

In the clinical area, risks include: introductionof PGx testing without adequate validation;suboptimal access to and use of PGx testing;testing without adequate consent; inappropriateuses of PGx testing as a result of direct marketing;discriminatory uses of PGx information by thirdparties; and secondary information conveyed byPGx results that may produce psychosocial harms.

E. Scientific and social factors that may affectthe development of PGx

The extent to which the benefits and risks ofPGx will be realized will depend on bothscientific and social factors.

Scientific factors. The range of genotypicvariability regarding drug response is perhaps thesingle most important scientific factor. Whether ornot PGx becomes a large-scale methodology thatplays a prominent role in clinical medicine willdepend upon whether there is genetic variationsufficiently associated with differences in drugresponse to make pharmacogenetic testingworthwhile, yet not so much variation that animpractically large number of PGx tests—and acorrespondingly large number of genotype-tailored drugs—would be necessary.

Two other important scientific factorsconcern the complexity and significance of PGxtests. First, in many cases, more than one geneinfluences drug response. Several genes may beneeded to produce the set of proteins that areresponsible for the drug response effect (e.g., howthe drug is distributed or absorbed) or there maybe counter-acting genes that affect drug response.

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Where several genes are involved, PGx testingmay be both more complex and less definitive asa predictor of drug response. Second, drugresponse is influenced not only by stable genotypeand gene expression, but also by a number ofother factors, including the individual’s state ofhealth (especially liver, kidney, and endocrinefunctions, and the immune system), environment(including workplace chemical exposure, food,alcohol, and tobacco intake, etc.), compliancewith drug treatment, and drug interaction.Consequently, PGx tests will not by themselvesprovide definitive guides to treatment. Complexclinical judgment will be required to determine (a)whether to administer a PGx test rather thanrelying on phenotypic tests, drug dose adjustmentbased on clinical studies or on trial and error witha particular patient, and (b) if the PGx test is used,how much weight to give its results in relation toother factors in making a therapeutic decision.

Social factors. Among the most significantsocial factors that will influence the direction,pace, and scale of PGx research and clinicalapplication are the following: (i) the willingnessof pharmaceutical and biotechnology companiesto invest in the technologies needed to developand deploy the methodology, (ii) the character ofregulation and oversight practices regarding PGxresearch and clinical use, (iii) the extent, quality,and distribution of knowledge about the potentialbenefits, costs, and risks of PGx among payers,health care administrators, providers, andconsumers, (iv) public attitudes toward geneticresearch and testing in general, including theability (or lack thereof) to distinguish betweenPGx tests and other genetic tests that may carryhigher psychosocial risks, and (v) the nature ofthe existing health care insurance and deliverysystems, and in particular the sorts ofreimbursement policies and cost-containmentstrategies that are pursued in drug use policies.

These social factors, which impact society asa whole or particular stakeholders, may interact incomplex ways. Whether pharmaceutical andbiotechnology companies will be willing to investsufficient resources in PGx research and test

development will depend in part upon theirpredictions of how likely it is that cost-consciousprivate insurers and government payers will viewPGx testing as a significant cost-saver rather than asyet another costly procedure of uncertain benefit.Insurers’ and payers’ initial resistance to adoptingPGx tests might be overcome if direct marketing oftests and the availability of information about theirpotential benefits on the internet serve to stimulatestrong consumer demand.

Public perception—or misperception—can alsoshape regulation and oversight, which may in turneither facilitate or inhibit PGx research or theintegration of PGx into clinical medicine. Negativeattitudes toward anything regarded as a genetictest, and hence as a possible source ofstigmatization or insurance or employmentdiscrimination, might prompt regulators to imposeoverly-stringent protections of confidentiality thatwill inhibit the development of this methodologyand reduce the benefits it could yield.

Incentives to develop PGx tests. In the not-too-distant future the health interests of patients maygenerally be served by PGx testing prior toprescription of a drug. However, the incentives todevelop such tests may vary across different parties.

Generally speaking, pharmaceuticalcompanies will have strong incentives to developPGx tests for safety for their own drugs, both toreduce liability and to avoid having approveddrugs taken off the market due to adversereactions. The same may not hold, however, forPGx tests for the efficacy of their own drugs.Pharmaceutical companies traditionally attempt todevelop “blockbuster” drugs that bring largerevenues annually throughout the life of thepatent. A pharmaceutical company’s financialinterest in sustaining sales of drugs may conflictwith patient, provider, insurer, and payer interestsin having PGx tests for efficacy performed ontheir drug. Some pharmaceutical companiesmight therefore be unwilling to develop—andmight even seek to prevent others fromdeveloping—PGX tests that would determine thattheir drugs are not appropriate for substantialnumbers of the individuals who are now taking

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them.12 The counter-argument is that it isdifficult to imagine a blockbuster that lackssubstantial efficacy in a significant segment of thepatient population. A drug that has marginalefficacy in a narrow segment of the patientpopulation will not bring large revenues annuallythroughout the life of the patent and hence wouldnot qualify as a blockbuster. An efficacy PGx testwould merely identify the suboptimal efficacy ofa drug earlier in the product’s life cycle.

Probably the bigger concern for apharmaceutical company with efficacy PGx is thatit may result in very narrow labeling indications.This in turn has the potential to reduce off-labeluse, which for many drugs represents a substantialcomponent of product revenue. However, apharmaceutical company might have a legitimateinterest in preventing the use of a PGx test forefficacy that it reasonably believed to beunreliable.

There may be a difference in incentives, so faras pharmaceutical companies are concerned,between established drugs and new drugs. If adrug can be initially marketed with a PGx test thatreliably predicts its safety and efficacy for asignificant population of patients, drug makersmay see this as a competitive advantage thatmakes the drug more attractive to providers andpayers. In addition, a pharmaceutical companymight see a PGx test for efficacy of one of theirdrugs in a more favorable light if it believed thatthe test would reveal that drug to be moreefficacious for a larger number of patients than acompetitor’s drug. As a broad generalization, itmay be the case that pharmaceutical companieswill have stronger incentives for using PGx in thedrug development process and for developingPGx tests for safety than for encouraging PGxtests for efficacy of their own drugs that havealready been approved and have provedsuccessful in the market.

Intellectual property. A detailedexamination of the complex and changinglandscape of intellectual property is not within thepurview of this Report. However, it is worthpointing out that there are two ways in which

intellectual property rights can affect thedevelopment of PGx. First, the possibility ofobtaining intellectual property rights and thefinancial rewards that flow from them canmotivate the development of PGx tests and thesearch for genetic markers that can be used inthem. Without an appropriate regime ofintellectual property rights, individuals andorganizations will be reluctant to incur the risksand costs of discovery and development becausewhatever they create or discover can simply beused by others, without financial benefit to them.Second, intellectual property rights can in somecases pose an impediment to development of atechnology. In the case of PGx the worry is that ifa number of different entities hold patents on thevarious genetic markers and other inputs neededfor PGx tests, then the costs of getting licenses forthe use of these components, and hence the costsof the tests themselves, will be prohibitive. This isthe concern about “patent bottlenecks.”13

F. The possible expansion of the methodologybeyond medicine

The basic methodology of PGx is not confinedto the discovery of correlations between medicaldrugs and the body’s responses to them. Anysubstance which when ingested affects the body,including not only workplace or environmentalchemicals, but also vitamin supplements, various“botanicals,” foods, and even biological warfareagents, may differ in its effects depending uponvariations in genotype. Given the size of themarket for special diet foods, botanicals, andvitamin supplements, it would not be surprising iftests are eventually marketed that purport to helpan individual determine which combination ofsupplements and diet, and even which regimensof exercise, are optimal for his or her health.

The methodology is also applicable todetermining the influence of genotype onresponses to alcohol and tobacco or to illicit drugssuch as cocaine. Researchers have recentlyreported success in developing an immunizationagainst certain addictive substances.14 In thefuture tests might be used to determine whichindividuals are genetically predisposed to

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addiction, in order to identify those who couldmost benefit from immunization.

What begins as a biomedical advance may,under the influence of demand stimulated byvigorous marketing, come to have quite differentapplications, some of which raise their owndistinctive ethical and regulatory issues. Whilenoting that it may be naive to assume that PGxwill remain a medical methodology largely withinthe control of medical professionals, this Reportwill address primarily the medical applications.

G. Clearing the way for productive ethicalanalysis

Ethics, risks, and benefits. For society theobjective is to realize the great potential benefitsof PGx to the fullest extent possible, consistentwith adherence to sound ethical principles. Butadherence to ethical principles is not costless. Itcan entail not only financial costs, but the forgoingof important benefits as well. For example, respectfor the dignity of the individual requires informedconsent for participation in research, yet having toobtain informed consent may make it moredifficult for researchers to pursue the morallyworthy goal of curing disease. So in determininghow robust the requirement of informed consentshould be—how much information about whatmagnitudes of risk, etc., must be disclosed—it isimportant to keep in mind the costs in terms offoregone potential benefits.

Similarly, sound ethical principles requireprotections against breaches of confidentialityconcerning access to stored biological samplesused in PGx and other research. However,requiring the most extensive protections possible,including permanent anonymizing of samples,would not only cripple the research endeavor, butalso preclude participants from being notifiedabout research findings from which they couldgreatly benefit.

In other words, efforts to maximizeprotections of confidentiality, like other efforts toreduce risks to zero, are virtually alwaysinappropriate because they sacrifice otherimportant values. The goal is not the reduction of

all risks to zero, not only because this is generallyimpossible, but because even to attempt to do sowould deprive us all of benefits we have moralreasons for seeking.

Unless the potential benefits are adequatelyappreciated, it is impossible to evaluate accuratelythe various options for reducing risks. Yet toooften ethical analyses of biomedical technologiesor methodologies (e.g., xenotransplantation) lookonly to risks and then propose policies to reducerisk, but fail to take seriously the ethical costs oftheir risk-reduction proposals. To avoid this alltoo common error, we have prefaced ourconsideration of the risks that may be associatedwith PGx with a discussion of the methodology’spotential benefits. What is needed is a sensitivebalancing of risks and benefits, not an exclusiveattention to either.

Avoiding three fallacies regarding thingsgenetic. In addition to the incorrect assumptionthat risk-reduction is ethically costless, there areseveral other misapprehensions that may result inconstraints that would unnecessarily limit thebenefits pharmacogenetics could deliver. Theseinclude (1) genetic exceptionalism, theassumption that all things genetic involveespecially serious or unique ethical risk andtherefore require novel ethical principles and/orspecial regulatory responses, (2) geneticdeterminism, the assumption that genes areautonomous, self-sufficient causes, whichoverlooks the importance of environment broadlyunderstood and consequently over-estimates therisks posed by information about genes, and(3) genetic overgeneralization, the failure toappreciate the heterogeneity of “genetic tests” andtheir results, so far as psychosocial risk isconcerned (for example, lumping together testsfor fatal single gene dominant disorders such asHuntington’s chorea with tests for drugefficacy).15 16 17 18 19

Genetic exceptionalism appears to bewidespread. Consider, for example, the fact thatlegislation is being adopted in many states toprohibit “genetic discrimination” by insurers,while at the same time little is said about the fact

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that insurance companies in some marketsroutinely refuse coverage or charge higherpremiums for those deemed to be at higher-riskdue to non-genetic factors beyond their control.

Genetic determinist thinking fuels geneticexceptionalism by portraying genes as all-powerful—as fate—but it can also lead tounrealistic expectations about the fruits of geneticscience, including PGx. Genetic deterministthinking may result in a PGx test being regarded asdefinitive, rather than as probabilistic informationto be balanced against other factors. And thisexaggeration of the significance of a PGx test mayin turn encourage an over-estimation of thepsychosocial risks associated with testing.

Finally, it may be misleading to apply therather uninformative term ‘genetic test’ to themany different types of DNA tests withoutexplaining their differences, since doing so mayencourage one to make assumptions aboutpsychosocial risk that apply to some tests but notothers. For example, a test for the “Alzheimer’ssusceptibility gene” (APOE4) may carry a muchhigher-risk of stigma, discrimination, andpsychological distress, than one for the mutationsassociated with hereditary hemochromatosis (acondition that can be effectively treated) or a PGxtest to determine whether one is likely to be alow-responder to one particular drug amongseveral that can be used to treat one’s condition.

II. RESEARCH

A. The need to integrate clinical,epidemiological, and research data20

Multiple sources of information. Researchto determine the influence of variations ingenotype on drug response requires not only thecollection, storage, and analysis of DNA samples,but also the ability to integrate this geneticinformation with information from theindividual’s medical record on a wide range offactors from general health status to currentmedications, other interventions, family history,and behavioral and environmental factors. Todetermine the extent and nature of genetic

variations, in order to ascertain which variationsaffect drug response, many studies will be neededwith proper sampling techniques to ensure theinclusion of the full range of genetic variation.

The flow of information. One of the mostimportant ethical challenges of PGx research is todevise structures and procedures that facilitateand at the same time properly control the flow ofinformation. The researcher needs access to DNAsamples and medical records, as well asepidemiological studies of genetic variationsacross large populations. The individual whoparticipates in PGx research has a legitimateinterest in having access to information that isbeneficial to him, but at the same time needsassurance that confidentiality and privacy will bemaintained. Thus it is necessary to consider boththe flow of information to the researcher and tothe research subject. These issues are not uniqueto PGx research, but the potential scale of theflow of information makes them particularlysalient.

B. Informed consentBefore information can begin to flow to the

researcher, the individuals to be included in thestudy must give informed consent. As in allhuman subjects research, informed consent isrequired for the collection of DNA samples forPGx research.21 22

The ethical basis of informed consent inresearch. Seeking informed consent showsrespect for the dignity of the individual, but it alsoprovides a protection against exploitation of thesubject under conditions in which the interests ofthe researcher and that of the subject may be inconflict. In the clinical context the presumption isthat the physician is a fiduciary whose primarycommitment is to the patient’s well-being. In theresearch context this presumption does not hold,and the researcher may have academic and/orcommercial interests that can conflict with what isin the best interest of the subject.23 For thisreason, as we shall see, the requirement ofinformed consent is both clearer and moredemanding in PGx research than in the clinicalapplication of the methodology. The same respect

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for individual dignity and well-being also requiresthe participant’s consent to the researcher’s accessto medical records.

The ethical issues of informed consent in PGxresearch can be analyzed under four headings: (1)the scope of informed consent, (2) the content ofinformed consent, (3) the proper terminology forthe informed consent process, and (4) whether theinformed consent process involves only theindividual research subject or also a group orcommunity of which the individual is a member.

Scope. The scope of consent includes both theperiod of time during which the researcher is to beallowed to store and have access to biologicalsamples and other information and the uses towhich the samples and information may be put,either by the current researcher or otherresearchers. At one extreme, the subject mightgive a blanket, time-unlimited consent for the useof his DNA sample and/or medical records forany research project the researcher or any otherresearcher chooses. At the other extreme, thesubject might give a very narrowly focusedconsent only for the use of the DNA sample andcertain specified information from the medicalrecord, only for a limited period of time, withrestricted genotyping, and only for this researcher.

Between these extremes there are manyvariations on the scope of consent. For example, asubject might consent to access to his DNAsample and all medical records for a specifiedresearch protocol studying response to a particularcancer drug and only for other, currentlyunspecified protocols for research of the sametype, to allow participation in future research onother cancer drugs. This consent might or mightnot include a stipulation that after a period of timethe DNA sample is to be destroyed or“permanently anonymized,” that is madeunlinkable to the subject by anyone.

Informed consent of relatively broad scopehas two apparent advantages. First it providesvaluable flexibility in an area where knowledgeand research capability is changing rapidly and insometimes unanticipated ways. This flexibility

can avoid substantial losses of research subjects,as well as intrusions into the subject’s life entailedby “re-consenting.” Moreover, during drugdevelopment, significant attrition of subjects, lossof time and additional cost could put an entirestudy on hold or even cause it to be terminated.Second, allowing the subject to give broad-scopeconsent might also be seen as more respectful ofindividual autonomy, whereas restricting his rightto grant access to the information by reducing thescope of consent might be viewed as paternalistic.

The disadvantage of such broad-scopedconsent is that it may not achieve the chiefpurposes of the requirement of informed consent.In addition to showing respect for the dignity ofthe individual, the requirement of informedconsent to research places the individual in aposition to understand and weigh the moresignificant costs and benefits of participation, onthe assumption that he is generally the best judgeof what is in his interest. But it is difficult to seehow one could in any meaningful fashion weighthe costs and benefits of participation in a whollyunspecified, indefinitely large range of possiblefuture uses of one’s DNA and medical records. Itis therefore implausible to argue that respect forthe individual’s autonomy requires the option ofconsent of extremely broad scope. It is notpaternalism to refrain from facilitating extremelyuninformed choices.

Nor is the other extreme regarding the scopeof consent an attractive option. Requiring specificconsent for every distinct protocol would becontrary to the interest not only of society at largein medical progress but also to the interest of theindividual research subject as well.

A reasonable policy is to secure a degree offlexibility by allowing the subject to consent to arange of related studies over time, at least if thereis a provision for specific consent to studies thatmay be especially problematic.24 For example, asubject might give blanket consent to use of hissample for any cancer drug studies conducted bythe investigator of the cancer drug study in whichhe is presently enrolled, but require specialconsent to any use of his DNA for other purposes

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in general or, say, for studies involving sensitiveissues. For instance, a subject might reasonablywish to be offered the opportunity for specialconsent to a protocol using his DNA for a studyof the relationship between race and susceptibilityto certain mental illness or to violent behavior orpoor impulse-control.

Content. The content of informed consent forPGx research should include at least fiveelements.25 (1) The risks and benefits ofparticipation must be impartially and accuratelyexplained in terms that are accessible to theindividual. Risks here include the possibility ofdeleterious effects of breaches of confidentialityregarding sensitive information and the minimalrisks of the various techniques for collectingbiological samples.26 (2) The individual should beinformed of the provisions for safe-guarding theconfidentiality of the sample and medical records(who will have access, for what purposes, whatcoding or anonymizing provisions will beemployed, if the sample or other information willbe destroyed after what period of time, and who isultimately responsible for preservingconfidentiality and privacy).27 (3) The sponsor ofthe research should be disclosed, as well as thepossibility that the sample and/or products of thestudy will be used for commercial purposes andwill generate revenue.28 (4) The informed consentprocess should include a discussion of thepossibility that information that is reliable andpotentially beneficial to the individual subjectwill be discovered in the course of the study.That discussion should make clear who isresponsible for this determination and whatstandards they will use, and who is responsiblefor disclosing such information to the subject andhow it will be provided. The subject should beable to opt to have such information provided,with suitable provisions for protecting theconfidentiality of other subjects whereappropriate. (5) The individual should beinformed of his right to withdraw from the studyat any time without penalty and withoutcompromising his access to medical careprovided independently of the study.29

The terminology of informed consent. The

need to avoid genetic exceptionalism raises aquestion about the precise terminology by whichthe nature of the research is to be described in theinformed consent process. In particular, is itnecessary for the informed consent process toemploy the vague but perhaps emotionally-charged term “genetic test” in the case of researchdesigned to discover links between genotype (orgene expression) and drug response, or toascertain the sensitivity, reliability, and specificityof an experimental PGx (or pharmacogenomic)test?

Collection and use of DNA samples should ofcourse be described as such in the informedconsent process. However, given the greatheterogeneity of “genetic tests” and the quitedifferent psychosocial implications of tests forsingle gene disorders or susceptibility to disease,on the one hand, and tests for likely responses todrugs, on the other, it may be unnecessary and insome instances even misleading to require that theindividual be informed that “genetic tests” will beperformed on his DNA sample. Instead, a moreaccurate statement would be that DNA extractedfrom the sample will be used to study therelationship between genetic variations amongindividuals and how they respond to drugs.

The fundamental issue here is what areasonable person would want to know in order toevaluate the risks and benefits of participation inresearch. An accurate description of the use towhich the sample will be put (namely, an attemptto correlate genetic variation and drug response)seems more apt than the vague label “genetictest,” especially since, due to the pervasiveness ofgenetic determinism and genetic exceptionalism,the latter might encourage the individual to over-estimate risks.30

Group-based harms and the limitations ofindividual consent. There is a growingrecognition that in some cases genetic informationmay contribute to “group-based harms.”31 Theseare harms that individuals suffer as a result ofbeing perceived to be members of ethnic or racialgroups (or other groups ranging from families tolarger groups such as “the disabled.”) For

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example, if PGx research were to reveal thatAfrican-Americans, Azkenazi Jews or certainNative American groups have a lower responserate to certain treatments, this might result instigmatization or discrimination to which allmembers of the group would be vulnerable. It hasbeen argued, therefore, that because geneticresearch on some member of a group may haveharmful effects on all or many members of thegroup, the informed consent process should not beexclusively individualistic, but rather shouldinclude some input and/or oversight from thegroup or its putative representatives.32

The first point to note is that presented in thisway, the case for group participation in theinformed consent process for PGx testing appearsto be an instance of genetic exceptionalism. Manytypes of research, including nongenetic and evennonmedical research have the potential for group-based harms. For example, studies that purport toshow that a particular racial or ethnic group incurshigher medical costs have the potential toreinforce negative stereotypes and to perpetuatepatterns of discrimination.

The most extreme form of the view that thepotential for group-based harms requires adeparture from the traditional individualisticparadigm of informed consent would confer aright on the group or its putative representativesto veto an individual member’s consent toparticipation in research.33 This view seemsunacceptable, because it wholly subordinatesindividual autonomy to group preference.

A less extreme and more plausible responseto the problem of group-based harms would be toallow group or community consultation at theearliest stages of enrolling individuals in cases inwhich there is a significant risk of group-basedharms—in particular where there is evidence thata group is at risk for negative stereotyping ordiscrimination. The intuitively plausible idea hereis that consultation would allow concerns aboutgroup-based harms to be voiced and properlyaddressed in the research design, including plansfor disseminating the results of the study.34

The notion of group consultation isproblematic, however. Two difficulties inparticular are worth noting. First, there is the issueof authentic representation.35 Conferring with allmembers of the group will generally beimpossible or at least impractical. But it may notbe clear who, if anyone, may serve as an authenticrepresentative of the group’s interests. Thisproblem is especially obvious in the case ofgroups (such as Azkenazi Jews) that are notpolitically organized and hence do not haveofficial representatives authorized to makeimportant decisions on behalf of the group. Buteven in cases in which certain individuals are dulyauthorized to speak for the group, questionsremain about whether they do in fact represent theinterests of all their constituents and about whichtypes of issues they are authorized to makedefinitive pronouncements. For example, triballeaders may have the authority to make a widerange of decisions, but it does not follow that theyhave the authority to prohibit members of theirtribes from participating in genetic research.

The second difficulty with the idea of group orcommunity consultation is that under certaincircumstances, mobilizing the group or itsputative representatives for consultation mayresult in the individual being subjected to unduepressure or even duress, thereby undercutting hisright to make an autonomous choice to participatein research. In some circumstances, groupconsultation would amount to a de facto groupveto over individuals’ decisions.

In spite of these difficulties, groupconsultation may achieve two worthy goals.36

First it can show respect for members of the groupand concern for their well-being, by allowing theissue of group-based harms to be addressed bythose who might suffer them. This may beespecially salutary in the case of groups, such asAfrican Americans, who have been subject todiscrimination or exploitation in the past,sometimes at the hands of medical researchers.37

Second, group consultation may encourage thecooperation of group members in the research.

To summarize: it is one thing to say that

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both researchers and individuals deciding whetherto participate in PGx research ought to take therisk of group-based harm into account and thatconsultation with other members of the groupmay facilitate this. It is quite another to assert thatthe potential for group-based harm—which maybe highly speculative—trumps the individual’sright to participate in research that he believeswill be valuable to himself or to others, includingmembers of the group; moreover, additionalresearch is needed concerning whether group-based harms are likely to occur. From thestandpoint of public policy and regulation, itwould be inappropriate to mandate groupconsultation, much less group consent, as ageneral requirement for genetic research,including PGx research. However, in particularcircumstances, for especially sensitive researchwith historically vulnerable groups, responsibleresearchers will seek to incorporate group inputinto the research design and informed consentprocess.

C. The problem of secondary informationIn some cases PGx test results, whether in the

research or clinical context, might convey any ofseveral types of secondary information that might,under certain circumstances, represent a risk ofpsychosocial harm, either to the person tested orto relatives. These risks must be discussed in theinformed consent process.

Types of secondary information. (1) A PGxtest result might be linkable to genetic disease or,more likely, to a genetic predisposition to disease,either because the genotype that influences drugresponse also plays a role in the disease process orbecause it is correlated with one that does.Whether such an eventuality poses a significantrisk will depend upon several factors, including:how probable it is that the individual will get thedisease, how serious the disease is, whether it istreatable, and whether the knowledge that aperson has the disease is stigmatizing.

It is also important to emphasize that theperception that an individual has a geneticsusceptibility to a disease is only potentially a

source of insurance or employment discriminationin a society in which insurers and employers areallowed to take genetic risk into account. Thetrend in the U.S. is to prohibit such genetic risk-rating by insurers, as well as geneticdiscrimination in employment.38

(2) Under certain conditions the informationthat an individual is likely to be a non-responderor an unsafe-responder to a particular drug orclass of drugs might itself have adverse insuranceand/or employment implications. For example, ifan individual has a genotype which indicates thatthe only effective drug (or group of drugs) for hisserious condition will not be efficacious for him,or cannot safely be taken by him, he might beclassified by insurers or employers as having anuntreatable serious illness. This risk would onlyarise in cases in which (a) there is no alternativeeffective treatment for the condition in question,or the alternative treatment is much moreexpensive, or (b) the condition is serious enoughto be of concern to insurers or employers, andinsurers and/or employers are able to take this sortof information into account in making decisions.

(3) Studies indicate that some individuals mayhave genotypes that confer susceptibility toaddiction to certain substances. If that genotype islinked to a marker that is associated with aparticular drug response, then a test for the latterwould indicate susceptibility to addiction.Information that an individual is susceptible toaddiction may pose a risk of stigma anddiscrimination, depending upon socialcircumstances, including the effectiveness andavailability of drug abuse treatments and theability of insurers and employers to act on theinformation that an individual has a predispositionto addiction.

(4) Information about genetic factors in drugresponse, like all genetic information, can haveimplications for relatives, not just for theindividual tested, for example, that they have ahigher than average risk of adverse reaction to aparticular drug or have a susceptibility to diseasethat is linked to the marker detected in the PGxtest. In some cases, PGx test results, in the context

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of other information, might convey informationregarding nonpaternity. For instance, if a PGx testreveals that the child is a “slow-acetylator” but itis also known that the presumed father does notcarry either of the alleles (gene-variations)responsible for this recessive trait, this couldindicate nonpaternity.

(5) If a particular drug is only prescribed forindividuals who have a particular genotype, thensimply knowing that the individual takes that drugcan convey the information that he has thatgenotype. Whether or not the latter knowledgewould carry any risk of psychosocial harm woulddepend upon whether the genotype in question isassociated with a susceptibility to disease or withsome other negatively valued characteristic,whether physical or behavioral.

The speculative nature of risks associatedwith secondary information. It should beemphasized that these concerns about secondaryinformation are rather speculative and arise onlyunder certain highly specific circumstances thatmay not occur with much frequency. Moreover,none of them is peculiar to PGx. Secondaryinformation that may pose a risk of psychosocialharm is revealed by other, more established formsof research and other medical tests. For example,tests for blood type have the potential to conveyinformation about genetic risk and aboutnonpaternity. Yet for these there is often noinformed consent or at least none that addressesthe risks associated with secondary information.Similarly, home pregnancy tests and HIV tests(both of which are self-administered, withoutbenefit of counseling or medical supervision)have the potential for psychosocial harm to theindividual tested as well as implications for otherpersons.

There is another important qualificationconcerning potential problems of secondaryinformation in drug response testing that seems tohave gone unnoticed in the literature to date. Thepotential for sensitive secondary informationabout others than the person tested may be limitedfor the most part to PGx tests, that is, DNA assaysthat correlate drug response with stable genotype,

not pharmacogenomic tests, which correlate drugresponse and gene expression. For as was noted inthe Introduction, information about geneexpression less frequently has implicationsregarding the genetic risks of relatives ornonpaternity.

Finally, how much secondary information isconveyed by a PGx test result will partially be afunction of the technology employed. Inparticular, some genetic markers correlated withdrug response may be relatively “clean,” carryinglittle or no secondary information about geneticpredisposition to disease, disease progression, etc.If it turns out that more than one marker can bereliably correlated with drug response, it may bepossible to select a “clean” one for use in a PGxtest.

D. Reducing the risks of secondary informationFire-walls versus prohibitions on uses of

information. Policy designed to reduce the risk ofpsychosocial harms from secondary informationshould distinguish between (1) the role of “fire-walls”39 —barriers to the dissemination ofsensitive information—and (2) the role ofregulation to prevent certain damaging uses ofinformation the dissemination of which may beimpossible or too costly to prevent. Codingtechnologies that create a barrier between medicalor research information and the identity of theindividual patient or subject are one instance ofthe fire-wall approach. Laws prohibiting “geneticdiscrimination” by employers and insurers areattempts to prevent certain uses of geneticinformation.

Another example of a fire-wall strategy is apolicy of including only the medicine responseresult in a laboratory report of PGx test results,but no secondary information—includinginformation about the genotypic features that areresponsible for the drug response result. However,as noted above, in some cases the drug responseresult itself, apart from any information about itsgenetic basis, may have damaging implications.For example, where there is no other effectivetreatment for a serious disease, a test indicating

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that the individual is a non-responder for a drugfor a serious condition would imply that he has anuntreatable serious condition and will thereforerepresent high costs.

A fire-wall strategy cannot completely protectthe individual against discrimination based on anunfavorable PGx test result. First, insurers andsometimes employers have access to medicalrecords, and these sometimes contain researchresults, especially when the researchers are theclinicians caring for the individual. Second, rigidfire-wall strategies may not allow for neededbreaches of security mechanisms for patient carepurposes. To reduce the risk of discrimination onthe basis of information that cannot be containedby fire-walls, regulations prohibiting insurers (andemployers) from using such information to thedetriment of the individual may be an importantingredient in a sound public policy.

How such legislation should be crafted is acomplex question.40 Among the issues to beconsidered are (1) whether and if so whatlimitations on liability for prohibited uses ofinformation are appropriate and (2) whetheremployment and insurance (or health versus lifeinsurance) should be covered by separatelegislation. Here again, PGx raises no new issues,but the eventual scale of the PGx researchenterprise may make old issues more acute.

Trusted intermediary entities. A differentapproach to reducing the risk of breaches ofconfidentiality, and one that is designed to allowfor recurring access to biological samples andother relevant data, is the use of “trustedintermediaries.”41 Such private or public entitieswould serve as secure repositories for biologicalsamples and information about the individualsfrom whom the samples are taken. Those seekingaccess to samples or information for clinical orresearch uses could only obtain it from theintermediary, on terms that are agreed to by theindividual and which are designed to protectprivacy and confidentiality.

At present there are several privateintermediary entities operating in the U.S. and in

some other countries large-scale publicrepositories for DNA samples already exist.42

Because this strategy concentrates a very largeamount of potentially sensitive information in thehands of the intermediary, any breach ofconfidentiality that occurs might be quite serious.Regulation specifying standards forconfidentiality and privacy and perhapsclarification of standards for liability in the caseof breaches may be needed to reduce this risk.

Most states provide some degree of legalprotection against unauthorized disclosure ofmedical information.43 These protections wouldalmost certainly apply to PGx test resultscontained in medical records in hospitals orphysicians’ offices. However, the scope of legalprotection varies widely across jurisdictions andmany holders of medical information may not bedirectly subject to legal restrictions. Recentlyissued federal privacy regulations under theHealth Insurance Protection and Portability Act(HIPAA) of 1996 would greatly extend protectionagainst unauthorized uses of medical and PGxinformation, although further measures may berequired.44

E. Disclosure of information to researchsubjects

So far we have considered the flow ofinformation from the subject to the researcher.But the flow of information may also go in theopposite direction. Although not likely to becommon at the early stages of PGx research, theremay be cases in which information of potentialbenefit to a research subject emerges during thecourse of a study. Such potentially valuableinformation might be either the object of the studyor adventitious.

The responsibility to inform. Researchershave an ethical obligation to provide subjects withthe option of having this potentially beneficialinformation disclosed to them. However, thisobligation carries an important qualification:information should not be disclosed unless itsreliability has been established.45

As noted above in our discussion of the

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content of informed consent, the possibility thatinformation of benefit to the subject may bediscovered in the course of the study ought to bebroached in the informed consent process, and atthat time the individual should be given the optionof disclosure of reliable information that ispotentially beneficial. In addition, the informedconsent process should explain who has theresponsibility for determining reliability and whatstandards will be used in its determination, andwho has the responsibility for disclosure if theindividual opts for it.

Generally speaking this will be the researcher,because it is with the researcher that the subjecthas the most contact and who is responsible forthe informed consent process. The alternative ofmaking the subject’s physician responsible for thedisclosure of potentially beneficial informationhas at least two serious drawbacks. First, somesubjects may not have a regular physician.Second, if the researcher communicates theinformation to the physician, there is the risk thatit will be incorporated into the medical record andthat a breach of confidentiality will occur. Ifinstead the researcher discloses the informationdirectly to the subject, the latter then can decidewhether or under what conditions to convey theinformation to his physician if he has one, or toseek medical care in the light of the information ifhe does not. This conclusion, that the researcherhas the primary responsibility for disclosure, mustbe qualified in those cases in which the researcherlacks the relevant clinical expertise or knowledgeof the individual subject.

The responsibilities of sponsors. Althoughthe researcher has the primary responsibility fordisclosure, sponsors of research, whether public orprivate, have a responsibility for oversight of theresearch they fund. This responsibility extends totaking reasonable steps to require that a properdisclosure policy is followed by the researcher.

The obligation of the researcher to disclosepotentially beneficial information to subjects whoopt for disclosure extends only to reliableinformation. The information must be sufficientlyaccurate that, given its potential benefit, a

reasonable individual would want to have it. Whatcounts as sufficient accuracy will varycontextually; sound judgment will be required todetermine how accurate the information must bebefore the researcher is obligated to disclose it tothe subject. If, for example, an experimental PGxtest indicates that the subject cannot safely take adrug that is likely to be prescribed for hiscondition, and the test is judged to be sufficientlyreliable, then this information should be disclosedto the subject if he has opted for disclosure in theinformed consent process.

How the information is disclosed also matters.In some cases the subject should be informed ofthe availability of counseling, and in all cases theinformation should be conveyed in a sensitivemanner and in terms the subject can understand.

F. Alternative models for controlling the flow ofinformation

After informed consent for PGx research isobtained, protection of the confidentiality ofinformation going to the researcher is necessary.Three distinct models for controlling the flow ofinformation to the researcher and for setting theconditions under which he may use theinformation can be distinguished for geneticresearch in general and PGx research inparticular: identified, coded, and permanentlyanonymized information. This way ofconceptualizing the alternatives draws upon and isconsistent with the terminology used by thePharmacogenetics Working Group(representatives of 13 pharmaceutical companies)and the European Agency for the Evaluation ofMedicinal Products Evaluation of Medicine forHuman Use (EMEA) Committee for ProprietaryMedicinal Products (CPMP).46 47

All three models, if properly employed,presuppose that informed consent has beenobtained to start the flow of information to theresearcher, but propose different ways ofproviding additional protection to the subject. Thesecond and third models, which rely on codingtechnologies, either to permanently anonymizesamples or to de-link samples from subjects by

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coding, provide fire-walls against breaches ofconfidentiality that lessen the burden of protectionto be borne by the consent requirement itself.

In the first model, the flow of informationbegins with an identifiable DNA sample, one thatthe researcher knows comes from a particularsubject, and the sample remains identifiablethroughout the process of investigation. Theadvantage of this model is that it allows theresearcher to know the identity of the source ofthe sample and therefore to be able to go back tothe subject’s medical record at any time duringthe research process. This enables the researcherto take advantage of new opportunities forgathering data the relevance of which might nothave been apparent at the beginning of the study.Another advantage of the first model is that theresearcher’s ability to link the DNA sample to thesubject and to his medical record may facilitatediscoveries that will benefit the clinicalmanagement of the subject’s condition.

The disadvantage of the first model is thatpotentially harmful secondary information, if itexists, will be linkable to the subject’s fullmedical record, which may contain someinformation that the subject would not want theresearcher to know and which may not even be ofany significance for the research in which thesubject has agreed to participate. The first modelplaces the full responsibility—and possible legalliability—on the researcher for ensuring thatsensitive information about the subject is notconveyed to other parties. (It will be impossible,however, for the researcher to prevent those whocontrol the subject’s medical record fromknowing that he is involved in a research project,because they will be authorized to release thisinformation to the researcher).

The second, or coding model, has twovariants. In a single-coding system the researcherholds the key that links the subject’s sample anddata with an identifying number. The researcherassigns an identifying number to the sampletaken, which is then used throughout the researchprocess. Therefore, the researcher does not haveready access to the identity of the subject from

whom a sample is taken. Although the subject’sidentity could be learned by breaking the code,this approach provides a fire-wall betweenpotentially sensitive information and parties otherthan the researcher.

In the second variant of the second model,double-coding, a second code or link is used andmaintained in a secure database affording anadditional level of protection. The researcher doesnot have access to the code that supplies the linkbetween the sample and identity of the subjectfrom whom it is taken. The researcher knows thesample and the research data only as “no. xxx,”and someone else holds a “key” linking thedesignation “no. xxx” to a subject’s identificationnumber, which in turn can be linked to thesubject’s medical records by those who hold therecords. Double-coding provides a fire-wallbetween the researcher as well as others, andpotentially sensitive information about the subjectof research. Generally speaking, double-codingentails more costs than single-coding.

In the third model the sample is permanentlyanonymized: the key linking the first and/orsecond codes between the sample, data and theparticular subject who is its source arepermanently severed, so that no one candetermine whose sample it is. In other words thesample and data do not carry any personalidentifiers. Once the key has been deleted thesubject’s research results can never be linked.

Comparing the models. The advantage ofthe permanent anonymization model is that itvirtually eliminates the possibility of breaches ofconfidentiality and hence of harms associatedwith secondary information. In addition, undercurrent U.S. regulations for the protection ofhuman subjects, existing biological samples thatare permanently anonymized may be used forresearch that meets IRB approval withoutinformed consent.48 (In many cases, adequateinformed consent was not given for the collectionof existing samples).

Several policy bodies, including the NationalBioethics Advisory Committee, have

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recommended that for any new samples collected,informed consent is required, even if the sample isto be permanently anonymized.49 50 51 Therationale for this stringent requirement is thatrespect for the individual’s dignity, quite apartfrom the protection against more tangible harmsthat informed consent is designed to provide inother research contexts, mandates that DNAsamples must not be collected without consent.

It is not so clear, however, that informedconsent for all new uses of permanentlyanonymized samples is in fact ethically requiredstrictly speaking. Much will depend upon howreliable the process of anonymization is and uponwhat other protections for confidentiality are inplace should a sample remain linkable to a subjectdue to an error. However, so long as the consentprocess is not unnecessarily elaborate, therequirement does not seem to be undulyburdensome.

The permanent anonymization model has fourdisadvantages. First, the researcher cannot linkthe sample to the subject’s medical record onceanonymization has occurred, and this greatlyreduces the value of the medical record in PGxresearch. The difficulty is that subsequent toanonymization it is not possible to collectadditional information from the medical record,and therefore not possible to determine whetherdrug responses observed in the course of theresearch are the result of genetic variations orinstead are due to other factors. Second, ifresearch conducted with the sample uncovers anyinformation from which the subject would benefit,it will not be possible to convey it to him or hisphysician. Third, if the subject withdraws fromthe study, it will not be possible to destroy thesample and information acquired about thesubject. Fourth, the audit trail needed forregulatory approval will be broken if the sampleand information are permanently anonymized.

The coding model, in both its single- anddouble-coding variants, reduces the risk ofbreaches of confidentiality to which identifiedsamples are vulnerable while at the same timeavoiding the disadvantages of permanent

anonymization. Though it may not be ethicallyrequired for all cases of PGx research, double-coding in particular has certain advantages. Witha double-coded sample, the researcher can requestthe “key-holder” to provide information from themedical record as need for this arises, withoutever having access to the medical record, andhence to the identity of the subject from whom thesample was taken. In addition, the third-party key-holder need not know the name of the samplesource: all he needs to have in order to meet theresearcher’s request for medical records is apatient identification number, supplied by thephysician’s office or hospital where the subject’smedical records are stored.

Finally, the use of double-coding alleviatessome of the burden placed on the informedconsent process in two ways. First, the use of thisparticular fire-wall protection lowers the risk ofbreaches of confidentiality concerning secondaryinformation, so that the subject’s weighing ofcosts and benefits in deciding whether toparticipate is simplified. Second, because theinformed consent process is not bearing the wholeweight of protecting the subject, there is less needfor an extremely detailed and rigorous informedconsent process, other things being equal.

Single- versus double-coding. Generally, acoding approach (in either of its variants) issuperior to both the identified information modeland permanent anonymization model. Usingeither the identified information model or thepermanent anonymization model for controllingthe flow of information to the researcher isproblematic and would require specialjustification. The choice between double-codingand single-coding is perhaps somewhat less clear-cut. From the standpoint of maximizing protectionof confidentiality, double-coding is superior.However, double-coding entails added expenseand time. Whether these costs are worth bearingwill depend upon an accurate assessment of therisks of a given research study.

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G. Inclusiveness and diversityAs noted in the Introduction to this Report,

one of the potential benefits of PGx is that it mayexpedite and reduce the costs of drug trials byenabling the researcher to exclude from thesubject pool those who are likely to be poor-responders or to experience adverse reactions dueto their specific genotypes. It might be objected,however, that such exclusion is inequitable, sincePGx information is only probabilistic, and somemembers of the genotypic subgroup that areexcluded might in fact benefit from the research.(A related, though distinct issue that we take up inpart II is the possibility that exclusion of certaingenotypic groups from drug research may resultin the unavailability of drugs for those groups).

The rationale for the requirement ofinclusion. The issue of inclusion has receivedattention prior to the emergence of PGx. CurrentNIH regulations concerning grants for medicaland other research encourage inclusion of groupsthat have traditionally been underrepresented inresearch: women, minorities, and children.52

However, the rationale for this inclusionrequirement does not apply to genotypic sub-groups that might be excluded on PGx groundsfrom drug research.

The rationale for inclusion of women,minorities, and children is that these groups haveoften been excluded from research from whichthere is every reason to believe they would havebenefited. But in the case of PGx exclusion, this isnot the case. Indeed in some cases it would likelyresult in harm.

Exclusion of racial or ethnic groups. Amore subtle form of the objection to exclusion onPGx grounds would arise if a researcher excludedcertain racial or ethnic groups, rather than groupsdirectly identified by genotype, from participationin a drug trial on the grounds that members of thegroup are known to not respond to the drug inquestion or to have adverse reactions to it. Theproblem is that race and ethnicity are at best verycrude, approximate markers for distinctgenotypes. (There may be more genetic variationwithin such groups than between them). Given

that this is so, there is something very troublingabout a researcher treating race or ethnicity as if itwere a scientific classification and therebyimplicitly endorsing a mistake that has played amajor role in discriminatory attitudes andpractices in the past.53

Because race and ethnicity are only crudemarkers for genotypic subgroups, a drug researchprotocol that excludes members of such a groupon the grounds that they are likely to be poor-responders may certainly exclude someindividuals who would have been good-responders and therefore deprive them of thebenefits of participation. Given the historicalabuses of racial and ethnic categories and thedangers of misconstruing them as scientificclassifications, it can be argued, then, that equityin access to research participation requiresresearchers to enroll subjects on the basis ofgenotype without considering racial or ethnicbackground.

For example, suppose, as now appears to bethe case, that African Americans as a group tendto be poor-responders to a particular medicationm, for congestive heart failure.54 Equity wouldseem to require that researchers not simplyexclude African Americans from clinical trials fora drug that is similar to m on the grounds that theyare poor-responders. Instead, it appears that theresearcher should attempt to get beyond race as acrude (and historically abused) marker and simplyenroll subjects based upon their likely response.If a serious adverse reaction was associated with aparticular race or ethnic group, exclusion of allmembers of the group would clearly be lessproblematic.

H. The availability of drugsOrphan genotypes? Several commentators

on PGx have noted that the integration of PGxinto the drug development process may result in“orphan genotypes.”55 The concern is that PGxmay reveal that an investigational drug is notlikely to be safe and effective for a particulargenotypic subgroup of the general population orthe population of those with a particular disease

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and that if this group is small enoughpharmaceutical companies may not find itworthwhile to try to develop an alternative drugfor it. For such groups, safe and effective drugswill be unavailable, not because they lackinsurance coverage for them, but because thedrugs have not been developed.52

PGx orphan diseases? A related concernmight be called the PGx orphan disease problem.The worry is that if it turns out that there is greatgenetically-based variation in drug responseamong those who have a particular disease, thenthe pharmaceutical industry might not find itfinancially worthwhile to try to develop drugs forthis disease. In other words, PGx research mightreveal that what had been thought to be a largemarket for a drug for all who have a particulardisease is in effect a collection of very smallmarkets composed of genotypic subgroups ofthose with the disease. If this occurs,pharmaceutical companies might decide to directtheir research toward treatments for other diseaseswhere drugs with larger markets are likely.

It is important not to over-estimate theprobability of the orphan genotype or PGx orphandisease scenarios occurring. For either scenario toeventuate and to be of serious ethical concern, thefollowing conditions would have to be satisfied.(1) There must be no alternative safe and effectivedrug or other treatment available for the disease.(2) The groups that are identified by PGx must beso small that even over the duration of thestandard drug patent period there will not besufficient market demand to make it worthwhileto produce the drug. (3) In the case of “orphangenotypes” the drug that is safe and effective forthe larger group of those having the disease mustprovide a substantial benefit for a seriouscondition.

Although large pharmaceutical companiesmight not find it worthwhile to try to develop adrug for a PGx-identified genotypic subgroup,smaller companies, including newerbiotechnology enterprises, might identify thegroup as a desirable market niche. What isfinancially attractive may vary with the scale of

the enterprise.

Identifying, not creating orphan groups.Furthermore, it is misleading to speak of PGx (orpharmaceutical companies) “creating” new orphangroups. PGx research merely identifies individualswho are not likely to respond to a drug or are likelyto suffer an adverse reaction, and this providesmedically useful information about them.

Finally, the PGx orphan disease scenario maynot in fact be coherent. If, as the scenarioassumes, there is so much genetically-basedvariation in drug response among those who havethe disease, then presumably any particular drugintended for all those with the disease would beruled out in Phase II trials anyway, because itwould not demonstrate sufficient efficacy tojustify a Phase III trial. But if this is the case,then a drug would not have been successfullydeveloped even in the absence of PGxinformation.

A different access problem. If, despite theabove considerations, the integration of PGx intothe drug development process should turn out toresult in “orphan genotypes” or “PGx orphandiseases,” the problem is best conceived as one ofaccess to medical care. This particular accessproblem deserves further attention.

The more familiar and discussed accessproblem occurs when some individuals are unableto secure medical services that are available andfrom which they would benefit, because they haveno health care insurance. The second accessproblem occurs when medical services fromwhich some individuals could benefit are simplynot available at all. This would be the case withorphan genotypes or PGx orphan diseases.Because there is insufficient market demand tomake it economically viable for thepharmaceutical industry to develop a special drugfor a small genotypic group or because there is somuch genetically-based drug response variationamong those who have a certain disease, themarket does not produce a treatment to meetimportant health care needs.

This is not a new problem, nor one that is

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peculiar to PGx. It has been widely discussed inthe context of the unavailability of treatments forcertain diseases that are common in the poorercountries but not in the richer ones. For example,even though a very large number of individuals inthe poorer countries suffer from certain parasiticdiseases, they may not represent sufficient marketdemand (in terms of ability to pay) to make itworthwhile for pharmaceutical companies to tryto develop drugs to treat these diseases.56

Access to health care in the first sensedistinguished above is a matter of social justice inthe most literal sense: there is a societalobligation to ensure that all have equitable accessto available health care services.57 The samebasic moral considerations that ground thissocietal obligation to ensure equitable access forall also speak in favor of an obligation to producethe drugs and other treatments required formeeting important health care needs. But thisobligation, like the obligation to ensure that allhave equitable access to the health care servicesthat are available, falls first and foremost onsociety as a whole, not upon particular privateentities such as pharmaceutical companies.

It is true that to ensure that these societalobligations are met, a social division of labor maybe needed—some way of authoritativelyassigning specific duties to identifiable andaccountable entities within society, with theoverall result that all have equitable access tohealth care benefits that meet the more importanthealth care needs of all. But in our society atpresent, there has been no assignment of dutiesthat includes a clear mandate for pharmaceuticalcompanies or other private entities to subordinatetheir legitimate business concerns to solving theaccess problem.58 Similarly, it may be the casethat everyone has a moral right to decent shelter,but from this it does not follow that home-builders are in default of an obligation if decenthomes are not available to some people.

It might be argued that pharmaceuticalcompanies benefit from massive publicinvestment in medical research and that thisbenefit grounds an obligation on their part to

ensure that safe and effective drugs are availableto meet everyone’s health care needs. There aretwo difficulties with this view. First, it can beargued that it is the public who is the primarybeneficiary of public subsidization of medicalresearch (as the public justifications for NIHbudgets, etc. explicitly state). Second, even if itwere true that public subsidies for medicalresearch somehow create an obligation on the partof pharmaceutical companies to produce publicbenefits, it would not follow that this requires anyparticular pharmaceutical company to incur thecosts of developing a particular drug for aparticular genotypic or disease group. Not only isthe requirement of producing public benefits toovague to entail any such specific duty, butpharmaceutical companies can argue that they arealready producing important benefits.

This is not to say, of course, thatpharmaceutical companies are immune to moralcriticism if they choose to develop only drugs thatare maximally profitable or choose not to offerdiscounted prices for urgently needed drugs forpersons in poor countries. A higher moral standardthan simply that of not violating anyone’s rights isoften appropriate for corporations, as it is forindividuals. The point, rather, is that it is dubioussimply to assume that if some people cannot affordneeded drugs or some drugs that would bebeneficial for some persons are not developed, thenpharmaceutical companies have violatedsomeone’s rights or failed to fulfill a duty thatsociety has assigned to them.

The existing orphan drug law59 and itsrationale are consonant with this analysis. Thatlaw does not assign a duty to pharmaceuticalcompanies to develop drugs that otherwise wouldnot be developed due to lack of market demand;nor does it assert or assume that every group has aright to whatever medications it needs. Rather, theAct creates market incentives for pharmaceuticalcompanies to develop drugs by granting a sevenyear period of market exclusivity, tax credits, andin some cases funds for orphan drug research andclinical trials.60 This approach makes sense on theassumption that the obligation to ensure the

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availability of care that meets all importantmedical needs is a societal obligation, not aspecific obligation of pharmaceutical companies.

If the integration of PGx into the drugdevelopment process should result in orphangenotypes or orphan diseases, there are two mainpolicy options which might be employed singly orin combination. The first is to rely on the existingOrphan Drug Act, with modifications as needed.The second is to rely more heavily on directpublic subsidies by reshaping NIH and otherprivate and public grant priorities to encouragethe development of drugs for smaller markets.For either strategy to work, there must besufficient rates of reimbursement for thesetreatments as they become available.

It would be inadvisable to pursue either optionat this time. It is simply too early to tell whetherthese problems will occur or be of sufficientmagnitude to justify the costs of such policies.Nevertheless, in anticipation of the need for suchpolicy initiatives, appropriate groups withmembership drawn from relevant public agenciesand private sector actors should be formed toexamine and address the grounds and extent ofthe societal obligation to develop new forms oftherapies for groups whose health care needswould not otherwise be met. Plainly the issue ofunmet health care needs extends far beyond PGx.

There is, of course, already public discussionof priorities for research, but too often it takes theform of a tug-of-war over resources by variousinterest groups, rather than a systematic inquiryinto the underlying principles of distributivejustice. There is much to be said for the idea thatsociety has an obligation to provide equitableaccess to at least some “adequate level” or“decent minimum” of health care for all.61 Butthis is not equivalent to the assertion thateveryone is entitled to whatever resources arerequired to assure him of a life free of disease oreven of normal functioning, regardless of cost. Soin considering policy options to deal with“orphan” problems that might become salient asPGx becomes an important factor in the drugdevelopment process, it should not be assumed

that the societal obligation to meet health careneeds is unlimited, that is, there is an obligation tosupply whatever resources are necessary toprovide cures for diseases that afflict very smallgroups. Whether or not the development of PGxhighlights the problem of “orphan groups,” theproblem of how to ensure that the researchenterprise results in products that address thehealth care needs of all is worthy of more explicitand systematic examination.

III. CLINICAL PRACTICE

Even the most scientifically valid andethically sound research does not translateautomatically into improved medical practice. AsPGx research advances, regulatory agencies willhave to decide whether and under what conditionsPGx tests and drugs for which there are PGx testsare to be approved for clinical use, physicians andpharmacists will have to learn the proper role ofPGx in the choice of therapies, private insurersand government payers will have to decidewhether and if so under what circumstances toreimburse for PGx tests and their interpretation,and health care administrators will have todetermine how existing structures, formularies,and procedures can be adapted to therequirements of this new methodology.

A. The role of regulatory agencies: Oversight ofthe introduction of PGx into clinical medicine

Accuracy and safety. The first step in theprocess of integrating any test into clinicalpractice is to ensure that the test is safe, accurate,and used appropriately. Safety of the test itself isnot an issue for PGx tests, since PGx tests arenoninvasive, requiring only a small blood sampleor a cheek swab to collect cells. So the firstethical issue is whether current oversightmechanisms are sufficient to assure the accuracyand appropriate use of PGx tests. (This Reportlimits its evaluation of the adequacy of oversightto the United States; an assessment of the manydifferent oversight regimes found in variouscountries would require a lengthy report in itself).

PGx tests will fall within FDA’s regulatory

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jurisdiction, on two distinct grounds. First, in theform of test kits, PGx tests are “diagnostics” thatmust have FDA approval before being sold ininterstate commerce.62 Makers of PGx test kitswill have to submit to FDA evidence of the test’sanalytical validity, clinical validity, and clinicalutility, so that users will be assured that they areeffective for the intended purpose. (A PGx test’sanalytic validity is how well it measures thepresence of a genetic marker correlated with drugresponse. A PGx test’s clinical validity is theaccuracy of the prediction of a drug response,given the presence of the genetic marker. Theclinical utility of a PGx test is expected healthbenefit that can be achieved by knowing apositive or negative test result).

Currently, FDA only applies these criteria totest kits, not to “home brews,” that is to testswhose ingredients are assembled by the userrather than purchased in kit form. There is nogood reason, however, to exclude home brewsfrom oversight. Accordingly, the Secretary’sAdvisory Committee on Genetic Testing (DHHS)and FDA are currently formulatingrecommendations for a process and criteria forreviewing genetic tests, whether in the form oftest kits or home brews, including PGx tests.

Second, PGx tests may also fall within theFDA’s jurisdiction when they are an integral partof a New Drug Application (NDA). As notedabove, a pharmaceutical company may investigatethe use of a drug to counter a disease process in apharmacogenetically-defined subgroup of thepopulation with that disease. In applying for FDAapproval of the drug, the company would have tosupport with appropriate data its claim that thedrug is sufficiently safe and effective for thegenotypic group in question. This raises the issueof what will count as sufficient safety andefficacy, a matter to be determined by the FDA.The FDA might then approve the drug, but onlyfor those having that genotype, thus in effectrequiring those who administer the drug to seethat the appropriate PGx test is performed beforedoing so. The conditional nature of this approvalwould be reflected in the labeling of the drug.

FDA labeling of drugs has utilized variouscategories, such as indications, contraindications,precautions, and warnings. How the conditionalnature of approval of new drugs with supportingPGx tests should be incorporated into labeling isan important regulatory issue requiring furtherattention.

Oversight and regulation. Although FDAregulation may be necessary to foster appropriateuse of PGx tests, it is not sufficient. The categoryof oversight is broader than regulation. To ensurethat PGx tests are employed appropriately as gate-keepers to access to drugs, physicians will have toknow when to perform the tests, pharmacists willneed to know which drugs should only be used inconjunction with PGx tests, and laboratories willhave to provide test results to physicians in anaccurate but “user-friendly” form. These broaderissues are taken up later in this Report.

Finally, all laboratories performing PGx testsshould meet CLIA (Clinical LaboratoryImprovement Act) standards. Whether CLIAstandards would require certain modificationswhen applied to PGx or other genetic tests is animportant question that is beyond the scope of thisReport, but which requires the immediateattention of policy makers.63 The system forregulation must allow parallel approval of a drugand a PGx test for safety or efficacy. Because thedrug and the associated test are intended to beused together, and therefore must be available atthe same time, the two sectors must function in acoordinated, timely fashion.

B. Physician acceptance of PGx testingThe key role of the physician. Perhaps the

greatest single factor affecting the penetration ofPGx into clinical practice and the pace at which itwill occur will be the knowledge and acceptanceof physicians. Studies indicate that manyphysicians lack basic knowledge of genetics andalso frequently fail to take into account availableinformation about drugs.64 65 It is therefore nowcommonplace to call for improved physicianeducation in genetics, and this, no doubt, isessential.

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The division of labor. However, it wouldclearly be impractical to require all physicians, oreven all primary care physicians or internists, tohave extensive knowledge of genetics generallyor of PGx in particular. Instead, a division of laborwill be necessary, taking advantage of the fact thatin order to be able to administer and properlyinterpret a PGx test a physician need not havemastered the full range of knowledge utilized inthe test. The extent and depth of knowledge thephysician needs will depend both upon the toolsavailable to him, including computer entrydiagnostic and prescription technologies, and hisaccess to the expertise of others, includingpharmacists and laboratory personnel.

For example, eventually physicians will beable to send a blood sample to a laboratory thatwill test the DNA for dozens, perhaps eventuallyhundreds of markers, including SNPs (singlenucleotide polymorphisms) that are known to becorrelated with drug response. One option wouldbe to require that laboratories meet high standardsfor accurate testing and interpretation of results,so that the information the laboratory sends backto the physician can generally simply statewhether a particular drug is likely to be safe andefficacious for the patient, without including aspecification of the complex genetic factors thatwent into this determination. Such an arrangementwould require a high level of expertise in arelatively small number of persons working intesting laboratories but would not requireextensive PGx knowledge on the part of tens ofthousands of physicians or pharmacists. Limitingthe genetic information sent back to the physician,as we suggested earlier, would also make sense asa fire-wall protection, because doing so wouldomit some information that is irrelevant to thetherapeutic decision but which might in somecases carry the potential for psychosocial harm.

Such an arrangement is only one hypotheticalillustration of how a carefully-crafted division oflabor might cope with the problem of physicians’lack of knowledge of PGx. Any such division oflabor would include an important role forpharmacists in providing an independent check onphysicians’ drug choices, assuming they have

access to relevant PGx information.

The extent to which PGx will be integratedinto clinical practice will depend in part, then,upon how user-friendly the technologies foremploying this methodology are from thestandpoint of physicians. And, of course, PGxtests that have high predictive value will be moreattractive to physicians, other things being equal,because they will reasonably be viewed as havingmore impact on decisions concerning the choiceof medications.

Most important, the individual physician willcome to rely on PGx tests if and when he becomesconvinced that the standard of practice demandsit. It is therefore necessary to explore the basisand scope of the physician’s duties regarding PGxtesting. When is the physician obligated to offer aPGx test and when, if ever, may he prescribe adrug for which there has been an unfavorable PGxtest?

C. Physicians’ responsibilities regarding the useof PGX testing

The duty to offer a PGx test. Other thingsequal, the higher the predictive value of a PGxtest, the more serious the risk of adverse reactionsto the drug in question, and the greater thepotential harm that would result from delay ineffective management due to time lost taking anineffective drug, the clearer the physician’s dutyto offer the test. If, in addition, the test hasreceived FDA approval, and especially if the testis mandatory according to the drug label, the casefor asserting that the physician has a duty to offerit is all the stronger.

This is not to say, however, that the duty islimited to FDA approved tests. If there is sound,peer-reviewed, published scientific evidence thatthe test has high reliability and that knowing theresult would be of significant benefit to thepatient, the physician may be obligated to offer iteven if it does not yet have FDA approval. If thetest has high predictive value and significantbenefit to the patient, but the patient’s healthinsurance does not cover it, the physician still hasan obligation to inform the patient that the test is

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indicated and that it can be provided at thepatient’s expense.

Informed consent. It might be tempting toassume that the conclusions derived aboveregarding informed consent in the researchcontext apply without modification to the clinicalvenue. If informed consent is mandatory in PGxresearch, should it not be required as well whenPGx tests are offered in clinical practice?

Some would argue that informed consent isnot required in the clinical setting, citing the factthat many diagnostic tests, including some genetictests such as screens for Down syndrome andneural tube defect conducted on blood samplesfrom pregnant women, are routinely administeredwithout anything approaching informed consent,without mention of the fact that a DNA assay isbeing undertaken, and indeed in many caseswithout any informed consent at all. Some mayalso argue that informed consent is not required inthose cases in which the payer for the caremandates the testing before the care can beprovided. Yet the lack of informed consent inthese cases could just as well be regarded as adeficiency. So the question remains: is informedconsent necessary for all PGx tests in the clinicalcontext?

Here it is important to note that the researchand clinical contexts are relevantly different. Acentral element of the case for informed consentin research, as we observed earlier in this Report,is that the researcher’s interests as a researchermay conflict with those of the subject. In contrast,the assumption in the clinical context is that thephysician’s role is to do what is in the patient’sbest interest. Accordingly, one should not assumethat if informed consent is required for PGxresearch then it is also necessary in the clinicalsetting.

Nevertheless, two facts lend support to theconclusion that informed consent is required inclinical practice as well. First, PGx tests, asalready noted, can carry sensitive secondaryinformation. Second, the public’s concern aboutgenetic privacy is well-documented and this in

itself provides a reason for treating PGx testsdifferently in research and clinical practice, thanother tests for which informed consent is routinelyomitted.

On the other side of the ledger, it might beprotested that many PGx tests will not carrysensitive secondary information, especially iftechnologies relying chiefly on “clean” markersare developed, and that there is much to be saidfor avoiding both genetic exceptionalism and theunfortunate tendency to lump all “genetic tests”together.

In addition, how strong the case for informedconsent in the clinical context is will depend uponwhat other mechanisms are in place to reduce therisk of damage from secondary information. If,for example, as a result of new regulations underHIPPA, medical records in general become moresecure, and if PGx tests results are reported insuch a way as to eliminate or reduce sources ofsecondary information that are unnecessary forconveying the drug response finding, then perhapsinformed consent will not be necessary.Moreover, there is the danger that a blanketrequirement of informed consent for all PGx tests,as for many other routine diagnostics, e.g., testingfor hypertension or hypercholesterolemia, willdegenerate into a meaningless ritual.

Until better protections for confidentiality ofmedical records are in place—and until the publicbecomes more accustomed to the medical uses ofgenetic information—the most reasonable courseis for physicians to adopt a general policy ofgaining informed consent before theadministration of a PGx test. Nevertheless,depending upon how the infrastructure forprotecting medical privacy evolves in the futureand depending also upon whether the currentpatchwork of laws prohibiting geneticdiscrimination becomes more comprehensive,requiring informed consent for all PGx tests inclinical practice may eventually becomeunnecessary.

What sort of consent? Assuming that for thepresent informed consent for PGx testing in

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clinical practice is the most reasonable policy allthings considered, the real question is howextensive the information conveyed to the patientmust be and how the risks and benefits should bepresented. Here our earlier discussion of consentin the research context is relevant. In general it isprobably better for the physician to tell the patientthat he would like to examine a sample of thepatient’s DNA to see what the likely response to adrug will be rather than to inform the patient thata “genetic test” is recommended.

Beyond this, how robust and rigorous theinformed consent process should be will dependprimarily upon an estimate of whether the testresult will carry secondary information that willeither be distressing to the patient or potentiallydamaging to him if others obtain it. If in mostcases PGx tests do not carry potentially damagingsecondary information, only a rather minimalinformed consent process will be necessary.

Our earlier warning about the error of over-generalizing from the most risky genetic tests isas pertinent in the clinical as in the researchcontext. It would be a mistake to require aninformed consent process for PGx tests modeledon what is appropriate for genetic testing forserious, untreatable genetic disorders such asHuntington’s disease, for susceptibility to seriousdiseases such as breast cancer or colon cancer,prenatal testing for Down syndrome or neuraltube defect, or carrier-status testing for cysticfibrosis or Tay-Sachs. It is difficult to imaginecircumstances in which anything approaching theextensive pre- and post-test counseling that isgenerally appropriate for such tests would beneeded for most PGx tests.66

The duty to prescribe according to PGx testresults. Once the PGx test is administered andthe results are obtained, how ought the physicianto take the results into account in treating thepatient? If the test has high predictive value, thenin general the result will strongly indicate whichclinical decision is appropriate. If instead the testresult has low predictive value, for example,indicating a 25% adverse effect rate withconsiderable variation in the severity of the

adverse effects, then the decision will be morecomplex and the physician’s duty less clear. Solong as the decision the physician makes fallswithin the range of acceptable decisions includedin the standard of practice, and the patient hasbeen duly informed of the risks and benefits andconsented to the treatment the physicianrecommends, the physician will not havebreached a duty to the patient.

Off-label and against-label uses of drugs.An off-label use is the use of a drug for a purposeother than that for which the drug was approvedby FDA. Physicians are allowed to use drugs forpurposes other than those for which they wereapproved, if the benefits to the patient canreasonably be expected to exceed the risks.Against-label use is the administration of a drugin circumstances that are inconsistent withlabeling of the drug.

In the context of PGx, an against-label usecould be the administration of a drug to anindividual after a reliable PGx test mentioned inthe labeling yielded the result that the patient isnot a good candidate for the drug. A second senseof “against-label” may also be distinguished: thedrug’s labeling includes the instruction that it isnot to be administered unless there has been afavorable PGx test, but the physician administersthe drug without doing the test. Is against-labeluse of drugs (in either the first or the secondsense) ever permissible? And if so, are there anycircumstances in which the patient would have theright to an against-label use of a drug?

There appears to be only one circumstance inwhich it would be permissible for a physician toadminister a drug after an unfavorable PGx testfor response to that drug: there is no alternativesafe and effective drug for the patient’s condition,the condition, if not treated, is a serious one, andthe patient is willing in spite of the PGx testresults to undergo the treatment in the hope ofrealizing net therapeutic benefit. Even under theseconditions, the patient would not have the rightthat the physician administer the drug, since hecannot have a right to an action the physician hasno duty to perform and the physician cannot have

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a duty to prescribe a drug for which a reliable testindicates a significant risk with regard to safety orefficacy.

Consider next the case in which a PGx test isavailable for the drug but the patient refuses totake it out of fear of a breach of his “geneticprivacy” or for some other reason. As we havealready argued, for the physician to fail to offerthe test, at least if it has high predictive value andis of significant benefit to the patient, would be aviolation of his duty to the patient. If the patientrefuses to take the test under these circumstances,he would not have a right to have the drugadministered without the test, because he cannothave a right to an action that the physician is notobligated to perform and the physician is notobligated to offer the drug without havingperformed the test.

One situation in which it could be argued thatthe physician may administer the drug eventhough the patient refuses to take the test wouldbe where the drug is covered by the patient’sinsurance but the test is not, the patient cannotafford to pay for the test out of pocket, and thedrug is the patient’s only prospect of ameliorationof a serious condition. But even in these specialcircumstances, the most that can be said is that itis permissible for the physician to prescribe thedrug without the test (after explaining that the testis recommended for this drug), not that he has anobligation to do so or that the patient has a rightthat he do so.

D. Direct marketing of and direct access to PGxtests

Beyond medical gate-keeping. Thediscussion thus far has proceeded on theassumption that the physician will be the gate-keeper of access to PGx tests. This may notalways be the case. PGx tests, as well as tests forseveral genetic diseases or genetic susceptibilitiesto diseases are already not only being directlymarketed to consumers but in some cases areprovided through self-administered test kits bywhich the individual collects a DNA sample bycheek swab and mails it to a laboratory.67

Individuals may utilize such kits either becausetheir insurance does not cover the test, becausethey have concerns about having a record of agenetic test in their medical record, or for otherpersonal reasons.

Current self-administered PGx tests use oneDNA sample to test likely response to a numberof drugs, including some nonprescription drugs.68

In the latter case, it would be implausible to holdthat an individual who can purchase a drugwithout medical supervision ought not to beallowed to take a test to determine whether thedrug is safe and effective for him without medicalsupervision, at least so long as the test meetsappropriate standards of analytic and clinicalvalidity, and the test results are conveyed in anaccurate and understandable manner. If theindividual has access through insurance to aprescription drug but not to a PGx test for it, thereis also a strong case for allowing him to utilize aself-administered test, again assuming that the testis reliable and the significance of the results isadequately explained.

Self-administered PGx tests. A governmentsponsored report on ethical and regulatory issuesin genetic testing produced by a prestigiousinterdisciplinary committee simply states that self-administered genetic tests are “to bediscouraged.”69 Not only is this rather peremptorydismissal of the topic naive in its apparentunderestimation of the power of the market forcesbehind such tests, but it also wrongly suggests thatindividuals have no legitimate interest in havingaccess to genetic tests without reliance on amedical gate-keeper. A case can be made,however, for the presumption that competentadults have the right to information about theirgenotype, if the information is accurate and itssignificance is conveyed to them in an appropriatemanner. For those who lack insurance coverage forthe test in question or for those who are concernedabout the risk of genetic discrimination orstigmatization posed by having a genetic test resultin their regular medical record, a self-administeredtest may be reasonable.

The need for safeguards. However, if direct

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marketing of and direct access to PGx testscontinue to expand, the ethics and regulation ofthis approach will require careful scrutiny. ThisReport does not attempt an extended discussion ofthese issues, but instead will only highlight threeareas of concern. First, regulation or some otherform of oversight may be needed to ensure thattests are marketed to consumers in an appropriateway. There is the danger that inappropriatemarketing will exploit common misperceptionsabout genetics, including genetic deterministthinking. Second, although concern aboutconfidentiality of the medical record is almostcertainly one reason why individuals use self-administered tests, at present there is no assurancethat the laboratories to which the sample is sentwill preserve confidentiality. Third, there isevidence that for some tests, parents aresubmitting DNA samples of their minorchildren.70 This raises complex questions aboutthe scope and limits of parents’ fiduciary dutiesand rights regarding the medical care of theirchildren. In addition, there is a more generalconcern: that current self-administered testtechniques may allow one person to collect DNAfrom another and submit it for testing without hispermission. Although through-the-mail tests forserious genetic diseases or for geneticsusceptibility to serious disease may be moretroubling than through-the-mail tests for drugresponse, in either case, the lack of medicalsupervision is worrisome in part because of theabsence of regulation.

As observed in the Introduction of this Report,the basic methodology employed in PGx testingfor response to medical drugs has much widerapplication and raises the possibility of anexpansion beyond the medical realm to testing forresponse to dietary regimens, vitaminsupplements, etc. If, as seems likely, insurers willbe unwilling to pay for such nonmedical PGxtests, then the same consumer demand that fuelsthe market for these nonmedical chemical agentsmay also produce a correspondingly broad marketfor self-administered tests. If this occurs, then theassumption of most who have commented onPGx—that it will remain exclusively within the

province of medical gate-keeping—will be utterlyundermined. Absent medical supervision, adifferent regulatory approach will almost certainlybe needed.

E. Payer-acceptance and access to PGx testsand to “PGx drugs”

Insurance coverage. Even if an extensivebattery of PGx tests comes to be included in mosthealth care insurance plans, over 40 millionAmericans may lack access to them simplybecause they have no health insurance. However,it is at present unclear to what extent these testswill be covered by private insurance or bygovernment programs such as Medicare andMedicaid, and if they are covered, whether drugsfor which PGx tests exist will be covered only iftheir use is preceded by PGx testing. WhetherPGx becomes an important element of clinicalpractice will depend upon whether it isreimbursed.

In the current climate of cost-consciousness,one of the most important factors determiningreimbursement decisions regarding PGx tests willbe whether private insurers and governmentpayers believe that PGx testing is cost-effective.Whether a favorable cost-effectiveness estimate ismade will depend upon whether PGx testing isseen simply as an additional cost for a particularprocedure viewed in isolation, or is understood tobe one important component of a larger strategyof evidence-based, integrated health care whosebenefits will accrue over a longer time frame andwill be great enough to justify significant start-upcosts. Chief among these benefits are a reductionof adverse drug reactions and of the costs oftreatment and the risk of liability associated withthem, and a reduction of the costs associated withinefficacious treatment.

Policy rationality versus individual patientrationality. Individual patients should in generalview the integration of PGx into clinical practiceas progress, since it is likely to reduce theirchance of adverse drug reactions and ineffectivedrug therapies. However, there are circumstancesin which a rational—and ethically justifiable—

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drug use policy utilizing PGx may result in anindividual not receiving a drug from which hewould benefit.

Suppose that a managed care organization, orMedicare, or for that matter a national healthsystem, adopts a rational drug use policy thatincludes the rule that a very expensive cancer drugwill only be covered for those who are classified as“high-responders” according to a reliable PGx test.The justification for this rule is that given the highcost of the drug and the severity of the side-effects,and given a limited budget from which care formany individuals must be provided, responsiblestewardship of resources requires providing thisdrug only to those who are most likely to benefitsignificantly from it. If this rule were notfollowed—if coverage was provided for “low-responders” as well as “high-responders”—thenthe dollars spent in providing the drug to “low-responders” would not be available for other usesthat would bring greater benefits to moreindividuals. It is not the case that “low-responders”will receive no benefit from the drug; it is their bestprospect for ameliorating their condition, but thebenefits they receive will not be as great as thosefor “high-responders.” To take a dramatic case:administration of the drug to “high-responders”produces 5-year survival rate of 90% while its usewith “low-responders” achieves a 2-year survivalrate of 30%.

Even for the most rational, morally-defensiblepolicy, there sometimes will be a divergencebetween what is best from the standpoint of awhole population and what is best for a particularindividual. In the case at hand, you may be a“low-responder” to the drug in question, but ifthat drug is your only prospect for surviving youmay be willing to take it anyway. If the nature ofthe test has been adequately explained to you, youwill understand not only that “low-responders”will receive some benefit from the drug, but alsothat the test’s predictive value is not 100%, so thatthere is a chance that you will have a higherresponse than predicted. In these circumstances itmay be rational for you to want the drug despiteyour unfavorable PGx test result; but it also may

be justifiable for the private insurer or governmentprogram to have a policy that denies it to you.

PGx tests can only reveal probabilities ofadverse reactions or probabilities of higher orlower efficacy. Deciding how low the probabilityof adverse reaction must be or how high thedegree of efficacy must be for the drug to be usedor to be reimbursable requires more than scientificknowledge; it requires ethical judgment, becausewhere the threshold is set will reflect a particularbalancing of individual versus group interest.

This discrepancy between individualrationality and rational policy is not in any waypeculiar to PGx, and in fact has nothing to do withthe methodology itself. It can arise in any numberof contexts in the practice of medicine, wherevera policy rules out providing each patient in everyinstance all the services that are of any expectedbenefit to that individual regardless of cost.

The use of PGx tests to identify “low-responders” is clearly an improvement over adrug policy that denies everyone coverage for thedrug under conditions in which the poor resultsfor “low-responders” are aggregated with thegood results for “high-responders,” resulting in anoverall response rate that is deemed too low tojustify costs. Nevertheless, the conflict of interestbetween the individual and the group is real, andincreasing efforts to implement rational drug usepolicies, stimulated in part by advances in PGx,may make this sort of conflict more salient andmore frequent. The difficulty is not with PGx, butwith the incompleteness of the tools of analysisfor rational drug use.

The limitations of pharmacoeconomics.Standard pharmacoeconomic analysis recognizesthree main types of values to be realized in arational drug use and/or reimbursement policy:economic (efficient use of dollars), clinical(maximal health outcomes), and humanistic.71

Under the heading of humanistic values,pharmacoeconomists include patient satisfactionand quality of life as estimated by the patient.However, pharmacoeconomic analysis typicallyincorporates these “humanistic” concerns in a

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purely aggregative, utilitarian fashion, summingup benefits across all individuals affected by thepolicy. What this means is that the analysis isblind to the potential conflict between what isrational as a population health policy and what isrational for a particular individual. Theaggregative approach is also insensitive toquestions of fairness and distributive justice thatarise when there is a conflict between what isrational policy for a population and what isbeneficial to an individual.

The difference between a purely utilitarian,aggregative approach to allocation of medicalservices under conditions of scarcity and one thattakes considerations of fairness into account canbe illustrated by elaborations on the precedinghypothetical example. If the rational drug usepolicy denies you access to the drug for whichyou have tested as a “low-responder” is basedpurely on a utilitarian calculation, this means thatthe fact that more overall benefit (for thepopulation for which the policy is designed) byitself is assumed to justify denying you access. Inthese circumstances you may complain that yourinterests have been ignored, or rather, sacrificedfor the good of the group. You may protest thatmaximizing overall benefit ought not to be theonly factor in a rational drug policy—that everymember of the population served ought to have afair chance at very important benefits, and thatthis will not be the case if the allocation isdecided by a purely utilitarian calculation.

Most contemporary theorists of distributivejustice would probably say that a purely utilitarianapproach is defective because it is insensitive toconsiderations of fairness and encouragesunjustified sacrifices of individuals for the sake ofmaximizing overall benefit. However, there ismuch controversy among non-utilitarian theoristsas to just how considerations of fairness should beincorporated into allocation decisions, and whatthe appropriate standards of fairness are. Forexample, even among theorists who agree that theworst-off should be given some priority inallocation—that their interests should countmore—there is dispute both about how one

determines who the worst-off are and about howmuch special weight their interests should beaccorded.

Furthermore, the possibility of conflictsbetween what is rational for the individual andwhat is a rational policy for a population remainseven if a purely utilitarian analysis is rejected andthe notion of fairness or of giving all a chance atimportant benefits are taken seriously. Fairness,after all, is often thought to involve a balancing ofconflicting interests, not the maximizing of theinterests of everyone involved. Nevertheless,conflicts between what is best for the individualand what is best for the group may be lesscommon or, at least more ethically acceptable, ifeach individual can say that the policy treated himfairly, even if it did not maximize benefit for him.

PGx does not create the problem of conflictsbetween individual and policy rationality.However, advances in PGx may focus moreattention on efforts to forge rational drug policies,with the result that the inadequacy of purelyutilitarian, aggregative approaches become moreapparent and the need for developing a principledconsensus on notions of fairness becomes moreundeniable.

GENERAL FINDINGS ANDRECOMMENDATIONS

Findings1. The risks of PGx are neither unique to PGx

nor unmanageable. With feasible andappropriate safeguards, the potentialbenefits of PGx are worth pursuing. Giventhe human and financial costs of ineffectiveand unsafe use of drugs, it is important todevelop this methodology and to integrateit into clinical practice, with appropriateprotections and guidelines.

2. PGx research and the development of PGxtesting take place internationally andwithin public and private entities. Whilethere is a recognized need for protectionsand guidelines for genetic research andgenetic testing, there has not been an

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adequate appreciation of the particularitiesof PGx.

3. In order for the benefits ofpharmacogenetics in drug developmentand clinical practice to be fully realized,informed and coordinated actions will beneeded on the part of pharmaceuticalcompanies, researchers, clinicians,insurers, and relevant governmentregulatory agencies.

Recommendations1. The development of the appropriate

protections and guidelines should avoidgenetic exceptionalism, geneticdeterminism and geneticovergeneralization.

2. Harmonization, both at the national andinternational levels, is required in thedevelopment of appropriate protectionsand guidelines. These protections andguidelines must take into account theparticularities of PGx and should beintegrated into a comprehensiveframework for the development of thismethodology that includes provisions forapproval and reimbursement.

3. Private and public agencies shouldcooperate to sponsor consensusconferences, advisory committees, andother suitable venues to ensure an on-goingdialogue in which all the relevant actorsrequired for the ethically sound andoptimally beneficial use ofpharmacogenetics can communicate freelywith one another and coordinate their efforts.

FINDINGS AND RECOMMENDATIONSREGARDING RESEARCH

Regulatory Oversight of Research

FindingsExisting regulatory requirements for research,at least in the U.S., do not pose constraints thatwould prevent the successful development ofPGx. However, the regulatory landscape for

research is in flux. Poorly craftedrequirements regarding informed consent forthe collection and use of biological samplesand for PGx tests or overly stringent rulesregarding the confidentiality of medicalinformation could unnecessarily limit thebenefits to be derived from the integration ofPGx into the drug development process.

RecommendationsIn developing appropriate guidelines orregulation regarding informed consent andconfidentiality of information, it is essentialboth to distinguish where possible betweenhighly speculative and more likely risks, andbetween more serious and less serious risks,and to take into account the human andfinancial costs associated with efforts toreduce risks.

Informed Consent

Findings1. Obtaining informed consent in research,

even when there are only modest risks tosubjects, shows respect for the dignity ofthe individual and provides protectionagainst exploitation of subjects.

2. In some PGx research, where there is thepossibility of group stigmatization ordiscrimination, genetic information maybe a source of group-based harms. Thisraises the issue of the need for groupconsultation in the informed consentprocess.

Recommendations1. As with all medical research, PGx

researchers are ethically obligated toobserve the requirement of informedconsent. Research participants should beinformed as to why a DNA sample isneeded for the research in question, thenature of the protections of confidentialityand privacy that will be employed, thetime frame of the research, potential otheruses, whether the sample will be destroyedupon completion of the research, and therisks and benefits of participation.

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Subjects should be given the option ofdisclosure of reliable, beneficialinformation. They should be informed asto how the research results will bedisclosed to them and by whom. Inaddition, if the DNA sample is to belinked to the participant’s personalmedical information, permission to accessthe latter must also be sought, and thesafeguards for maintaining privacy andconfidentiality of this information mustalso be explained. The sponsorship of theresearch and the possibility of commercialuses of the research data should also bedisclosed. In most cases, a reasonablepolicy is to obtain consent to a range ofrelated studies (conducted either by theinitial researcher or by other researchers)over a defined period of time, with specialprovision for specific consent for studiesthat may be especially problematic to thesubject.

2. In cases of sensitive research with groups,responsible researchers should seek toincorporate group input into the researchdesign and informed consent process, butthis should not infringe the individual’sfreedom to decide whether to participate inresearch.

Privacy and Confidentiality

FindingsPGx research will require a sophisticatedinformation infrastructure within whichepidemiological data, individual medicalrecords, and human biological samples can becorrelated and studied over time. In order toensure adequate protection for privacy andconfidentiality while at the same time makinginformation accessible for the benefit of theindividual and society, discerning policychoices will be needed. These choices shouldreflect an accurate appraisal of the likelihoodof psychosocial harms from PGx rather thanfrom genetic testing in general.

RecommendationsThe most promising strategies for protectingconfidentiality of information include (a)reliance on “fire-walls” to prevent thedissemination of information to certain parties(such as insurers) for certain uses, (b) trustedintermediary entities to serve as securerepositories for and gate-keepers of access toinformation, and (c) laws and other public andprivate policies prohibiting discriminatoryuses of information. As this informationinfrastructure takes shape, new forms ofpublic and private oversight may be required.

Disclosure to Subject

FindingsIn some cases, information that may be ofsignificant benefit to research subjects mayemerge in the course of PGx research.

RecommendationsPGx researchers are obligated to offer to theresearch subject the option of disclosure ofresearch information when its reliability hasbeen established and when the disclosure is ofpotential benefit to the subject. The sponsorand researcher should incorporate into theresearch protocol a plan for how theinformation is to be disclosed.

Controlling the Flow of Information:Alternative Models

FindingsModels for controlling the flow of informationrange from the researcher having knowledgeof the identity of the subject from whom thesample is taken, to the sample beingpermanently anonymized so that no one hasknowledge of the identity of the subject.

RecommendationsGenerally speaking, the use of identified (non-coded) tissue samples and related informationis not advisable. In some cases permanentanonymization may be appropriate, but its usewill generally require special justification.Despite the added expense and time involved

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in the process, a system of double-coding isgenerally preferable from the standpoint ofreducing the risk of breaches ofconfidentiality. In such a system, there is akey-holder independent from the researcherwho can provide a link between the sampleand the relevant information about the subjectfrom whom the sample comes, but neither theresearcher nor the key-holder knows theidentity of the subject from whom the samplecomes. Whether single-coding is sufficient ina particular research study will depend upon abalancing of the possibly greater risks ofbreaches of confidentiality as compared withdouble-coding, against the benefit of its lowercosts of single-coding.

Participation in Research

FindingsRecent policy efforts to expand participationin research by historically under-representedgroups are compatible with the exclusion ofsubjects based on safety or efficacy issues inthe context of PGx research.

RecommendationsDrug researchers should use available reliablePGx information in subject selection to reducerisk to research subjects, and may excludepotential subjects who are unlikely to respondor for whom the drug would be harmful.

The Impact of PGx on the Research Agenda andthe Availability of Drugs

Findings1. The integration of PGx into the drug

development process may result insituations in which some genotypicsubgroups of the population, or somedisease groups, are deemed by commercialdrug developers to represent insufficientmarket demand.

2. The prospect of such “orphan” groups mayfocus public attention on a distinct accessproblem: is there an ethical obligation todevelop safe and effective therapies for

groups that have health care needs that arenot met by existing therapies and, if so,upon whom does that obligation fall? Thewidespread use of PGx testing to segmentthe population into those for whomexisting drugs or investigational drugs arebeneficial and those for whom they are notraises the question of whether the existingpublic processes by which groups competeto determine the targets for health careresearch is equitable and efficient.

Recommendations1. It may be necessary to modify existing

Orphan Drug legislation to promote thedevelopment of drugs for these groups.Alternatively, subsidies could be providedto encourage development of drugs forthese groups. In either case, there must besufficient rates of reimbursement for thesetreatments as they become available.However, any such policy initiative isunwarranted unless insufficient marketdemand occurs.

2. In anticipation of the need for such policyinitiatives, appropriate groups drawn fromrelevant public agencies and privateconstituencies should be formed toexamine and address the issues of socialobligations to develop new forms oftherapies for groups whose health careneeds would otherwise not be met.

FINDINGS AND RECOMMENDATIONSREGARDING CLINICAL APPLICATION

Regulatory Oversight

FindingsIn the clinical context PGx testing will serve a“gate-keeper” function, helping to determinewho will have access to specific drug therapies.Because these decisions may have profoundeffects on an individual’s well-being, theaccuracy and proper use of PGx tests arecritical to the ethically acceptable use of PGx.

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RecommendationsCurrent regulatory requirements and processesin the U.S. appear to be appropriate, ingeneral, for clinical application of PGx tests.However, at least the following three areasdeserve further regulatory attention: (a) FDAshould extend its approval oversight to include“home brew” PGx tests, not simply test kitsthat are licensed and marketed; (b) FDAshould ascertain the best mechanism forincorporating information about, or the needfor, PGx testing in drug labeling; and (c) CLIAstandards, with appropriate modifications asneeded, should be extended to all laboratoriesthat perform PGx tests.

Physician Acceptance and Responsibilities

Findings1. Physicians lack sufficient knowledge

about and decision support tools forgenetics generally and in particular aboutwhen to use PGx tests and how to take theresults into account in clinical decision-making.

2. In the clinical context the issue ofinformed consent to PGx testing issomewhat more ambiguous than inresearch. Generally speaking, PGx testscarry lower psychosocial risk than genetictests that confirm the diagnosis of, orpredict genetic diseases, or that identifycarrier status for genetic diseases. In manycases, a PGx test, like many diagnostictests that are now routinely administeredwith at most minimal informed consent,will carry no significant risk ofpsychosocial harm. However, dependingupon the nature of the secondaryinformation, if any, that is conveyed by thePGx test result and the social, economic,and cultural context in which the testoccurs, some PGx tests may carrysignificant risk of psychosocial harm. Inaddition, there appears to be considerablepublic concern about genetic privacy, inpart because no comprehensive system for

safeguarding confidentiality and privacyof genetic information presently exists.

3. The risk of sensitive secondaryinformation may vary depending upon thechoice of genetic markers used in PGxtests.

4. There is a need to provide reasonableassurance to the public about geneticconfidentiality. The use of “fire-walls”and other devices can reduce the risk ofbreaches of confidentiality; however, theseprotections will never be foolproof.

5. The integration of PGx into clinicalpractice will raise questions regardingstandards of care for uses of PGx testingand of drugs for which there are PGx tests.

Recommendations1. If the potential benefits of PGx are to be

realized, physicians must become betterinformed about this methodology. Thiswill require additions to medical schooland postgraduate medical trainingcurricula related to genetics and PGx, andcontinuing education efforts forphysicians. In addition, physicians andother providers will need access to clinicaldecision support tools and the training touse them.

2. Protections for confidentiality andprovisions for informed consent will needto be developed for PGx testing that arecommensurate with the risk entailed bythe test in question. In most instances, allthat will be required is a simple statementthat the physician wishes to test a sampleof the patient’s DNA to determine whetherit is likely that a particular drug or class ofdrugs will be safe and effective for thepatient and that this is the only use towhich the sample will be put. In caseswhere the PGx test conveys sensitivesecondary information, a more extensiveinformed consent discussion may beappropriate. As a broad generalization, thegreater the reliance on markers that carry a

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minimum of secondary information, themore reliable the “fire-walls” to preventinappropriate dissemination of information,and the more comprehensive the legalprotections against discriminatory uses ofinformation, the more appropriate it is totreat PGx tests like routine diagnostic testsfor which only “basic” informed consent isrequired. Practice guidelines will have tobe developed to help clinicians distinguishbetween “low-risk” PGx tests that requireonly minimal informed consent and“higher-risk” PGx tests that require fullerinformed consent. The process ofdeveloping such guidelines should be acooperative effort, with input from test-producers, laboratories, professionalorganizations, and government regulatoryagencies.

3. Research should be devoted to theidentification of markers of highpredictive value that convey the leastsecondary information, and preferenceshould be given to the use of PGx testsemploying these markers.

4. A sound policy approach to the issue ofconfidentiality will almost certainlyinclude both fire-walls and carefullycrafted legal prohibitions ondiscriminatory uses of PGx information.

5. The standard of care for use of PGx testsshould include a duty to offer PGx testingin certain cases, the right to refuse toprescribe certain drugs if patients refuseindicated PGx testing, and the discretionto prescribe off- or against-label undercertain conditions.

Direct Marketing of and Consumer Access toPGx

FindingsDemand for and access to PGx tests will notbe solely a function of the decisions ofphysicians. PGx tests are already beingmarketed directly to consumers. In addition,self-administered test sample collection kits

are already available which allow theindividual, without the benefit of any medicalsupervision, to collect a DNA sample andsend it to a laboratory for testing. Directmarketing of tests and self-administered DNAsample collection raise important ethicalissues about which a reasoned public andprofessional dialogue is needed. At presentthe public lacks sufficient knowledge aboutthe risks and benefits of PGx and is unlikelyto be able to distinguish between PGx testsand genetic tests that have different purposesand different associated risks.

RecommendationsIn the absence of input from a physician as a“learned intermediary,” assurance of theaccuracy of tests and accurate representationto the public of the predictive value andsignificance of tests results is all the moreimportant. This may require new forms ofregulation and other oversight mechanisms,both public and private. FDA shouldundertake a thorough review of the specialissues raised by the direct marketing of PGxtests to consumers, including tests that involvecollection of DNA samples by the personundergoing the test. As required by existingconsumer protection laws, marketers of PGxtests should represent the predictive value ofPGx tests accurately and in an understandablefashion. Scrupulous fulfillment of thisobligation is especially crucial in the case ofdirect marketing to consumers, where theprotective fiduciary function of the medicalprofessional is absent.

Payer Acceptance

Findings1. The decision whether to prescribe a drug

will depend not only upon an assessmentof PGx information and other factorsaffecting drug response (such as theindividual’s general state of health, renalfunction, disease severity, etc.), but alsoupon assumptions about the stewardship oflimited medical resources. In some cases adrug use policy that is rational from the

37

standpoint of providing health care for apopulation (as in a managed care plan,Medicare, or a national health caresystem) may not be preferable from thestandpoint of a particular patient. PGxdoes not create this conflict of interests.But because PGx has the potential tobecome a powerful tool in the context ofefforts to rationalize drug use practices, itsintegration into clinical practice mayhighlight the fact that pharmacoeconomicanalysis is not an ethically neutralenterprise, thereby bringing fundamentaldisagreements about distributive justice tothe fore.

2. Whether PGx tests are included in standardinsurance benefits will presumably bedetermined by the interplay of marketforces, interest-group politicalcompetition, and evolving standards ofcare endorsed by the relevant medicalprofessionals.

Recommendations1. Pharmacoeconomic analysis must be

enriched by considerations of distributivejustice as well as cost-effectivenessanalysis.

2. PGx tests that provide reliable predictionsof serious adverse reactions to widelyprescribed drugs should receive priorityfor inclusion in standard health insurancebenefits, both on ethical grounds and as away of reducing unnecessary costs.

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ENDNOTES

1 L.J. Lesko and J. Woodcock,“Pharmacogenomic-guided Drug Development:Regulatory Perspective,” The PharmacogenomicsJournal (2002): 20-24.

2 National Institute of General Medical Science:National Institute of Health(www.nigms.nih.gov/pharmacogeneticsindex.html). Accessed March 2002.

3 C. R. Wolf, G. Smith, and R. L. Smith,“Science, Medicine, and the Future:Phramacogenetics,” BMJ 320 (2000): 987-990.

4 E. Y. Krynetski and W. E. Evans,“Pharmacogenetics as a Molecular Basis forIndividualized Drug Therapy: The ThiopurineS-methyltransferase Paradigm,”Pharmaceutical Research 16, 3 (1999): 342-349.

5 M. P. Murphy, et al., “Prospective CYP2D6Genotyping as an Exclusion Criterion forEnrollment of a Phase III Clinical Trial,”Pharmacogenetics 10 (2000): 583-590.

6 M. Pirmohamed and B. K. Park, “GeneticSusceptibility to Adverse Drug Reactions,”TRENDS in Pharmacological Sciences22, 6 (2001): 298-305.

7 J. Drazen, et al., “Pharmacogenetic AssociationBetween ALOX5 Promoter Genotype and theResponse to Anti-Asthma Treatment,”Nature Genetics 22 (1999): 168-170.

8 A. Serretti, et al., “Serotonin Transporter GeneAssociated With Lithium Prophylaxis in MoodDisorders,” Pharmacogenomics Journal 1 (2001):71-77.

9 J. A. Kuivenhoven, et al., “The Role of aCommon Variant of the Cholesteryl Ester TransferProtein Gene in the Progression of CoronaryAtherosclerosis,” New England Journal ofMedicine 338, 2 (1998): 86-93.

10 M. Arranz, et al., “Association BetweenClozapine Response and Allelic Variation in 5-HT2a Receptor Gene,” Lancet 346 (1995): 281-282.

11 Wolf, et. al., supra note 3, Roses infra note 15,and Roses, infra note 16.

12 G. Anand, “Big Drug Makers Try to PostponeCustom Regimens,” The Wall Street Journal,18 June 2001.

13 M.A. Heller and R.S. Eisenberg, “Can PatentsDeter Innovation? The Anticommons inBiomedical Research,” Science 280 (1998):698-701.

14 Results of research reported by CantabPharmaceuticals (www.cantab.co.uk), presentedat the 61st Annual Scientific Meeting of theAmerican College of Problems of DrugDependence. Accessed March 2002.

15 A. D. Roses, “Pharmacogenetics and FutureDrug Development and Delivery,”Lancet 355 (2000): 1358-1361.

16 A. D. Roses, “Pharmacogenetics and thePractice of Medicine,” Nature 405 (2000):857-865.

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17 A. D. Roses, “Genetic Testing for AlzheimerDisease: Practical and Ethical Issues,”Archives of Neurology 54 (1997): 1226-1229.

18 T. Murray, “Genetic Exceptionalism and‘Future Diaries’: Is Genetic Information Differentfrom other Medical Information?,” in Rothstein,Mark A., ed., Genetic Secrets: Protecting Privacyand Confidentiality in the Genetic Era. YaleUniversity Press. New Haven, CT, 1997: 60-73.

19 A. Buchanan, et al., From Chance to Choice:Genetics and Justice, Cambridge: CambridgeUniversity Press (2000).

20 PharmGKB: The Pharmacogenetics andPharmacogenomics Knowledge Base (http://www.pharmgkb.org). Accessed March 2002.

21 National Bioethics Advisory Committee,Research Involving Human Biological Materials,Washington D.C.: Government Printing Office(August 1999), Recommendations 6-12.

22 Medical Research Council, Human Tissues andBiological Samples for Use in Research(April 2001) (http://www.mrc.ac.uk/pdf-tissue_guide_fin.pdf), Section 6.Accessed March 2002.

23 R. Spece, D. Shimm, and A. Buchanan, eds.,Conflicts of Interest in Clinical Practice andResearch. New York: Oxford University Press(1996).

24 National Bioethics Advisory Commission,supra note 21, Recommendations 8, 9; MedicalResearch Council, supra note 22: Section 6.2.

25 See the sample consent form in M. Deschenes,K. Cardinal, B. Knoppers, and K. C. Glass,“Human Genetic Research, DNA Banking andConsent: A Question of Form?” Clinical Genetics59 (2000): 221-239. See also B. Knoppers,M. Hirtle, S. Lormeau, C. Laberge, andM. Laflamme, “Control of DNA Samples andInformation,” Genomics 50 (1998): 385-401.

26 Department of Health and Human Services,“Final Regulations Amending Basic HHS Policyfor the Protection of Human Research Subjects,”45 CFR 46.116 (January 1981), (a)2,3.

27 45 CFR 46.116 (a)5; European Commission,Ethical Aspects of Human Tissue Banking (DraftOpinion of the Group of Advisers on the EthicalImplications of Biotechnology, Brussels (1998)(http://europa.eu.int/comm/european_group_ethics/docs/avis11_en.pdf).Accessed March 2002.

28 World Medical Association, Declaration ofHelsinki, (2000) (http://www.wma.net/e/policy/17-c_e.html), Section 22. Accessed March 2002;Medical Research Council, supra note 22,Section 8.

29 45 CFR 46.116 (a)8.

30 Buchanan, et al., supra note 19.

31 R. Sharp and M. Foster, “Involving StudyPopulations in the Review of Genetic Research,”Journal of Law, Medicine, and Ethics 28 (2000):41-51.

40

32 North American Regional Committee of theHuman Genome Diversity Project, “ProposedModel Ethical Protocol for Collecting DNASamples,” Houston Law Review 33 (1997):1431-1473.

33 C. Weijer and E. J. Emanuel, “ProtectingCommunities in Biomedical Research,”Science 289 (2000): 1142-1144.

34 National Bioethics Advisory Committee,supra note 21, Recommendation 17; CanadianTri-Council Policy Statement, Ethical Conduct forResearch Involving Humans (1998) (http://www.sshrc.ca/english/programinfo/policies/ethics.htm), Section 6. Accessed March 2002.

35 C. Weijer, G. Goldsand, and E.J. Emanuel,“Protecting Communities in Research: CurrentGuidelines and Limits of Extrapolation,”Nature Genetics 23 (1999):275-80.

36 Ibid.

37 S. Reverby, ed., Tuskegee’s Truths: Rethinkingthe Tuskegee Syphilis Study, Chapel Hill: TheUniversity of North Carolina Press (2000).

38 NIH-DOE Working Group on Ethical, Legal, andSocial Implications of Human Genome Research,Genetic Information and Health Insurance(May 1993); Nuffield Council on Bioethics,Genetic Screening: Ethical Issues (December 1993);National Conference of State Legislatures, StateGenetic Privacy Laws (http://www.ncsl.org/programs/health/Genetics/prt.htm). Accessed July, 2001.

39 B. Rock and E. Congress, “The NewConfidentiality for the 21st Century in a ManagedCare Environment,” Social Work 44, 3 (1999):253-62.

40 G. Annas, “The Limits of State Laws to ProtectGenetic Information,” The New England Journalof Medicine 345, 5 (2001): 385-388.

41 The HHS Data Council, Privacy and HealthResearch (May 1997)(http://aspe.hhs.gov/datacncl/PHR.htm#Contents).Accessed March 2002.

42 For example, see First Genetic Trust (http://www.firstgenetic.net/). Accessed March 2002.

43 National Conference of State Legislatures,supra note 38.

44 L. Gostin, “National Health InformationPrivacy: Regulations Under the Health InsurancePortability and Accountability Act.”JAMA, 285, 23 (2001): 3015-3021.

45 National Bioethics Advisory Committee,supra note 21, Recommendations 14-16; MedicalResearch Council, supra note 22, Section 8.

46 The Pharmacogenetics Working Group,“Terminology for Sample Collection in ClinicalGenetic Studies,” The Pharmacogenetics Journal1 (2001): 101-103.

47 The European Agency for the Evaluation ofMedicinal Products Evaluation of Medicines forHuman Use, Committee for Proprietary MedicinalProducts Position Paper on Terminology inPharmacogenetics (Released for consultationDecember 2001) (http://www.emea.eu.int/htms/human/press/pp.htm) Accessed March, 2002.

48 45 CFR 46.101 (b)4.

41

49 National Bioethics Advisory Committee,supra note 21, Recommendation 9.

50 Medical Research Council, supra note 22,Section 6.

51 Knoppers, et. al., supra note 25.

52 Department of Health and Human Services,“NIH Guidelines on the Inclusion of Women andMinorities as Subjects in Clinical Research,”59 CFR 11146 (March 1994); Department ofHealth and Human Services, NIH Guidelines onthe Inclusion of Children as Participants inResearch Involving Human Subjects (March1998) (http://grants1.nih.gov/grants/guide/notice-files/not98-024.html). Accessed March 2002.

53 E. Juengst, “Groups as Gatekeepers to GenomicResearch: Conceptually Confusing, MorallyHazardous, and Practically Useless,” KennedyInstitute of Ethics Journal 8 (1998): 183-200.

54 The Beta-Blocker Evaluation of Survival TrialInvestigators, “A Trial of the Beta-BlockerBucindolol in Patients With Advanced ChronicHeart Failure,” The New England Journal ofMedicine 344 (2001): 1659-67.

55 M. Rothstein and P. Epps, “Ethical and LegalImplications of Pharmacogenetics,”Nature Reviews-Genetics 2 (2000):228-231.

56 A. Dove, “New Economic Analysis Draws BigMoney to Malaria,” Nature Medicine 6 (2000):612.

57 The President’s Commission for the Study ofEthical Problems in Medicine and Biomedicaland Behavioral Research, Securing Access toHealth Care, Volume 1. Washington, D.C.:U.S. Government Printing Office (1983).

58 D. Brock and A. Buchanan, “Ethical Issues inFor-Profit Health Care,” in Institute of Medicine:Committee on Implications of For-ProfitEnterprise in Health Care, For-Profit Enterprisein Health Care. Washington, D.C.:National Academy Press (1986).

59 The Orphan Drug Act, Public Law 97-414(1983).

60 M. Thamer, N. Brennan, and R. Semansky,“A Cross National Comparison of Orphan DrugPolicies,” Journal of Health, Politics, Policy,and Law 23 (1998): 265-290.

61 Buchanan, et. al., supra note 19.

62 Lesko and Woodcock, supra note 1, pp. 23-34for an illuminating discussion of the steps FDA isalready taking in anticipation of the growing roleof PGx in drug development and clinical practice.

63 65 CFR 25928.

64 F.M. Giardiello, J. D. Brensinger, andG. M. Petersen, et al., “The Use andInterpretation of Commercial APC Gene Testingfor Familial Adenomatous Polyposis,” NewEngland Journal of Medicine 336, 12 (1997):823-827.

42

65 Robertson J., “Human Embryonic Stem CellResearch: Ethical and Legal Issues,”Nature Reviews: Genetics 2 (2001): 74-78

66 Roses, supra note 15 and Roses, supra note 16.

67 See Genelex Corp. (www.healthanddna.com)and Ardais Corp. (http://www.ardais.com)for just two examples.

68 Ibid.

69 Task Force on Genetic Testing, PromotingSafe and Effective Genetic Testing in the UnitedStates: Final Report of the Task Force onGenetic Testing (September 1997)(http://www.nhgri.nih.gov/ELSI/TFGT:final).Accessed March 2002.

70 Cheryl Goodman, Human Genetics Laboratory,Michigan State University(personal communication).

71 J. L. Bootman, R.J. Townsend and W.F.McGhan, Principles of Pharmacoeconomics.2nd ed. Cincinnati, OH: Harvey Whitney Books Co(1996).

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