Science and society: Integrating pharmacogenetics into society: in search of a model

29. Jones, B. C. et al. Quantitative-trait loci analysis of cocaine-related behaviours andneurochemistry. Pharmacogenetics 9, 607–617(1999).

30. Port, J. D. & Bristow, M. R. Altered β-adrenergicreceptor gene regulation and signaling in chronic heartfailure. J. Mol. Cell Cardiol. 33, 887–905 (2001).

31. van Campen, L. C., Visser, F. C. & Visser, C. A.Ejection fraction improvement by β-blocker treatmentin patients with heart failure: an analysis of studiespublished in the literature. J. Cardiovasc. Pharmacol.32 Suppl. 1, S31–S35 (1998).

32. Mason, D. A., Moore, J. D., Green, S. A. & Liggett, S. B. A gain-of-function polymorphism in a G-protein coupling domain of the human β1-adrenergic receptor. J. Biol. Chem. 274,12670–12674 (1999).

AcknowledgementsSupported by National Institutes of Health grants.

Competing interests statementThe author declares no competing financial interests.

Online Links

DATABASESThe following terms in this article are linked online to:Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geneADRB1 | ADRB2 | CFTR | CYP1A2 | CYP2D6 | CYP2E1 |CYP3A4 | TPMT | OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMcystic fibrosisAccess to this interactive links box is free online.

NATURE REVIEWS | GENETICS VOLUME 5 | SEPTEMBER 2004 | 663

F O C U S O N P H A R M A C O G E N E T I C S

and selling a range of specialist services tothe pharmaceutical industry. This coregroup is described in TABLE 1. Most of thesefirms have been formed since 1997 and aremainly located in the United States. Between1997 and 2000, there was a steady growth inthe number of small to medium enterprisesworking with PGx. However, in 2001 thisgrowth slowed, and in 2002 consolidation ofthe sector started to take place, with fivemergers and acquisitions of small PGx firmsbetween 2001 and 2002.

Secondly, there are about 30 large pharma-ceutical companies who are investing in PGx,either internally or through collaborationswith smaller PGx firms. The main players —primarily global firms — are listed in BOX 1.GlaxoSmithKline, Roche and Pfizer are amongthe larger investors in this technology. How-ever, it should be stressed that investment bymajor pharmaceutical companies can be mea-sured along a ‘spectrum’of commitment, withsome companies more committed to PGx thanothers, at this point in time. In addition tothese two main groups, a number of specialistdiagnostic companies (for example, BecktonDickinson) and US health-care providers (forexample, Kaiser Permanente) are also investingin the technology through the formation ofcollaborations with smaller firms.

Since the first collaboration on PGxbetween Genset and Abbott in 1997, a fur-ther 180 industrial alliances have beenformed around the technology. A similarpattern to the growth of dedicated firms canbe seen, with a steady increase in the numberof collaborations until 2001, followed by adeclining rate of growth (FIG. 1). This patternindicates that some of the momentum behindthe technology might have plateaued recently,partly because of complications in getting itto ‘work’ effectively, and partly as a result of astabilizing of investment3.

Options for the development of PGx. There isno single or principal model for adoptingPGx technology. Instead, the development ofthe field can be understood in terms of aprocess of experimentation and the search forviable techniques, with the technology beingapplied at multiple points in the drug discov-ery and development process. We have identi-fied five broad innovation options for theapplication of PGx (BOX 2).

The first of these is aimed at improving thediscovery of new drugs. Options 2 and 3 aremostly concerned with using PGx to improvethe safety and efficacy of prospective drugsthrough the re-design of clinical trials. Finally,PGx is also being used to improve the safetyand efficacy of medicines that have already

Abstract | There has been considerablescientific, corporate and policy interest in the more effective use of genetics in both drug development and delivery.Pharmacogenetics — the study of therelationship between an individual’s geneticmakeup and response to medicinal drugs —has attracted global interest, but will it live upto its promise? Looking beyond the hype thathas accompanied much of the commentaryin the area, the future of pharmacogeneticswill depend on how competing interests andoptions are resolved.

Pharmacogenetics (PGx) is concerned withunderstanding and, in the clinical setting,managing the relationship between geneticvariation and an individual’s response to med-icinal products. It provides the possibility oftargeting drugs according to a person’s geneticmake-up — so-called ‘personalized medicine’— although it will probably be used to stratifypatient populations into groups determinedby their genotype1. Stratification along theselines might significantly improve the develop-ment, testing and use of drugs. However, real-izing these benefits will depend on thedevelopment of viable commercial strategiesand clinical delivery in the next few years. Itmight also require new approaches to regu-lation, drug approval and PHARMACOVIGILANCE atnational and international levels.

Given its potential, PGx has gained con-siderable interest in the pharmaceuticalindustry and among clinical researchers —such as in the US-based National Institutes of

Health Pharmacogenetics Research Network,as well as among national health policy agen-cies, as indicated by the UK government’srecent White Paper on the introduction ofPGx (and other genetic techniques) into thehealth service2.

PGx is on the threshold of making a majorimpact in commercial labs and in the clinic.But, despite its promise and the heavy invest-ment made in the technology, many compa-nies still question whether there is a coherentbusiness, health policy or regulatory modelemerging to shape the future development ofPGx. Here, on the basis of detailed researchconducted on the social, economic and reg-ulatory factors shaping PGx during the past2 years (P.M., G.L., A.S. and A.W., FalsePositive? The Clinical and CommercialDevelopment of Pharmacogenetics, TheWellcome Trust report, also see Online linksbox), we aim to provide at least a partialanswer to this question. After reviewingPGx in the commercial sector, and identify-ing the different strategies being pursued,we discuss its likely clinical role, the regula-tory regime that is emerging, and the widerpolicy implications that it raises, especiallyfor advanced health-care systems.

The development of PGx technologyWho is developing PGx? There are twobroad groups involved in the commercialdevelopment of PGx. Firstly, about 30 smallbiotechnology and genomics firms areinvolved in conducting PGx associationstudies, developing specific genetic tests,

Integrating pharmacogenetics intosociety: in search of a modelAndrew Webster, Paul Martin, Graham Lewis and Andrew Smart

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

© 2004 Nature Publishing Group

664 | SEPTEMBER 2004 | VOLUME 5 www.nature.com/reviews/genetics

individuals’ genetic profiles as part of the USFood and Drug Administration (FDA)-imposed post-marketing commitments. ThisPGx-based research involves the prospectivecollection and analysis of samples from addi-tional trials. The aim of this research is toidentify SNPs or haplotypes that can predictadverse events in patients and to determinethe genotype of polymorphic cytochromeprotein 450 (CYP450) enzymes that areresponsible for the drug’s metabolism (REF. 7,and Roses, A., unpublished data).

Specialist diagnostics firms and health-care providers show the greatest interest in thepre-prescription genotyping of patients, toimprove the safety and efficacy of establishedproducts and the development of drug-testcombinations. Both aims offer the prospect ofnew diagnostics markets and reduced health-care costs. Although this might point to aclear business model, the situation is morecomplicated in relation to the development ofnew products, as larger firms will inevitably beinvolved. New drugs that are developed usingstratified clinical trials on the basis of PGx testswill often require a dedicated drug-test combi-nation to be licensed. In such cases, it is in theinterests of pharmaceutical companies toundertake drug-test development, eitherthemselves or through collaboration withspecialist companies.

The smaller PGx firms offer a range ofproducts and services across all the differentoptions, with many working on more thanone approach. Options (1–5, as outlinedabove) for the development of PGx, and therelationships of the main groups of firmsinvolved in each option, are shown schemati-cally in FIG. 2.

Assessing the medium-term development ofPGx. In summary, the pharmaceutical andbiotechnology industries are making animportant but varied investment in PGx.However, exactly which options are adopteddepends on many crucial factors, includingtechnical feasibility, commercial attractive-ness, regulatory considerations and the abilityto integrate the technology into routine clini-cal practice. So, whereas the application of PGxto the development of new drugs seems likely,given the backing of big pharmaceutical com-panies, the introduction of pre-prescriptiongenetic testing for drug response in regard toexisting drugs is much less certain, and it ishere that investment by smaller diagnosticfirms and health-care providers will probablybe important. However, even with this invest-ment, there is the real prospect of general‘market failure’; that is, the priorities of bothlarge and small firms might not deliver the

fore, markets (for example, ABACAVIR (Ziagen;GlaxoSmithKline)). There has also been somelimited investment in option 4, the best exam-ple being the case of alosetron hydrochloride(Lotronex; GlaxoSmithKline). This drug,which is used for the treatment of irritablebowel syndrome, was approved then quicklywithdrawn voluntarily by the manufacturerbecause of a number of adverse drug reac-tions (ADRs)5. It was subsequently approvedagain in the United States under ‘RESTRICTED

MARKETING’ TERMS as a result of doctor/patientdemand6. Consequently, research by themanufacturer, GlaxoSmithKline, now aims toidentify the relationship between ADRs and

been licensed, mainly through the use of pre-prescription patient genotyping (options 4and 5).

A detailed analysis (P.M., G.L., A.S. andA.W., The Wellcome Trust report) of PGxinvestments and collaborations reveals thatmost of the large pharmaceutical companiesinvest mainly in options 1–3 — aimed atimproving internal processes, reducing costsand enhancing the efficiency of drug discov-ery and development4. These companies havelittle commercial interest in applications ofPGx that are aimed at already licensedmedicines, except where value can be addedby extending product licences and, there-

P E R S P E C T I V E S

Table 1 | Biotechnology and genomics companies developing pharmacogenetics

Company Founded Location Focus

Acadia Pharmaceuticals 1997 US Pharmacogenomic drug discovery inpsychiatry

Affymetrix 1992 US Gene chips for pharmacogeneticapplications

Axis-Shield 1982. UK Clinical diagnostics

Celera Diagnostics 2000 US Clinical PGx diagnostics

Curagen 1996 US PGx association and toxicogenomicstudies

DeCODE (Encode) 1996 (1999) Iceland Clinical PGx diagnostics(pharmacogenomics CRO)

DiaDexus 1997 US Clinical PGx diagnostics

DNAPrint Genomics 2000 US Clinical PGx diagnostics

DxS 2001 UK PGx genetic analysis services

Epidauros 1997 Germany PGx assays and services

Epigenomics 1998 Germany Clinical PGx diagnostics

Exon Hit Therapeutics 1997 France Clinical PGx diagnostics

First Genetic Trust 2000 US Genetic banking services

Gaifar 1997 Germany Clinical PGx diagnostics (viralgenotyping)

GAG Biosciences 2000 Germany PGx genotyping services

Genaissance 1997 US PGx services and diagnostics

Gene Logic 1994 US Toxicogenomic serivces

Genelex 1987 US Direct to consumer PGx testing

Genomics Health 2000 US PGx patient testing services

Genset (Serono) 1989 France Association studies of drug (Switzerland) response

Gentris 2001 US Clinical PGx diagnostics

Interleukin Genetics 1999 US PGx diagnostics

Millennium 1993 US Clinical PGx diagnostics/pharmacogenomic drug discovery

Myriad Genetics 1991 US Clinical PGx association studies

Orchid Biosciences 1995 US and UK PGx genotyping services

Oxagen 1997 UK PGx association studies

Perlegen 2000 US PGx association studies

Sciona 2000 UK PGx diagnostics

Third Wave 1993 US Clinical PGx diagnostics

Vita Genomics 2001 Taiwan PGx association studies

CRO, clinical research organization; PGx, pharmacogenetics; UK, United Kingdom; US, United States.


mental-health settings. Even if a test for ‘goodresponders’ can be proven, the availability of anear categorical answer still might not justify adenial of treatment, as clozapine is often a ‘lastresort’ drug. Furthermore, patients deemed‘genetically suitable’ could remain clinicallyunsuitable, for the same reasons that currentlylimit prescription, such as a lack of personaland/or social stability, a patient’s unwillingnessto have regular blood monitoring, or simplypatient non-compliance with the drug regime.Finally, there are also concerns that PGx mightadd further complexity to an already cumber-some clinical prescription process.

Whilst these barriers might not be insur-mountable, they illustrate not only the type ofconcerns voiced by some clinicians about theadoption of PGx, but also how potential bar-riers are specific to clinical context. In light ofthis, we identify some key points, covering arange of cases, that highlight the generalproblems associated with establishing a clini-cal model for PGx.

Clinicians currently have little evidenceof the utility, or even the validity, of PGx inclinical contexts9. Assuming that validity(analytical and clinical) can be proven, util-ity remains a conspicuous hurdle; this iswhere visions of PGx meet the reality ofexisting clinical practice. Generic criteriathat have been suggested for judging theclinical use of PGx tests have included thevalue that is added to treatment objectives(such as prompt therapeutic response), theexistence of other treatments, the size of the

greatest public health benefits (for example,testing for non-responders to widely used,already licensed drugs, such as the selectiveserotonin-reuptake inhibitors).

Translation into clinical practiceDiscussions about PGx are approaching theissue of adoption in clinical practice8–12.However, there is little evidence about thepractical and professional issues that mighthelp or hinder its adoption in specific clinicalcontexts.

We recently examined the factors thataffect the adoption of PGx through case stud-ies of four drugs in distinct clinical contexts:CLOZAPINE (Clozaril; Novartis), WARFARIN, theTHIOPURINES (6-mercaptopurine and azathio-prine) and ISONIAZID (P.M., G.L., A.S. andA.W., The Wellcome Trust report). Thesedrugs were chosen because they are knownproduce different responses depending ongenotype and require monitoring regimes toensure patient safety. We found that, in gen-eral, improved practices in prescribing drugsor patient experience (by getting the rightdose earlier and avoiding ADRs), and thechance to refocus health service costs (byavoiding wasteful treatment), were theimportant factors behind the introduction ofPGx in these cases13–15. However, there wereconcerns about the use and practicality ofPGx in specific clinical contexts and about theweakness of the current evidence on whichsupport for its introduction was based8,9,11,12.

To illustrate these points, we will makesome brief suggestions on the basis of ouranalysis of clozapine, which is used as anantipsychotic drug for patients with schizo-phrenia who do not respond to, or cannot tol-erate, other drugs. Clozapine is effective in upto 50% of patients who do not respond toother drugs and 80% of those who sufferfrom intolerable side effects from otherdrugs16. However, the drug itself is associatedwith potentially fatal blood disorders (notablyAGRANULOCYTOSIS), which necessitates a labori-ous and time-consuming blood monitoring

process. PGx testing could, in principle, beused to identify not only those who suffer thisresponse, but also those who are likely to be‘good responders’17,18. By prescribing the drugonly to patients who do not suffer agranulo-cytosis and who meet the second criteria, theoverall level of ADRs could be reduced.

Our research with clinical practitionersindicates that the perceived problems associ-ated with the adoption of PGx testing forclozapine relate to the specific context of itsuse. These problems include the difficulty ofvalidating a genetic marker for drug response,given the problem of establishing measurablebiological endpoints in the diagnosis andtreatment of schizophrenia. Although repli-cating small association studies in large ran-domized trials might close the ‘credibilitygap’ between a genetic marker and clinicaloutcomes, there are concerns about the practi-calities and ethics of conducting such trials in



Box 1 | Pharmacogenetics investors

US-basedAbbott Laboratories, 4 | Amgen, 1 | Becton Dickinson, 2 | Biogen, 3 | Bristol-Myers Squibb, 5 | Dade Behring, 1 | Janssen, 1 | Lilly, 2 | Merck, 3 | Pfizer*, 10 | Schering Plough, 1 | Wyeth, 1

European Union-basedAstraZeneca, 5 | Aventis‡, 5 | Bayer, 4 | Biomeriux, 1 | Boehringer Ingelheim, 1 | GlaxoSmithKline§,11 | Novartis, 2 | Novo Nordisk, 1 | Roche, 2 | Roche Diagnostics, 3 | Sanofi Syntholabo, 1

Japanese companiesDaiichi, 2 | Ono Pharmaceuticals, 1 | Sankyo, 1

*Includes Parke-Davis, Warner Lambert and Pharmacia. ‡Includes Rhone Poulenc Rorer.§Includes SmithKline Beecham. Numbers refer to number of alliances with other companies.

Year

Num

ber

of c

olla

bora

tions

1997 1998 1999 2000 2001 2002 2003

250

200

150

100

50

0

TotalNew

Figure 1 | Commercial collaborations based on pharmacogenetics. Whereas commercialcollaborations have increased from 1 in 1997 to almost 200 in 2003 (pink line), there has been a decline intheir rate of growth since 2001 (blue line).



number of ‘orphan patients’ that had beendenied access to mainstream drugs developedfor the more common, most responsive geno-type21,22,24.

It therefore seems unlikely that profes-sional acceptance will be forthcoming wherecurrent practice is considered acceptable andthe use and/or practicality of PGx is unclear.Much remains to be done to verify the useand practicality of PGx in specific treatmentcontexts before professionals are likely toadopt it as a routine or widespread part ofclinical practice. So, the gradual use of PGxtesting in the context of oncology, for example,reflects both the scale and importance of thisdisease area. It also demonstrates the need toimprove the therapeutic value of existingdrugs: results from studies on gene expressionprofiling in the cancer field to predict drugresponse illustrates how PGx testing mightbegin to meet the twin demands of use andpracticality 25,26.

The emerging regulatory regimeCurrent regulatory approval of any drug isgiven on the basis of an assessment of efficacyand safety, which is based on data generatedby a series of clinical trials. Clinical trials arebased on the notion that the findings fromstudies of trials are ‘generalizable’ to the wholepopulation. By contrast, the fundamentalprinciple of PGx is that the drug is targeted atpatients according (at least in part) to theirgenetically determined response, whether interms of efficacy or ADRs. What does thismean for regulation?

Given the promised precision of PGx to determine drug response, it might be

generate a need for (re-) education of healthprofessionals10–12. Finally, there might be ethi-cal concerns associated with denying treat-ment21,22 as a result of a person being assignedinto a particular category of genotype23. Forexample, patients might be excluded fromusing a particular drug as a result of a PGxtest that indicated that they are ‘at risk’ fromADR, when evidence for this might only beprobabilistic; it has been argued that clinicaldecision-making in regard to drug therapyshould not solely be on the basis of gene asso-ciation, but on a detailed patient history24.Moreover, there are wider ethical implica-tions, for example, if PGx led to a significant

patient population and the scale of negativeeffects that might be avoided9,11,12,19. It hasalso been recommended that PGx tests areverified, with reference to reliability, infor-mation provided, and the frequency andmagnitude of the response that it predicts11.

However, in routine clinical decision-making, information about drug responsecan be just one of the many influencing fac-tors. Furthermore, because drug response isaffected by several biological and environ-mental factors, even accurate PGx informa-tion might have limited value12. We foundthat, from the clinician’s perspective, judge-ments about the use of a PGx test are likely tobe highly context-specific, relating to thepatient, their illness and the overall objectivesand costs/benefits of treatment. As such, thedegree of certainty that the PGx test offers wasreported as a crucial factor for judging its use-fulness. To encourage clinical adoption, it willbe imperative for health practitioners to be inpossession of clear information that linksgenotypes to clinical outcomes, and to havespecific advice on how this might affect pre-scribing decisions, or alter drug dosage.

Practical barriers to the adoption of PGxmight include the potential for increased timeand workload burdens for laboratories andclinics, especially if informed consent andcounselling are deemed necessary9,11,12. Thereare also likely to be resource implications,given the anticipated high costs of this newtechnology20. However, tests that assist in theallocation of scarce resources might be wellreceived by health-care payers and cliniciansalike. More generally, PGx might require aculture shift in prescribing practice and might


Box 2 | Potential applications of pharmacogenetics (PGx)

Option 1: using PGx to discover better drugsDiscovering drugs for specific genomic sub-groups (allelic variants of drug target).Discovering drugs that work in all sub-groups (ensuring leads work in all allelic variants).

Option 2: PGx to improve the safety of new drugs in developmentEarly stage trial design and/or monitoring (for example, ensuring balanced trial population ofcytochrome P450 variants).‘Rescue’ of drugs that fail clinical trials owing to safety problems.

Option 3: PGx to improve the efficacy of new drugs in developmentTargeting late-stage trials as ‘good responders’ (prospective).‘Rescue’ of drugs that fail clinical trials owing to lack of efficacy (retrospective).

Option 4: improving the safety of licensed drugsPre-prescription patient testing for risk of adverse drug reactions (ADRs) (for example,thiopurine methyltransferase).Label and market extension of drugs that have been restricted by ADRs (for example, abacavir).Improved post-marketing surveillance.

Option 5: improving the efficacy of licensed drugsPre-prescription patient testing to identify good responders.The use of efficacy data in drug marketing.

Discovery Development Marketing Use

Lead discovery

I

DiagnosticfirmsEfficacy

Discovery II III Launch/ IV

Drug development companies

Safety

2 21 3 4 5 5

5

44Pharmacogenetics firms

Clinical trial phase

CROs

Hea

lth-c

are

prov

ider

s

Figure 2 | Collaborative links and strategic options for the use of pharmacogenetics (PGx).The five options for commercially exploiting pharmacogenetics (1–5, see BOX 2) range from its use at theearly stages of lead discovery (1) to its use when health care is being provided to patients (5). Differentinterests and needs lead to differing option priorities among actors in the PGx field. Dotted arrows in the figure indicate points of intervention in the drug development process, whereas solid arrows indicate potential PGx products. CROs, clinical research organizations; I–IV refers to the different phases of clinical development.


considering whether PGx can provide suchbenefits more widely. For example, the avail-ability of PGx data might change the risk/benefit assessment and trigger review of analready licensed drug31. Widespread adoptionof such a policy could have important impli-cations. Moreover, from a practical point ofview, this broadening of the role of PGx (aswell as its more commercially driven form)will mean that regulators will have to managea massive increase in data, on a much widerrange of treatments.

There is also the possibility of ‘conflict ofinterest’ situations developing, in which themain source of knowledge about a treatmentor indication resides in industry. Regulatorsmight become ever more reliant on companysources for expertise.

The futureAt present, it is unclear how regulatorsmight use PGx data. Indications are that gene

assumed that regulatory agencies (such as theFDA and the European Medicines EvaluationAgency (EMEA)), will demand that everydrug undergo PGx testing. However, it isdoubtful that this will be the case. PGx testingfor a particular drug will probably be decidedon the basis of the genetic factors that deter-mine the drug’s DISPOSITION, on its PHARMACO-

DYNAMIC CHARACTERISTICS and on its THERAPEUTIC

INDEX.Regulators, at present, have the opinion

that PGx will not be applicable for all types ofdrug, for both therapeutic and commercialreasons. The most suitable areas for the appli-cation of PGx therapy will be those in whichnew treatments are being developed andwhere existing treatments have a narrow ther-apeutic index24.

The response of regulatorsOver the past 18 months, the FDA (and theEMEA) has begun to collaborate with indus-try on PGx issues. Interventions by senior FDAstaff, and statements by the recently departedFDA Commissioner, Mark McClellan, indicatethat the FDA advocates the use of pharmaco-genetic strategies to optimize clinical trials. Theactive encouragement of PGx by regulatoryagencies today is in stark contrast to theposition in 2001, when there was little indi-cation of regulatory engagement with PGx.

However, the inconsistent evidence aboutthe impact of PGx on therapy has lead to reg-ulatory agencies adopting a number of proce-dures to enable a more ‘united’ form of regu-latory review, notably the FDA’s ‘voluntarypharmacogenomic data submission’, or ‘safeharbour’, proposal27. Initiating this proposalhas required the FDA to encourage submis-sion of pharmacogenomic data (defined datafrom pharmacogenomic or pharmacogenetictests) early in the development process. Thisthen helps discussion between the regulatorsand industry; provides more information onhow useful such data could be, and attemptsto address industry concerns about the use ofsuch submitted data28. Concerns about thisprocess focus on the possibility that data sub-mitted might, for one reason or another,eventually form part of the formal assessmentprocedures. For example, corporations areconcerned about how regulators might reactif PGx data indicates that a potential safetyissue is likely to emerge over time.

In Europe, the EMEA is developing asimilar ‘safe harbour’ framework throughits ‘briefing sessions’ format29. However,European regulators face a similar ‘trust prob-lem’ to that of the FDA with regards to thestatus of submitted data. In the Europeancase, care is being taken to distinguish

between ‘briefing sessions’ and the currentformal ‘scientific advice’ procedure, underwhich companies can seek advice about thetype of data that regulators are likely to wantincluded in a Marketing AuthorizationApplication. Senior FDA staff have alsostated that assessment will include what canbroadly be defined as ‘clinician acceptance’issues, particularly regarding the question ofwhether a PGx product can and will be usedas specified30.

It is possible that the important healthbenefits that result from PGx will come fromtargeted therapy using existing generic drugs,such as warfarin, the statins, 6-mercaptop-urine and so on. From a regulatory perspec-tive, PGx offers the opportunity to enhancepatient benefit by improved targeting andmore effective prescribing. In some cases,most notably in cancer therapy, genetic test-ing is already widely used to aid prescrip-tion decisions. The FDA has stated that it is



Glossary

ABACAVIR

An antiviral drug, used, in conjunction with othermedicines, for the treatment of HIV.

AGRANULOCYTOSIS

A condition in which there is an insufficient number of white blood cells called neutrophils or granulocytes.This can be caused by a failure of the bone marrow to make sufficient neutrophils or when white blood cells are destroyed faster than they can beproduced. Affected people are susceptible to infections.

BIOBANKS

Public or private tissue collections (derived from blood,DNA or other sources) comprising samples taken fromspecific disease groups or healthy populations. Theirlong-term purpose is to build biological banks that willprovide new sources of (genetic) information aboutdisease that have clinical value.

CLOZAPINE

An antipsychotic drug that works by decreasingabnormal excitement in the brain, used primarily to treat patients with schizophrenia who either fail torespond to or are unable to take other antipsychotictreatments.

DISPOSITION

Refers to all processes involved in the absorption,distribution metabolism and excretion of drugs in aliving organism.

INVESTIGATIONAL NEW DRUG APPLICATION

(IND). An application that a drug sponsor must submitto FDA before beginning tests of a new drug on humans.The IND contains the plan for the study and is supposedto give a complete picture of the drug, including itsstructural formula, animal test results, andmanufacturing information.

ISONIAZID

An antibacterial drug used to treat tuberculosis.

NEW DRUG APPLICATION

An application requesting FDA approval to market a new drug for human use in interstate commerce. Theapplication must contain, among other things, data fromspecific technical viewpoints for FDA review — includingchemistry, pharmacology, medical, biopharmaceutics,statistics and, for anti-infectives, microbiology.

PHARMACODYNAMIC CHARACTERISTICS

The characteristics of a drug that determine itsbiochemical and physiological effects and itsmechanisms of action.

PHARMACOVIGILANCE

The process of monitoring medicines to identifypreviously unrecognised adverse effects; assessing therisks and benefits of medicines in order to determinewhat action, information and subsequent monitoring, ifany, is necessary to improve their safe use.

THERAPEUTIC INDEX

The therapeutic index of a drug is the ratio of the toxicdose to the therapeutic (that is, effective) dose, often usedas a measure of the relative safety of the drug for aparticular treatment. PGx is more likely to be clinicallyuseful where the therapeutic index is narrow (i.e. whenthere is a smaller amount of difference between toxic andefficacious doses).

‘RESTRICTED MARKETING’ TERMS

A drug may have such serious adverse effects thatregulatory approval is given for use in a specific patientgroup only, for whom it can be used safely.

THIOPURINES

A family of chemotherapeutics used to treat leukaemia,as well as arthritis and inflammatory bowel disease.

WARFARIN

Used to prevent blood clots from forming or growinglarger (anticoagulant). Typically used for patients withatrial fibrillation and those with a venousthromboembolism.



the future use of biobanks and the emergenceof genetic epidemiology will probably aim tolink to phenotypic information that relatesto PGx in the clinic. In this instance, patientswould be asked to give consent for this infor-mation to be used, which might eventuallyindicate links to a predisposition to geneticdisease. In short, genetics will be applied toa wider range of projects than at present(primarily specialized genetics services). Thebalance between competing demands andexpectations might become the main task forpolicy-makers, counsellors, clinicians andusers. At present, there is no obvious publichealth policy model, owing to the differentperceived opportunities and risks of PGx.

An important criticism of an over-emphasison PGx policy is that it distracts attentionfrom more simple and cost-effective ways inwhich ADRs might be dealt with. Researchestimates that up to 95% of such effects couldbe prevented on the basis of current knowl-edge and a better management of drugs byprescribing clinicians36.

So, the problem is how to maintain thestrategic capacity to invest (in both a publicand private sense) without getting trappedinto a policy, business or clinical model thatwill fail and might well lead to a misuse ofcurrent knowledge and resources. We advo-cate an approach that emphasises publicfunding of research to help create a better evi-dence base for PGx; active steps to help stabi-lize some of the (regulatory and ethical)uncertainties; measures to prevent marketfailure; and investment in the PGx testinginfrastructure, as well as in the long-term,improved strategies at national and interna-tional levels of pharmacovigilance.

Andrew Webster and Graham Lewis are at theScience and Technology Studies Unit, University of

York, York YO10 5DD, United Kingdom.

Paul Martin is at the Institute for Study ofGenetics, Biorisks and Society, University of

Nottingham, Nottingham NG7 2RD,United Kingdom.

Andrew Smart is at the Oxford GeneticsKnowledge Park, University of Oxford, Oxford

OX3 7LF, United Kingdom.

doi:10.1038/nrg1430

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2. Department of Health. Our Inheritance, Our Future –Realising the Potential of Genetics in the NHS (TheStationary Office, London, 2003).

3. Frantz, S. & Smith, A. New drug approvals for 2002.Nature Rev. Drug Discov. 2, 95–96 (2003)

4. Brazell, C., Freeman, A. & Mosteller, M. Maximizing thevalue of medicines by including pharmacogeneticresearch in drug development and surveillance. Br. J.Clin. Pharmacol. 53, 224–231 (2002).

5. Food and Drug Administration. Glaxo Wellcome Decideto Withdraw Lotronex from the Market.<http://www.fda.gov/bbs/topics/answers/ANS01058.html> (Office of Public Affairs, Washington, 2000).

labs — so-called ‘home-brew’ tests — areexempt from regulations that apply to mar-keted tests, although the FDA is expected totighten controls on such tests in the future.

Policy implicationsThis paper has summarized some of the maininitiators and constraints on the wider imple-mentation and exploitation of PGx techniquesin the contemporary health-care system. Thereare many options and competing interestsinvolved that reflect not only the relativeimmaturity of the field (at least with regard toits role in drug development and clinical deliv-ery) but also conflicting interests as to wherepriorities might lie (for example, betweencommercial and public health agendas). Thefive ‘options’ that are outlined in this paper arenot all mutually exclusive, although from ourevidence it is clear that the first three tend to befavoured by companies, whereas the last twoare favoured by public health agencies. From agovernmental perspective, where ‘wealth andhealth’compete, this is an indication that thereis no single strategy that presents itself as a self-evident candidate for setting policy priorities.The various overviews of the field that haverecently emerged draw attention to these policyuncertainties characterizing the developmentof PGx12,24.

Nonetheless, we can identify a number offorces that are at work, shaping the futureagenda at a global level. First, as detailedabove, commercial interests are activelyexploring the uses of PGx, especially in theearly stages of drug development, whereasregulatory agencies are moving more rapidlytowards building a regulatory review processin conjunction with industry. In turn, publichealth systems are keen to reduce their drugsbill and derive health gains from PGx35,36.However, these developments are impeded byvarious barriers, such as clinician reluctance,ongoing commercial re-positioning (withmany PGx firms shifting their focus down-stream to drug development), and uncertain-ties within regulatory agencies about thewider implications of PGx for whole classes ofdrug24.

There will be attempts, as in any complexsocio-technical system, to try to bring orderand stability to the deployment of this newtechnology, but an equilibrium point mighttake some time to reach. In part, this isbecause, beyond the confines of PGx itself,wider developments in pharmacogenomics,complex disease genetics, BIOBANKS and func-tional genomics put pressure on the PGx fieldand disturb any hard-won ethical, commer-cial and clinical stability23,24. For example, thephenotypic information that will be crucial to

expression data, as well as the currently morecommon CYP450 data (both of which affectdrug response) will feature in both ‘voluntarysubmission’ and formal INVESTIGATIONAL NEW

DRUG APPLICATION (IND) and/or NEW DRUG APPLI-

CATION (NDA) submissions. However, boththe technology and, more importantly, itsinterpretation, are at an early stage. Tech-nologies are available to survey the expressionlevels and variability in genes that are involvedin drug response, but the question for bothindustry and regulators is how to use them. Atpresent, the FDA does not have the under-standing or expertise to interpret such data,although it is taking steps towards resolvingthis32.

Regarding the underlying approach, it isunlikely that PGx testing will become partof regulatory requirements for all drugs. Adrug that is highly efficacious across mostof the population, has a wide therapeuticindex and that shows little inter-individualvariability in kinetics and dynamics shouldnot necessarily require PGx testing. It wouldnot be cost effective to do so. However, adrug that is efficacious in 30% of the popu-lation and that has a narrow therapeuticindex, as do some current antipsychotics,should arguably be subject to PGx testingprior to prescription.

Despite uncertainty at this early stage, wecan expect regulators to adopt this kind ofapproach when assessing PGx-based applica-tions. In terms of drug development, constantdialogue between the industry and regulatoryagencies will be important to ensure that thedrug development process is as efficient aspossible, whilst maintaining standards. PGxdata have reportedly already been included in70–80 NDAs and INDs submitted to theFDA30. Owing to confidentiality rules, it is notpossible to determine in detail the type ofinformation that these submissions contain.However, extrapolating from the picture in2002, most are likely to refer to pharmaco-genetic variability in CYP450 enzymes.

Regulatory regimes for diagnostic tests arecomplex and vary across countries. Historic-ally, diagnostics have been subject to lessscrutiny than medicinal products, with respon-sibility for approval often residing with a dif-ferent agency. The harmonization of medicinalproduct regulation in Europe has led, in effect,to European-wide approval for innovativeproducts33.

Responsibility for diagnostic products,however, remains with national agencies,although adoption of the European in vitrodiagnostics directive34 will bring aboutgreater coordination in the future. In theUnited States, tests developed by commercial



Online links

FURTHER INFORMATIONEncyclopedia of Life Sciences: http://www.els.net/pharmacogeneticsInstitute for the Study of Genetics, Biorisks and Society:http://www.nottingham.ac.uk/igbisLewis’ homepage:http://www.york.ac.uk/org/satsu/Staff/graham/graham.htmOxford Genetics Knowledge Park:http://www.oxfordgkp.orgPharmacogenetics research at SATSU:http://www.york.ac.uk/res/pgxUniversity of York Science and Technology Studies Unit:www.york.ac.uk/org/satsuWebster’s homepage:http://www.york.ac.uk/depts/soci/s_webs.htmlAccess to this interactive links box is free online.

6. Food and Drug Administration. FDA Approves restrictedmarketing of Lotronex. <http://www.fda.gov/bbs/topics/NEWS/2002/NEW00814.html> (Department of Health andHuman Services, Washington, 2002).

7. Houn, F. Letter, NDA-21-107/S-005, Office of DrugEvaluation II, Centre for Drug Evaluation and Research<http://www.fda.gov/cder/foi/appletter/2002/21107s5ltr.pdf> (Food and Drug Administration to GlaxoSmithKline,2002).

8. Goldstein, D. B. Pharmacogenetics in the laboratory andthe clinic. N. Engl. J. Med. 348, 553–556 (2003).

9. Holtzman, N. A. in Pharmacogenomics: Social, Ethical,and Clinical Dimensions (ed. Rothstein, M. A.) 163–186(Wiley-Liss, Hoboken, New Jersey, 2003).

10. Omenn, G. & Motulsky, A. in Pharmacogenomics: Social,Ethical, and Clinical Dimensions (ed. Rothstein, M. A.)137–162 (Wiley-Liss, Hoboken, New Jersey, 2003).

11. Nuffield Council of Bioethics. Pharmacogenetics: EthicalIssues (Nuffield Council of Bioethics, London, 2003).

12. Melzer, D. et al. My Very Own Medicine: What Must IKnow? <http://www.phpc.cam.ac.uk/epg/Report.pdf>(Department of Public Health and Primary Care, Univ.Cambridge, Cambridge, 2003).

13. Lindpaintner, K. Pharmacogenetics and the future ofmedical practice. Br. J. Clin. Pharmacol. 54, 221–230(2002).

14. Pirmohamed, M. & Park, B. K. Genetic susceptibility toadverse drug reactions. Trends Pharmacol. Sci. 22,298–305 (2001).

15. Roses, A. Pharmacogenetics and the practice of medicineNature, 405, 857–865 (2000).

16. Clozapine Summary Sheet SS95/09<www.keele.ac.uk/depts/mm/MTRAC/ProductInfo/summaries/C/CLOZAPINEs.html> (MTRAC, Department ofMedicines Management, Keele Univ, Keele, 1995)

17. Arranz, M. J. et al. Pharmacogenetic prediction of clozapine response. Lancet 355, 1615–1616 (2000).

18. Mancama, D., Arranz, M. J. & Kerwin, R. W. Geneticpredictors of therapeutic response to clozapine: currentstatus of research. CNS Drugs 16, 317–324 (2002).

19. Holtzman, N. A. & Watson, M. S. (eds) Promoting Safeand Effective Genetic Testing in the United States. FinalReport. (Johns Hopkins Univ. Press, Baltimore,Maryland, 1998).

20. Robertson, J. A., Brody, B., Buchannan, A., Kahn, J. &McPherson, E. Pharmacogenetic challenges for the healthcare system. Health Aff. 21, 155–167 (2002).

21. Rothstein, M. A. & Epps, P. G. Ethical and legalimplications of pharmacogenomics. Nature Rev. Genet. 2,228–231 (2001).

22. Issa, A. M. Ethical perspectives on pharmacogenomicprofiling in the drug development process. Nature Rev.Drug Discov. 1, 300–308 (2002).

23. Smart, A., Parker, M. & Martin, P. Tailored medicine: whowill it fit? The ethics of patient and disease stratification.Bioethics (in the press).

24. Pirmohamed, M & Lewis, G. in RegulatingPharmaceuticals in Europe: Striving For Efficiency, Equityand Quality (eds Mossialos, E., Mrazek, M. & Walley, T.)279–296 (Open Univer. Press, Maidenhead, 2004).

25. Stearns, V., Davidson, N. E. & Flockhart, D.Pharmacogenetics in the treatment of breast cancer.Pharmacogenetics 4, 143–153 (2004).

26. Marsh, S. & McLeod, H. Cancer pharmacogenetics. Brit.J. Cancer 90, 8–11 (2004).

27. Department of Health and Human Services. Draft guidancefor industry: pharmacogenomic data submissions<http://www.fda.gov/OHRMS/DOCKETS/98fr/03d-0497-nad0001vol1.pdf> (Food and Drug Administration, 2003).

28. Savage, D. R. FDA guidance on pharmacogenomicsdata submission. Nature Rev. Drug Discov. 2, 937–938(2003).

29. The European Agency for the Evaluation of MedicinalProducts. Concept paper on pharmacogenetics —briefing matters. CPMP/4445/03<http://www.emea.eu.int/pdfs/human/pharmacogenetics/444503en.pdf> (The European Agency for the Evaluationof Medicinal Products, 23 Jan 2003).

30. Lesko, L. J. & Woodcock, J. Pharmacogenomic-guideddrug development: regulatory perspective.Pharmacogenomics J. 2, 20–24 (2002).

31. Ratner, M. L. Pharmacogenomic data and labeling: a less-safe harbor for existing drugs? Windhover’s Update<http://www/windhover.com/update/05252003/2003800094> (2003).

32. Anonymous. FDA’s Lesko says pharmacogenomicsguidance paper due mid-year. PharmacogenomicsReporter (New York) 6 (17 Jan 2003).

33. Abraham, J. & Lewis, G. Regulating Medicines in Europe(Routledge, London, 2000).

34. European Commission. The in vitro diagnostic medicaldevices directive (98/79/EC). Official J. Eur. CommunitiesL331/1 (27 Oct 1998).

35. Danzon, P. & Towse, A. The economics of genetherapy and of pharmacogenetics. Value Health 5,5–13 (2002).

36. Audit Commission. A spoonful of medicine: medicinesmanagement in NHS hospitals. <http://www.audit-commission.gov.uk/Products/NATIONAL-REPORT/E83C8921-6CEA-4b2c-83E7-F80954A80F85/nrspoonfulsugar.pdf> (Audit Commission, London, 2001).

AcknowledgementsThis research on which this paper is based was supported by aWellcome Trust grant titled ‘The clinical and commercial develop-ment of Pharmacogenetics’.

Competing interests statementThe authors declare no competing financial interests.



(FIG. 1). PGx has the potential to identify theparticular drug and the dose of drug that ismost likely to be effective and safe for eachpatient. This has become one of the maingoals of modern drug therapy, and is fre-quently described as ‘personalized medicine’.But in spite of its importance in explainingthe diversity of responses to drugs, the inte-gration of PGx into clinical practice has metconsiderable challenges.

The history of PGx reflects the evolutionof human genetics and genomics, of molecu-lar pharmacology and modern drug therapy.The field has had its visionaries and god-fathers, who realized its importance early inits history. These early pioneers laid the foun-dations for the landmark discoveries thatform the basis of present concepts andapproaches (TIMELINE).

The gestation of a disciplineSir Archibald Garrod, the perceptive physi-cian-scientist. Around the year 1898 theBritish physician Archibald Garrod was inter-ested in urinary pigments and studiedpatients at St. Bartholomew’s Hospital inLondon that had ALCAPTONURIA (see Glossary)and patients that had PORPHYRIA that wascaused by sulphonal (a hypnotic) 1,2. Garrodwas probably the first to realize the inheritedpredisposition of certain individuals to alcap-tonuria1 and other conditions. In particular,

Abstract | Physicians have long beenaware of the subtle differences in theresponses of patients to medication. Therecognition that a part of this variation isinherited, and therefore predictable,created the field of pharmacogenetics fiftyyears ago. Knowing the gene variants thatcause differences among patients has thepotential to allow ‘personalized’ drugtherapy and to avoid therapeutic failureand serious side effects.

Pharmacogenetics (PGx) deals with geneti-cally determined variation in how individualsrespond to drugs . Observations implying thatgenetic variation was responsible for the diver-sity in some drug responses were already beingmade five decades ago. We now know that thetherapeutic failure of drugs as well as seriousadverse side effects of drugs on individuals orsubpopulations of patients can both have agenetic component. The toll that such varia-tion takes in terms of individual suffering,high healthcare costs, and even lives, is increas-ingly being recognized. Recent developmentsin genomics, and associated technologicalinnovations, have invigorated the study ofsuch variation. Pharmacogenetic research hasseen an explosion of interest by physicians,geneticists and the pharmaceutical industry— as reflected in the rapid increase in thenumber of publications that contain this term

Pharmacogenetics – five decades of therapeutic lessons from genetic diversity

Urs A. Meyer

T I M E L I N E


Science and society: Integrating pharmacogenetics into society: in search of a model

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