Integrating Pharmacogenetics Into Society: in Search of a Model

F OCUS ON PHARMACOGENETICS

29. Jones, B. C. et al. Quantitative-trait loci Acknowledgements and selling a range of specialist services to analysis of cocaine-related behaviours and Supported by National Institutes of Health grants. neurochemistry. Pharmacogenetics 9, 607–617 the pharmaceutical industry. This core Competing interests statement (1999). group is described in TABLE 1.Most of these 30. Port, J. D. & Bristow, M. R. Altered β-adrenergic The author declares no competing financial interests. receptor gene regulation and signaling in chronic heart firms have been formed since 1997 and are failure. J. Mol. Cell Cardiol. 33, 887–905 Online Links mainly located in the United States. Between (2001). 31. van Campen, L. C., Visser, F. C. & Visser, C. A. DATABASES 1997 and 2000, there was a steady growth in Ejection fraction improvement by β-blocker treatment The following terms in this article are linked online to: in patients with heart failure: an analysis of studies Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/ the number of small to medium enterprises published in the literature. J. Cardiovasc. Pharmacol. query.fcgi?db=gene working with PGx. However, in 2001 this 32 Suppl. 1, S31–S35 (1998). ADRB1 | ADRB2 | CFTR | CYP1A2 | CYP2D6 | CYP2E1 | 32. Mason, D. A., Moore, J. D., Green, S. A. & CYP3A4 | TPMT | growth slowed, and in 2002 consolidation of Liggett, S. B. A gain-of-function polymorphism in a OMIM: http://www.ncbi.nlm.nih.gov/entrez/ the sector started to take place, with five β query.fcgi?db=OMIM G-protein coupling domain of the human 1- adrenergic receptor. J. Biol. Chem. 274, cystic fibrosis mergers and acquisitions of small PGx firms 12670–12674 (1999). Access to this interactive links box is free online. between 2001 and 2002. Secondly, there are about 30 large pharmaceutical companies who are investing in PGx, either internally or through collaborations SCIENCE AND SOCIETY with smaller PGx firms. The main players — primarily global firms — are listed in BOX 1. GlaxoSmithKline, Roche and Pfizer are among Integrating pharmacogenetics into the larger investors in this technology. How- ever, it should be stressed that investment by major pharmaceutical companies can be mea- society: in search of a model sured along a ‘spectrum’ of commitment, with some companies more committed to PGx than Andrew Webster, Paul Martin, Graham Lewis and Andrew Smart others, at this point in time. In addition to these two main groups, a number of specialist Abstract | There has been considerable Health Pharmacogenetics Research Network, diagnostic companies (for example, Beckton scientific, corporate and policy interest in as well as among national health policy agen- Dickinson) and US health-care providers (for the more effective use of genetics in cies, as indicated by the UK government’s example, Kaiser Permanente) are also investing both drug development and delivery. recent White Paper on the introduction of in the technology through the formation of Pharmacogenetics — the study of the PGx (and other genetic techniques) into the collaborations with smaller firms. relationship between an individual’s genetic health service2. Since the first collaboration on PGx makeup and response to medicinal drugs — PGx is on the threshold of making a major between Genset and Abbott in 1997, a fur- has attracted global interest, but will it live up impact in commercial labs and in the clinic. ther 180 industrial alliances have been to its promise? Looking beyond the hype that But, despite its promise and the heavy invest- formed around the technology. A similar has accompanied much of the commentary ment made in the technology, many compa- pattern to the growth of dedicated firms can in the area, the future of pharmacogenetics nies still question whether there is a coherent be seen, with a steady increase in the number will depend on how competing interests and business, health policy or regulatory model of collaborations until 2001, followed by a options are resolved. emerging to shape the future development of declining rate of growth (FIG. 1).This pattern PGx. Here, on the basis of detailed research indicates that some of the momentum behind Pharmacogenetics (PGx) is concerned with conducted on the social, economic and reg- the technology might have plateaued recently, understanding and, in the clinical setting, ulatory factors shaping PGx during the past partly because of complications in getting it managing the relationship between genetic 2 years (P.M., G.L., A.S. and A.W., False to ‘work’ effectively, and partly as a result of a variation and an individual’s response to med- Positive? The Clinical and Commercial stabilizing of investment3. icinal products. It provides the possibility of Development of Pharmacogenetics,The targeting drugs according to a person’s genetic Wellcome Trust report, also see Online links Options for the development of PGx. There is make-up — so-called ‘personalized medicine’ box), we aim to provide at least a partial no single or principal model for adopting — although it will probably be used to stratify answer to this question. After reviewing PGx technology. Instead, the development of patient populations into groups determined PGx in the commercial sector, and identify- the field can be understood in terms of a by their genotype1.Stratification along these ing the different strategies being pursued, process of experimentation and the search for lines might significantly improve the develop- we discuss its likely clinical role, the regula- viable techniques, with the technology being ment, testing and use of drugs. However, real- tory regime that is emerging, and the wider applied at multiple points in the drug discov- izing these benefits will depend on the policy implications that it raises, especially ery and development process. We have identi- development of viable commercial strategies for advanced health-care systems. fied five broad innovation options for the and clinical delivery in the next few years. It application of PGx (BOX 2). might also require new approaches to regu- The development of PGx technology The first of these is aimed at improving the lation, drug approval and PHARMACOVIGILANCE at Who is developing PGx? There are two discovery of new drugs. Options 2 and 3 are national and international levels. broad groups involved in the commercial mostly concerned with using PGx to improve Given its potential, PGx has gained con- development of PGx. Firstly, about 30 small the safety and efficacy of prospective drugs siderable interest in the pharmaceutical biotechnology and genomics firms are through the re-design of clinical trials. Finally, industry and among clinical researchers — involved in conducting PGx association PGx is also being used to improve the safety such as in the US-based National Institutes of studies, developing specific genetic tests, and efficacy of medicines that have already

Table 1 | Biotechnology and genomics companies developing pharmacogenetics individuals’ genetic profiles as part of the US Food and Drug Administration (FDA)- Company Founded Location Focus imposed post-marketing commitments. This Acadia Pharmaceuticals 1997 US Pharmacogenomic drug discovery in psychiatry PGx-based research involves the prospective collection and analysis of samples from addi- Affymetrix 1992 US Gene chips for pharmacogenetic applications tional trials. The aim of this research is to identify SNPs or haplotypes that can predict Axis-Shield 1982. UK Clinical diagnostics adverse events in patients and to determine Celera Diagnostics 2000 US Clinical PGx diagnostics the genotype of polymorphic cytochrome Curagen 1996 US PGx association and toxicogenomic protein 450 (CYP450) enzymes that are studies responsible for the drug’s metabolism (REF.7, DeCODE (Encode) 1996 (1999) Iceland Clinical PGx diagnostics and Roses, A., unpublished data). (pharmacogenomics CRO) Specialist diagnostics firms and health- DiaDexus 1997 US Clinical PGx diagnostics care providers show the greatest interest in the DNAPrint Genomics 2000 US Clinical PGx diagnostics pre-prescription genotyping of patients, to DxS 2001 UK PGx genetic analysis services improve the safety and efficacy of established Epidauros 1997 Germany PGx assays and services products and the development of drug-test Epigenomics 1998 Germany Clinical PGx diagnostics combinations. Both aims offer the prospect of new diagnostics markets and reduced health- Exon Hit Therapeutics 1997 France Clinical PGx diagnostics care costs. Although this might point to a First Genetic Trust 2000 US Genetic banking services clear business model, the situation is more Gaifar 1997 Germany Clinical PGx diagnostics (viral complicated in relation to the development of genotyping) new products, as larger firms will inevitably be GAG Biosciences 2000 Germany PGx genotyping services involved. New drugs that are developed using Genaissance 1997 US PGx services and diagnostics stratified clinical trials on the basis of PGx tests Gene Logic 1994 US Toxicogenomic serivces will often require a dedicated drug-test combi- Genelex 1987 US Direct to consumer PGx testing nation to be licensed. In such cases, it is in the Genomics Health 2000 US PGx patient testing services interests of pharmaceutical companies to undertake drug-test development, either Genset (Serono) 1989 France Association studies of drug (Switzerland) response themselves or through collaboration with specialist companies. Gentris 2001 US Clinical PGx diagnostics The smaller PGx firms offer a range of Interleukin Genetics 1999 US PGx diagnostics products and services across all the different Millennium 1993 US Clinical PGx diagnostics/ options, with many working on more than pharmacogenomic drug discovery one approach. Options (1–5, as outlined Myriad Genetics 1991 US Clinical PGx association studies above) for the development of PGx, and the Orchid Biosciences 1995 US and UK PGx genotyping services relationships of the main groups of firms Oxagen 1997 UK PGx association studies involved in each option, are shown schemati- Perlegen 2000 US PGx association studies cally in FIG. 2. Sciona 2000 UK PGx diagnostics Assessing the medium-term development of Third Wave 1993 US Clinical PGx diagnostics PGx. In summary, the pharmaceutical and Vita Genomics 2001 Taiwan PGx association studies biotechnology industries are making an CRO, clinical research organization; PGx, pharmacogenetics; UK, United Kingdom; US, United States. important but varied investment in PGx. However, exactly which options are adopted depends on many crucial factors, including been licensed, mainly through the use of pre- fore, markets (for example, ABACAVIR (Ziagen; technical feasibility, commercial attractive- prescription patient genotyping (options 4 GlaxoSmithKline)). There has also been some ness, regulatory considerations and the ability and 5). limited investment in option 4, the best exam- to integrate the technology into routine clini- A detailed analysis (P.M., G.L., A.S. and ple being the case of alosetron hydrochloride cal practice. So, whereas the application of PGx A.W., The Wellcome Trust report) of PGx (Lotronex; GlaxoSmithKline). This drug, to the development of new drugs seems likely, investments and collaborations reveals that which is used for the treatment of irritable given the backing of big pharmaceutical com- most of the large pharmaceutical companies bowel syndrome, was approved then quickly panies, the introduction of pre-prescription invest mainly in options 1–3 — aimed at withdrawn voluntarily by the manufacturer genetic testing for drug response in regard to improving internal processes, reducing costs because of a number of adverse drug reac- existing drugs is much less certain, and it is and enhancing the efficiency of drug discov- tions (ADRs)5.It was subsequently approved here that investment by smaller diagnostic ery and development4.These companies have again in the United States under ‘RESTRICTED firms and health-care providers will probably little commercial interest in applications of MARKETING’ TERMS as a result of doctor/patient be important. However, even with this invest- PGx that are aimed at already licensed demand6.Consequently, research by the ment, there is the real prospect of general medicines, except where value can be added manufacturer, GlaxoSmithKline, now aims to ‘market failure’; that is, the priorities of both by extending product licences and, there- identify the relationship between ADRs and large and small firms might not deliver the

mental-health settings. Even if a test for ‘good Box 1 | Pharmacogenetics investors responders’ can be proven, the availability of a US-based near categorical answer still might not justify a Abbott Laboratories, 4 | Amgen, 1 | Becton Dickinson, 2 | Biogen, 3 | Bristol-Myers Squibb, 5 | denial of treatment, as clozapine is often a ‘last Dade Behring, 1 | Janssen, 1 | Lilly, 2 | Merck, 3 | Pfizer*, 10 | Schering Plough, 1 | Wyeth, 1 resort’ drug. Furthermore, patients deemed European Union-based ‘genetically suitable’ could remain clinically AstraZeneca, 5 | Aventis‡,5 | Bayer,4 | Biomeriux, 1 | Boehringer Ingelheim, 1 | GlaxoSmithKline§, unsuitable, for the same reasons that currently 11 | Novartis, 2 | Novo Nordisk, 1 | Roche, 2 | Roche Diagnostics, 3 | Sanofi Syntholabo, 1 limit prescription, such as a lack of personal and/or social stability, a patient’s unwillingness Japanese companies Daiichi, 2 | Ono Pharmaceuticals, 1 | Sankyo, 1 to have regular blood monitoring, or simply patient non-compliance with the drug regime. ‡ *Includes Parke-Davis, Warner Lambert and Pharmacia. Includes Rhone Poulenc Rorer. Finally, there are also concerns that PGx might §Includes SmithKline Beecham. Numbers refer to number of alliances with other companies. add further complexity to an already cumber- some clinical prescription process. greatest public health benefits (for example, process. PGx testing could, in principle, be Whilst these barriers might not be insur- testing for non-responders to widely used, used to identify not only those who suffer this mountable, they illustrate not only the type of already licensed drugs, such as the selective response, but also those who are likely to be concerns voiced by some clinicians about the serotonin-reuptake inhibitors). ‘good responders’17,18.By prescribing the drug adoption of PGx, but also how potential bar- only to patients who do not suffer agranulo- riers are specific to clinical context. In light of Translation into clinical practice cytosis and who meet the second criteria, the this, we identify some key points, covering a Discussions about PGx are approaching the overall level of ADRs could be reduced. range of cases, that highlight the general issue of adoption in clinical practice8–12. Our research with clinical practitioners problems associated with establishing a clini- However, there is little evidence about the indicates that the perceived problems associ- cal model for PGx. practical and professional issues that might ated with the adoption of PGx testing for Clinicians currently have little evidence help or hinder its adoption in specific clinical clozapine relate to the specific context of its of the utility, or even the validity, of PGx in contexts. use. These problems include the difficulty of clinical contexts9.Assuming that validity We recently examined the factors that validating a genetic marker for drug response, (analytical and clinical) can be proven, util- affect the adoption of PGx through case stud- given the problem of establishing measurable ity remains a conspicuous hurdle; this is ies of four drugs in distinct clinical contexts: biological endpoints in the diagnosis and where visions of PGx meet the reality of CLOZAPINE (Clozaril; Novartis), WARFARIN, the treatment of schizophrenia. Although repli- existing clinical practice. Generic criteria THIOPURINES (6-mercaptopurine and azathio- cating small association studies in large ran- that have been suggested for judging the prine) and ISONIAZID (P.M., G.L., A.S. and domized trials might close the ‘credibility clinical use of PGx tests have included the A.W., The Wellcome Trust report). These gap’ between a genetic marker and clinical value that is added to treatment objectives drugs were chosen because they are known outcomes, there are concerns about the practi- (such as prompt therapeutic response), the produce different responses depending on calities and ethics of conducting such trials in existence of other treatments, the size of the genotype and require monitoring regimes to ensure patient safety. We found that, in general, improved practices in prescribing drugs 250 or patient experience (by getting the right dose earlier and avoiding ADRs), and the New Total chance to refocus health service costs (by avoiding wasteful treatment), were the 200 important factors behind the introduction of PGx in these cases13–15.However,there were concerns about the use and practicality of 150 PGx in specific clinical contexts and about the weakness of the current evidence on which support for its introduction was based8,9,11,12. To illustrate these points, we will make 100 some brief suggestions on the basis of our Number of collaborations analysis of clozapine, which is used as an antipsychotic drug for patients with schizo- 50 phrenia who do not respond to, or cannot tol- erate, other drugs. Clozapine is effective in up to 50% of patients who do not respond to other drugs and 80% of those who suffer 0 from intolerable side effects from other 1997 1998 1999 2000 2001 2002 2003 drugs16.However, the drug itself is associated Year with potentially fatal blood disorders (notably Figure 1 | Commercial collaborations based on pharmacogenetics. Whereas commercial AGRANULOCYTOSIS), which necessitates a labori- collaborations have increased from 1 in 1997 to almost 200 in 2003 (pink line), there has been a decline in ous and time-consuming blood monitoring their rate of growth since 2001 (blue line).

Box 2 | Potential applications of pharmacogenetics (PGx) number of ‘orphan patients’ that had been denied access to mainstream drugs developed Option 1: using PGx to discover better drugs for the more common, most responsive geno- Discovering drugs for specific genomic sub-groups (allelic variants of drug target). type21,22,24. Discovering drugs that work in all sub-groups (ensuring leads work in all allelic variants). It therefore seems unlikely that profes- Option 2: PGx to improve the safety of new drugs in development sional acceptance will be forthcoming where Early stage trial design and/or monitoring (for example, ensuring balanced trial population of current practice is considered acceptable and cytochrome P450 variants). the use and/or practicality of PGx is unclear. ‘Rescue’ of drugs that fail clinical trials owing to safety problems. Much remains to be done to verify the use Option 3: PGx to improve the efficacy of new drugs in development and practicality of PGx in specific treatment Targeting late-stage trials as ‘good responders’ (prospective). contexts before professionals are likely to ‘Rescue’ of drugs that fail clinical trials owing to lack of efficacy (retrospective). adopt it as a routine or widespread part of clinical practice. So, the gradual use of PGx Option 4: improving the safety of licensed drugs testing in the context of oncology, for example, Pre-prescription patient testing for risk of adverse drug reactions (ADRs) (for example, reflects both the scale and importance of this thiopurine methyltransferase). disease area. It also demonstrates the need to Label and market extension of drugs that have been restricted by ADRs (for example, abacavir). Improved post-marketing surveillance. improve the therapeutic value of existing drugs: results from studies on gene expression Option 5: improving the efficacy of licensed drugs profiling in the cancer field to predict drug Pre-prescription patient testing to identify good responders. response illustrates how PGx testing might The use of efficacy data in drug marketing. begin to meet the twin demands of use and practicality 25,26. patient population and the scale of negative generate a need for (re-) education of health The emerging regulatory regime effects that might be avoided9,11,12,19.It has professionals10–12. Finally, there might be ethi- Current regulatory approval of any drug is also been recommended that PGx tests are cal concerns associated with denying treat- given on the basis of an assessment of efficacy verified, with reference to reliability, infor- ment21,22 as a result of a person being assigned and safety, which is based on data generated mation provided, and the frequency and into a particular category of genotype23.For by a series of clinical trials. Clinical trials are magnitude of the response that it predicts11. example, patients might be excluded from based on the notion that the findings from However, in routine clinical decision- using a particular drug as a result of a PGx studies of trials are ‘generalizable’ to the whole making, information about drug response test that indicated that they are ‘at risk’ from population. By contrast, the fundamental can be just one of the many influencing fac- ADR, when evidence for this might only be principle of PGx is that the drug is targeted at tors. Furthermore, because drug response is probabilistic; it has been argued that clinical patients according (at least in part) to their affected by several biological and environ- decision-making in regard to drug therapy genetically determined response, whether in mental factors, even accurate PGx informa- should not solely be on the basis of gene asso- terms of efficacy or ADRs. What does this tion might have limited value12.We found ciation, but on a detailed patient history24. mean for regulation? that, from the clinician’s perspective, judge- Moreover, there are wider ethical implica- Given the promised precision of PGx ments about the use of a PGx test are likely to tions, for example, if PGx led to a significant to determine drug response, it might be be highly context-specific, relating to the patient, their illness and the overall objectives and costs/benefits of treatment. As such, the degree of certainty that the PGx test offers was Discovery Development Marketing Use reported as a crucial factor for judging its use- Pharmacogenetics firms 4 4 fulness. To encourage clinical adoption, it will Safety Lead Diagnostic be imperative for health practitioners to be in discovery 5 firms possession of clear information that links Efficacy genotypes to clinical outcomes, and to have 134522 5 specific advice on how this might affect prescribing decisions, or alter drug dosage. CROs Practical barriers to the adoption of PGx might include the potential for increased time Clinical trial phase Health-care providers Health-care and workload burdens for laboratories and Discovery I II III Launch/ IV clinics, especially if informed consent and counselling are deemed necessary9,11,12.There Drug development companies are also likely to be resource implications, given the anticipated high costs of this new Figure 2 | Collaborative links and strategic options for the use of pharmacogenetics (PGx). technology 20.However, tests that assist in the The five options for commercially exploiting pharmacogenetics (1–5, see BOX 2) range from its use at the early stages of lead discovery (1) to its use when health care is being provided to patients (5). Different allocation of scarce resources might be well interests and needs lead to differing option priorities among actors in the PGx field. Dotted arrows in received by health-care payers and clinicians the figure indicate points of intervention in the drug development process, whereas solid arrows alike. More generally, PGx might require a indicate potential PGx products. CROs, clinical research organizations; I–IV refers to the different culture shift in prescribing practice and might phases of clinical development.

666 | SEPTEMBER 2004 | VOLUME 5 www.nature.com/reviews/genetics © 2004 Nature Publishing Group F OCUS ON PHARMACOGENETICS assumed that regulatory agencies (such as the between ‘briefing sessions’ and the current considering whether PGx can provide such FDA and the European Medicines Evaluation formal ‘scientific advice’ procedure, under benefits more widely. For example, the avail- Agency (EMEA)), will demand that every which companies can seek advice about the ability of PGx data might change the risk/ drug undergo PGx testing. However, it is type of data that regulators are likely to want benefit assessment and trigger review of an doubtful that this will be the case. PGx testing included in a Marketing Authorization already licensed drug31.Widespread adoption for a particular drug will probably be decided Application. Senior FDA staff have also of such a policy could have important impli- on the basis of the genetic factors that deter- stated that assessment will include what can cations. Moreover, from a practical point of mine the drug’s DISPOSITION,on its PHARMACO- broadly be defined as ‘clinician acceptance’ view, this broadening of the role of PGx (as DYNAMIC CHARACTERISTICS and on its THERAPEUTIC issues, particularly regarding the question of well as its more commercially driven form) INDEX. whether a PGx product can and will be used will mean that regulators will have to manage Regulators, at present, have the opinion as specified30. a massive increase in data, on a much wider that PGx will not be applicable for all types of It is possible that the important health range of treatments. drug, for both therapeutic and commercial benefits that result from PGx will come from There is also the possibility of ‘conflict of reasons. The most suitable areas for the appli- targeted therapy using existing generic drugs, interest’ situations developing, in which the cation of PGx therapy will be those in which such as warfarin, the statins, 6-mercaptop- main source of knowledge about a treatment new treatments are being developed and urine and so on. From a regulatory perspec- or indication resides in industry. Regulators where existing treatments have a narrow ther- tive, PGx offers the opportunity to enhance might become ever more reliant on company apeutic index24. patient benefit by improved targeting and sources for expertise. more effective prescribing. In some cases, The response of regulators most notably in cancer therapy, genetic test- The future Over the past 18 months, the FDA (and the ing is already widely used to aid prescrip- At present, it is unclear how regulators EMEA) has begun to collaborate with indus- tion decisions. The FDA has stated that it is might use PGx data. Indications are that gene try on PGx issues. Interventions by senior FDA staff, and statements by the recently departed FDA Commissioner, Mark McClellan, indicate Glossary that the FDA advocates the use of pharmacogenetic strategies to optimize clinical trials. The ABACAVIR NEW DRUG APPLICATION An antiviral drug, used, in conjunction with other An application requesting FDA approval to market a active encouragement of PGx by regulatory medicines, for the treatment of HIV. new drug for human use in interstate commerce. The agencies today is in stark contrast to the application must contain, among other things, data from position in 2001, when there was little indi- AGRANULOCYTOSIS specific technical viewpoints for FDA review — including cation of regulatory engagement with PGx. A condition in which there is an insufficient number chemistry, pharmacology, medical, biopharmaceutics, of white blood cells called neutrophils or granulocytes. statistics and, for anti-infectives, microbiology. However, the inconsistent evidence about This can be caused by a failure of the bone marrow the impact of PGx on therapy has lead to reg- to make sufficient neutrophils or when white PHARMACODYNAMIC CHARACTERISTICS ulatory agencies adopting a number of proce- blood cells are destroyed faster than they can be The characteristics of a drug that determine its dures to enable a more ‘united’ form of regu- produced. Affected people are susceptible to biochemical and physiological effects and its latory review, notably the FDA’s ‘voluntary infections. mechanisms of action. pharmacogenomic data submission’,or ‘safe BIOBANKS PHARMACOVIGILANCE 27 harbour’,proposal .Initiating this proposal Public or private tissue collections (derived from blood, The process of monitoring medicines to identify has required the FDA to encourage submis- DNA or other sources) comprising samples taken from previously unrecognised adverse effects; assessing the sion of pharmacogenomic data (defined data specific disease groups or healthy populations. Their risks and benefits of medicines in order to determine long-term purpose is to build biological banks that will what action, information and subsequent monitoring, if from pharmacogenomic or pharmacogenetic provide new sources of (genetic) information about any, is necessary to improve their safe use. tests) early in the development process. This disease that have clinical value. then helps discussion between the regulators THERAPEUTIC INDEX and industry; provides more information on CLOZAPINE The therapeutic index of a drug is the ratio of the toxic how useful such data could be, and attempts An antipsychotic drug that works by decreasing dose to the therapeutic (that is, effective) dose, often used abnormal excitement in the brain, used primarily as a measure of the relative safety of the drug for a to address industry concerns about the use of to treat patients with schizophrenia who either fail to particular treatment. PGx is more likely to be clinically 28 such submitted data .Concerns about this respond to or are unable to take other antipsychotic useful where the therapeutic index is narrow (i.e. when process focus on the possibility that data sub- treatments. there is a smaller amount of difference between toxic and mitted might, for one reason or another, efficacious doses). eventually form part of the formal assessment DISPOSITION Refers to all processes involved in the absorption, ‘RESTRICTED MARKETING’ TERMS procedures. For example, corporations are distribution metabolism and excretion of drugs in a A drug may have such serious adverse effects that concerned about how regulators might react living organism. regulatory approval is given for use in a specific patient if PGx data indicates that a potential safety group only, for whom it can be used safely. issue is likely to emerge over time. INVESTIGATIONAL NEW DRUG APPLICATION (IND). An application that a drug sponsor must submit THIOPURINES In Europe, the EMEA is developing a to FDA before beginning tests of a new drug on humans. A family of chemotherapeutics used to treat leukaemia, similar ‘safe harbour’ framework through The IND contains the plan for the study and is supposed as well as arthritis and inflammatory bowel disease. its ‘briefing sessions’ format29.However, to give a complete picture of the drug, including its European regulators face a similar ‘trust prob- structural formula, animal test results, and WARFARIN manufacturing information. Used to prevent blood clots from forming or growing lem’ to that of the FDA with regards to the larger (anticoagulant). Typically used for patients with status of submitted data. In the European ISONIAZID atrial fibrillation and those with a venous case, care is being taken to distinguish An antibacterial drug used to treat tuberculosis. thromboembolism.

NATURE REVIEWS | GENETICS VOLUME 5 | SEPTEMBER 2004 | 667 © 2004 Nature Publishing Group PERSPECTIVES expression data, as well as the currently more labs — so-called ‘home-brew’ tests — are the future use of biobanks and the emergence common CYP450 data (both of which affect exempt from regulations that apply to mar- of genetic epidemiology will probably aim to drug response) will feature in both ‘voluntary keted tests, although the FDA is expected to link to phenotypic information that relates submission’ and formal INVESTIGATIONAL NEW tighten controls on such tests in the future. to PGx in the clinic. In this instance, patients DRUG APPLICATION (IND) and/or NEW DRUG APPLI- would be asked to give consent for this infor- CATION (NDA) submissions. However, both Policy implications mation to be used, which might eventually the technology and, more importantly, its This paper has summarized some of the main indicate links to a predisposition to genetic interpretation, are at an early stage. Tech- initiators and constraints on the wider imple- disease. In short, genetics will be applied to nologies are available to survey the expression mentation and exploitation of PGx techniques a wider range of projects than at present levels and variability in genes that are involved in the contemporary health-care system. There (primarily specialized genetics services). The in drug response, but the question for both are many options and competing interests balance between competing demands and industry and regulators is how to use them. At involved that reflect not only the relative expectations might become the main task for present, the FDA does not have the under- immaturity of the field (at least with regard to policy-makers, counsellors, clinicians and standing or expertise to interpret such data, its role in drug development and clinical deliv- users. At present, there is no obvious public although it is taking steps towards resolving ery) but also conflicting interests as to where health policy model, owing to the different this32. priorities might lie (for example, between perceived opportunities and risks of PGx. Regarding the underlying approach, it is commercial and public health agendas). The An important criticism of an over-emphasis unlikely that PGx testing will become part five ‘options’ that are outlined in this paper are on PGx policy is that it distracts attention of regulatory requirements for all drugs. A not all mutually exclusive, although from our from more simple and cost-effective ways in drug that is highly efficacious across most evidence it is clear that the first three tend to be which ADRs might be dealt with. Research of the population, has a wide therapeutic favoured by companies, whereas the last two estimates that up to 95% of such effects could index and that shows little inter-individual are favoured by public health agencies. From a be prevented on the basis of current knowl- variability in kinetics and dynamics should governmental perspective, where ‘wealth and edge and a better management of drugs by not necessarily require PGx testing. It would health’ compete, this is an indication that there prescribing clinicians36. not be cost effective to do so. However, a is no single strategy that presents itself as a self- So, the problem is how to maintain the drug that is efficacious in 30% of the popu- evident candidate for setting policy priorities. strategic capacity to invest (in both a public lation and that has a narrow therapeutic The various overviews of the field that have and private sense) without getting trapped index, as do some current antipsychotics, recently emerged draw attention to these policy into a policy, business or clinical model that should arguably be subject to PGx testing uncertainties characterizing the development will fail and might well lead to a misuse of prior to prescription. of PGx12,24. current knowledge and resources. We advo- Despite uncertainty at this early stage, we Nonetheless, we can identify a number of cate an approach that emphasises public can expect regulators to adopt this kind of forces that are at work, shaping the future funding of research to help create a better evi- approach when assessing PGx-based applica- agenda at a global level. First, as detailed dence base for PGx; active steps to help stabi- tions. In terms of drug development, constant above, commercial interests are actively lize some of the (regulatory and ethical) dialogue between the industry and regulatory exploring the uses of PGx, especially in the uncertainties; measures to prevent market agencies will be important to ensure that the early stages of drug development, whereas failure; and investment in the PGx testing drug development process is as efficient as regulatory agencies are moving more rapidly infrastructure, as well as in the long-term, possible, whilst maintaining standards. PGx towards building a regulatory review process improved strategies at national and interna- data have reportedly already been included in in conjunction with industry. In turn, public tional levels of pharmacovigilance. 70–80 NDAs and INDs submitted to the health systems are keen to reduce their drugs Andrew Webster and Graham Lewis are at the 30 35,36 FDA .Owing to confidentiality rules, it is not bill and derive health gains from PGx . Science and Technology Studies Unit, University of possible to determine in detail the type of However, these developments are impeded by York,York YO10 5DD, United Kingdom. information that these submissions contain. various barriers, such as clinician reluctance, Paul Martin is at the Institute for Study of However, extrapolating from the picture in ongoing commercial re-positioning (with Genetics, Biorisks and Society, University of 2002, most are likely to refer to pharmaco- many PGx firms shifting their focus down- Nottingham, Nottingham NG7 2RD, genetic variability in CYP450 enzymes. stream to drug development), and uncertain- United Kingdom. Regulatory regimes for diagnostic tests are ties within regulatory agencies about the Andrew Smart is at the Oxford Genetics complex and vary across countries. Historic- wider implications of PGx for whole classes of Knowledge Park, University of Oxford, Oxford OX3 7LF, United Kingdom. ally, diagnostics have been subject to less drug24. scrutiny than medicinal products, with respon- There will be attempts, as in any complex doi:10.1038/nrg1430 1 . Smart, A. & Martin, P. The promise of personalised sibility for approval often residing with a dif- socio-technical system, to try to bring order medicine? Assessing the prospects for disease and ferent agency. The harmonization of medicinal and stability to the deployment of this new patient stratification. Stud. Hist. Philos. Biol. Biomed. Sci. (in the press). product regulation in Europe has led, in effect, technology, but an equilibrium point might 2. Department of Health. Our Inheritance, Our Future – to European-wide approval for innovative take some time to reach. In part, this is Realising the Potential of Genetics in the NHS (The 33 Stationary Office, London, 2003). products . because, beyond the confines of PGx itself, 3. Frantz, S. & Smith, A. New drug approvals for 2002. Responsibility for diagnostic products, wider developments in pharmacogenomics, Nature Rev. Drug Discov. 2, 95–96 (2003) 4. Brazell, C., Freeman, A. & Mosteller, M. Maximizing the however, remains with national agencies, complex disease genetics, BIOBANKS and func- value of medicines by including pharmacogenetic although adoption of the European in vitro tional genomics put pressure on the PGx field research in drug development and surveillance. Br. J. Clin. Pharmacol. 53, 224–231 (2002). diagnostics directive34 will bring about and disturb any hard-won ethical, commer- 5. Food and Drug Administration. Glaxo Wellcome Decide 23,24 to Withdraw Lotronex from the Market. greater coordination in the future. In the cial and clinical stability .For example, the (Office of Public Affairs, Washington, 2000).

6. Food and Drug Administration. FDA Approves restricted 34. European Commission. The in vitro diagnostic medical marketing of Lotronex. (Department of Health and L331/1 (27 Oct 1998). Human Services, Washington, 2002). 35. Danzon, P. & Towse, A. The economics of gene FURTHER INFORMATION 7. Houn, F. Letter, NDA-21-107/S-005, Office of Drug therapy and of pharmacogenetics. Value Health 5, Encyclopedia of Life Sciences: http://www.els.net/ Evaluation II, Centre for Drug Evaluation and Research 5–13 (2002). pharmacogenetics (Food and Drug Administration to GlaxoSmithKline, management in NHS hospitals. (Audit Commission, London, 2001). Oxford Genetics Knowledge Park: 9. Holtzman, N. A. in Pharmacogenomics: Social, Ethical, http://www.oxfordgkp.org and Clinical Dimensions (ed. Rothstein, M. A.) 163–186 Acknowledgements Pharmacogenetics research at SATSU: (Wiley-Liss, Hoboken, New Jersey, 2003). This research on which this paper is based was supported by a http://www.york.ac.uk/res/pgx 10. Omenn, G. & Motulsky, A. in Pharmacogenomics: Social, Wellcome Trust grant titled ‘The clinical and commercial develop- University of York Science and Technology Studies Unit: Ethical, and Clinical Dimensions (ed. Rothstein, M. A.) ment of Pharmacogenetics’. www.york.ac.uk/org/satsu 137–162 (Wiley-Liss, Hoboken, New Jersey, 2003). Webster’s homepage: 11. Nuffield Council of Bioethics. Pharmacogenetics: Ethical Competing interests statement http://www.york.ac.uk/depts/soci/s_webs.html Issues (Nuffield Council of Bioethics, London, 2003). The authors declare no competing financial interests. Access to this interactive links box is free online. 12. Melzer, D. et al. My Very Own Medicine: What Must I Know? (Department of Public Health and Primary Care, Univ. Cambridge, Cambridge, 2003). 13. Lindpaintner, K. Pharmacogenetics and the future of medical practice. Br. J. Clin. Pharmacol. 54, 221–230 (2002). TIMELINE 14. Pirmohamed, M. & Park, B. K. Genetic susceptibility to adverse drug reactions. Trends Pharmacol. Sci. 22, 298–305 (2001). 15. Roses, A. Pharmacogenetics and the practice of medicine Nature, 405, 857–865 (2000). Pharmacogenetics – five decades 16. Clozapine Summary Sheet SS95/09 (MTRAC, Department of of therapeutic lessons from Medicines Management, Keele Univ, Keele, 1995) 17. Arranz, M. J. et al. Pharmacogenetic prediction of clozapine response. Lancet 355, 1615–1616 (2000). genetic diversity 18. Mancama, D., Arranz, M. J. & Kerwin, R. W. Genetic predictors of therapeutic response to clozapine: current status of research. CNS Drugs 16, 317–324 (2002). 19. Holtzman, N. A. & Watson, M. S. (eds) Promoting Safe Urs A. Meyer and Effective Genetic Testing in the United States. Final Report. (Johns Hopkins Univ. Press, Baltimore, Maryland, 1998). Abstract | Physicians have long been (FIG. 1). PGx has the potential to identify the 20. Robertson, J. A., Brody, B., Buchannan, A., Kahn, J. & McPherson, E. Pharmacogenetic challenges for the health aware of the subtle differences in the particular drug and the dose of drug that is care system. Health Aff. 21, 155–167 (2002). responses of patients to medication. The most likely to be effective and safe for each 21. Rothstein, M. A. & Epps, P. G. Ethical and legal implications of pharmacogenomics. Nature Rev. Genet. 2, recognition that a part of this variation is patient. This has become one of the main 228–231 (2001). inherited, and therefore predictable, goals of modern drug therapy, and is fre- 22. Issa, A. M. Ethical perspectives on pharmacogenomic profiling in the drug development process. Nature Rev. created the field of pharmacogenetics fifty quently described as ‘personalized medicine’. Drug Discov. 1, 300–308 (2002). years ago. Knowing the gene variants that But in spite of its importance in explaining 23. Smart, A., Parker, M. & Martin, P. Tailored medicine: who will it fit? The ethics of patient and disease stratification. cause differences among patients has the the diversity of responses to drugs, the inte- Bioethics (in the press). potential to allow ‘personalized’ drug gration of PGx into clinical practice has met 24. Pirmohamed, M & Lewis, G. in Regulating therapy and to avoid therapeutic failure Pharmaceuticals in Europe: Striving For Efficiency, Equity considerable challenges. and Quality (eds Mossialos, E., Mrazek, M. & Walley, T.) and serious side effects. The history of PGx reflects the evolution 279–296 (Open Univer. Press, Maidenhead, 2004). of human genetics and genomics, of molecu- 25. Stearns, V., Davidson, N. E. & Flockhart, D. Pharmacogenetics in the treatment of breast cancer. Pharmacogenetics (PGx) deals with geneti- lar pharmacology and modern drug therapy. Pharmacogenetics 4, 143–153 (2004). cally determined variation in how individuals The field has had its visionaries and god- 26. Marsh, S. & McLeod, H. Cancer pharmacogenetics. Brit. J. Cancer 90, 8–11 (2004). respond to drugs . Observations implying that fathers, who realized its importance early in 27. Department of Health and Human Services. Draft guidance genetic variation was responsible for the diver- its history. These early pioneers laid the foun- for industry: pharmacogenomic data submissions (Food and Drug Administration, 2003). made five decades ago. We now know that the form the basis of present concepts and 28. Savage, D. R. FDA guidance on pharmacogenomics data submission. Nature Rev. Drug Discov. 2, 937–938 therapeutic failure of drugs as well as serious approaches (TIMELINE). (2003). adverse side effects of drugs on individuals or 29. The European Agency for the Evaluation of Medicinal Products. Concept paper on pharmacogenetics — subpopulations of patients can both have a The gestation of a discipline briefing matters. CPMP/4445/03 genetic component. The toll that such varia- Sir Archibald Garrod, the perceptive physi- (The European Agency for the Evaluation tion takes in terms of individual suffering, cian-scientist. Around the year 1898 the of Medicinal Products, 23 Jan 2003). high healthcare costs, and even lives, is increas- British physician Archibald Garrod was inter- 30. Lesko, L. J. & Woodcock, J. Pharmacogenomic-guided drug development: regulatory perspective. ingly being recognized. Recent developments ested in urinary pigments and studied Pharmacogenomics J. 2, 20–24 (2002). in genomics, and associated technological patients at St. Bartholomew’s Hospital in 31. Ratner, M. L. Pharmacogenomic data and labeling: a less- safe harbor for existing drugs? Windhover’s Update innovations, have invigorated the study of London that had ALCAPTONURIA (see Glossary) (2003). 1,2 32. Anonymous. FDA’s Lesko says pharmacogenomics seen an explosion of interest by physicians, caused by sulphonal (a hypnotic) . Garrod guidance paper due mid-year. Pharmacogenomics geneticists and the pharmaceutical industry was probably the first to realize the inherited Reporter (New York) 6 (17 Jan 2003). 33. Abraham, J. & Lewis, G. Regulating Medicines in Europe — as reflected in the rapid increase in the predisposition of certain individuals to alcap- (Routledge, London, 2000). number of publications that contain this term tonuria1 and other conditions. In particular,