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Integrating pharmacogenetics into society: in search of a model
Author: A. Webster
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"29. Jones, B. C. et al. Quantitative-trait loci analysis of cocaine-related behaviours and neurochemistry. Pharmacogenetics 9, 607?617 (1999). 30. Port, J. D. & Bristow, M. R. Altered ?-adrenergic receptor gene regulation and signaling in chronic heart failure. J. Mol. Cell Cardiol. 33, 887?905 (2001). 31. van Campen, L. C., Visser, F. C. & Visser, C. A. Ejection fraction improvement by ?-blocker treatment in patients with heart failure: an analysis of studies published 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 ? 1 - adrenergic receptor. J. Biol. Chem. 274, 12670?12674 (1999). Acknowledgements Supported by National Institutes of Health grants. Competing interests statement The author declares no competing financial interests. Online Links DATABASES The following terms in this article are linked online to: Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?db=gene ADRB1 | ADRB2 | CFTR | CYP1A2 | CYP2D6 | CYP2E1 | CYP3A4 | TPMT | OMIM: http://www.ncbi.nlm.nih.gov/entrez/ query.fcgi?db=OMIM cystic fibrosis Access to this interactive links box is free online. NATURE REVIEWS | GENETICS VOLUME 5 | SEPTEMBER 2004 | 663 F OCUS ON PHARMACOGENETICS and selling a range of specialist services to the pharmaceutical industry. This core group is described in TABLE 1.Most of these firms have been formed since 1997 and are mainly located in the United States. Between 1997 and 2000, there was a steady growth in the number of small to medium enterprises working with PGx. However, in 2001 this growth slowed, and in 2002 consolidation of the sector started to take place, with five mergers and acquisitions of small PGx firms between 2001 and 2002. Secondly, there are about 30 large pharma- ceutical companies who are investing in PGx, either internally or through collaborations with smaller PGx firms. The main players ? primarily global firms ? are listed in BOX 1. GlaxoSmithKline, Roche and Pfizer are among the larger investors in this technology. How- ever, it should be stressed that investment by major pharmaceutical companies can be mea- sured along a ?spectrum? of commitment, with some companies more committed to PGx than others, at this point in time. In addition to these two main groups, a number of specialist diagnostic companies (for example, Beckton Dickinson) and US health-care providers (for example, Kaiser Permanente) are also investing in the technology through the formation of collaborations with smaller firms. Since the first collaboration on PGx between Genset and Abbott in 1997, a fur- ther 180 industrial alliances have been formed around the technology. A similar pattern to the growth of dedicated firms can be seen, with a steady increase in the number of collaborations until 2001, followed by a declining rate of growth (FIG. 1).This pattern indicates that some of the momentum behind the technology might have plateaued recently, partly because of complications in getting it to ?work? effectively, and partly as a result of a stabilizing of investment 3 . Options for the development of PGx. There is no single or principal model for adopting PGx technology. Instead, the development of the field can be understood in terms of a process of experimentation and the search for viable techniques, with the technology being applied at multiple points in the drug discov- ery and development process. We have identi- fied five broad innovation options for the application of PGx (BOX 2). The first of these is aimed at improving the discovery of new drugs. Options 2 and 3 are mostly concerned with using PGx to improve the safety and efficacy of prospective drugs through the re-design of clinical trials. Finally, PGx is also being used to improve the safety and efficacy of medicines that have already Abstract | There has been considerable scientific, corporate and policy interest in the more effective use of genetics in both drug development and delivery. Pharmacogenetics ? the study of the relationship between an individual?s genetic makeup and response to medicinal drugs ? has attracted global interest, but will it live up to its promise? Looking beyond the hype that has accompanied much of the commentary in the area, the future of pharmacogenetics will depend on how competing interests and options are resolved. Pharmacogenetics (PGx) is concerned with understanding and, in the clinical setting, managing the relationship between genetic variation and an individual?s response to med- icinal products. It provides the possibility of targeting drugs according to a person?s genetic make-up ? so-called ?personalized medicine? ? although it will probably be used to stratify patient populations into groups determined by their genotype 1 .Stratification along these lines might significantly improve the develop- ment, testing and use of drugs. However, real- izing these benefits will depend on the development of viable commercial strategies and clinical delivery in the next few years. It might also require new approaches to regu- lation, drug approval and PHARMACOVIGILANCE at national and international levels. Given its potential, PGx has gained con- siderable interest in the pharmaceutical industry 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?s recent White Paper on the introduction of PGx (and other genetic techniques) into the health service 2 . PGx is on the threshold of making a major impact 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 coherent business, health policy or regulatory model emerging to shape the future development of PGx. Here, on the basis of detailed research conducted on the social, economic and reg- ulatory factors shaping PGx during the past 2 years (P.M., G.L., A.S. and A.W., False Positive? The Clinical and Commercial Development of Pharmacogenetics,The Wellcome Trust report, also see Online links box), we aim to provide at least a partial answer to this question. After reviewing PGx 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 wider policy implications that it raises, especially for advanced health-care systems. The development of PGx technology Who is developing PGx? There are two broad groups involved in the commercial development of PGx. Firstly, about 30 small biotechnology and genomics firms are involved in conducting PGx association studies, developing specific genetic tests, Integrating pharmacogenetics into society: in search of a model Andrew Webster, Paul Martin, Graham Lewis and Andrew Smart SCIENCE AND SOCIETY � 2004 Nature Publishing Group 664 | SEPTEMBER 2004 | VOLUME 5 www.nature.com/reviews/genetics individuals? genetic profiles as part of the US Food and Drug Administration (FDA)- imposed post-marketing commitments. This PGx-based research involves the prospective collection and analysis of samples from addi- tional trials. The aim of this research is to identify SNPs or haplotypes that can predict adverse events in patients and to determine the genotype of polymorphic cytochrome protein 450 (CYP450) enzymes that are responsible for the drug?s metabolism (REF. 7, and Roses, A., unpublished data). Specialist diagnostics firms and health- care providers show the greatest interest in the pre-prescription genotyping of patients, to improve the safety and efficacy of established products and the development of drug-test combinations. Both aims offer the prospect of new diagnostics markets and reduced health- care costs. Although this might point to a clear business model, the situation is more complicated in relation to the development of new products, as larger firms will inevitably be involved. New drugs that are developed using stratified clinical trials on the basis of PGx tests will often require a dedicated drug-test combi- nation to be licensed. In such cases, it is in the interests of pharmaceutical companies to undertake drug-test development, either themselves or through collaboration with specialist companies. The smaller PGx firms offer a range of products and services across all the different options, with many working on more than one approach. Options (1?5, as outlined above) for the development of PGx, and the relationships of the main groups of firms involved in each option, are shown schemati- cally in FIG. 2. Assessing the medium-term development of PGx. In summary, the pharmaceutical and biotechnology industries are making an important but varied investment in PGx. However, exactly which options are adopted depends on many crucial factors, including technical feasibility, commercial attractive- ness, regulatory considerations and the ability to integrate the technology into routine clini- cal practice. So, whereas the application of PGx to the development of new drugs seems likely, given the backing of big pharmaceutical com- panies, the introduction of pre-prescription genetic testing for drug response in regard to existing drugs is much less certain, and it is here that investment by smaller diagnostic firms and health-care providers will probably be important. However, even with this invest- ment, there is the real prospect of general ?market failure?; that is, the priorities of both large and small firms might not deliver the fore, markets (for example, ABACAVIR (Ziagen; GlaxoSmithKline)). There has also been some limited 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 irritable bowel syndrome, was approved then quickly withdrawn voluntarily by the manufacturer because of a number of adverse drug reac- tions (ADRs) 5 .It was subsequently approved again in the United States under ?RESTRICTED MARKETING? TERMS as a result of doctor/patient demand 6 .Consequently, research by the manufacturer, GlaxoSmithKline, now aims to identify the relationship between ADRs and been licensed, mainly through the use of pre- prescription patient genotyping (options 4 and 5). A detailed analysis (P.M., G.L., A.S. and A.W., The Wellcome Trust report) of PGx investments and collaborations reveals that most of the large pharmaceutical companies invest mainly in options 1?3 ? aimed at improving internal processes, reducing costs and enhancing the efficiency of drug discov- ery and development 4 .These companies have little commercial interest in applications of PGx that are aimed at already licensed medicines, except where value can be added by extending product licences and, there- PERSPECTIVES Table 1 | Biotechnology and genomics companies developing pharmacogenetics Company Founded Location Focus Acadia Pharmaceuticals 1997 US Pharmacogenomic drug discovery in psychiatry Affymetrix 1992 US Gene chips for pharmacogenetic applications Axis-Shield 1982. UK Clinical diagnostics Celera Diagnostics 2000 US Clinical PGx diagnostics Curagen 1996 US PGx association and toxicogenomic studies 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 (viral genotyping) 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. � 2004 Nature Publishing Group mental-health settings. Even if a test for ?good responders? can be proven, the availability of a near categorical answer still might not justify a denial of treatment, as clozapine is often a ?last resort? drug. Furthermore, patients deemed ?genetically suitable? could remain clinically unsuitable, for the same reasons that currently limit prescription, such as a lack of personal and/or social stability, a patient?s unwillingness to have regular blood monitoring, or simply patient non-compliance with the drug regime. Finally, there are also concerns that PGx might add further complexity to an already cumber- some clinical prescription process. Whilst these barriers might not be insur- mountable, they illustrate not only the type of concerns voiced by some clinicians about the adoption of PGx, but also how potential bar- riers are specific to clinical context. In light of this, we identify some key points, covering a range of cases, that highlight the general problems associated with establishing a clini- cal model for PGx. Clinicians currently have little evidence of the utility, or even the validity, of PGx in clinical contexts 9 .Assuming that validity (analytical and clinical) can be proven, util- ity remains a conspicuous hurdle; this is where visions of PGx meet the reality of existing clinical practice. Generic criteria that have been suggested for judging the clinical use of PGx tests have included the value that is added to treatment objectives (such as prompt therapeutic response), the existence 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 selective serotonin-reuptake inhibitors). Translation into clinical practice Discussions about PGx are approaching the issue of adoption in clinical practice 8?12 . However, there is little evidence about the practical and professional issues that might help or hinder its adoption in specific clinical contexts. We recently examined the factors that affect the adoption of PGx through case stud- ies of four drugs in distinct clinical contexts: CLOZAPINE (Clozaril; Novartis), WARFARIN, the THIOPURINES (6-mercaptopurine and azathio- prine) and ISONIAZID (P.M., G.L., A.S. and A.W., The Wellcome Trust report). These drugs were chosen because they are known produce different responses depending on genotype and require monitoring regimes to ensure patient safety. We found that, in gen- eral, improved practices in prescribing drugs or patient experience (by getting the right dose earlier and avoiding ADRs), and the chance to refocus health service costs (by avoiding wasteful treatment), were the important factors behind the introduction of PGx in these cases 13?15 .However,there were concerns about the use and practicality of PGx in specific clinical contexts and about the weakness of the current evidence on which support for its introduction was based 8,9,11,12 . To illustrate these points, we will make some brief suggestions on the basis of our analysis of clozapine, which is used as an antipsychotic drug for patients with schizo- 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 from intolerable side effects from other drugs 16 .However, the drug itself is associated with potentially fatal blood disorders (notably AGRANULOCYTOSIS), which necessitates a labori- ous and time-consuming blood monitoring process. PGx testing could, in principle, be used to identify not only those who suffer this response, but also those who are likely to be ?good responders? 17,18 .By prescribing the drug only to patients who do not suffer agranulo- cytosis and who meet the second criteria, the overall level of ADRs could be reduced. Our research with clinical practitioners indicates that the perceived problems associ- ated with the adoption of PGx testing for clozapine relate to the specific context of its use. These problems include the difficulty of validating a genetic marker for drug response, given the problem of establishing measurable biological endpoints in the diagnosis and treatment of schizophrenia. Although repli- cating small association studies in large ran- domized trials might close the ?credibility gap? between a genetic marker and clinical outcomes, there are concerns about the practi- calities and ethics of conducting such trials in NATURE REVIEWS | GENETICS VOLUME 5 | SEPTEMBER 2004 | 665 F OCUS ON PHARMACOGENETICS Box 1 | Pharmacogenetics investors US-based Abbott 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-based AstraZeneca, 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 companies Daiichi, 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 Number of collaborations 1997 1998 1999 2000 2001 2002 2003 250 200 150 100 50 0 TotalNew Figure 1 | Commercial collaborations based on pharmacogenetics. Whereas commercial collaborations have increased from 1 in 1997 to almost 200 in 2003 (pink line), there has been a decline in their rate of growth since 2001 (blue line). � 2004 Nature Publishing Group 666 | SEPTEMBER 2004 | VOLUME 5 www.nature.com/reviews/genetics number of ?orphan patients? that had been denied access to mainstream drugs developed for the more common, most responsive geno- type 21,22,24 . It therefore seems unlikely that profes- sional acceptance will be forthcoming where current practice is considered acceptable and the use and/or practicality of PGx is unclear. Much remains to be done to verify the use and practicality of PGx in specific treatment contexts before professionals are likely to adopt it as a routine or widespread part of clinical practice. So, the gradual use of PGx testing in the context of oncology, for example, reflects both the scale and importance of this disease area. It also demonstrates the need to improve the therapeutic value of existing drugs: results from studies on gene expression profiling in the cancer field to predict drug response illustrates how PGx testing might begin to meet the twin demands of use and practicality 25,26 . The emerging regulatory regime Current regulatory approval of any drug is given on the basis of an assessment of efficacy and safety, which is based on data generated by a series of clinical trials. Clinical trials are based on the notion that the findings from studies of trials are ?generalizable? to the whole population. By contrast, the fundamental principle of PGx is that the drug is targeted at patients according (at least in part) to their genetically determined response, whether in terms of efficacy or ADRs. What does this mean for regulation? Given the promised precision of PGx to determine drug response, it might be generate a need for (re-) education of health professionals 10?12 . Finally, there might be ethi- cal concerns associated with denying treat- ment 21,22 as a result of a person being assigned into a particular category of genotype 23 .For example, patients might be excluded from using a particular drug as a result of a PGx test that indicated that they are ?at risk? from ADR, when evidence for this might only be probabilistic; it has been argued that clinical decision-making in regard to drug therapy should not solely be on the basis of gene asso- ciation, but on a detailed patient history 24 . Moreover, there are wider ethical implica- tions, for example, if PGx led to a significant patient population and the scale of negative effects that might be avoided 9,11,12,19 .It has also been recommended that PGx tests are verified, with reference to reliability, infor- mation provided, and the frequency and magnitude of the response that it predicts 11 . However, in routine clinical decision- making, information about drug response can be just one of the many influencing fac- tors. Furthermore, because drug response is affected by several biological and environ- mental factors, even accurate PGx informa- tion might have limited value 12 .We found that, from the clinician?s perspective, judge- ments about the use of a PGx test are likely to 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 reported as a crucial factor for judging its use- fulness. To encourage clinical adoption, it will be imperative for health practitioners to be in possession of clear information that links genotypes to clinical outcomes, and to have specific advice on how this might affect pre- scribing decisions, or alter drug dosage. Practical barriers to the adoption of PGx might include the potential for increased time and workload burdens for laboratories and clinics, especially if informed consent and counselling are deemed necessary 9,11,12 .There are also likely to be resource implications, given the anticipated high costs of this new technology 20 .However, tests that assist in the allocation of scarce resources might be well received by health-care payers and clinicians alike. More generally, PGx might require a culture shift in prescribing practice and might PERSPECTIVES Box 2 | Potential applications of pharmacogenetics (PGx) Option 1: using PGx to discover better drugs Discovering 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 development Early stage trial design and/or monitoring (for example, ensuring balanced trial population of cytochrome P450 variants). ?Rescue? of drugs that fail clinical trials owing to safety problems. Option 3: PGx to improve the efficacy of new drugs in development Targeting 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 drugs Pre-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 drugs Pre-prescription patient testing to identify good responders. The use of efficacy data in drug marketing. Discovery Development Marketing Use Lead discovery I Diagnostic firms Efficacy Discovery II III Launch/ IV Drug development companies Safety 2213455 5 4 4Pharmacogenetics firms Clinical trial phase CROs Health-car e pr oviders 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 the early stages of lead discovery (1) to its use when health care is being provided to patients (5). Different interests 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. � 2004 Nature Publishing Group considering whether PGx can provide such benefits more widely. For example, the avail- ability of PGx data might change the risk/ benefit assessment and trigger review of an already licensed drug 31 .Widespread adoption of such a policy could have important impli- cations. Moreover, from a practical point of view, this broadening of the role of PGx (as well as its more commercially driven form) will mean that regulators will have to manage a massive increase in data, on a much wider range of treatments. There is also the possibility of ?conflict of interest? situations developing, in which the main source of knowledge about a treatment or indication resides in industry. Regulators might become ever more reliant on company sources for expertise. The future At present, it is unclear how regulators might use PGx data. Indications are that gene assumed that regulatory agencies (such as the FDA and the European Medicines Evaluation Agency (EMEA)), will demand that every drug undergo PGx testing. However, it is doubtful that this will be the case. PGx testing for a particular drug will probably be decided on 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 of drug, for both therapeutic and commercial reasons. The most suitable areas for the appli- cation of PGx therapy will be those in which new treatments are being developed and where existing treatments have a narrow ther- apeutic index 24 . The response of regulators Over the past 18 months, the FDA (and the EMEA) has begun to collaborate with indus- try on PGx issues. Interventions by senior FDA staff, and statements by the recently departed FDA Commissioner, Mark McClellan, indicate that the FDA advocates the use of pharmaco- genetic strategies to optimize clinical trials. The active encouragement of PGx by regulatory agencies today is in stark contrast to the position in 2001, when there was little indi- cation of regulatory engagement with PGx. However, the inconsistent evidence about the 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 ?voluntary pharmacogenomic data submission?, or ?safe harbour?, proposal 27 .Initiating this proposal has required the FDA to encourage submis- sion of pharmacogenomic data (defined data from pharmacogenomic or pharmacogenetic tests) early in the development process. This then helps discussion between the regulators and industry; provides more information on how useful such data could be, and attempts to address industry concerns about the use of such submitted data 28 .Concerns about this process focus on the possibility that data sub- mitted might, for one reason or another, eventually form part of the formal assessment procedures. For example, corporations are concerned about how regulators might react if PGx data indicates that a potential safety issue is likely to emerge over time. In Europe, the EMEA is developing a similar ?safe harbour? framework through its ?briefing sessions? format 29 .However, European regulators face a similar ?trust prob- lem? to that of the FDA with regards to the status of submitted data. In the European case, care is being taken to distinguish between ?briefing sessions? and the current formal ?scientific advice? procedure, under which companies can seek advice about the type of data that regulators are likely to want included in a Marketing Authorization Application. Senior FDA staff have also stated that assessment will include what can broadly be defined as ?clinician acceptance? issues, particularly regarding the question of whether a PGx product can and will be used as specified 30 . It is possible that the important health benefits that result from PGx will come from targeted 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 enhance patient benefit by improved targeting and more 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 NATURE REVIEWS | GENETICS VOLUME 5 | SEPTEMBER 2004 | 667 F OCUS ON PHARMACOGENETICS Glossary ABACAVIR An antiviral drug, used, in conjunction with other medicines, 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 be produced. Affected people are susceptible to infections. BIOBANKS Public or private tissue collections (derived from blood, DNA or other sources) comprising samples taken from specific disease groups or healthy populations. Their long-term purpose is to build biological banks that will provide new sources of (genetic) information about disease that have clinical value. CLOZAPINE An antipsychotic drug that works by decreasing abnormal excitement in the brain, used primarily to treat patients with schizophrenia who either fail to respond to or are unable to take other antipsychotic treatments. DISPOSITION Refers to all processes involved in the absorption, distribution metabolism and excretion of drugs in a living organism. INVESTIGATIONAL NEW DRUG APPLICATION (IND). An application that a drug sponsor must submit to FDA before beginning tests of a new drug on humans. The IND contains the plan for the study and is supposed to give a complete picture of the drug, including its structural formula, animal test results, and manufacturing 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. The application must contain, among other things, data from specific technical viewpoints for FDA review ? including chemistry, pharmacology, medical, biopharmaceutics, statistics and, for anti-infectives, microbiology. PHARMACODYNAMIC CHARACTERISTICS The characteristics of a drug that determine its biochemical and physiological effects and its mechanisms of action. PHARMACOVIGILANCE The process of monitoring medicines to identify previously unrecognised adverse effects; assessing the risks and benefits of medicines in order to determine what action, information and subsequent monitoring, if any, is necessary to improve their safe use. THERAPEUTIC INDEX The therapeutic index of a drug is the ratio of the toxic dose to the therapeutic (that is, effective) dose, often used as a measure of the relative safety of the drug for a particular treatment. PGx is more likely to be clinically useful where the therapeutic index is narrow (i.e. when there is a smaller amount of difference between toxic and efficacious doses). ?RESTRICTED MARKETING? TERMS A drug may have such serious adverse effects that regulatory approval is given for use in a specific patient group 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 growing larger (anticoagulant). Typically used for patients with atrial fibrillation and those with a venous thromboembolism. � 2004 Nature Publishing Group 668 | SEPTEMBER 2004 | VOLUME 5 www.nature.com/reviews/genetics the future use of biobanks and the emergence of genetic epidemiology will probably aim to link to phenotypic information that relates to PGx in the clinic. In this instance, patients would be asked to give consent for this infor- mation to be used, which might eventually indicate links to a predisposition to genetic disease. In short, genetics will be applied to a wider range of projects than at present (primarily specialized genetics services). The balance between competing demands and expectations might become the main task for policy-makers, counsellors, clinicians and users. At present, there is no obvious public health policy model, owing to the different perceived opportunities and risks of PGx. An important criticism of an over-emphasis on PGx policy is that it distracts attention from more simple and cost-effective ways in which ADRs might be dealt with. Research estimates that up to 95% of such effects could be prevented on the basis of current knowl- edge and a better management of drugs by prescribing clinicians 36 . So, the problem is how to maintain the strategic capacity to invest (in both a public and private sense) without getting trapped into a policy, business or clinical model that will fail and might well lead to a misuse of current knowledge and resources. We advo- cate an approach that emphasises public funding 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 market failure; and investment in the PGx testing infrastructure, as well as in the long-term, improved strategies at national and interna- tional levels of pharmacovigilance. Andrew Webster and Graham Lewis are at the Science and Technology Studies Unit, University of Yo rk,York YO10 5DD, United Kingdom. Paul Martin is at the Institute for Study of Genetics, Biorisks and Society, University of Nottingham, Nottingham NG7 2RD, United Kingdom. Andrew Smart is at the Oxford Genetics Knowledge Park, University of Oxford, Oxford OX3 7LF, United Kingdom. doi:10.1038/nrg1430 1 . Smart, A. & Martin, P. The promise of personalised medicine? Assessing the prospects for disease and patient stratification. Stud. Hist. Philos. Biol. Biomed. Sci. (in the press). 2. Department of Health. Our Inheritance, Our Future ? Realising the Potential of Genetics in the NHS (The Stationary 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 the value of medicines by including pharmacogenetic research in drug development and surveillance. Br. J. Clin. Pharmacol. 53, 224?231 (2002). 5. Food and Drug Administration. Glaxo Wellcome Decide to Withdraw Lotronex from the Market. <http://www.fda.gov/bbs/topics/answers/ANS01058.ht ml> (Office of Public Affairs, Washington, 2000). labs ? so-called ?home-brew? tests ? are exempt from regulations that apply to mar- keted tests, although the FDA is expected to tighten controls on such tests in the future. Policy implications This paper has summarized some of the main initiators and constraints on the wider imple- mentation and exploitation of PGx techniques in the contemporary health-care system. There are many options and competing interests involved that reflect not only the relative immaturity of the field (at least with regard to its role in drug development and clinical deliv- ery) but also conflicting interests as to where priorities might lie (for example, between commercial and public health agendas). The five ?options? that are outlined in this paper are not all mutually exclusive, although from our evidence it is clear that the first three tend to be favoured by companies, whereas the last two are favoured by public health agencies. From a governmental perspective, where ?wealth and health? compete, this is an indication that there is no single strategy that presents itself as a self- evident candidate for setting policy priorities. The various overviews of the field that have recently emerged draw attention to these policy uncertainties characterizing the development of PGx 12,24 . Nonetheless, we can identify a number of forces that are at work, shaping the future agenda at a global level. First, as detailed above, commercial interests are actively exploring the uses of PGx, especially in the early stages of drug development, whereas regulatory agencies are moving more rapidly towards building a regulatory review process in conjunction with industry. In turn, public health systems are keen to reduce their drugs bill and derive health gains from PGx 35,36 . However, these developments are impeded by various barriers, such as clinician reluctance, ongoing commercial re-positioning (with many PGx firms shifting their focus down- stream to drug development), and uncertain- ties within regulatory agencies about the wider implications of PGx for whole classes of drug 24 . There will be attempts, as in any complex socio-technical system, to try to bring order and stability to the deployment of this new technology, but an equilibrium point might take some time to reach. In part, this is because, beyond the confines of PGx itself, wider developments in pharmacogenomics, complex disease genetics, BIOBANKS and func- tional genomics put pressure on the PGx field and disturb any hard-won ethical, commer- cial and clinical stability 23,24 .For example, the phenotypic information that will be crucial to expression data, as well as the currently more common CYP450 data (both of which affect drug response) will feature in both ?voluntary submission? and formal INVESTIGATIONAL NEW DRUG APPLICATION (IND) and/or NEW DRUG APPLI- CATION (NDA) submissions. However, both the technology and, more importantly, its interpretation, are at an early stage. Tech- nologies are available to survey the expression levels and variability in genes that are involved in drug response, but the question for both industry and regulators is how to use them. At present, the FDA does not have the under- standing or expertise to interpret such data, although it is taking steps towards resolving this 32 . Regarding the underlying approach, it is unlikely that PGx testing will become part of regulatory requirements for all drugs. A drug that is highly efficacious across most of the population, has a wide therapeutic index and that shows little inter-individual variability in kinetics and dynamics should not necessarily require PGx testing. It would not be cost effective to do so. However, a drug that is efficacious in 30% of the popu- lation and that has a narrow therapeutic index, as do some current antipsychotics, should arguably be subject to PGx testing prior to prescription. Despite uncertainty at this early stage, we can expect regulators to adopt this kind of approach when assessing PGx-based applica- tions. In terms of drug development, constant dialogue between the industry and regulatory agencies will be important to ensure that the drug development process is as efficient as possible, whilst maintaining standards. PGx data have reportedly already been included in 70?80 NDAs and INDs submitted to the FDA 30 .Owing to confidentiality rules, it is not possible to determine in detail the type of information that these submissions contain. However, extrapolating from the picture in 2002, most are likely to refer to pharmaco- genetic variability in CYP450 enzymes. Regulatory regimes for diagnostic tests are complex and vary across countries. Historic- ally, diagnostics have been subject to less scrutiny than medicinal products, with respon- sibility for approval often residing with a dif- ferent agency. The harmonization of medicinal product regulation in Europe has led, in effect, to European-wide approval for innovative products 33 . Responsibility for diagnostic products, however, remains with national agencies, although adoption of the European in vitro diagnostics directive 34 will bring about greater coordination in the future. In the United States, tests developed by commercial PERSPECTIVES � 2004 Nature Publishing Group Online links FURTHER INFORMATION Encyclopedia of Life Sciences: http://www.els.net/ pharmacogenetics Institute for the Study of Genetics, Biorisks and Society: http://www.nottingham.ac.uk/igbis Lewis? homepage: http://www.york.ac.uk/org/satsu/Staff/graham/graham.htm Oxford Genetics Knowledge Park: http://www.oxfordgkp.org Pharmacogenetics research at SATSU: http://www.york.ac.uk/res/pgx University of York Science and Technology Studies Unit: www.york.ac.uk/org/satsu Webster?s homepage: http://www.york.ac.uk/depts/soci/s_webs.html Access to this interactive links box is free online. 6. Food and Drug Administration. FDA Approves restricted marketing of Lotronex. <http://www.fda.gov/bbs/topics/ NEWS/2002/NEW00814.html> (Department of Health and Human Services, Washington, 2002). 7. Houn, F. Letter, NDA-21-107/S-005, Office of Drug Evaluation II, Centre for Drug Evaluation and Research <http://www.fda.gov/cder/foi/appletter/2002/21107s5ltr.p df> (Food and Drug Administration to GlaxoSmithKline, 2002). 8. Goldstein, D. B. Pharmacogenetics in the laboratory and the 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: Ethical Issues (Nuffield Council of Bioethics, London, 2003). 12. Melzer, D. et al. My Very Own Medicine: What Must I Know? <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 of medical practice. Br. J. Clin. Pharmacol. 54, 221?230 (2002). 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). 16. Clozapine Summary Sheet SS95/09 <www.keele.ac.uk/depts/mm/MTRAC/ProductInfo/summ aries/C/CLOZAPINEs.html> (MTRAC, Department of Medicines 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. 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 and Effective Genetic Testing in the United States. Final Report. (Johns Hopkins Univ. Press, Baltimore, Maryland, 1998). 20. Robertson, J. A., Brody, B., Buchannan, A., Kahn, J. & McPherson, E. Pharmacogenetic challenges for the health care system. Health Aff. 21, 155?167 (2002). 21. Rothstein, M. A. & Epps, P. G. Ethical and legal implications of pharmacogenomics. Nature Rev. Genet. 2, 228?231 (2001). 22. Issa, A. M. Ethical perspectives on pharmacogenomic profiling in the drug development process. Nature Rev. Drug Discov. 1, 300?308 (2002). 23. Smart, A., Parker, M. & Martin, P. Tailored medicine: who will it fit? The ethics of patient and disease stratification. Bioethics (in the press). 24. Pirmohamed, M & Lewis, G. in Regulating Pharmaceuticals in Europe: Striving For Efficiency, Equity and 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 guidance for 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 pharmacogenomics data submission. Nature Rev. Drug Discov. 2, 937?938 (2003). 29. The European Agency for the Evaluation of Medicinal Products. Concept paper on pharmacogenetics ? briefing matters. CPMP/4445/03 <http://www.emea.eu.int/pdfs/human/pharmacogenetics/ 444503en.pdf> (The European Agency for the Evaluation of Medicinal Products, 23 Jan 2003). 30. Lesko, L. J. & Woodcock, J. Pharmacogenomic-guided drug 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/05252003/2003800 094> (2003). 32. Anonymous. FDA?s Lesko says pharmacogenomics guidance paper due mid-year. Pharmacogenomics Reporter (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 medical devices directive (98/79/EC). Official J. Eur. Communities L331/1 (27 Oct 1998). 35. Danzon, P. & Towse, A. The economics of gene therapy and of pharmacogenetics. Value Health 5, 5?13 (2002). 36. Audit Commission. A spoonful of medicine: medicines management in NHS hospitals. <http://www.audit- commission.gov.uk/Products/NATIONAL-REPORT/ E83C8921-6CEA-4b2c-83E7-F80954A80F85/ nrspoonfulsugar.pdf> (Audit Commission, London, 2001). Acknowledgements This research on which this paper is based was supported by a Wellcome Trust grant titled ?The clinical and commercial develop- ment of Pharmacogenetics?. Competing interests statement The authors declare no competing financial interests. NATURE REVIEWS | GENETICS VOLUME 5 | SEPTEMBER 2004 | 669 F OCUS ON PHARMACOGENETICS (FIG. 1). PGx has the potential to identify the particular drug and the dose of drug that is most likely to be effective and safe for each patient. This has become one of the main goals of modern drug therapy, and is fre- quently described as ?personalized medicine?. But in spite of its importance in explaining the diversity of responses to drugs, the inte- gration of PGx into clinical practice has met considerable challenges. The history of PGx reflects the evolution of 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 in its history. These early pioneers laid the foun- dations for the landmark discoveries that form the basis of present concepts and approaches (TIMELINE). The gestation of a discipline Sir Archibald Garrod, the perceptive physi- cian-scientist. Around the year 1898 the British physician Archibald Garrod was inter- ested in urinary pigments and studied patients at St. Bartholomew?s Hospital in London that had ALCAPTONURIA (see Glossary) and patients that had PORPHYRIA that was caused by sulphonal (a hypnotic) 1,2 . Garrod was probably the first to realize the inherited predisposition of certain individuals to alcap- tonuria 1 and other conditions. In particular, Abstract | Physicians have long been aware of the subtle differences in the responses of patients to medication. The recognition that a part of this variation is inherited, and therefore predictable, created the field of pharmacogenetics fifty years ago. Knowing the gene variants that cause differences among patients has the potential to allow ?personalized? drug therapy and to avoid therapeutic failure and serious side effects. Pharmacogenetics (PGx) deals with geneti- cally determined variation in how individuals respond to drugs . Observations implying that genetic variation was responsible for the diver- sity in some drug responses were already being made five decades ago. We now know that the therapeutic failure of drugs as well as serious adverse side effects of drugs on individuals or subpopulations of patients can both have a genetic 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 developments in genomics, and associated technological innovations, have invigorated the study of such variation. Pharmacogenetic research has seen an explosion of interest by physicians, geneticists and the pharmaceutical industry ? as reflected in the rapid increase in the number of publications that contain this term Pharmacogenetics ? five decades of therapeutic lessons from genetic diversity Urs A. Meyer TIMELINE � 2004 Nature Publishing Group "
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