Participant organisation name
Participant organisation short name
Scientific team leader
CoordinatorUniversity of WarwickWarwickProf Donald Singer CoventryUnited Kingdom2 University of Warwick Warwick Dr Dimitris GrammatopoulosCoventry United Kingdom3University of Leicester Leicester Prof Nilesh SamaniLeicester United Kingdom4University Hospital MaastrichtMaastrichtProf Peter de LeeuwMaastricht Netherlands 5Southampton General Hospital Southampton Dr Andrew CollinsSouthamptonUnited Kingdom 6University of Iceland Ethics Prof Vilhjalmur ArnasonReykjavikIceland7University of Warwick Warwick Dr Teresa PawlikowskaCoventry United Kingdom 8AstraZeneca ABAstraZenecaProf Andreas KindmarkMolndalSweden9Evangelismos Hospital EvangelismosDr George AndrikopoulosAthens Greece10Aristotle University of ThessalonikiAristotle Prof C ZamboulisThessalonika Greece11Euroclinic of Athens General HospitalEuroclinic Dr Dimitri RichterAthens Greece 12Athens Medical SchoolHippokration Prof Pavlos ToutouzasAthens Greece 13University of Aarhus Aarhus Prof Michael Mulvany Aarhus Denmark 14Catholic University of LeuvenLeuvenDr Jan StaessenLeuvenBelgium15University of Warwick Warwick Prof Margaret Thorogood Coventry United Kingdom 16Karolinska Institute Karolinska Prof Magnus Ingelman-SundbergStockholmSweden 17Utrecht Institute of Pharmaceutical Sciences Utrecht Prof Olaf Klungel Utrecht Netherlands 18University of Manchester Manchester Prof Anthony Heagerty Manchester United Kingdom19Hospital 12 de Octubre Madrid Prof Luis Ruilope Madrid Spain 20University of Warwick Warwick Prof Maj Hulten Coventry United Kingdom 21Uppsala University Uppsala Prof Jan DumanskiUppsala Sweden 22University of Manchester Manchester Prof Matti Hayry Manchester United Kingdom 23Lancaster University Lancaster Prof Ruth Chadwick Lancaster United Kingdom 24University of Oxford Oxford Dr Jane Kaye Oxford United Kingdom 25Lund University Lund Dr Lena Halldenius Lund Sweden 26 University of Tartu TartuProf Margit SutropTartu Estonia 27University of Central Lancashire Lancashire Prof Gardar ArnasonPreston United Kingdom 28University of Warwick Warwick Prof Wendy L Currie Coventry United Kingdom 29Jagiellonian University JagiellonianProf Adam Windak CracowPoland 30Hampton Medical Conferences LtdHampton Mrs Gerry McCarthy Middlesex United Kingdom 31Up-to-date Technologies Up-to-dateMr Jurg RohrerOberurnenSwitzerland 32Hopital de Barbois Nancy Prof Athanase Benetos Vandoeuvre Les NancyFrance 33 Universita Vita e Salute Milan Prof Giuseppe BianchiMilan Italy
Coordinator e-mail: Donald.email@example.com
Coordinator fax: +44 2476 968653
Table of Contents
Participant list 1
Project abstract 4
B 1 Scientific and technological objectives of
the project and state of the art 5
B 2 Relevance to the objectives of the specific
B 3 Potential Impact 9
5.1 Contributions to standards 9
5.2 Contribution to policy developments 9
5.3 Risk assessment and related communication strategy 10
B 4 Outline implementation plan 10
4.1 RTD and innovation 11
4.2 Demonstration activities 15
4.3 Training activities 15
4.4 Management activities 15
B 5 Description of the consortium 15
5.1 New participants 24
5.2 Sub-contracting 24
5.3 Other countries 24
B 6 Description of project management 24
B 7 Project resources 27
Integrated Project Management: justification of 27
resources and budget
B 8 Detailed 18 month implementation plan 28
8.1 Work planning Gantt 29
8.2 IP interdependence chart 30
8.3 Work Package list 31
8.4 Deliverables list 32
8.5 Work Package descriptions 33
B 9 Ethical Issues 38
B 10 Gender issues 41
Proposal summary page
Pharmacogenomics in Hypertension: Evaluation of Adverse Drug Reactions
and Response to Treatment
Research topic addressed
LSH-2005-1.2.1-2 Pharmacogenomics for individualised medicines
Heart attack and stroke are major burdens on populations and health economies in the European Union and worldwide. Effective control of high blood pressure is a key component of programmes aimed at preventing these and other important disorders of the circulation. However this requires long term treatment which is complicated by the occurrence of adverse drug reactions. These may lead to poor concordance with treatment and increased pressures on primary and secondary care services.
A major opportunity to improve therapeutic management arises from the fact that occurrence of adverse drug reactions (ADRs) can be associated with genetic polymorphisms linked to poor drug metabolism by cytochrome enzymes. Reduced efficacy of treatment and increased ADRs may also occur in response to genetic differences in drug transporters and in metabolic pathways influenced by drug treatments. Pharmacogenetic profiling thus carries the potential both to reduce incidence of ADRs and to reduce pressures on acute medical services. Reduced frequency of development of subtle as well as more serious side effects associated with long term preventive treatment could also improve efficacy of cardiovascular risk factor management.
Little is known about the benefits of pharmacogenetic profiling in clinical practice. There is great need for prospective studies to evaluate evidence for the clinical value of pharmacogenetic profiling. We aim, with joint Academic, Health Service and Industry involvement, to study prospective pharmacogenetic testing in the context of management of chronic cardiovascular disease. We shall use cohort studies of blood pressure therapeutic control and associated adverse drug reactions to test proof of concept. We shall also assess ethical, legal, patients’ and health service users’ and industry perspectives on pharmacogenetic testing and explore health economic aspects of this challenging new technology.
B.1 Scientific and technological objectives of the project and state of the art
Establishing the value in clinical practice of pharmacogenetic screening in clinical therapeutic areas is a very important research goal. Current long term treatment for chronic disorders is limited by a significant prevalence of minor but troublesome and potentially avoidable adverse drug reactions which in turn contribute to poor concordance with treatment. Adverse drug reactions (1) increase contact with medical services, 2) when severe can lead to admission to hospital and (3) contribute to poor concordance with long term treatment aimed at prevention of chronic disease, discomfort and psychological stress. High blood pressure is a very common health problem which increases in prevalence with age, affecting up to 50% of patients by the age of 70 in many populations in the European Union and worldwide. On therapy with a single blood pressure lowering agent, around 20% of patients will have mild ADRs with most new classes of treatment. The majority of patients with high blood pressure when treated to achieve evidence-based progressively lower levels of BP, will need 2 or more different treatments, compounding the chance of side-effects occurring. A broader long-term issues regarding clinical application of PG testing which will be informed by important clinically focused projects such as PGHEART is whether there may in future be an advantage to determine pharmacogenomic profiles early in life, as this will aid prescribing decisions throughout life by providing individual guidance to future treatment efficacy and to risk of avoidable ADRs.
Heart attack and stroke are major burdens on populations and health economies in the European Union and worldwide. High blood pressure is a major reversible risk factor for disorders for common disorders of heart, brain and circulation such as heart attack, heart failure and stroke. Effective control of high blood pressure is a key component of programmes aimed at preventing these important disorders. However this requires long term treatment which is complicated by the occurrence of adverse drug reactions. These may lead to poor concordance with treatment and increased pressures on primary and secondary care services.
A major opportunity to improve therapeutic management arises from the fact that occurrence of adverse drug reactions (ADRs) can be associated with genetic polymorphisms linked to poor drug metabolism by cytochrome enzymes (CYP). ADRs may also occur in response to genetic differences in durg transporters and in metabolic pathways influenced by drug treatments used in individuals. Pharmacogenetic profiling thus carries the potential both to reduce incidence of ADRs and to reduce pressures on acute medical services. Reduced frequency of development of subtle as well as more serious side effects associated with long term preventive treatment could also improve efficacy of cardiovascular risk factor management.
However little is known about the benefits of pharmacogenetic profiling in clinical practice. There is great need for prospective studies to evaluate evidence for the clinical value of pharmacogenetic profiling. We aim, with joint Academic, Health Service and Industry involvement, to study prospective pharmacogenetic testing in the context of management of chronic cardiovascular disease. We shall use cohort studies of blood pressure therapeutic control and associated adverse drug reactions to test proof of concept. A focused bioinformatics strategy is key to the success of our integrated project. We shall also assess ethics, patients’, health service users’ and industry perspectives on pharmacogenetic testing and explore health economic aspects of this challenging new technology.
Efforts to date considering the role of genetic testing in predicting clinical responsiveness have largely focused on pathways directly involved in treatment efficacy as major gene tests of interest. Our key focus involves detailed consideration of an integrated approach to understanding the clinical relevance of profiling based both on genetic determinants of medicines safety and of treatment efficacy. In particular, we aim to test the hypotheses that pharmacogenetic testing can be used to predict:
poorer therapeutic control of clinical end-points, with higher blood pressure levels used as proof of concept; poor compliance with chronic treatment; individuals at risk of more contact with medical services, more changes in medication and/or greater likelihood of stopping therapy.
We also aim to consider cultural issues influencing uptake of pharmacogenetic testing in different European populations and to compare genetic epidemiology in different European populations. This will be important in developing power calculations to inform health economic cost benefit analysis of pharmacogenetic testing in clinical practice in different regions of the EU.
Rationale and background to the project
Pharmacogenetics applies discoveries arising from genomic studies to improve the efficacy and safety of medicines. A key goal is tailoring selection of medicines for individual patients based on affordable gene testing. Adverse drug reactions (ADRs) are one of largest preventable problems facing Health Services in the European Union and beyond, contributing up to 7% of hospital admissions in the UK and over 100,000 deaths annually in the USA. ADRs are often due to prescribing errors, however may result from genetically-determined abnormal drug metabolism. Poor compliance with treatment and thus poorer control of important medical problems may arise from genetically-determined differences in pathways associated with ADRs, drug transport or drug responsiveness.
Pharmacogenetic targets These include gene differences for drug metabolizing enzymes as well as for drug transporters and pathways influencing response to treatment. Single nucleotide polymorphisms (SNPs) in members of the cytochrome P450 (CYP) enzyme family are increasingly recognized as determinants of inter-individual and ethnic differences in drug metabolism and responsiveness Around 40% of cytochrome P450-dependent drug metabolism is catalysed by polymorphic enzymes [Kalow], including important cardiovascular drugs. Around 60% of drugs cited in ADR studies are metabolised by polymorphic enzymes, with CYP enzymes accounting for 86% of these. Genetic profiling can identify patients as poor, intermediate, extensive and ultra-rapid (UR) metabolizers of drugs [Phillips et al 2001]. Poor metabolizer (PM) patients would be expected to have high drug plasma levels at standard doses and therefore be at increased risk of ADRs. UR genotypes would be expected to reduce efficacy of treatment by leading to lower than expected drug levels at a given dose of blood pressure-lowering treatment. At least 50 million people in the European Union are likely to have one or more genotypic variants resulting in poor or ultra-rapid metabolism by major drug-metabolizing enzymes or abnormalities in drug transporters or drug effector pathways. These genetic differences could predispose to poor treatment outcomes and ADRs in several ways, including effects on specific treatment for disease, effects on other treatments taken by individual patients at the same time and by influencing metabolism of disease causing metabolic pathways.
Relevance of the integrated project IP HEART will provide excellent integration of the interface between European pharmacogenetics and cardiovascular research. This will stimulate and increase excellence in the clinical application of pharmacogenetics to improving prevention of adverse drug reactions and improving efficacy of treatment aimed at reducing disorders of the heart, brain and circulation in the European and world health care systems. The IP will be developed in conjunction with SMEs, and with active sharing of expertise and facilities between academia and industry. The objectives follow a vertical path from basic genetic and clinical science to industrial implementation. This Integrated Project will thus provide the research and industrial synergy that the European Union Commission wishes to encourage.
Objectives in the EU context The key objective of this Integrated Project is thus to develop and strengthen scientific and technological excellence in the EU in the field of pharmacogenetic testing applied to medicines efficacy and safety. This will be achieved by integration of research potential and expertise in this field, at international, national and regional levels.
Contingency planning A key element will be realistic sample size based on power calculations for major end points arising from the PG diagnostic array agreed by WP members. Our consortium has ample capacity to expand recruitment of cohort centres to ensure that sufficient sample size is available for the studies proposed.
B.2 Relevance to the objectives of the LifeSciHealth Priority
The objectives of the proposed PGHEART Integrated Project clearly address the global and specific visions of ‘Thematic priority 1: Life sciences, genomics and biotechnology for health’. In particular, it aims to advance the objectives of the thematic area ‘Development of new diagnostics’, with a focus on the structuring of efforts devoted to the development of non-invasive tools for screening and predictive diagnosis in the therapeutic arena, towards the goal of individual approaches to profiling efficacy and safety of medicines. The planned integration activities of the IP fully support the objectives of this topic area in that PGHEART will focus on the structuring of currently fragmented efforts devoted to the development of non-invasive tools by co-ordinating the translation of genomic data into diagnostic applications for guiding clinical prescribing practice. Our focus on the cardiovascular clinical arena supports a key clinical goal of the Commission. Integrating tools will be established to facilitate close collaboration:
between academia, clinicians and industry in order to expand the available set of markers for informed choice concerning clinical pharmacogenetic testing;
between academia, industry, ethical bodies and regulatory authorities in order to enable efficient and effective translation of this research.
PGHEART is addressing the challenge of vertical integration across a diverse technical arena, as this is key to revolutionary change, innovation and the active involvement of different stakeholders and will provide a strategic route to social understanding of the advancement of science. PGHEART will serve as the foundation of a European Virtual Institute involving leading research groups in academia working closely together with industrial partners, in order to advance the creation and assessment of new tools and non-invasive methods for pharmacogenetic diagnostic applications. Integration activities will be fostered by technology transfer visits, exchange of scientists, sharing of sample materials reagents and tools as well as innovative use of the internet, while respecting the input of academic and industrial partners. The clinicians will have access to a large number of samples and prospective phenotypic information not normally available to the primary scientists. Of primary importance will be the sharing of resources with respect to the initial clinical evaluation of diagnostic tests.
Each of the overarching research activities would be impossible to tackle in an individual laboratory, as they require a careful integration of skills and resources recruited from the European research community. The establishment of a robust, interactive, dynamic and open project consortium of European centres of excellence, integrating national and international biotechnological efforts in this area will therefore meet the objectives of the LifeSciHealth Priority and will have a real impact on human health. In terms of its planned integration activities, PGHEART will set up efficient communication structures taking advantage of novel on-line developments that will support virtual and interactive working among PGHEART members.
Facilities for on-line conferences, working groups, and presentations with secure sites for PGHEART partners and public sites for consultation and dissemination will be established. PGHEART will thus establish a virtual institute to facilitate links between research groups and key stakeholders. This is extremely important in addressing the scientific, technical, socio-economic and policy objectives of the LifeSciHealth Priority in the area concerned through development of research infrastructure, research activities, and knowledge and skills across Europe. PGHEART will also provide a platform for student and post-doc training and exchange programmes to improve skills and employment prospects for young scientists and to foster joint activities. This will include applications by PGHEART participants for Marie Curie Research Training Networks and ERASMUS WORLD programs, as well as related industry-academia exchange programmes (run on both national and European-wide levels) that aim at the integration of newly associated member states of the EU. PGHEART will also use its electronic platform to provide links to enable the participation of wider stakeholders in the information technology society. This will involve providing links for effective communication with representatives from industry, charities, patient groups, policy makers, the media, medical and other professional societies, hospital trusts, Universities and other research and education centres, and new member states and associated member states.
Based on the integration infrastructure, PGHEART will organise on-line learning and training resources for researchers and stakeholders. This will comprise conferences with joint participation of the scientific and the stakeholder communities, training workshops, public lectures, and the provision of educational material. An important requirement will be the extension of information exchange between the research community and stakeholders, as this will form the basis for the identification of societal needs, wider promotion of the research, and education. PGHEART will therefore promote an information and consultation strategy that provides for the efficient translation of research information for stakeholder groups. The results of the research activities will therefore be disseminated to the research community as valuable tools and resources as well as to key stakeholders. We therefore expect that the impact of the project consortium's research activities will extend beyond the boundaries of the IP partners. In the context of efficient recruitment of research potential and dissemination to the community, it is therefore essential that the IP partners see themselves as representatives of a far wider community.
In supporting this IP application, it is important to note that leading European researchers have indicated their willingness to pool their expertise with a common goal in mind: the development of effective pharmacogenomic approaches for guiding therapeutic decisions. Such an objective would not be directly possible without the integrating activities, jointly executed research programme, and spreading of excellence, which the IP proposes.
B.3 Potential impact
Pharmacogenetic testing technologies in Europe and beyond are just beginning to emerge in routine use. This therefore is a critical time for this emerging and clinically important area of molecular diagnostics. PGHEART will provide a crucial contribution to assessing the impact in clinical practice of this new diagnostic technology. Testing that is provided at present is rarely performed as a clinical diagnostic test, and when performed limited to provision by specialist diagnostic laboratories or provided ad hoc by laboratories engaged in research and development. This results in a wide variety of methodologies with little or no attempt to standardise.
The PGHEART IP consortium will develop a range of measures to ensure the maximization of shared resources and infrastructure to enhance the effective evaluation of pharmacogenetic testing in the clinical setting in Europe, using the cardiovascular therapeutic area for test of concept. These measures will include recruitment of scientists that will be trained in academic and industry institutions and will disseminate technical skills throughout the entire consortium. The PGHEART IP will also co-ordinate the application for Marie Curie Research Training Networks and ERASMUS Worlds programs between consortium countries. Key staff will also be recruited to provide administrative and scientific support for the definition and implementation of standards for genotyping procedures. PGHEART integrating activities will develop fundamental instruments to support introduction and development of clinical pharmacogenetic predictive testing in Europe and beyond. Our procedures will be applied to the introduction of additional assays beyond those currently in use and being developed within the PGHEART consortium. During the first 18 months, PGHEART will focus its resources in the further development of technology to underpin PG genotyping in the clinical setting. Plans to host a series of Workshops and Symposia that will include the establishment of standards for clinical PG implementation will ensure that PGHEART will remain at the forefront of EU-based and worldwide pharmacogenetic predictive diagnostics well beyond the EU funded phase of the work.
It is inevitable that during the lifetime of the PGHEART project, greater exploitation of intellectual property associated with PG testing will occur. A central resource at the University of Warwick will ensure that intellectual property of all PGHEART members is adequately protected, and wherever possible patents provide the potential for PGHEART and PGHEART-derived SMEs to engage actively in the commercial exploitation of this intellectual property.