Introduction
General
Resource issues
Objectives and definitions
Review
General considerations
Pharmacogenomics and response and toxicity to drugs
Disease area | Host genotype | Treatment | References |
---|---|---|---|
Optimizing drug efficacy
| |||
Chronic hepatitis C |
IL28B
| Pegylated interferon alpha, Ribavirin | |
Breast cancer, other tumors | Anthracyclines, poly(adenosine diphosphate-ribose) polymerase inhibition | ||
Preventing drug toxicities
| |||
HIV type 1 |
(HLA)-B*5701
| Abacavir | |
Rheumatic and inflammatory bowel disorders |
Thiopurine methyl transferase genotypes | Azathioprine | |
HLA-B*58:01
| Allopurinol | ||
Gastrointestinal cancers | Dehydropyrimidine dehydrogenase deficiency | 5-fluorouracil | [136] |
UGT1A1 polymorphism | Irinotecan | [137] |
Biomarkers to target treatment approaches
Disease | Biomarker | Drug | References |
---|---|---|---|
Colorectal cancer |
KRAS
| Cetuximab, panitumumab | |
Breast cancer | Estrogen receptor | Tamoxifen | |
Breast cancer | Human Epidermal Growth Factor Receptor 2 (HER 2) | Trastuzumab, pertuzumab, lapatinib, trastuzumab emtansine (TDM1) | |
Melanoma |
BRAF
| Vemurafenib, dabrafenib | |
Non-small cell lung cancer | Epidermal Growth Factor Receptor (EGFR) | Gefitinib, erlotinib, afatinib | |
Non-small cell lung cancer | Anaplastic Lymphoma Kinase (ALK) inhibitors | Crizotinib | |
Chronic myeloid leukemia | Philadelphia chromosome levels | Imatinib, nilotinib, dasatinib | |
CCR5-tropic HIV | CXCR4, CCR5 receptors | Maraviroc | [170] |
Cystic fibrosis |
G551D mutation | Ivacaftor | [88] |
Challenges and concerns for routine use of diagnostic tests
Future research priorities including strategies between the US Food and Drugs Administration and the European Medicines Agency
Key issues for healthcare and funding bodies
General
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Improvements in clinical effectiveness through tailoring treatments including their impact on length and quality of life as well as number of patients needed to treat
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Improvements in drug safety profiles/reductions in adverse drug reactions increasing the number of patients needed to harm rates
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Relevance of surrogate results (diagnostic technologies)
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Opportunities for preventive measures and interventions
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Proportion of patents affected/re-classified
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Need for post-marketing follow-up (post-introduction assessment) and not just pharmacovigilance
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Improved knowledge of pharmacogenomics among physicians
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Reassessing existing drugs and other technologies
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Redefining existing regulatory policies
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Need for including biomarkers that support indications and clinical decision making
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Maintenance of citizens’ autonomy
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Legal liability associated with targeted tests
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Protection of any patient information generated
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Whether professional ethical guidelines become statutes or mandatory guidelines
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Harmonization of laws in different contexts
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Patients’ autonomy
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Advertising - particularly direct-to-consumer advertising
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Harmonization of free movement of services to avoid or reduce citizens’ misconceptions and potentially unlawful practices
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Reduction in costs to healthcare systems with greater personalized approaches
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Who pays for diagnosis - healthcare systems, manufacturers or patients? This especially with current fragmentation of care and budgets
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Budget impact of new technologies and other considerations for reimbursement and funding including cost and Quality Adjusted Life Year considerations
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Whether the inclusion of biomarkers will lead to more clearly defined subpopulations and indications for reimbursement (in addition to regulatory considerations)
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Potential changes in reimbursement considerations and policies with smaller populations and targeted treatments
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Redefining the conditions for orphan status for new targeted treatments
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Financial incentives for citizens; active role of the citizen in his/her own health and wealth
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Co-development of drugs and genome-based diagnostics that more tightly define indications or subpopulations - requirements for approval and/or incentives for reimbursement at premium prices
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Change in the concept of health and disease (prediction)
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Ownership of the information (not only genomic)
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Sufficient understanding to justify population-based genome sequencing
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Accessibility of diagnostic tests and targeted treatments within and across countries with companies seeking ‘orphan status’ for new targeted treatments
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Patients’ understanding and patients’ role in future decision making
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Human dignity - potential for stigmatization and discrimination
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Human integrity - how this affects moral convictions, preferences and commitments
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Empowerment and increasing autonomy of patients and their relatives
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Stigmatization of certain subpopulations according to their genomic, clinical and environmental data
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Current technology makes internationalization of data possible
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Policies to promote the implementation of personalized health services:
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Legal barriers concerning different reimbursement and pricing policies that have an impact on the implementation of personalized healthcare services and products. This can cause inequity or unequal access to new technologies if not addressed
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Emphasis on wellness and disease prevention
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Change in health services paradigm with primary care and public health playing a greater role with greater stratification of patients resulting in potential changes in work- and patient-flow processes
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Greater patient empowerment and shared decision-making:
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Potential centralization of diagnostic services
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Potential decentralization of decision-making processes
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Monitoring of physician adherence to any tightly defined subpopulations; potential ways to enhance adherence where concerns
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Funds made available for data protection and complex computing systems
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To instigate Pan-European central, online, open-access repositories of biomarker and potential genomic tests of personalized therapy including their clinical utility and therapeutic implications. The data should be made readily and openly available to all key stakeholder groups.
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To establish respected groups in each country that can assess the value of new genetic tests prior to and during reimbursement or funding discussions. This builds on current activities in France, the National Institute for Health and Care Excellence, UK, the UK Genetic Testing Network and the Medicines and Healthcare Products Regulatory Agency in the UK, and the EGAPP working group in the US. This also builds on developments among HTA bodies (below).
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To introduce stricter definitions of orphan drug status to reduce the number of targeted drugs seeking this definition and their anticipated high acquisition costs, that is, 5 out of 100,000 rather than the current 5 out of 10,000 (below).
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To explore collaborative opportunities with groups such as the European Union Personalised RNA Interference to Enhance the Delivery of Individualised Cytotoxic and Targeted therapeutics consortium, and other European bodies, to deliver education to providers, practitioners and patients. This would address some of the complexities and misunderstanding that exists among key stakeholder groups regarding personalized medicine.
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To establish and support networks of professional medical institutions including Drug and Therapeutic Committees to promote critical drug evaluation peri-launch and scientifically founded recommendations. This also includes groups to assess the sensitivity and specificity of new diagnostic and prognostic tests and the implications across populations building on, for instance, the classification criteria developed by the EGAPP working group.
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To evaluate new ways of organizing care with personalized medicine placing particular emphasis on wellness and disease prevention replacing hospital-centerd care provision. This includes increased time between patients and physicians in primary care to fully explain the findings from any test to sufficiently empower patients in their decision making.
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To fully consider the legal consequences of personalized care including citizens’ autonomy, legal liability and the protection of any information generated.
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To refine new models of care broken down by pre-, per- and post-launch activities that enhance the utilization of new diagnostic technologies and new targeted treatments that can improve the care of patients.
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To extend current Horizon Scanning, early assessment and alert systems as well as budget impact analyses to include new diagnostic and prognostic biomarkers and genetic tests. The objective is to ensure that independent information regarding the clinical utility of new tests, including issues surrounding their sensitivity and specificity as well as their overall predictive value, including data on the extent of false positives and false negatives, is available when new diagnostic approaches and new drugs are being considered for reimbursement. This may mean working initially with limited evidence while new data is generated. Such services can build on the activities of International Networks and EuroScan as well as Horizon Scanning activities in for instance Germany, Italy, Sweden and the UK. This should include an assessment of the likely budget impact of new diagnostic and prognostic approaches as well as new targeted treatments, including any costs avoided. It should also be ascertained beforehand whether tissue samples can be analyzed locally, for example, tissue samples have to be sent from Scotland to the US before initiating treatment with maraviroc, adding to the cost of treatment.
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As part of this, to initiate early dialogue with groups such as the European Network for HTA, country HTA bodies and the European Medicines Agency, as well as groups developing mathematical models and system biology approaches to interpret the findings from pharmacogenomics studies and their implications for subsequent patient care.
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Through such dialogue, facilitate discussions on whether new care pathways and facilities are needed prior to launch, as well as how new diagnostic and prognostic tests will be funded, especially if there is still fragmentation in funding care.
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Where pertinent and feasible, seek partnerships between health authorities, academic institutions and commercial organizations to accelerate developments that can improve care at reduced costs - especially through greater use of generic therapies.
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If necessary, to adjust the process of HTA and other assessment bodies to robustly handle the diagnostic component of new targeted treatments.
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To consider developing new quality indicators around new targeted therapies together with key stakeholder groups. This builds on existing processes. This should include their assessment in practice acknowledging that any indicators developed must have validity in terms of content, face, concurrence, construct and prediction.
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To seek to include new indicators in any new guidance and guidelines associated with new targeted treatments, as well as potentially to consider their inclusion in any ongoing financial incentive schemes for physicians.
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To be critical of any proposed risk-sharing arrangements including targeted therapies and biomarkers and to be mindful of the potential administration costs. However, also aware that such arrangements post-launch could facilitate reimbursement and funding of new premium-priced drugs.
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Continually checking likely launch dates for new treatments with the relevant pharmaceutical companies to improve financial planning, especially given the premium prices requested for new targeted treatments.
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To integrate regular reviews of any reimbursement, funding or guidance especially as more data becomes available.
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To monitor physician adherence to any agreed guidance or reimbursement restrictions for new targeted treatments.
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To instigate additional demand-side measures such as educational initiatives and financial incentives if needed where there are concerns with adherence rates to any agreed guidance or subpopulations.
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To develop and refine new methodological approaches that take into account potential changes in clinical trials and increasing use of models in systems biology-based personalized medicine approaches - especially around defining subpopulations.
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Possibly to include progression of constructive technology assessments until more data become available. However, to be mindful of concerns with surrogate data.
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Possibly to involve HTA units with discussions to modify the legal framework as well as regulatory and approval processes as more information regarding personalized medicines become available.
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To assist with post-launch follow-up of drugs particularly to reassess product safety in routine clinical care, as well as to provide guidance where concerns.
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To focus and promote comprehensive critical research and education to understand and explore the benefits and risks with personalized diagnostic and treatment strategies.
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To assist with policy analysis and involvement in education on issues relating to personalized medicine among specialists, researchers and in the public area.
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To provide independent advice into clinical trial design for new biomarkers that are disease based; alternatively aimed at differentiating patients or populations based on either differences in drug metabolism, drug transporter capacity or receptor variants.
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To help design trials that improve our understanding of the sensitivity and specificity of new diagnostic tests, thereby reducing the uncertainty with their use. Such studies could include cohort studies with samples and data collected prospectively. Nested case–control studies are also potentially useful so long as blinding is maintained.
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To assist with the design of technology platforms and mathematical models that help with future decision making for individual patients as the complexity of biological systems unfold. By doing so, to improve the translation of research results into clinical practice.
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To push for ongoing independent reinterpretation of the implications of genetic tests and therapies in the light of new discoveries. This will be achieved through using trained clinical pharmacologists and physicians specializing in areas such as molecular oncology. This builds on the current controversies surrounding the pre-testing of patients prescribed clopidogrel or warfarin.
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To help translate the language of genomics into lay language to assist patients with their decision making, including the benefit:risk ratio of treatments. This will necessarily include improved knowledge of genomics among physicians from current low rates.
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To work with health authorities and health insurance companies pre-launch to critically review new targeted treatments, especially where there are concerns about their potential value in practice.
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As part of this, to provide guidance to health authorities and health insurance companies about potential new quality indicators.
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To provide input into discussions on the potential value of new pharmacogenetic tests that optimize the use of new drugs post-launch especially where there are considerable uncertainties regarding their clinical value.
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To assist with the design of any patient registries or expansion in Electronic Health Records prior to launch, and follow this up after launch building on the experiences with, for instance, natalizumab.
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To help authorities critically assess proposed risk sharing arrangements, especially regarding the potential administrative burden.
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To assist hospital and ambulatory care Drugs and Therapeutic Committees with critically evaluating new targeted treatments, as well as to promote interface arrangements to improve the co-ordination of care between primary and secondary care physicians.
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To help with the development of educational materials for physicians and patients peri- and post-launch based on agreed guidance.
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To support the development of patient registries and electronic record systems that help identify patients with specific genotypes to improve their care in the future.
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Where pertinent, to work with all key stakeholder groups regarding potential goals for the sensitivity and specificity of new molecular and diagnostic genetic tests alone or in combination to reduce uncertainty with their use, especially if there is reluctance to fund ‘coverage with evidence’ schemes.
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To help authorities and physicians involved in the development of personalized medicine translate the results of research findings into lay language to assist patients with future decision making.
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To seek to be an integral part of national discussions concerning the ethics and implications of genetic testing for other family members.
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To help authorities incorporate personalized medicine into patient education schemes to enhance their understanding of this complex field for better informed discussions with physicians.
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To work with authorities to make sure that patients’ dignities and integrities are preserved with greater knowledge of their genetic make-up, and that specific groups are not excluded from societies (building on earlier comments).
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To provide input to health authority and health insurance companies pre-launch discussions regarding key issues for new diagnostic tests or new targeted treatments from a patient’s perspective.
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To support the development of patient registries or other data collection activities around new targeted approaches; the results of which can also be used to inform future clinical trials and future decision making.
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To help with the design and distribution of any patient information regarding new drugs, especially where there are potential safety issues.
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To help with the development of new quality indicators for new targeted drugs from a patient’s perspective to improve their validity.
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To provide input into the assessment of the potential value of new technologies especially where the findings, including potential biomarkers, are inconclusive.
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To help refine information for patients as more knowledge becomes available about new diagnostic approaches or new drugs, especially with respect to major adverse reactions and their implications.
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To help disseminate factual information to patients, especially where there are exaggerated claims unduly raising expectations among patients or where key issues regarding the potential side-effects of treatments have not been fully explained or adequately disseminated.
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To make explicit in the trial design for new genetic tests and biomarkers whether they are dealing with diagnostic or prognostic; alternatively, disease-based or patient- or population-based technologies. This acknowledges that different trial populations will be needed, as well as different performance characteristics for different tests. For example, new screening biomarkers need high specificity to avoid generating an excessive number of false positives whereas high sensitivity is needed for new prognostic biomarkers to avoid denying treatment to patients who could potentially benefit.
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To make the objectives of any trial design specific to answer key questions. This includes potential subpopulations where the health gain of new targeted drugs is greatest. It also includes designing studies to specifically answer questions about the sensitivity and specificity of new diagnostic and prognostic tests including the extent of any false positives and false negatives.
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To instigate realism into corporate discussions regarding potential requested prices for new diagnostic tests or targeted treatments, acknowledging that the cost of providing tests includes both the acquisition costs as well as facility costs as resource pressures grow. This becomes even more important if multiple genetic tests are needed to plan future care.
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As part of this, to avoid the temptation to seek ‘orphan status’ for new targeted therapies as resource pressures grow. This may avoid rejection or delayed funding even with risk-sharing or patient access schemes to lower acquisition costs. This includes recognition that without targeting new products are increasingly unlikely to achieve premium prices as more standard drugs become available as generics and niche areas diminish.
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To acknowledge that the definition of orphan drug status may need redefining to smaller patient populations, especially with the increasing costs of orphan drugs and growing resource pressures.
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To seek scientific advice from relevant registration, HTA and funding bodies pre-launch on the potential need and relevance for developing markers and tests concurrently with developing new drugs, especially for small and medium-sized companies as part of their development process.
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Similarly, seek scientific advice for new drugs that require associated genetic testing to maximize their value especially for clinical trials that could include small subgroups of patients.
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To explore possible partnerships between diagnostic and pharmaceutical companies to provide a combined package at launch, for example, combined worldwide sales of trastuzumab and imatinib, both using established tests, were US$9.6 billion in 2010.
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To initiate possible discussions concerning rebates or discounts peri-launch to enhance the value of new targeted treatments - recognizing the complexities of current funding arrangements.
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greater cohesion of what is meant by personalized medicine and associated training
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the Human Microbiome Project
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DTC advertising
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evidence-based classification of genomic tests
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funding of new targeted tests and therapies.
Future direction and training
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ensuring a regulatory and funding environment that allows early patient access to novel and effective personalized medicine
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increasing research and development funding to develop new personalized medicines
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improving the education and training of healthcare professionals regarding personalized medicine and the various approaches
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acknowledging that new approaches may be needed for reimbursement and HTA assessment, which are required for patient access to personalized medicine and recognition of their value
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increasing awareness and understanding of personalized medicine among all stakeholder groups.
Human Microbiome Project
Direct-to-consumer advertising of genetic testing
Evidence-based classification of genomic tests in clinical practice
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level of evidence
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level of certainty - from low to high
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risk benefit profile - from unknown, unfavorable to favorable
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extent of additional research needed
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potential health impact
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evidence recommendations and actions.