Clinical pharmacology, biomarkers and personalized medicine: Education please

Biomarkers in Medicine

Volumn 3, Issue 6, 2009, Pages 685-700

  De Koning, Paul ^a   Keirns, James ^b  

^a Astellas Pharma Global Development   (Netherlands)

^b ASTELLAS PHARMA GLOBAL DEVELOPMENT   (United States)

Author keywords

Biomarker; Clinical pharmacology; Clinical practice; Education; Personalized medicine; Pharmacogenomics; PK PD modeling and simulation; Translational science

Indexed keywords

ABACAVIR; ANTIDEPRESSANT AGENT; BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; BIOLOGICAL MARKER; CETUXIMAB; CLOPIDOGREL; DASATINIB; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EZETIMIBE PLUS SIMVASTATIN; GLUCURONOSYLTRANSFERASE 1A1; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IMATINIB; IRINOTECAN; MARAVIROC; NILOTINIB; OMEPRAZOLE; PANITUMUMAB; PEGINTERFERON ALPHA; PLACEBO; RIBAVIRIN; ROFECOXIB; ROSIGLITAZONE; SPYRACEL; STEM CELL FACTOR RECEPTOR; SUNITINIB; TAMOXIFEN; TRASTUZUMAB; TROGLITAZONE; UNCLASSIFIED DRUG; UNINDEXED DRUG; WARFARIN;

BREAST CANCER; CHRONIC MYELOID LEUKEMIA; CLINICAL PHARMACOLOGY; CLINICAL PRACTICE; COLORECTAL CANCER; DRUG EFFICACY; DRUG INDUSTRY; DRUG METABOLISM; DRUG RESEARCH; DRUG RESPONSE; DRUG SAFETY; DRUG TARGETING; FAMILIAL HYPERCHOLESTEROLEMIA; GENETIC VARIABILITY; HEALTH CARE MANAGEMENT; HEPATITIS C; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYPERBILIRUBINEMIA; LIVER TOXICITY; MEDICAL EDUCATION; MEDICAL SOCIETY; NEUTROPENIA; NONHUMAN; ONCOLOGY; PHARMACODYNAMICS; PHARMACOGENOMICS; REVIEW; STATISTICAL MODEL;

EID: 75149161969     PISSN: 17520363     EISSN: None     Source Type: Journal    
DOI: 10.2217/bmm.09.53     Document Type: Review

References (109)

1. Kola I, Landis J: Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug. Discov. 3(8), 711-715 (2004). ■■ Deals with the fiscal pressures that face the pharmaceutical industry from the perspective of research and development, and addresses how productivity can be improved.
2. Drews J: Strategic trends in the drug industry. Drug. Discov. Today 8(9), 411-420 (2003).
3. Owens J: 2006 drug approvals: finding the niche. Nat. Rev. Drug Discov. 6(2), 99-101 (2007).
4. Dollery CT: Clinical pharmacology - the first 75 years and a view of the future. Br. J. Clin. Pharmacol. 61(6), 650-665 (2006).
5. Nestorov I: Whole body pharmacokinetic models. Clin. Pharmacokinet. 42 (10), 883-908 (2003).
6. Johnson TN, Rostami-Hodjegan A, Tucker GT: Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin. Pharmacokinet. 45(9), 931-956 (2006).
7. Garnett CE, Beasley N, Bhattaram VA et al.: Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. J. Clin. Pharmacol. 48(1), 13-18 (2008).
8. Bertilsson L: Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin. Pharmacokinet. 29(3), 192-209 (1995).
9. Desta Z, Zhao X, Shin JG, Plockhart DA: Clinical significance ofthe cytochrome P450 2C19 genetic polymorphism. Clin. Pharmacokinet. 41(12), 913-958 (2002).
10. Aronson JK, Cohen A, Lewis LD: Clinical pharmacology - providing tools and expertise for translational medicine. Br. J. Clin. Pharmacol. 65(2), 154-157 (2008). ■ Highlights the role of pharmacogenomics, biomarkers and other types of new techniques in translational science.
11. Sheiner LB: Learning versus confirming in clinical drug development. Clin. Pharmacol. Ther. 61(3), 275-291 (1997). ■■ Describes learning and confirming as distinct activities in drug development, each implying different goals, study designs and analysis modes.
12. Biomarkers Definitions Working Group: Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 69(3), 89-95 (2001). ■ Proposes terms, definitions and a conceptual model of the relationship of biomarkers, surrogate end points and the process of evaluating therapeutic interventions.
13. Lathia CD, Amakye D, Dai W et al.: The value, qualification, and regulatory use of surrogate end points in drug development. Clin. Pharmacol. Ther. 86(1), 32-43 (2009).
14. Woodcock J, Witter J, Dionne RA: Stimulating the development of mechanismbased, individualized pain therapies. Nat. Rev. Drug Discov. 6(9), 703-710 (2007).
15. Arendt-Nielsen L, Curatolo M, Drewes A: Human experimental pain models in drug development: translational pain research. Curr. Opin. Investig. Drugs 8(1), 41-53 (2007).
16. Chizh BA, Priestley T, Rowbotham M, Schaffler K: Predicting therapeutic efficacy - experimental pain in human subjects. Brain Res. Rev. 60(1), 243-254 (2009).
17. Lappin G, Stevens L: Biomedical accelerator mass spectrometry: recent applications in metabolism and pharmacokinetics. Expert Opin. Drug Metab. Toxicol. 4(8), 1021-1033 (2008).
18. Piquette-Miller M, Grant DM: The art and science of personalized medicine. Clin. Pharmacol. Ther. 81(3), 311-315 (2007). ■ Provides a brief historical perspective on personalized medicine and describes barriers to the translation of significant progress in pharmacogenomic research into clinical practice.
19. Lazarou J, Pomeranz BH, Corey PN: Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279(15), 1200-1205 (1998).
20. Pirmohamed M, James S, Meakin S et al.: Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ 329(7456), 15-19 (2004).
21. Budnitz DS, Shehab N, Kegler SR, Richards CL: Medication use leading to emergency department visits for adverse drug events in older adults. Ann. Intern. Med. 147(11), 755-765 (2007).
22. Hoonhout LH, de Bruijne MC, Wagner C et al.: Direct medical costs of adverse events in Dutch hospitals. BMC Health Serv. Res. 9, 27(2009).
23. Woodcock J: Chutes and ladders on the critical path: comparative effectiveness, product value, and the use of biomarkers in drug development. Clin. Pharmacol. Ther. 86(1), 12-14 (2009).
24. Lee JW, Devanarayan V, Barrett YC et al.: Fit-for-purpose method development and validation for successful biomarker measurement. Pharm. Res. 23(2), 312-328 (2006).
25. Altar CA, Amakye D, Bounos D et al.: A prototypical process for creating evidentiary standards for biomarkers and diagnostics. Clin. Pharmacol. Ther. 83(2), 368-371 (2008). ■■ Presents a framework for developing evidentiary standards for qualification of biomarkers, along with the results from initial testing of the framework.
26. Nissen SE, Wolski K: Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356(24), 2457-2471 (2007).
27. Kastelein JJ, Akdim F, Stroes ES et al.: Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl. J. Med. 358(14), 1431-1443 (2008).
28. No authors listed: Mismanaged measures. Surrogate end points can be helpful in clinical trials - but only if they are used with care. Nature 452(7187), 504 (2008).
29. Ledford H: Drug markers questioned. Nature 452(7187), 510-511 (2008).
30. Amur S, Frueh FW, Lesko U, Huang S-M: Integration and use of biomarkers in drug development, regulation and clinical practice: a US regulatory perspective. Biomarkers Med. 2(3), 305-311 (2008). ■ Reviews the application of biomarkers in different phases of drug development, regulation and clinical practice.
31. Judson I, Demetri G: Advances in the treatment of gastrointestinal stromal tumours. Ann. Oncol. 18(Suppl. 10), x20-x24 (2007).
32. Melo JV, Chuah C: Novel agents in CML therapy: tyrosine kinase inhibitors and beyond. Hematol Am. Soc. Hematol Educ. Program 2008, 427-435 (2008).
33. Dahabreh IJ, Linardou H, Siannis F, Fountzilas G, Murray S: Trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials. Oncologist 13, 620-630 (2008).
34. Slamon DJ, Clark GM, Wong SG et al.: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785), 177-182 (1987).
35. Harris L, Fritsche H, Mennel R et al.: American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. J. Clin. Oncol. 25(33), 5287-5312 (2007).
36. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F et al.: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res. 67(6), 2643-2648 (2007).
37. Lièvre A, Bachet JB, Boige V et al.: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Onco1.26(3), 374-379 (2008).
38. De Roock W, Piessevaux H, De Schutter J et al.: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann. Oncol. 19(3), 508-515 (2008).
39. Amado RG, Wolf M, Peeters M et al.: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26(10), 1626-1634 (2008).
40. Mack GS: FDA holds court on post hoc data linking KRAS status to drug response. Nat. Biotechnol. 27(2):110-112 (2009).
41. Innocenti F, Undevia SD, Iyer L et al.: Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J. Clin. Oncol. 22(8), 1382-1388 (2004).
42. Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL: UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J. Natl Cancer. Inst. 99(17), 1290-1295(2007).
43. Singer JB, Shou Y, Giles F et al.: UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia. Leukemia 21(11), 2311-2315 (2007).
44. Mallal S, Nolan D, Witt C et al.: Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359(9308), 727-732 (2002).
45. Mallal S, Phillips E, Carosi G et al.: HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med. 358(6), 568-579 (2008).
46. Vrolijk JM, de Knegt RJ, Veldt BJ, Orlent H, Schalm SW: The treatment of hepatitis C: history, presence and future. Neth. J. Med. 62(3), 76-82(2004).
47. van Soest H, Boland GJ, van Erpecum KJ: Hepatitis C: changing genotype distribution with important implications for patient management. Neth. J. Med. 64(4), 96-99 (2006).
48. de Bruijne J, Buster EH, Gelderblom HC et al.: Treatment of chronic hepatitis C virus infection - Dutch national guidelines. Neth. J. Med. 66(7), 311-322 (2000).
49. Dienstag JL, McHutchison JG: American Gastroenterological Association medical position statement on the management of hepatitis C. Gastroenterology 130(1), 225-230 (2006).
50. Dezentjé VO, Guchelaar HJ, Nortier JW, van de Velde CJ, Gelderblom H: Clinical implications of CYP2D6 genotyping in tamoxifen treatment for breast cancer. Clin. Cancer. Res. 15(1), 15-21 (2009).
51. Schroth W, Antoniadou L, Fritz P et al.: Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J. Clin. Oncol. 25(33), 5187-5193 (2007).
52. Mega JL, Close SL, Wiviott SD et al.: Cytochrome p-450 polymorphisms and response to clopidogrel. N. Engl. J. Med. 360(4), 354-362 (2009).
53. Simon T, Verstuyft C, Mary-Krause M et al.: Genetic determinants of response to clopidogrel and cardiovascular events. N. Engl. J. Med.360(4), 363-375 (2009).
54. Schwarz UI, Ritchie MD, Bradford Y et al.: Genetic determinants of response to warfarin during initial anticoagulation. N. Engl. J. Med. 358(10), 999-1008 (2000).
55. The International Warfarin Pharmacogenetics Consortium: Klein TE, Altman RB, Eriksson N et al.: Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl. J. Med. 360(8), 753-764 (2009).
56. Woodcock J, Lesko LJ: Pharmacogenetics - tailoring treatment for the outliers. N. Engl. J. Med. 360(0), 811-813 (2009).
57. Ioannidis JPA: Personalized genetic prediction: too limited, too expensive, or too soon? Ann. Intern. Med. 150(2), 139-141 (2009).
58. Wilson C, Schulz S, Waldman SA: Biomarker development, commercialization, and regulation: individualization of medicine lost in translation. Clin. Pharmacol. Ther. 81(2), 153-155 (2007).
59. Altman RB: Direct-to-consumer genetic testing: failure is not an option. Clin. Pharmacol. Ther. 86(1), 15-17 (2009).
60. Schickedanz AD, Herdman RC: Direct-to-consumer genetic testing: the need to get retail genomics right. Clin. Pharmacol. Ther. 86(1), 17-20 (2009).
61. Parkinson DR, Ziegler J: Educating for personalized medicine: a perspective from oncology. Clin. Pharmacol. Ther. 86(1), 23-25 (2009).
62. Maxwell SR, Webb DJ: Clinical pharmacology - too young so die? Lancet 367(9513), 799-800 (2006).
63. Schellens JH, Grouls R, Guchelaar HJ et al.: The Dutch vision of clinical pharmacology. Clins. Pharmacol. Ther. 85(4), 366-368 (2009).
64. US FDA: Innovation or Stagnation? Challenge and Opportunity on the Critical Path to New Medical Products. www.fda.gov/downloads/ScienceResearch/ SpecialTopics/CriticalPathInitiative/Critical PathOpportunitiesReports/ ucm113411.pdf (Accessed March 2004) ■■ The US FDA's call for the need for applied research thar bridges the gap between basic scientific research and drug development.
65. Innovative Medicines Initiative (IMI). http://imi.europa.eu/index-en.html
66. European Medicines Agency: Position Paper on Terminology in Pharmacogenetics. www.emea.europa.eu/pdfs/human/press/pp/30700en.pdf (Accessed November 2002)
67. US FDA: Guidance for Indusery - E15 Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories. www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129296.pdf (Accessed March 2008)
68. US FDA: Guidance for Industry and FDA Staff - Pharmacogenetic Tests and Genetic Tests for Heritable Markers. www.fda.gov/downloads/MedicalDevices/ DeviceRegulationandGuidance/GuidanceDocuments/ucm071075.pdf (Accessed June 2007)
69. TI Pharma: Mechanism-based PK-PD modeling platform. www.tipharma.com/ prol/general/start.asp?i=2&j =4&ck=0&p= 0&itemid=344
70. US FDA: Guidances (Drugs). www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/default.htm
71. US FDA: Guidance for Industry - Exposure-Response Relationships - Study Design, Data Analysis, and Regulatory Applications. www.fda.gov/downloads/Drugs/ Guidance ComplianceRegulatoryInformation/Guidances/ucm072109.pdf (Accessed April 2003)
72. US FDA: Pharmacometrics Staff. www.fda.gov/AboutFDA/CentersOffices/CDER/ ucm167032.htm
73. PriceWaterhouseCoopers: Personalized Medicine: The Emerging Pharmacogenomics Revolution. http://pwchealth.com/pdf/pharmacogenomics.pdf (Accessed February 2005)
74. Frueh FW: Co-Development of Drug and Test - Is It a Special Challenge with PGx? www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/ Pharmacogenetics/ucm085626.pdf (Accessed March 2006)
75. US FDA: Table of Valid Genomic Biomarkers in the Context of Approved Drug Labels. www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ ucm083378.htm (Accessed June 2009)
76. Prilosec (omeprazole) drug label (for USA). http://dailymed.nlm.nih.gov/ dailymed/drugInfo.cfm?id=7526
77. Advisory Committee For Pharmaceutical Science (ACPS), Clinical Pharmacology Subcommittee (CPSC): Case study: a quantitative approach to assess the benefits of incorporating pharmacogenomic testing in a Phase III clinical study. www.fda.gov/OHRMS/DOCKETS/ac/05/briefing/2005-4194B1-04-Topic-2.pdf (Accessed November 2005)
78. US FDA: Guidance for Industry - Pharmacogenomic Data Submissions. www.fda.gov/downloads/Regulatory Information/Guidances/ucm126957.pdf (Accessed March 2005)
79. US FDA: FDA May Issue More White Papers on Rx/Dx Codevelopment, Woodcock Says At Meeting. www.genomeweb.com/dxpgx/fda-may-issuemore-white-papers-rxdx- codevelopmentwoodcock-says-meeting (Accessed April 2009)
80. US FDA: Innovation or Stagnation? Critical Path Opportunities Report. www.fda.gov/downloads/ScienceResearch/SpecialTopics/CriticalPathInitiative/ CriticalPathOpportunitiesReports/UCM077254.pdf (Accessed March 2006)
81. European Commission RESEARCH. http://ec.europa.eu/research/fp6
82. European Commission RESEARCH. http://ec.europa.eu/research/fp7
83. European Medicines Agency: Guideline on Strategies to Identify and Mitigate Risks for First-In-human Clinical Trials with Investigational Medicinal Products. www.emea.europa.eu/pdfs/human/swp/2836707enfin.pdf (Accessed July 2007)
84. US FDA: Guidance for Industry, Investigators, and Reviewers - Exploratory IND Studies. www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM078933.pdf (Accessed January 2006)
85. US FDA: Guidance for Industry - Safety Testing of Drug Metabolites. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ ucm079266.pdf (Accessed February 2008)
86. US FDA: Guidance for Industry - Clinical Pharmacology Section of Labeling for Human Prescription Drug and Biological Products - Content and Format (Draft Guidance). www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm109739.pdf (Accessed February 2009)
87. Personalized Medicine Coalition: The case for personalized medicine. www.personalizedmedicinecoalition.org/communications/ TheCaseforPersonalizedMedicine-11-13.pdf (Accessed November 2006)
88. US FDA: FDA Issues Public Health Advisory on Vioxx as its Manufacturer Voluntarily Withdraws the Product. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/2004/ucm108361.htm (Accessed September 2004)
89. US FDA: Rezulin To Be Withdrawn From The Market. www.fda.gov/ohrms/ dockets/ac/00/backgrd/3634b1a-tab6c.htm (Accessed March 2000)
90. US FDA: Guidance for Industry: Bioanalytical Method Validation www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM070107.pdf
91. Code of Federal Regulations: Title 42, Vol. 3. Clinical Laboratory Improvement Amendment (CLIA) wwwn.cdc.gov/clia/regs/toc.aspx
92. National Committee for Clinical Laboratory Standards (CLSI): Document EP5-A: Evaluation of Precision Performance of Clinical Chemistry Devices: Approved Guideline, 1999. Document EP6-P: Evaluation of the Linearity of Quantitative Analytical Method: Proposed Guideline, 1986. Document EP7-P: Interfering Testing in Clinical Chemistry: Proposed Guideline, 1986. Document EP9-A: Method Comparison and Bias Estimation Using Patient Samples: Approved Guideline, 1995. www.clsi.org/Source/Custom/sortby.cfm?Section=Current-Versions- of-CLSI-Documents
93. Camptosar (irinotecan hydrochloride) drug label (for USA). http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=8789
94. Tasigna (nilotinib) drug label (for USA). http://dailymed.nlm.nih.gov/ dailymed/drugInfo.cfm?id=6261
95. Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf (Accessed November 2008)
96. Ziagen (abacavir sulfate) drug label (for USA). http://dailymed.nlm.nih. gov/dailymed/search.cfm?startswith=ziagen&x=9&y=5
97. Ziagen (abacavir sulfate) drug label (for EU). www.emea.europa.eu/ humandocs/PDFs/EPAR/Ziagen/H-252-PI-en.pdf
98. European Medicines Agency: Reflection Paper on the Use of Pharmacogenetics in the Pharmacokinetic Evaluation of Medicinal Products. www.emea.europa.eu/pdfs/human/pharmacogenetics/12851706enfin.pdf (Accessed May 2007)
99. Nolvaldex (tamoxifen citrate) drug label (for USA). http://dailymed.nlm. nih.gov/dailymed/search.cfm?startswith=tamoxifen
100. Plavix (clopidogrel bisulfate) drug label (for USA). http://dailymed.nlm. nih.gov/dailymed/search.cfm?startswith=plavix
101. Coumadin (warfarin sodium) drug label (for USA). http://dailymed.nlm.nih. gov/dailymed/search.cfm?startswith=coumadin&x=15&y=7
102. US FDA: FDA Clears Genetic Lab Test for Warfarin Sensitivity. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108984.htm (Accessed September 2007)
103. European Medicines Agency: Guideline on Clinical Medicinal Products Intended for the Treatment of Neuropathic Pain. www.emea.europa.eu/pdfs/human/ ewp/025203enfin.pdf (Accessed January 2007)
104. Predictive Safety Testing Consortium. www.c-path.org/pstc.cfm
105. The Biomarkers Consortium. www.biomarkersconsortium.org
106. TI Pharma. www.tipharma.com/pro1/general/home.asp
107. FDA and EMEA Conclude that New Renal Safety Biomarkers are Qualified for Specific Regulatory Purposes. www.c-path.org/pdf/PSTC-nephro-VXDS-summary-final. pdf (Accessed June 2008)
108. Department of Health & Human Services USA: Realizing the Potential of Pharmacogenomics: Opportunities and Challenges. Report of the Secretary's Advisory Committee on Genetics, Health, and Society. http://oba.od.nih.gov/oba/ SACGHS/reports/SACGHS-PGx-report.pdf (Accessed May 2008)
109. Personalized Medicine Coalition: Medco Health Solutions (2009). www.personalizedmedicinecoalition.org/about/pmc-members.php