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Changing the Paradigm for Risk Assessment

Changing the Paradigm for Risk Assessment. Penelope K. Manasco, M.D. Chief Medical Officer First Genetic Trust. Adverse Drug Reactions: A Growing Problem. Drug-related mortality and morbidity estimated to cost U.S. health care system $177Bn in 2000

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Changing the Paradigm for Risk Assessment

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  1. Changing the Paradigm for Risk Assessment Penelope K. Manasco, M.D. Chief Medical Officer First Genetic Trust

  2. Adverse Drug Reactions: A Growing Problem • Drug-related mortality and morbidity estimated to cost U.S. health care system $177Bn in 2000 • Represents over 10% of total U.S. health care spending • Nearly double the 1995 estimate • Approximately equal to the costs of medicines • Ernst and Grizzle, J. Am Pharm Assoc 2001; 41:192-9 • During the past 25 years, 1 in 5 medicines were found to have serious side effects that were not recognized at the time of marketing • Lasser et. Al. JAMA 287(17):2215-2220. • The rate of drug withdrawals has not changed over time

  3. Advances enable new methodology • Pharmacogenomics • IT security, infrastructure, and scaling • Network connectivity

  4. Key Requirements for Functional & Clinical Genomics Well phenotyped patients  dynamic & longitudinal clinical profiles Full Genome SNP Map IT infrastructures and molecular data sets  DIC, high security, & functional integration Robust, cost effective genotyping technology

  5. TPMT Polymorphisms Direct Dosing for Thiopurine Drugs The diagram illustrates the use of TPMT pharmacogenetics to optimize 6-MP therapy for childhood ALL, as a model to demonstrate the prospective use of genotype to guide treatment. This approach requires prospective validation before it can be recommended for broad application in the optimization of thiopurine therapy. McLeod and Siva, Pharmacogenomics 3(1):89-98, 2002. ALL: Acute lymphoblastic leukemia; 6-MP: 6-Mercaptopurine; TPMT: Thiopurine methyltransferase.

  6. UDPGT1A1 mutation(TA)nis a susceptibility polymorphism for Gilbert’s syndrome • ATATATATATATATAA = 6 repeats or ATATATATATATATATAA = 7 repeats • Number of repeats correlates with baseline levels of bilirubin • 92% of Tranilast hyperbilirubinemia patients in Presto trial with susceptibility to drug-induced Gilbert’s patients are 7/7, a few 7/6, no 6/6; controls with 7/7 did not develop hyperbilirubinemia with Tx

  7. Association of HLA-B57 and HSR The presence of HLA-B57 is more common in cases (46%) than controls (4%) 95% CI around the point estimate of .46 is (.31,.61)

  8. Is the association of HLA B-57 found in minority samples? (CNA30032 Subjects: Summary of Allelic Test Results)

  9. Summary of Results for Drug B These are single marker analyses

  10. IT Infrastructure Can Address Privacy, Education, Reporting, Scaling and Connectivity

  11. NetMeDS Collaborative Network A Partnership with the Provider Industry

  12. Recommendations • Stronger language requiring genetic sample collection • Implement test programs for active surveillance in periapproval process • Complete reporting • Biosample collection • Broader populations • Demonstration projects for OTC/Generic Drugs developing and validating pharmacogenetic safety markers

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