Changing the Paradigm for Risk Assessment

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
  41192-9
• 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)n is a susceptibility
polymorphism for Gilberts 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
  Gilberts 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