Abacavir Hypersensitivity A model for Personalized Medicine Test Adoption

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Abacavir Hypersensitivity - A model for
Personalized Medicine Test
Adoption Hawazin Faruki, DrPH VP, Clinical
Development Laboratory Corporation of
America 10/27/09
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Profile of Laboratory Corporation of America

• National clinical reference laboratory
• Offers more than 4,400 routine and
  esoteric/genomic tests through a network of 36
  primary testing locations and 1,600 patient
  service centers
• Conducts testing on more than 400,000 specimens
  daily and delivering gt1.4 million tests results
  daily
• Provides quality lab services to more than
  220,000 physicians and other health care
  providers

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Clinical Reference Laboratory
Biomarker Identification
Market Adoption
Standard of Care Payer Adoption
Market Launch
Physician Endorsement
Slide courtesy Tom Kaminski
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Abacavir Hypersensitivity

• Abacavir (GSK) licensed for treatment of HIV in
  1998
• Hypersensitivity (HSR) in 2-9 of patients
  characterized by fever, rash, GI, respiratory,
  and constitutional symptoms
• Abacavir HSR is treatment limiting and
  potentially life threatening (rechallenge rxn)
• GSK implemented a clinical risk management
  program including physician education to increase
  awareness and clinical vigilance
• Racial differences in risk of HSR

Hughes AR, et al. Pharmacogenomics Jrnl 2008.
doi10.1038/tpj.2008.3
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Abacavir Hypersensitivity and HLA- B5701

• Association of HLA-B5701 with abacavir
  hypersensitivity first identified in 2001
• Strength of association varied by geographic
  region and by race (Sensitivity 8-57 depending
  on racial group)
• Clinical utility of the test questioned
  (potential misuse of a negative result to justify
  rechallenge)
• Skin patch testing introduced and used to
  supplement clinical case ascertainment initially
  in Australia (2004)

Hughes AR, et al. Pharmacogenomics Jrnl 2008.
doi10.1038/tpj.2008.3
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Skin Patch Testing

• Confirmation of abacavir HSR in patients with
  clinically defined hypersensitivity
• Application of abacavir to the skin via a patch
• 24-48 hours later, cutaneous reaction at the
  patch site confirms an HSR case
• Useful only if the patient has already been
  exposed to abacavir

Phillips EJ et al. AIDS 2002 162223-5 Phillips
EJ et al. AIDS 2005 19979-87
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Human Leukocyte Antigen (HLA)

• Major Histocomaptibility Complex Genes on
  Chromosome 6
• Multiple hypervariable regions within each gene.
• Polymorphic loci in the human genome related to
  immune function

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Levels of Resolution

• DRB113XX Low resolution (serological
  equivalent)
• DRB113AB Intermediate resolution (1301 or
  1302)
• results may be anywhere in a range of low/high
  resolution
• DRB11301 High resolution (4 digit
  allele-level)
• DRB1130101 Synonymous variation
• 130101 and 130102 encode the same AA sequence
• Additional digits indicate non-coding or
  expression variants

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HLA Typing at LabCorp

• In-house molecular HLA assays performed since
  1991
• High volume molecular HLA typing for the National
  Marrow Donor Program since 1992
• Blood or non-invasive buccal swab testing
• Low, intermediate of high resolution testing
• Fully accredited by CAP, ASHI, AABB, NYState
• Millions of total molecular HLA typings
  performed/yr

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HLA B5701 Initial Testing Experience in U.S.

• Physician awareness limited in 2004
• A few HIV practitioners ordered generic HLA B
  typing
• The test was often ordered inappropriately (e.g.,
  for African Americans, not for recommended
  screening application, confusion with HLA B27
  for ankylosing spondylitis,)
• LabCorp introduces a specific test for HLA-B5701
  in December 2004

Faruki H et al. Pharmacogenet Genomics 2007
17857-860
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HLA B5701 Initial Testing Experience (cont.)

• Supportive tools for physicians were provided to
  ensure proper use and interpretation of test
  results
• Report format variable sensitivity in different
  racial groups
• Educational materials including need for
  clinical vigilance
• Genetic counselors contact physicians offices to
  ensure all results are accurately interpreted
• GSK continues to investigate the hypersensitivity
  cases looking for clinical or genetic predictors
  of risk.
• Fail to identify universal markers with
  sufficient sensitivity
• Simultaneous independent studies from Australia

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HLA B5701 Initial Testing Experience (cont.)

• 2004 First study using skin patch testing
  conducted in Australia
• 78 sensitivity without skin patch testing and
  94 sensitivity with skin patch testing
• Differences in sensitivity possibly due to
  differences in hypersensitivity case definitions
• 2006 GSK Predict-1 clinical trial LabCorp
  provides testing
• July 2007 preliminary data released HLA-B5701
  screening universally applicable and effective
• August 2007 genetic counselor follow-up education
  call discontinued

Faruki H et al. Pharmacogenet Genomics 2007
17857-860
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Prospective Randomized Trial of HLA-B5701
Screening (PREDICT-1)

• Multicenter study - 1956 HIV infected patients
  from 19 countries
• Screening pre-abacavir vs. no screen
  pre-abacavir
• Immunologically confirmed abacavir
  hypersensititivity (skin patch testing)
• 0 of screened group vs. 2.7 of controls
  (plt0.001)
• Clinical diagnosis of abacavir hypersensitivity
  
• 3.4 of screened group vs. 7.8 of controls
  (plt0.001)
• Negative predictive value was 100
• Positive predictive value was 47.9

Mallal et al. NEJM 2008 358568-79
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Landmark Studies for HLA-B5701 Acceptance

• PREDICT-1 study definitively demonstrating
  clinical utility in reducing risk of abacavir HSR
• SHAPE study indicating generalizability of
  HLA-B5701 to non-white HIV patients - test
  universally applicable
• Other studies in Australia, UK, and France
  demonstrating similar results (2006-2007)

Saag M et al. Clin Infect Dis 2008
461111-8 Mallal S et al. NEJM 2008 358568-579
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HLA-B5701 At LabCorp 2005-2008

• Positivity rate decreased from 7.1 in the first
  6 months of 2005 to 3.65 in 2nd Qr 2008.
• Decreasing orders for evaluation of an allergic
  rxn and more screening orders.

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Following Establishment of Clinical Utility

• Practice guideline and/or consensus statement
  inclusion
• Government endorsement and inclusion - DHHS, CMS
  policy statements
• Payer policy statements - Insurance and managed
  care
• LabCorp experience with other examples
• HIV genotyping Viradapt GART
• HPV testing - ALTS study
• HCV genotyping Hepatitis Interventional
  Therapy Group

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Goldman Faruki 2008 Genetics in Medicine
10874-78
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Other Potential Modifiers of Test Adoption Curve

• Access to test (laboratory and/or specimen
  requirements)
• Regulatory Approval
• Reimbursement limitations
• Physician group involved

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Regulatory Factors Impacting Test Adoption

• Historically, FDA approval key to assay adoption
• More recently FDA drug labeling changes and test
  kit approvals have not resulted in test uptake
• Warfarin, UGTA1A, Cytochrome P450 chip,
• Tests with established clinical utility have been
  adopted prior to specific FDA action
• HLA-B5701, HIV resistance testing in 2000, CF
  testing in 2001
• Abacavir drug labeling update July 2008

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Tests Where Adoption Has Not Yet Occurred

• Warfarin drug labeling (2007) and FDA cleared
  test kits (2008)
• Questions of dosing
• Clinical utility still being established
• UGTA1A FDA cleared test in 2006
• Questions of utility depending on irinotecan dose
• Variable performance in different racial and
  ethnic groups
• Cytochrome P450 amplichip FDA cleared in 2005
• clinical utility not clearly established
• Drug application not yet fully defined (SSRIs
  and EGAPP)

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Other Payer and Reimbursement Limitations

• Sometimes no applicable existing CPT code
• New CPT code is a multi year process
• Multiples of the same CPT codes can be limited by
  payers denying payment
• Cost effectiveness data may suggest lower pricing
• Licensing and royalty burden may be limiting
• For HLA-B5701 CPT coding already well
  established
• Cost effectiveness studies for HLA-B5701
  demonstrating effectiveness

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Test (HLA-B5701) Adoption Influenced by
Physician Group Involved

• HIV Practitioners
• small closely-knit group
• good education network already established
• well versed in molecular diagnostics
• accustomed to adjusting drug regimens based on
  molecular viral load and resistance testing
• Expected to incorporate new developments into
  their practice on a regular basis

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HLA-B5701 Test Adoption Summary

• Well controlled and adequately powered studies
  demonstrating definitive clinical utility drive
  test adoption.
• Label revisions and regulatory guidance
  accompanied test adoption but did not
  necessarily drive test adoption.
• Reimbursement limitations and CPT coding may slow
  adoption however reimbursement was well
  established in this case.
• Other considerations test access, specimen
  requirements, and physician group involved,
  facilitated test adoption