Studies of Inhibitors Opportunities for Harmonization

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Studies of InhibitorsOpportunities for
Harmonization

• World Federation of Hemophilia
• Global Forum
• Montreal, Canada
• September 25, 2009

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Inhibitor Importance

• Serious complication of treatment
• Life-changing experience for patients
• Results in vastly increased cost of care
• Risk of inhibitors likely affects care
• May be a barrier to availability of new and novel
  products
• Difficulties in the assessment of inhibitor risk
  in clinical trials of new products

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FDA Requests

• 2003 FDA Workshop on Clinical Study Design
• Inhibitor titers done at a central lab
• Number of exposure days should be captured
• Genomic screening of enrollees
• Any product switch should be recorded
• Any lack of effect (defined as increase in dose
  or frequency of dosing) should be recorded
• International collaboration

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EMEA Guidelines

• Expert meeting held in February 2006
• Detailed information on product exposure
• Inhibitor testing
• Should use Nijmegen method
• Quality control is important
• Testing on regular basis, prior to product switch
  and in response to a clinical indication of
  inhibitor
• Hemophilia gene defect
• International harmonization of datasets

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Global Harmonization

• 2006 ISTH FVIII FIX Subcommittee meeting
• Comparison of US and UK data elements
• Suggestions for possible harmonization
• Sharing of data collection instruments
• 2007 ISTH FVIII FIX Subcommittee meeting
• Presentation of plan by UK and Germany for
  harmonized data collection on inhibitors

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Inhibitor Research Challenges

• Characterization and risk assessment of rare
  adverse events is methodologically difficult
• Evaluation of treatment product risk using a
  probabilistic model is imperfect
• Clinical trial methodology is problematic
• Sample size not adequate to fully assess risk
• Incomplete assessment of risk factors
• Randomization to larger population is problematic

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Epidemiologic Issues

• Estimates of risk based on probability
• 100 certainty possible with entire population
• Practical approach is to take a sample
• Confidence about estimate related to sample size
• Larger the sample the more confidence
• Other factors that drive sample size
• Magnitude of the risk that is being measured
• The number of risk factors under examination

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Problems with Inhibitors

• Hemophilia is a rare disorder study population
  is widely distributed
• Inhibitors are a rare event must study a large
  population to achieve adequate case numbers
• Many possible risk factors
• Genetic (e.g., mutation, immune modifiers, family
  history, race)
• Environmental (e.g., factor product,
  circumstances of infusion)

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What is being done?

• Several studies are underway examining various
  aspects of inhibitor development
• What are the variations in
• Study methodologies
• Target populations
• Data elements
• To what extent have the studies been harmonized?
• Are there opportunities for harmonization and
  collaboration?

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Objectives

• Review some of the current inhibitor studies
• Examine the data collected
• Evaluate the level of harmonization
• Explore opportunities for harmonization
• Discuss possible collaborations
• Identify strategies moving forward

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Pilot Study of Surveillancefor Inhibitors in the
U.S.

• Data coordinator support for factor exposure data
  and to ensure annual blood testing
• Explore methodologies to collect required
  treatment and bleeds information
• Centralized inhibitor testing at CDC
• Hemophilia gene sequencing at CDC
• 12 HTCs selected for pilot each to enroll 50
  patients (3 sites to enroll babies)

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Study Design

• Prospective cohort
• Eligibility Hemophilia A or B lt50 FA all
  ages
• Ongoing factor exposure data collection
• Inhibitor testing
• Annually
• Prior to planned product switch
• Clinical indication
• Complete gene sequencing

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Inhibitor Methods

• Modification of Nijmegen-Bethesda method
• Commercially-prepared buffered normal pooled
  plasma (BNPP)
• FVIII-deficient plasma with VWF present
• Plasma of known titer run with each assay
• Screen with 31 mix of patient and BNPP
• Positives repeated at multiple dilutions

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Mutation Analysis Methods

• Inversions of intron 22 and intron 1 in the FVIII
  gene are examined by PCR.
• The FVIII and FIX genes are resequenced in both
  directions by automated sequencer, using
  equipment and protocols from Applied Biosystems.
• The promoter, exons, intron-exon junction
  regions, and the 3 untranslated regions of both
  genes are examined on all patients.

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Cumulative Enrollment
Enrollment
2007
2006
2008
2009
Total enrollment as of 07/28/2009 850
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Study Population Demographics

• Age
• Mean 22.4 years
• Range Age 6 months 87 years
• 11 under 6 years of age
• Race
• White 82.1
• African American 7.1
• Hispanic 6.2
• Asian 1.3

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Study Population

• Factor Deficiency
• VIII 81.3
• IX 18.7
• Historical exposure days (ED) at enrollment
• 0 20 ED in 22.8
• 21 100 ED in 14.1
• 101 150 ED in 7.9
• gt 150 ED in 55.2
• History of an Inhibitor 13.7

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Follow-Up Time

• 1754.41 person-years follow up
• Mean follow-up time 2.1 years
• Range 1 month 3.55 years
• Withdrawal rate is about 8
• 6.3 lack of compliance with logs
• Patient transfers and other reasons

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Inhibitor Surveillance Pilot ProjectSpecimens
Received as of 7/31/2009
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FVIII Inhibitor Test Results in 930 Specimens
from Patients with No History of Inhibitor
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Mutation Analyses

• 241 unique FVIII mutations found
• 117 (47) not reported in HAMSTeRS or
  publications
• 48 unique FIX mutations found
• 8 not reported in the hemophilia B mutation
  database

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Pilot Sites

• Emory University, Atlanta GA
• Vanderbilt University Medical Center, Nashville,
  TN
• Kansas City Regional Hemophilia Center, Kansas
  City, MO
• New England Hemophilia Center, Worcester, MA
• Comprehensive Bleeding Disorders Center, Peoria,
  IL
• University of Iowa Hospitals Clinics, Iowa
  City, IA
• University of Michigan Hemophilia and Coagulation
  Disorders, Ann Arbor, MI
• Virginia Commonwealth University, Richmond, VA
• Indiana Hemophilia and Thrombosis Center,
  Indianapolis, IN
• Childrens Healthcare of Atlanta, Atlanta, GA
• Mountain States Regional Hemophilia and
  Thrombosis Center, Denver, CO
• Phoenix Children's Hospital Hemophilia Center,
  Phoenix, AZ

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Acknowledgements
Inhibitor Working Group

• Barbara Konkle, MD
• Nigel Key, MD
• Brian Wicklund, MD
• Pam Bryant, RN
• Ann Forsberg, MA, MPH
• Jan Kuhn, RN

• Art Thompson, MD, PhD
• Donna DiMichele, MD
• Mark Weinstein, PhD
• Jay Lozier, PhD
• Robert Janco, MD

Funding support from Wyeth Pharmaceuticals and
Baxter Healthcare through the CDC Foundation
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Study Comparisons 1
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Study Comparisons 2
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Study Comparisons 3
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Study Comparisons 4
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Study Comparisons 5