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Studies of Inhibitors Opportunities for Harmonization

Inhibitor Importance. Serious complication of treatmentLife-changing experience for patientsResults in vastly increased cost of careRisk of inhibitors likely affects careMay be a barrier to availability of new and novel productsDifficulties in the assessment of inhibitor risk in clinical trials

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Studies of Inhibitors Opportunities for Harmonization

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    1. Studies of Inhibitors Opportunities for Harmonization World Federation of Hemophilia Global Forum Montreal, Canada September 25, 2009

    2. 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

    3. 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

    4. 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

    5. 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

    6. 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

    7. 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

    8. 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)

    9. 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?

    10. 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

    12. Pilot Study of Surveillance for 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)

    13. Study Design Prospective cohort Eligibility – Hemophilia A or B; <50% FA; all ages Ongoing factor exposure data collection Inhibitor testing Annually Prior to planned product switch Clinical indication Complete gene sequencing

    14. 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 3:1 mix of patient and BNPP Positives repeated at multiple dilutions

    15. 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.

    16. Cumulative Enrollment

    17. 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%

    18. 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% > 150 ED in 55.2% History of an Inhibitor: 13.7%

    19. 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

    20. Inhibitor Surveillance Pilot Project Specimens Received as of 7/31/2009

    22. 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

    23. 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 Children’s Healthcare of Atlanta, Atlanta, GA Mountain States Regional Hemophilia and Thrombosis Center, Denver, CO Phoenix Children's Hospital Hemophilia Center, Phoenix, AZ

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

    25. Study Comparisons 1

    26. Study Comparisons 2

    27. Study Comparisons 3

    28. Study Comparisons 4

    29. Study Comparisons 5

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