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Rare Coagulation Disorders: The Way Forward

Rare Coagulation Disorders: The Way Forward. ATHN Data Summit 2008 July 31, 2008 Presenters: Donna DiMichele, M.D. and Amy Shapiro, M.D. The Need.

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Rare Coagulation Disorders: The Way Forward

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  1. Rare Coagulation Disorders: The Way Forward ATHN Data Summit 2008 July 31, 2008 Presenters: Donna DiMichele, M.D. and Amy Shapiro, M.D.

  2. The Need • Patients with rare coagulation disorders (RCDs) need safe and effective therapies and deserve excellent long term health outcomes • Many RCD patients still have no treatment options other than non-virally attenuated plasma products or non-specific PCC’s • RCD patients may not have access to new product trials • Industry sponsors and investigators need special incentives to develop products for and conduct trials on rare disease populations

  3. Objectives • Prioritize rare coagulation disorder-related initiatives for ATHN • Explore the clinical need and current evidence base of support for RCD product development • Begin to formulate a work plan for RCD data collection that ensures coordination among national and international efforts with the 3 primary goals of: • Developing an evidence base for the clinical care of RCD patients • Promoting and supporting RCD product development • Stimulate clinical and basic research in this filed

  4. ATHN’s Strategic Direction Network Infrastructure Data Management Public Health and Safety Outcomes Improvement Data Analysis and Research Develop electronic database capacity Data safety, back-up, and portability Support surveillance and patient safety Use data to drive quality, service, and patient centered care Facilitate knowledge creation and advocacy

  5. ATHN’s Strategic Opportunities • Gain and engage ATHN Affiliates re: database • Build community trust • Expand local capacity by funding and training data managers • Establish regional data management structure • Define and establish the core dataset: rare coagulation disorders Network Infrastructure Develop electronic database capacity

  6. The Current State of Understanding :RCD Epidemiology, Pathophysiology and Treatment Options

  7. Rare Bleeding Disorders

  8. Rare Clotting Protein Disorders Prevalence Rare Bleeding Disorders (Deficiencies of Factors II, VII, X, V, XIII, Fibrinogen & Dysfibrinogenemia) Prevalence – 1 in 500,000 to 1 in 1,000,000 ( 0.0002%) Source: D DiMichele

  9. Data derived from RBDD are concordant with those of the WFH survey (2006) WFH survey RBDD survey Prevalence of Patients Affected by RBDs RBDD survey (www.rbdd.org) WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

  10. RBD distribution from National Registry data reported during the SSC 2006-2007 F. Peyvandi

  11. Data derived from RBDD are concordant with those of the WFH survey (2006) WFH survey RBDD survey Prevalence of Patients Affected by RBDs RBDD survey (www.rbdd.org) WFH survey (www.wfh.org/2/7/7_0_Link7_GlobalSurvey2005.htm)

  12. severe moderate mild Distribution Results (Families)

  13. FVIII Fibrinogen FII FV FVII FV+FVIII FX FXIII FXI 70% 77% 34% 32% 15% 60% 57% 64% 72% Nose bleeding 0% 50% 58% 8% 35% 75% 50% 60% 50% Uterine bleeding 0% 0% 3% Haematuria 7% 6% 10% 25% 10% 25% GI bleeding 0% 7% 0% 15% 6% 14% 38% 10% 13% 50% 26% 21% 25% Joint bleeding 38% 69% 29% 55% 75% 0% 7% 38% 29% 12% 66% 32% 58% Muscle bleeding 81% 5% 4% 9% 0% 16% 7% 6% 17% 25% CNS bleeding Cord bleeding 75% 0% 22% 28% 0% 15% 3% 73% Post-partum, -operation bleeding 40% 63% 84% 23% 43% 55% 75% 70% 51% 20% 55% 48% 46% 57% 66% Oral cavity bleeding 90% Clinical Manifestations

  14. North American Rare Bleeding Disorder Registry ( NARBDR) • HTC’s U.S. and Canada (26% RR) • 94 / 3809 – (2.4%) adults • 200 / 4583 - (4.4%) children • Age: 0-73 yrs (median – 7 yrs) • Family history - 50% • Gene studies - 5.4% Source: Acharya et al. J. Thromb Haemost 2000;2:248

  15. N.A. Rare Bleeding Disorders Registry Ethnicity and Rare Factor Deficiencies *p < 0.00001 Source: D DiMichele

  16. N.A. Rare Bleeding Disorders RegistryDisease Related Complications* Source: D DiMichele *Numbers refer to % of each group with the symptoms

  17. Rare Bleeding Disorders: General Treatment Principles • For the rare factor deficiencies fresh frozen plasma and cryoprecipitate infusions have been the primary therapeutic strategy for the treatment or prevention of bleeding episodes. • This treatment modality has disadvantages • potential viral contamination • volume overload • allergic reactions (Source: D DiMichele)

  18. NA Rare Bleeding Disorder RegistryTreatment Related Complications • Allergic reactions 26% • CVAD – related 14% • Inhibitor development 3% • Viral seropositivity • Hepatitis A 15% • Hepatitis C 25% • HIV 1%

  19. Summary of Factor Replacement Source: D DiMichele

  20. New Product Development: Underway but Challenging • Fibrinogen concentrate (Haemocomplettan; CSL- Behring) • FXIII concentrate (Fibrogammin ( CSL- B); rFXIII (NovoNordisk) • FXI concentrate (HemEleven; LFB) • FX concentrate (BPL) • FV concentrate (Kedrion) • Possibly, plasminogen Source: D. DiMichele

  21. Rare Platelet Disorders

  22. Collagen Defects

  23. Need for Standardized Data • Demonstrate service delivery. • Better understand the epidemiology, clinical presentation, genetics and natural history of the disorders; • Facilitate the development of standards of care; • Support advocacy for drug development; • Identify population subsets for special study; • Identify subjects eligible for clinical trials of new products; • Aid in post-marketing surveillance; • Analyze clinical outcomes; • Identify care providers with patients to facilitate communication & networking;

  24. Proportion of Patients in UDC Source: CDC Division of Blood Disorders, Updated July, 2008

  25. RBD UDC Working Group • Collaboration of the Lab Tracker (web) development to ultimately capture and report data to RDB UDC working group • Formed July 2007; Multi-disciplinary • Work on data collection forms started in August 2007 (demographics; diagnosis; bleeding manifestations; treatment; complications) • Coordination with the CC and CDC grant research priorities (Diane Nugent, Chair)

  26. ATHN Initiatives : Present and Future

  27. ATHN Roles and Activities:Stewardship of A Secure National Database • Present platform: Lab Tracker • Conversion to web based system • Server housed at CDC Patient Types Entered into Lab Tracker 85% 64% (Based on 61 users of the 78 responding HTCs)

  28. ATHN Roles and Activities:Coagulation Disorder Resource Room • Planned link from ATHN to NHF, WFH and NATT web sites to help disseminate peer-reviewed information to providers, researchers and patients • Spearheaded by Amy Shapiro MD • 17 manuscripts (e.g., clinical manifestations, treatments, diagnostic testing, etc.) • Publication date Sept. – Nov. 2008 • All manuscripts in final stages of review & revisions

  29. ATHN Role and Activities:Rare Disorders Projects • Plasminogen registry • In process • International harmonization • Exploring data sharing/interface with EN-RBD • Development of a data collection module & training more specific to rare disorders for national database • Just starting

  30. U.S. Rare Bleeding and Clotting Disorder Database Pilot Project • ATHN funded by Baxter for next 2 years • Uses the infrastructure funded by Novo Nordisk • The purpose is to support the development and testing of standardized data collection and supporting components for rare coagulation factor deficiencies that is compatible with the ATHN infrastructure. • Conference call held May 08 to discuss plans • Members of MASAC RDB subcommittee included

  31. Three Components to the Grant • Rare coagulation deficiency standardized data collection • Review existing data collection efforts; • Identify data elements for rare disorders; • Validate applicability of existing data fields in Lab Tracker (web) • Integrate changes to Lab Tracker (web) data dictionary and data collection templates • National system for patient identifier • Portal for development of data collection forms

  32. Desire to Collaborate and Harmonize • HDS Reporting • UDC Women Study, Rare Bleeding Disorder Group • Rare Bleeding Disorder Resource Room • EN-RBD approach • ISTH RBD Working Group • World Federation of Hemophilia efforts • Others

  33. Example Disease Specific TemplatePlasminogen Activator Inhibitor 1 (PAI-1) DeficiencyRegistration Form - Draft • Demographics • Diagnosis (phenotypic and genotypic) • Birth history (gestation, method of delivery, therapy, complications) • Bleeding history (symptoms, provider intervention) • Reproductive/gynecologic history (gynecologic abnormalities, menses, pregnancy) • Other health impairments • Treatment history (product, dose, frequency, regimen, first exposure, home infusion) • Complications (anemia, infection, musculoskeletal, allergies, death) Source: A. Shapiro

  34. European Network on Rare Bleeding Disorders (EN-RBD) • Type and severity of deficiency • Demographics • Family • Bleeding manifestation and treatment (frequency, localization, duration, trigger, treatment, outcome, prophylaxis, complications) • Surgery management (major/minor/delivery type, age, bleeding type, duration, treatment, outcome, prophylaxis, complications) • Other associated diseases • Phenotype studies • Molecular defect / Polymorphisms Source: F. Peyvandi

  35. Beginnings of a Work Plan: Journey Initiated

  36. Advance The Web-Based Infrastructure • ATHN should enable centers to collect the full spectrum of historical and cross sectional data needed to: • Care for patients and anticipate their issues • Design studies • Enroll patients in studies • Complete study requirements • Track impact of interventions on care • To get started, ATHN can provide guidance to centers to maximize the benefit

  37. Staging Rare Disorder Data Collection

  38. Staging Rare Disorder Data Collection

  39. Synchronize with CDC • Enter data into Lab Tracker today • Encourage sites to start enrolling rare coagulation disorder patients in UDC • Encourage CDC Coordinating Committee to include in the Data Sharing Agreement under development, the ability to share data with ATHN to facilitate study coordination and site recruitment through ATHN

  40. Aid Implementation by Study Sites • ATHN should aid HTCs and other potential study sites with implementation of studies • Communications network to share knowledge of studies • Database to identify subjects for study • Access to central IRB • Standardized templates for consent/data capture • Patients flags in Lab Tracker for easy reference • Ability to re-use data once captured • Funding to help cover costs

  41. Help Companies Coordinate Studies • ATHN should begin to build capacity to help companies coordinate studies in the U.S. • Refer to experts to frame studies • Identification of study sites • Active tracking of site interest • Data to help define data points • Outcomes data to determine that the product is working • Aid in post-marketing surveillance

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