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Dalteparin ( Fragmin  ) NDA 20-287 S-035

Dalteparin ( Fragmin  ) NDA 20-287 S-035 . FDA Oncologic Drugs Advisory Committee Meeting September 6, 2006. Introduction. Connie Newman, M.D. Executive Director Worldwide Regulatory Affairs Pfizer Inc. Proposed Indication Dalteparin sNDA 20-287 S-035.

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Dalteparin ( Fragmin  ) NDA 20-287 S-035

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  1. Dalteparin (Fragmin)NDA 20-287 S-035 FDA Oncologic Drugs Advisory Committee Meeting September 6, 2006

  2. Introduction Connie Newman, M.D. Executive Director Worldwide Regulatory Affairs Pfizer Inc

  3. Proposed IndicationDalteparin sNDA 20-287 S-035 Dalteparin sodium (Fragmin) is also indicated for the extended treatment of symptomatic venous thromboembolism [(VTE), proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE)] to reduce the recurrence of VTE in patients with cancer

  4. Agenda

  5. Consultants Available to the Committee

  6. Regulatory HistoryDalteparin (Fragmin) • First approved in Germany in 1985 for anticoagulation during hemodialysis and hemofiltration • Currently approved in over 80 countries worldwide • Approved for extended treatment of symptomatic VTE to reduce the recurrence of VTE in patients with cancer in 19 countries • First US approval 1994, for prophylaxis of deep vein thrombosis (DVT) which may lead to pulmonary embolism (PE) in patients undergoing abdominal surgery who are at risk for thromboembolic complications

  7. Approved Dalteparin Indications US Package Insert • Prophylaxis of DVT which may lead to PE in; • Patients undergoing abdominal surgery (December 22,1994) • Patients undergoing hip replacement surgery (March 30, 1999) • Medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness (December 10, 2003) • Prophylaxis of ischemic complications in unstable angina and non-Q-wave MI when concurrently administered with aspirin therapy (May 25, 1999)

  8. Regulatory BackgroundDalteparin sNDA 20-287 S-035 • March 16, 2004 - Pfizer submitted sNDA for an indication in patients with VTE and cancer supported by data from the “CLOT” trial* • January 14, 2005 - FDA issued “approvable” letter of sNDA • March 14, 2006 - FDA issued “non-approvable” letter • June 9, 2006 - FDA advised Pfizer of intention to have Oncologic Drugs Advisory Committee evaluate the “CLOT” trial results * Randomized Comparison of Low Molecular Weight Heparin versus Oral Anticoagulant Therapy for Long-Term Anticoagulation in Cancer Patients with Venous Thromboembolism

  9. Agenda

  10. Background: VTE & Cancer Craig Eagle, M.D. Pfizer, Inc Medical Director

  11. VTE is a Common Complication in Patients with Malignancy • Association of VTE and cancer first noted by Trousseau in 1865 • 4 to 7-fold increase in risk of venous thrombosis in cancer patients • The estimated annual incidence of VTE in cancer patients is about 1:200 • VTE causes symptoms and signs by venous obstruction, inflammation and embolization

  12. Clinical Problem • Patients with deep vein thrombosis have a painful swollen leg which limits their mobility

  13. Clinical Problem • Thrombus in a deep vein can fragment and embolize to the lung • Patients with pulmonary embolism frequently present with shortness of breath and chest pain Ventilation Perfusion

  14. Clinical Problem • Pulmonary embolism can be fatal

  15. Treatment for VTE Initial treatment 5 to 7 days (until INR >2) LMWH or UFH Long-term therapy ≥ 3 months Vitamin K antagonist OAC (INR 2.0 - 3.0) 7th ACCP anti-thrombotic guidelines Chest 2004; 126: 401S-428S

  16. Cumulative Incidence of Recurrent VTE During Anticoagulant Therapy Hazard ratio 3.2 (95% CI 1.9, 5.4) Prandoni P, et al, Blood. 2002;100:3484-3488

  17. Comparison of Warfarin and LMWH

  18. Dalteparin Studies for Initial Treatment of VTE 1. study: 86-96-291; 2. studies 88-96-297, 89-96-060 3. studies: 94-96-414, 93-96-549, 94-96-235; 4. studies: 91-96-389, 91-96-544; 5. study: 88-96-259

  19. Conclusion: VTE Management in Cancer Patients is Suboptimal • Cancer patients with VTE are at increased risk of recurrent VTE compared to non-cancer patients • No FDA approved medication for prevention of recurrent VTE in cancer patients • LMWH therapy has the potential to confer clinical benefit in the management of VTE • Dalteparin has been shown to be effective for initial treatment of VTE • CLOT study was designed to evaluate extended use of dalteparin in cancer patients

  20. Agenda

  21. CLOT Study Design & Results Agnes Y. Y. Lee, M.D.

  22. CLOT Study Study Question: Is long-term therapy with LMWH dalteparin more effective than oral anticoagulant (OAC) therapy in preventing recurrent venous thromboembolism (VTE) in patients with cancer? Lee AYY et al. New Engl J Med 2003;349:146-153.

  23. Control Group (Standard): Dalteparin + OAC Cancer patients with proximal DVT, PE or both R Experimental Group: Dalteparin alone Study Design • Multi-national, multi-center, randomized, open-label study • Follow-up for 6 months (or until death) • Telephone contact every 2 weeks • Clinic visits at 1 week, months 1, 3, and 6 • Follow-up for survival up to 12 months

  24. Study Treatments Control Group dalteparin 200 IU/kg OD oral anticoagulant (INR 2.0 to 3.0) x 6 mo randomization Experimental Group dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo 5 to 7 days 1 month 6 months

  25. Outcome Events Primary endpoint* • Objectively documented, symptomatic recurrence of DVT, PE or both Secondary endpoints • Composite endpoint of symptomatic and objectively documented recurrence of PE, DVT or central venous thrombosis of upper limbs, neck or chest • Bleeding (major and all) • Death * Originated as a two co-primary endpoint study (VTE and Major bleed) redefined by Steering Committee March 24, 1999 based on ICH guidelines E9, 1998 and prior to first patient enrolled May 3, 1999. Protocol amendment dated September 13, 1999

  26. Efficacy:Ascertainment and Adjudication Suspected VTE investigated by objective testing following pre-specified diagnostic algorithms Details sent to a blinded central adjudication committee for confirmation of VTE Patients contacted every 2 weeks to ascertain symptoms of VTE Patients instructed to report urgently symptoms of VTE to investigators

  27. Safety: Ascertainment and Adjudication • Bleeding Events • Clinically overt • Blinded central adjudication committee • Reviewed and categorized as major or minor according to standard definitions • Deaths • Cause of death determined by blinded central adjudication committee first 6 months • Cause of death determined by local investigator from 6-12 months

  28. Efficacy Analysis Recurrent VTE Intention-to-treat population (all randomized subjects) Included all events up to 6-month visit or death Time to first recurrent VTE event Log-Rank (LR) test (2-sided alpha = 0.05) Safety Analysis Bleeding As-treated population (at least one dose) Included events up to 48 hours after stopping study drug Time to first bleed (major and any) LR test (2-sided alpha = 0.05) Overall survival ITT population Included all deaths over 6 and 12 months LR test (2-sided alpha = 0.05) Statistical Analysis

  29. CLOT Study Results

  30. First patient enrolled May 1999 Last patient enrolled October 2001 Last 6-month follow-up April 2002 Results first presented at ASH, December 2002 Published N Engl J Med July 2003 Study Milestones

  31. Analysis Populations 677 Randomized* dalteparin n=338 OAC n=338 Efficacy ITT 3 Subjects not dosed Safety As Treated n=338 n=335 Completed Treatment n=180 n=163 * Includes one subject randomized to OAC without having given written informed consent

  32. Baseline Characteristics

  33. Baseline Characteristics

  34. Frequency of Follow-Up

  35. Efficacy Endpoints • Primary: • Symptomatic recurrent DVT and/or PE • Secondary: • Symptomatic DVT, PE or central venous thrombosis of upper limb, neck, chest

  36. Efficacy Endpoint:Recurrent VTE (ITT Analysis) Dalteparin OAC Risk Reduction = 52% HR 0.48 (95% CI 0.30, 0.77) Log-rank p = 0.0017 Recurrent VTE Days Post Randomization

  37. Subgroup Analyses Favors Dalteparin Favors OAC *adjusting for factors found to be prognostic for outcome (extent of tumor, type of tumor, smoking status and age)

  38. Secondary Endpoint: Recurrent DVT, PE, or CVT Dalteparin OAC Risk Reduction = 49% HR 0.51 (95% CI 0.32, 0.80) Log-rank p=0.003 Recurrent VTE Days Post Randomization

  39. Safety Endpoints • Bleeding (major and any) • Death • Adverse Events

  40. Safety Endpoint:Bleeding

  41. Time to First Adjudicated-positive Major Bleeding - (As-treated Population) Dalteparin OAC Log-rank p=0.28 Incidence of Bleeding Days from Randomization

  42. Time to First Adjudicated-positive Bleeding (Major/Minor) (As-treated Population) Dalteparin OAC Log-rank p=0.05 Incidence of Bleeding Days from Randomization

  43. Investigator Reported Reasons for Treatment Discontinuation

  44. Overall Survival: ITT Population Overall population Dalteparin (n=338) OAC (n=338) Survival 6-month HR = 0.93 95% CI (0.73, 1.18) Log-rank p= 0.56 12-month HR = 0.94 95% CI (0.77, 1.15) Log-rank p= 0.57 Days After Randomization

  45. Adjudicated Cause of Death During First 6 Months * 1 fatal PE in dalteparin and 1 fatal PE in OAC occurred after a previous PE and so were not counted as a fatal PE endpoint ** 2 cases in dalteparin group and 1 case in OAC occurred >48 h after study drug discontinuation, so were not included in summary of major bleeds

  46. Drug-Related Treatment Emergent Adverse Events ≥3% (As-Treated)

  47. Conclusions from CLOT In cancer patients with acute VTE, • Long-term dalteparin therapy substantially reduced the risk of symptomatic, recurrent VTE by 52% compared to OAC therapy • Risk of bleeding similar between dalteparin and OAC therapy • No difference in overall mortality between dalteparin and OAC therapy

  48. Agenda

  49. CLOT Study – Interpretation and Discussion Craig Eagle, M.D. Pfizer, Inc Medical Director

  50. Points of Discussion • Key characteristics of the CLOT trial design • On-treatment mortality analysis • Robustness of data • Risk/Benefit

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