ppt - Pfizer Slides - Fragmin

2,269 views

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
2,269
On SlideShare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
46
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • <number>
    January 30, 2015
  • ppt - Pfizer Slides - Fragmin

    1. 1. 1 Dalteparin (Fragmin® ) NDA 20-287 S-035 FDA Oncologic Drugs Advisory Committee Meeting September 6, 2006
    2. 2. 2 Introduction Connie Newman, M.D. Executive Director Worldwide Regulatory Affairs Pfizer Inc
    3. 3. 3 Proposed Indication Dalteparin 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. 4. 4 Agenda  Regulatory Background Connie Newman, M.D.  Background on VTE and Cancer Craig Eagle, M.D.  CLOT Study Design Results Agnes Y. Y. Lee, M.D.  Interpretation and Discussion Craig Eagle, M.D.  Conclusions Craig Eagle, M.D.
    5. 5. 5 Consultants Available to the Committee Agnes Y. Y. Lee, M.D., MSc, FRCPC Associate Prof., Medicine, McMaster University Hamilton Health Sciences Henderson Hospital Hamilton, ON Steven Piantadosi, M.D., Ph.D. Prof. of Oncology Director of Biostatistics Johns Hopkins Oncology Center Baltimore, MD Mark Levine, M.D., MSc, FRCPC Prof., Departments of Clinical Epidemiology & Biostatistics, and Medicine, McMaster University Henderson Research Centre Buffett Taylor Chair in Breast Cancer Research McMaster University Hamilton, ON Frederick R. Rickles, M.D., FACP Prof. of Medicine, Pediatrics and Pharmacology and Physiology The George Washington University Fellow, Center for Science and Technology Healthcare Division Mitretek Systems, Inc. Falls Church, VA
    6. 6. 6 Regulatory History Dalteparin (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. 7. 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. 8. 8 Regulatory Background Dalteparin 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. 9. 9 Agenda  Regulatory Background Connie Newman, M.D.  Background on VTE and Cancer Craig Eagle, M.D.  CLOT Study Design Results Agnes Y. Y. Lee, M.D.  Interpretation and Discussion Craig Eagle, M.D.  Conclusions Craig Eagle, M.D.
    10. 10. 10 Background: VTE & Cancer Craig Eagle, M.D. Pfizer, Inc Medical Director
    11. 11. 11  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 VTE is a Common Complication in Patients with Malignancy
    12. 12. 12 Clinical Problem  Patients with deep vein thrombosis have a painful swollen leg which limits their mobility
    13. 13. 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. 14. 14 Clinical Problem  Pulmonary embolism can be fatal
    15. 15. 15 Vitamin K antagonist OAC (INR 2.0 - 3.0) ≥ 3 months LMWH or UFH 5 to 7 days (until INR >2)Initial treatment Long-term therapy Treatment for VTE 7th ACCP anti-thrombotic guidelines Chest 2004; 126: 401S-428S
    16. 16. 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. 17. 17 Comparison of Warfarin and LMWH Warfarin Problem LMWH Advantages Reduces the function of coagulation factors including prothrombin Inhibits activated coagulation factors in particular factor Xa Difficulty maintaining therapeutic control More predictable anticoagulant response Interruption & reversal of OAC for thrombocytopenia and procedures Only interrupted if platelets very low. Much simpler to handle if procedure required Venous access Does not require lab monitoring Multiple interactions with drugs No or few interactions with drugs
    18. 18. 18 Dalteparin Studies for Initial Treatment of VTE Comparator Patients Total Patients Cancer Dalteparin dose Duration Heparin + OAC1 56 6 4000-7500 IU BID + OAC 5-7 days Heparin + OAC2 179 23 100-120 IU/kg BID + OAC 5-10 days Heparin + OAC3 802 70 200 IU/kg/d + OAC 5-10 days Dalteparin Adjusted dose & 200 IU/kg/d4 223 22 100 IU/kg BID 5-10 days Heparin5 194 64 ≤ 15 000 IU 5-10 days 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. 19. 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. 20. 20 Agenda  Regulatory Background Connie Newman, M.D.  Background on VTE and Cancer Craig Eagle, M.D.  CLOT Study Design Results Agnes Y. Y. Lee, M.D.  Interpretation and Discussion Craig Eagle, M.D.  Conclusions Craig Eagle, M.D.
    21. 21. 21 CLOT Study Design & Results Agnes Y. Y. Lee, M.D.
    22. 22. 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. 23. 23 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 R Cancer patients with proximal DVT, PE or both Control Group (Standard): Dalteparin + OAC Experimental Group: Dalteparin alone
    24. 24. 24 5 to 7 days dalteparin 200 IU/kg OD oral anticoagulant (INR 2.0 to 3.0) x 6 mo Control Group dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo Experimental Group randomization 1 month 6 months Study Treatments
    25. 25. 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. 26. 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. 27. 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. 28. 28 Statistical Analysis 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)
    29. 29. 29 CLOT Study Results
    30. 30. 30 Study Milestones  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
    31. 31. 31 677 Randomized* dalteparin n=338 OAC n=338 Analysis Populations 3 Subjects not dosed n=335n=338 Efficacy ITT Safety As Treated * Includes one subject randomized to OAC without having given written informed consent n=163n=180 Completed Treatment
    32. 32. 32 Baseline Characteristics Dalteparin n=338 OAC n=338 Gender Female (%) Male (%) 179 (53.0) 159 (47.0) 169 (50.0) 169 (50.0) Median age (range) 64 (22-85) 64 (28-89) Smoker (%) 33 (9.8) 42 (12.4) Previous VTE (%) 39 (11.5) 36 (10.7) Qualifying VTE DVT only (%) PE only (%) PE/DVT (%) 235 (69.5) 64 (18.9) 39 (11.5) 230 (68.0) 65 (19.2) 43 (12.7)
    33. 33. 33 Baseline Characteristics Dalteparin n=338 (%) OAC n=338 (%) ECOG PS 0 1 2 3 80 (23.7) 135 (39.9) 118 (34.9) 5 ( 1.5) 63 (18.6) 150 (44.4) 122 (36.1) 3 ( 0.9) Solid tumor No evidence Localized Metastatic 298 (88.2) 36 (10.7) 39 (11.5) 223 (66.0) 308 (91.1) 33 ( 9.8) 43 (12.7) 232 (68.6) Hematological malignancy 40 (11.8) 30 ( 8.9)
    34. 34. 34 Frequency of Follow-Up Dalteparin n=338 OAC n=338 Scheduled Visits (avg per patient) 1024 (3.0) 954 (2.8) Telephone Contacts (avg per patient) 2327 (6.9) 2286 (6.8) Unplanned Visits (avg per patient) 354 (1.0) 390 (1.2) Total Contacts (avg per patient) 3705 (11.0) 3630 (10.7)
    35. 35. 35 Efficacy Endpoints  Primary:  Symptomatic recurrent DVT and/or PE  Secondary:  Symptomatic DVT, PE or central venous thrombosis of upper limb, neck, chest
    36. 36. 36 0 30 60 90 120 150 180 210 0% 5% 10% 15% 20% 25% Days Post Randomization RecurrentVTE 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
    37. 37. 37 RR 95% CI n COX Model* 0.51 (0.32 ,0.81) 676 Tumor Type Solid Tumor 0.45 (0.28, 0.71) 606 Breast 0.83 (0.12, 5.68) 108 Gastrointestinal 0.54 (0.23, 1.26) 164 Lung 0.35 (0.14, 0.85) 90 Genitourinary 0.41 (0.13, 1.24) 155 Other 0.59 (0.22, 1.63) 89 Hematological 6.80 (0.38, 121.74) 70 Extent of Malignancy Metastatic 0.43 (0.27, 0.71) 455 Non-metastatic 0.61 (0.15, 2.45) 151 0.1 1 10 100 1000 Subgroup Analyses *adjusting for factors found to be prognostic for outcome (extent of tumor, type of tumor, smoking status and age) Favors Dalteparin Favors OAC
    38. 38. 38 0 30 60 90 120 150 180 210 0% 5% 10% 15% 20% 25% Secondary Endpoint: Recurrent DVT, PE, or CVT Days Post Randomization Dalteparin OAC RecurrentVTE Risk Reduction = 49% HR 0.51 (95% CI 0.32, 0.80) Log-rank p=0.003
    39. 39. 39 Safety Endpoints  Bleeding (major and any)  Death  Adverse Events
    40. 40. 40 Safety Endpoint: Bleeding Dalteparin n=338 (%) OAC n=335 (%) Log-rank p-value Major bleed 19 (5.6) 12 (3.6) 0.28 Associated with death 1 0 Critical site (intracranial, intraspinal, intraocular, pericardial, or retroperitoneal) 4 3 Transfusion of > 2 units of packed RBC or drop in hemoglobin of at least 2.0 g/dL 14 9 Any bleed 46 (13.6) 62 (18.5) 0.05
    41. 41. 41 0 30 60 90 120 150 180 210 0.0 0.1 0.2 0.3 0.4 0.5 Time to First Adjudicated-positive Major Bleeding - (As-treated Population) Dalteparin OAC IncidenceofBleeding Days from Randomization Log-rank p=0.28
    42. 42. 42 0 30 60 90 120 150 180 210 0.0 0.1 0.2 0.3 0.4 0.5 Time to First Adjudicated-positive Bleeding (Major/Minor) (As-treated Population) Days from Randomization Dalteparin OAC IncidenceofBleeding Log-rank p=0.05
    43. 43. 43 Investigator Reported Reasons for Treatment Discontinuation Dalteparin n=338 n (%) OAC n=335 n (%) Recurrent VTE 21 (6.2) 47 (14.0) Death / due to cancer 56 (16.6) / 52 (15.4) 24 (7.2) / 17(5.1) Contraindication to Rx 12 (3.6) 25 (7.5) Bleeding 10 (3.0) 19 (5.7) Other 2 (0.6) 6 (1.8) AE / Abnormal lab values 22 (6.5) 24 (7.2) Underlying cancer 17 (5.0) 21 (6.3) Investigator decision 1 (0.3) 5 (1.5) Patient decision 20 (5.9) 14 (4.2) Patient unable to swallow 0 (0.0) 4 (1.2) Other 9 (2.7) 8 (2.4) Total discontinued 158 (46.7) 172 (51.3)
    44. 44. 44 0 30 60 90 120 150 180 210 240 270 300 330 360 390 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Overall Survival: ITT PopulationSurvival Days After Randomization Overall population Dalteparin (n=338) OAC (n=338) 12-month HR = 0.94 95% CI (0.77, 1.15) Log-rank p= 0.57 6-month HR = 0.93 95% CI (0.73, 1.18) Log-rank p= 0.56
    45. 45. 45 * 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 Adjudicated Cause of Death During First 6 Months Dalteparin n=131 deaths OAC n=137 deaths Progressive cancer 119 124 Fatal PE* 6 8 Fatal bleed** 3 1 Other 3 4
    46. 46. 46 Drug-Related Treatment Emergent Adverse Events ≥3% (As-Treated) System Organ Class (disorders) Preferred Term Dalteparin n=337 OAC n=331 N % N % Blood & Lymphatic System Anaemia NOS 5 1.5 11 3.3 Thrombocytopenia 15 4.5 7 2.1 General & Administration Site Condition Fatigue 8 2.4 12 3.6 Injection site reaction 34 10.1 5 1.5 Investigations Alanine aminotransferase ↑ 12 3.6 2 0.6 Aspartate aminotransferase ↑ 11 3.3 3 0.9 Gamma-glutamyltransferase ↑ 19 5.6 3 0.9 International normalized ratio ↑ - - 18 5.4 Prothrombin time prolonged 1 0.3 11 3.3 Skin & Subcutaneous tissues Ecchymosis 29 8.6 9 2.7
    47. 47. 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. 48. 48 Agenda  Regulatory Background Connie Newman, M.D.  Background on VTE and Cancer Craig Eagle, M.D.  CLOT Study Design Results Agnes Y. Y. Lee, M.D.  Interpretation and Discussion Craig Eagle, M.D.  Conclusions Craig Eagle, M.D.
    49. 49. 49 CLOT Study – Interpretation and Discussion Craig Eagle, M.D. Pfizer, Inc Medical Director
    50. 50. 50 Points of Discussion  Key characteristics of the CLOT trial design  On-treatment mortality analysis  Robustness of data  Risk/Benefit
    51. 51. 51 Key Characteristics of the CLOT Trial Design  Open label study design  Initial treatment regimen  Dalteparin dosing  6 month treatment duration
    52. 52. 52 CLOT Study: Design Rationale Rationale for open label study:  Unsafe to blindly manage anticoagulant therapy (e.g. thrombocytopenia, surgery, invasive procedures)  Easy to unblind (off-study coagulation tests common)  Difficult for sham INRs to mimic reality (multiple clinical factors in each case can determine INR levels)  Undesirable to do sham blood work (frequent venipuncture, painful procedures, extra blood taken from cancer patients who can be anemic)  Undesirable and impractical to do placebo subcutaneous injections (can cause hematoma at placebo injection sites)
    53. 53. 53 CLOT Study: Minimize Bias Safeguards to minimize bias:  A priori definition of VTE recurrence based on objective investigations  Telephone check every 2 weeks on follow-up in both groups  Diagnostic algorithms for recurrent VTE  Independent blinded Central Adjudication Committee reviewed and adjudicated all primary and secondary outcome events
    54. 54. 54 CLOT Study: Initial Treatment Regimen Rationale  Use of dalteparin in both arms for initial treatment was adopted after careful consideration by the CLOT Steering Committee  No LMWH was approved for use in cancer patients at the time of trial conception  Limit the number of variables in the trial  Documented effectiveness of dalteparin
    55. 55. 55 CLOT Study: Dalteparin Dosing Rationale  Efficacy of Dalteparin 200 IU/kg shown in acute VTE treatment (previous trials and literature) 1st Month  Increased risk of recurrent VTE highest in 1st month after initial occurrence (exacerbated in cancer patients), therefore, higher dose administered Following 5 months  Dose lowered to 150 IU/kg reflecting decreased risk of recurrent VTE and need to minimize bleeding
    56. 56. 56 CLOT Study: 6 Month Treatment Duration Rationale  Potential advantages of dalteparin vs. OAC in long-term treatment of patients with cancer Long-term OAC Standard of Care:  Patients with extensive cancer treated with OAC often until death  Patients without evidence of active cancer treated with OAC for a minimum of 3-6 months
    57. 57. 57 Points of Discussion  Key characteristics of the CLOT trial design  On-treatment mortality analysis  Robustness of data  Risk/Benefit
    58. 58. 58 0 50 100 150 200 On-Treatment Mortality Analyses 0 50 100 150 200 0% 25% 50% 75% 100% Log-rank p-value < 0.001 Log-rank p-value = 0.23 1 day definition 14 day definition Dalteparin OAC SurvivalDistribution Analysis time (days)
    59. 59. 59 Mortality Analyses On-Treatment 1 day ITT Dalteparin OAC Dalteparin OAC 54 14 54 14 4 5 4 5 1 0 1 0 0 2 0 2 0 0 12 34 0 0 42 67 0 0 18 15 Number of Deaths Included in Analysis 59 21 131 137 X X 6 Months X X Discontinuation of study medication due to clinical management VTE or CVT DeathX Study drug treatment Discontinuation due to other reasons X X X
    60. 60. 60 0 30 60 90 120 150 180 210 240 270 300 330 360 390 0% 20% 40% 60% 80% 100% Conclusions for Mortality Analysis  On-treatment mortality analysis is biased due to informative censoring  The appropriate analysis of mortality follows intention to treat (ITT) principle and shows no difference between the two treatment arms Survival Days After Randomization
    61. 61. 61 Points of Discussion  Key characteristics of the CLOT trial design  On-treatment mortality analysis  Robustness of data  Risk/Benefit
    62. 62. 62 Robustness of Data  Magnitude of the benefit  Consistency of subgroups  Competing risk
    63. 63. 63 0 30 60 90 120 150 180 210 0% 5% 10% 15% 20% 25% Days Post Randomization Primary Endpoint: Recurrent VTE Dalteparin OAC Risk Reduction = 52% HR 0.48 (95% CI 0.30, 0.77) Log-rank p= 0.0017 RecurrentVTE
    64. 64. 64 RR 95% CI n COX Model* 0.51 (0.32 ,0.81) 676 Tumor Type Solid Tumor 0.45 (0.28, 0.71) 606 Breast 0.83 (0.12, 5.68) 108 Gastrointestinal 0.54 (0.23, 1.26) 164 Lung 0.35 (0.14, 0.85) 90 Genitourinary 0.41 (0.13, 1.24) 155 Other 0.59 (0.22, 1.63) 89 Hematological 6.80 (0.38, 121.74) 70 Extent of Malignancy Metastatic 0.43 (0.27, 0.71) 455 Non-metastatic 0.61 (0.15, 2.45) 151 0.1 1 10 100 1000 Subgroup Analyses *adjusting for factors found to be prognostic for outcome (extent of tumor, type of tumor, smoking status and age) Favors Dalteparin Favors OAC
    65. 65. 65 CLOT Study: A Single Pivotal Trial to Support Clinical Effectiveness  Compelling p-value for primary efficacy analysis  Two sided p value <0.0025 provides strength of evidence of 2 independent trials with p<0.05*  Consistency across subgroups  Dalteparin is proven to be an effective anticoagulant for primary prophylaxis in various clinical settings * T. Fleming and B. Richardson JID 2004:190;666-74 Some Design Issues in Trials of Microbicides for the Prevention of HIV Infection. JID 2004:190, pg 666-674
    66. 66. 66 Robustness of Data  Magnitude of the benefit  Consistency of subgroups  Competing risk
    67. 67. 67 Competing Risk: Death and Recurrence of VTE  Could mortality account for the significant dalteparin benefit?  Two scenarios in which mortality would be informative regarding the relative risk of VTE: 1. The mortality rate would have to be different between the two treatment groups 2. The mortality censoring would have to affect the probability of VTE differentially in the treatment groups
    68. 68. 68 Competing Risk: Death and Recurrence of VTE Scenario One: Mortality rates are different between the treatment groups  Cumulative mortality at all times within the 6-month observation period was almost identical in the two treatment groups  Therefore the degree of mortality censoring is non- informative regarding the relative risk
    69. 69. 69 Competing Risk: Death and Recurrence of VTE Scenario Two: The mortality censoring would have to affect the probability of VTE differentially in the treatment groups  Most (> 90%) deaths in both treatment groups were due to cancer  Therefore it is unlikely that the probability of VTE for subjects who died relative to the observed probability would have differed between the two groups
    70. 70. 70 Competing Risk: Death and Recurrence of VTE Mortality Censoring and benefit within the initial 30 days  Most deaths occurred after the benefit of dalteparin was established in the initial 30 days and during the period (days 30-180) when the probability of VTE was relatively low Dalteparin OAC Censored 23 (6.8%) 22 (6.5%) VTEs* 12 (3.6%) 34 (10.1%) *VTE RR=0.35, p=0.001
    71. 71. 71 Competing Risk: Death and Recurrence of VTE Conclusion  In the CLOT study, the benefit of dalteparin relative to OAC is estimated accurately despite the high cancer mortality
    72. 72. 72 Points of Discussion  Key characteristics of the CLOT trial design  On-treatment mortality analysis  Robustness of data  Risk/Benefit
    73. 73. 73 Risk/Benefit: VTE vs. Major Bleed Incidence per 30 Days Exposure 0.00 0.02 0.04 0.06 0.08 0.10 0.12 Day 1-7 Day 8-30 Day 31+ Total 0.00 0.02 0.04 0.06 0.08 0.10 0.12 Day 1-7 Day 8-30 Day 31+ Total VTE Major Bleed Fragmin OAC IncidencePer30DaysExposure
    74. 74. 74 Risk/Benefit Summary Dalteparin n=338 OAC n=338 VTE 27 53 Major Bleeds 19 12 Death due to: PE 6 8 Major Bleeds 1 0 Results applicable to clinical practice:  Different tumor types and extent of cancer were included  Self-injections shown to be feasible and acceptable  Treatment is well-tolerated over extended period, flexible and can be continued until end of life Control arm results consistent with previous studies
    75. 75. 75 Agenda  Regulatory Background Connie Newman, M.D.  Background on VTE and Cancer Craig Eagle, M.D.  CLOT Study Design Results Agnes Y. Y. Lee, M.D.  Interpretation and Discussion Craig Eagle, M.D.  Conclusions Craig Eagle, M.D.
    76. 76. 76 Conclusion Craig Eagle, M.D. Pfizer, Inc Medical Director
    77. 77. 77 VTE Management in Cancer Patients is Suboptimal  In patients with cancer:  VTE recurrence is more common (HR 3.2)  VTE complicates management of cancer  No FDA approved medication for the extended use in reducing recurrence of VTE without concomitant warfarin requiring blood monitoring  Oral anti-coagulant (OAC)  Difficult to maintain and manage  Dalteparin  Established efficacy and safety in prophylaxis of VTE in non-cancer patients  Predictable dosing and reduced need for monitoring
    78. 78. 78 Summary of CLOT Study  Highly significant (p=0.0017) reduction in recurrence rate of VTE (52% reduction dalteparin vs OAC)  Compelling p-value  Results consistent across study subsets  Favorable risk/benefit profile  Builds on previous clinical trial experience with dalteparin in VTE
    79. 79. 79 Conclusion  Dalteparin provides cancer patients with VTE:  An effective treatment (52% reduction in recurrence of VTE)  A favorable treatment in terms of risk/benefit  A more manageable therapeutic option

    ×