1 Dalteparin (Fragmin  ) NDA 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 Indication Dalteparin sNDA 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  Regulatory BackgroundConnie Newman, M.D.  Background on VTE and Cancer Craig Eagle, M.D.  CLOT Study  Design  Results Agnes Y. Y. Lee, M.D.  Interpretation and DiscussionCraig Eagle, M.D.  ConclusionsCraig Eagle, M.D.

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 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 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 Background Dalteparin sNDA S-035  March 16, Pfizer submitted sNDA for an indication in patients with VTE and cancer supported by data from the “CLOT” trial*  January 14, FDA issued “approvable” letter of sNDA  March 14, FDA issued “non-approvable” letter  June 9, 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  Regulatory BackgroundConnie Newman, M.D.  Background on VTE and Cancer Craig Eagle, M.D.  CLOT Study  Design  Results Agnes Y. Y. Lee, M.D.  Interpretation and DiscussionCraig Eagle, M.D.  ConclusionsCraig Eagle, M.D.

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

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 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 VentilationPerfusion

14 Clinical Problem  Pulmonary embolism can be fatal

15 Vitamin K antagonist OAC (INR ) ≥ 3 months LMWH or UFH 5 to 7 days (until INR >2) Initial treatment Long-term therapy Treatment for VTE 7 th 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:

17 Comparison of Warfarin and LMWH Warfarin ProblemLMWH 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 accessDoes not require lab monitoring Multiple interactions with drugsNo or few interactions with drugs

18 Dalteparin Studies for Initial Treatment of VTE ComparatorPatients Total Patients Cancer Dalteparin doseDuration Heparin + OAC IU BID + OAC 5-7 days Heparin + OAC IU/kg BID + OAC 5-10 days Heparin + OAC IU/kg/d + OAC 5-10 days Dalteparin Adjusted dose & 200 IU/kg/d IU/kg BID5-10 days Heparin ≤ IU5-10 days 1. study: ; 2. studies , studies: , , ; 4. studies: , ; 5. study:

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  Regulatory BackgroundConnie Newman, M.D.  Background on VTE and Cancer Craig Eagle, M.D.  CLOT Study  Design  Results Agnes Y. Y. Lee, M.D.  Interpretation and DiscussionCraig Eagle, M.D.  ConclusionsCraig Eagle, M.D.

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:

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 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 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, 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 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 CLOT Study Results

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

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 Baseline Characteristics Dalteparin n=338 OAC n=338 Gender Female (%) Male (%) 179 (53.0) 159(47.0) 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 Baseline Characteristics Dalteparin n=338 (%) OAC n=338 (%) ECOG PS (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 malignancy40 (11.8)30 ( 8.9)

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

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

37 RR95% CI n COX Model* 0.51(0.32,0.81)676 Tumor Type Solid Tumor0.45(0.28, 0.71)606 Breast0.83(0.12, 5.68)108 Gastrointestinal0.54(0.23, 1.26)164 Lung0.35(0.14, 0.85)90 Genitourinary0.41(0.13, 1.24)155 Other0.59(0.22, 1.63)89 Hematological6.80(0.38, )70 Extent of Malignancy Metastatic0.43(0.27, 0.71)455 Non-metastatic0.61(0.15, 2.45)151 Subgroup Analyses *adjusting for factors found to be prognostic for outcome (extent of tumor, type of tumor, smoking status and age) Favors DalteparinFavors OAC

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

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

40 Safety Endpoint: Bleeding Dalteparin n=338 (%) OAC n=335 (%) Log-rank p-value Major bleed19 (5.6)12 (3.6)0.28 Associated with death10 Critical site (intracranial, intraspinal, intraocular, pericardial, or retroperitoneal) 43 Transfusion of > 2 units of packed RBC or drop in hemoglobin of at least 2.0 g/dL 149 Any bleed46 (13.6)62 (18.5)0.05

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

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

43 Investigator Reported Reasons for Treatment Discontinuation Dalteparin n=338 n (%) OAC n=335 n (%) Recurrent VTE21(6.2)47(14.0) Death / due to cancer56 (16.6) / 52 (15.4)24 (7.2) / 17(5.1) Contraindication to Rx12(3.6)25(7.5) Bleeding10(3.0)19(5.7) Other2(0.6)6(1.8) AE / Abnormal lab values22(6.5)24(7.2) Underlying cancer17(5.0)21(6.3) Investigator decision1(0.3)5 (1.5) Patient decision20(5.9)14(4.2) Patient unable to swallow0(0.0)4(1.2) Other9(2.7)8(2.4) Total discontinued158(46.7)172(51.3)

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

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 Fatal PE*68 Fatal bleed**31 Other34

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 Thrombocytopenia General & Administration Site Condition Fatigue Injection site reaction Investigations Alanine aminotransferase  Aspartate aminotransferase  Gamma-glutamyltransferase  International normalized ratio  Prothrombin time prolonged Skin & Subcutaneous tissues Ecchymosis

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  Regulatory BackgroundConnie Newman, M.D.  Background on VTE and Cancer Craig Eagle, M.D.  CLOT Study  Design  Results Agnes Y. Y. Lee, M.D.  Interpretation and DiscussionCraig Eagle, M.D.  ConclusionsCraig Eagle, M.D.

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

51 Key Characteristics of the CLOT Trial Design  Open label study design  Initial treatment regimen  Dalteparin dosing  6 month treatment duration

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 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 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 CLOT Study: Dalteparin Dosing Rationale  Efficacy of Dalteparin 200 IU/kg shown in acute VTE treatment (previous trials and literature) 1 st Month  Increased risk of recurrent VTE highest in 1 st 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 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 Points of Discussion  Key characteristics of the CLOT trial design  On-treatment mortality analysis  Robustness of data  Risk/Benefit

58 On-Treatment Mortality Analyses Log-rank p-value < 0.001Log-rank p-value = day definition14 day definition Dalteparin OAC Survival Distribution Analysis time (days)

59 Mortality Analyses On-Treatment 1 day ITT DalteparinOACDalteparinOAC Number of Deaths Included in Analysis X X 6 Months X X Discontinuation of study medication due to clinical management VTE or CVT Death X Study drug treatment Discontinuation due to other reasons X X X

60 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 Points of Discussion  Key characteristics of the CLOT trial design  On-treatment mortality analysis  Robustness of data  Risk/Benefit

62 Robustness of Data  Magnitude of the benefit  Consistency of subgroups  Competing risk

63 Days Post Randomization Primary Endpoint: Recurrent VTE Dalteparin OAC Risk Reduction = 52% HR 0.48 (95% CI 0.30, 0.77) Log-rank p= Recurrent VTE

64 RR95% CI n COX Model* 0.51(0.32,0.81)676 Tumor Type Solid Tumor0.45(0.28, 0.71)606 Breast0.83(0.12, 5.68)108 Gastrointestinal0.54(0.23, 1.26)164 Lung0.35(0.14, 0.85)90 Genitourinary0.41(0.13, 1.24)155 Other0.59(0.22, 1.63)89 Hematological6.80(0.38, )70 Extent of Malignancy Metastatic0.43(0.27, 0.71)455 Non-metastatic0.61(0.15, 2.45)151 Subgroup Analyses *adjusting for factors found to be prognostic for outcome (extent of tumor, type of tumor, smoking status and age) Favors DalteparinFavors OAC

65 CLOT Study: A Single Pivotal Trial to Support Clinical Effectiveness  Compelling p-value for primary efficacy analysis  Two sided p value < 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; Some Design Issues in Trials of Microbicides for the Prevention of HIV Infection. JID 2004:190, pg

66 Robustness of Data  Magnitude of the benefit  Consistency of subgroups  Competing risk

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 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 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 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 ) when the probability of VTE was relatively low DalteparinOAC Censored23 (6.8%)22 (6.5%) VTEs*12 (3.6%)34 (10.1%) *VTE RR=0.35, p=0.001

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

73 Risk/Benefit: VTE vs. Major Bleed Incidence per 30 Days Exposure VTEMajor Bleed Fragmin OAC Incidence Per 30 Days Exposure

74 Risk/Benefit Summary Dalteparin n=338 OAC n=338 VTE2753 Major Bleeds1912 Death due to: PE68 Major Bleeds10  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 Agenda  Regulatory BackgroundConnie Newman, M.D.  Background on VTE and Cancer Craig Eagle, M.D.  CLOT Study  Design  Results Agnes Y. Y. Lee, M.D.  Interpretation and DiscussionCraig Eagle, M.D.  ConclusionsCraig Eagle, M.D.

76 Conclusion Craig Eagle, M.D. Pfizer, Inc Medical Director

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 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 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