ppt - Pfizer Slides - Fragmin

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 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

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.

Consultants Available to the Committee

Agnes Y. Y. Lee, M.D., MSc, FRCPCAssociate 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., FACPProf. 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

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

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)

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

Agenda

Craig Eagle, M.D.

Background: VTE & Cancer

Craig Eagle, M.D. Pfizer, Inc

Medical Director

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

Clinical Problem

Patients with deep vein thrombosis have a painful swollen leg which limits their mobility

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

Clinical Problem

Pulmonary embolism can be fatal

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

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

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

Dalteparin Studies for Initial Treatment of VTE

Comparator PatientsTotal

Patients Cancer

Dalteparin dose Duration

Heparin + OAC1

56 64000-7500 IU BID

5-7 days

Heparin + OAC2 179 23100-120 IU/kg BID

5-10 days

Heparin + OAC3 802 70200 IU/kg/d

5-10 days

DalteparinAdjusted 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

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

Agenda

Craig Eagle, M.D.

CLOT Study Design & Results

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.

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

RCancer patients with proximal DVT, PE or both

Control Group (Standard):Dalteparin + OAC

Experimental Group:Dalteparin alone

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

1 month 6 months

Study Treatments

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

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

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

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)

CLOT Study Results

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

677 Randomized*

dalteparinn=338

OACn=338

Analysis Populations

3 Subjects

not dosed n=335n=338

EfficacyITT

Safety As Treated

* Includes one subject randomized to OAC without having given written informed consent

n=163n=180Completed Treatment

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)

Baseline Characteristics

Dalteparin n=338 (%)

OAC n=338 (%)

ECOG PS

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)

Frequency of Follow-Up

Dalteparin

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)

Efficacy Endpoints

Primary: Symptomatic recurrent DVT and/or PE

Secondary: Symptomatic DVT, PE or central venous

thrombosis of upper limb, neck, chest

0 30 60 90 120 150 180 2100%

Days Post Randomization

EEfficacy Endpoint:Recurrent VTE (ITT Analysis)

DalteparinOACRisk Reduction = 52%

HR 0.48 (95% CI 0.30, 0.77)Log-rank p = 0.0017

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

0 30 60 90 120 150 180 2100%

Secondary Endpoint: Recurrent DVT, PE, or CVT

DalteparinOAC

Risk Reduction = 49%HR 0.51 (95% CI 0.32, 0.80)Log-rank p=0.003

Safety Endpoints

Bleeding (major and any)

Adverse Events

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)

Transfusion of > 2 units of packed RBC or drop in hemoglobin of at least 2.0 g/dL

Any bleed 46 (13.6) 62 (18.5) 0.05

0 30 60 90 120 150 180 2100.0

Time to First Adjudicated-positive Major Bleeding - (As-treated Population)

DalteparinOAC

Days from Randomization

Log-rank p=0.28

0 30 60 90 120 150 180 2100.0

Time to First Adjudicated-positive Bleeding (Major/Minor) (As-treated Population)

Days from Randomization

DalteparinOAC

Log-rank p=0.05

Investigator Reported Reasons for Treatment Discontinuation

Dalteparin

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)

0 30 60 90 120 150 180 210 240 270 300 330 360 3900%

Overall Survival: ITT PopulationS

Days After Randomization

Overall population Dalteparin (n=338)OAC (n=338)

12-monthHR = 0.9495% CI (0.77, 1.15) Log-rank p= 0.57

6-monthHR = 0.93 95% CI (0.73, 1.18) Log-rank p= 0.56

* 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

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

System Organ Class (disorders) Preferred Term

Dalteparinn=337

OACn=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

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

Agenda

Craig Eagle, M.D.

CLOT Study – Interpretation and Discussion

Craig Eagle, M.D.Pfizer, Inc

Medical Director

Points of Discussion

Key characteristics of the CLOT trial design

On-treatment mortality analysis

Robustness of data

Risk/Benefit

Key Characteristics of the CLOT Trial Design

Open label study design

Initial treatment regimen

Dalteparin dosing

6 month treatment duration

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)

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

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

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

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

Robustness of data

Risk/Benefit

0 50 100 150 200

On-Treatment Mortality Analyses

0 50 100 150 2000%

Log-rank p-value < 0.001 Log-rank p-value = 0.23

1 day definition 14 day definition

DalteparinOAC

Analysis time (days)

Mortality Analyses

On-Treatment1 day

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

6 Months

Discontinuation of study medication due to clinical management

VTE or CVT

DeathXStudy drug treatment

Discontinuation due to other reasons

0 30 60 90 120 150 180 210 240 270 300 330 360 3900%

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

Days After Randomization

Robustness of data

Risk/Benefit

Robustness of Data

Magnitude of the benefit

Consistency of subgroups

Competing risk

0 30 60 90 120 150 180 2100%

Primary Endpoint: Recurrent VTE

DalteparinOACRisk Reduction = 52%

HR 0.48 (95% CI 0.30, 0.77)Log-rank p= 0.0017

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

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;666-74Some Design Issues in Trials of Microbicides for the Prevention of HIV Infection. JID 2004:190, pg 666-674

Robustness of Data

Magnitude of the benefit

Consistency of subgroups

Competing risk

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

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

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

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

Conclusion

In the CLOT study, the benefit of dalteparin relative to OAC is estimated accurately despite the high cancer mortality

Robustness of data

Risk/Benefit

Risk/Benefit: VTE vs. Major BleedIncidence per 30 Days Exposure

Day1-7

Day8-30

Day31+

Day1-7

Day8-30

Day31+

VTE Major Bleed

Fragmin

Risk/Benefit Summary

Dalteparinn=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 lifeControl arm results consistent with previous studies

Agenda

Craig Eagle, M.D.

Conclusion

Craig Eagle, M.D. Pfizer, Inc

Medical Director

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

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

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

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