Dalteparin Fragmin NDA 20287 S035

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

• FDA Oncologic Drugs Advisory Committee Meeting
• September 6, 2006

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Introduction

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

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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

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Agenda
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Consultants Available to the Committee
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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

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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)

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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
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Agenda
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Background VTE Cancer

• Craig Eagle, M.D.
• Pfizer, Inc
• Medical Director

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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 1200
• VTE causes symptoms and signs by venous
  obstruction, inflammation and embolization

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Clinical Problem

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

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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
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Clinical Problem

• Pulmonary embolism can be fatal

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Treatment for VTE
5 to 7 days (until INR 2)
Initial treatment
LMWH or UFH
3 months
Long-term therapy
Vitamin K antagonist OAC (INR 2.0 - 3.0)
7th ACCP anti-thrombotic guidelines Chest 2004
126 401S-428S
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Cumulative Incidence of Recurrent VTE During
Anticoagulant Therapy
Hazard ratio 3.2 (95 CI 1.9, 5.4)
Prandoni P, et al, Blood. 20021003484-3488
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Comparison of Warfarin and LMWH
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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
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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

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Agenda
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CLOT Study Design Results

• Agnes Y. Y. Lee, M.D.

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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 2003349146-153.
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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

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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
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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
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EfficacyAscertainment and Adjudication
Patients contacted every 2 weeks to ascertain
symptoms of VTE
Patients instructed to report urgently symptoms
of VTE to investigators

• Suspected VTE investigated by objective testing
  following pre-specified diagnostic algorithms
• Details sent to a blinded central adjudication
  committee for confirmation of VTE

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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

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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)

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CLOT Study Results
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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

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Analysis Populations
677 Randomized
dalteparin n338
OAC n338
Efficacy ITT
3 Subjects not dosed
Safety As Treated
n335
n338
Completed Treatment
n163
n180
Includes one subject randomized to OAC without
having given written informed consent
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Baseline Characteristics
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Baseline Characteristics
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Frequency of Follow-Up
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Efficacy Endpoints

• Primary
• Symptomatic recurrent DVT and/or PE
• Secondary
• Symptomatic DVT, PE or central venous thrombosis
  of upper limb, neck, chest

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Efficacy EndpointRecurrent 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)
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Secondary Endpoint Recurrent DVT, PE, or CVT
Dalteparin OAC
Risk Reduction 49 HR 0.51 (95 CI 0.32,
0.80) Log-rank p0.003
Recurrent VTE
Days Post Randomization
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Safety Endpoints

• Bleeding (major and any)
• Death
• Adverse Events

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Safety Endpoint Bleeding
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Time to First Adjudicated-positive Major Bleeding
- (As-treated Population)
Dalteparin OAC
Log-rank p0.28
Incidence of Bleeding
Days from Randomization
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Time to First Adjudicated-positive Bleeding
(Major/Minor) (As-treated Population)
Dalteparin OAC
Log-rank p0.05
Incidence of Bleeding
Days from Randomization
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Investigator Reported Reasons for Treatment
Discontinuation
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Overall Survival ITT Population
Overall population
Dalteparin (n338) OAC (n338)
Survival
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
Days After Randomization
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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
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Drug-Related Treatment Emergent Adverse Events
3 (As-Treated)
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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

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Agenda
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CLOT Study Interpretation and Discussion

• Craig Eagle, M.D.
• Pfizer, Inc
• Medical Director

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Points of Discussion

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

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Key Characteristics of the CLOT Trial Design

• Open label study design
• Initial treatment regimen
• Dalteparin dosing
• 6 month treatment duration

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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)

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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

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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

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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

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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

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Points of Discussion

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

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On-Treatment Mortality Analyses
1 day definition
14 day definition
Survival Distribution
Log-rank p-value Log-rank p-value 0.23
Analysis time (days)
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Mortality Analyses
6 Months
X
X
X
X
X
X
X
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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
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Points of Discussion

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

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Robustness of Data

• Magnitude of the benefit
• Consistency of subgroups
• Competing risk

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Primary Endpoint Recurrent VTE
Dalteparin OAC
Risk Reduction 52 HR 0.48 (95 CI 0.30,
0.77) Log-rank p 0.0017
Recurrent VTE
Days Post Randomization
64
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)
65
CLOT Study A Single Pivotal Trial to Support
Clinical Effectiveness

• Compelling p-value for primary efficacy analysis
• Two sided p value evidence of 2 independent trials with p
• Consistency across subgroups
• Dalteparin is proven to be an effective
  anticoagulant for primary prophylaxis in various
  clinical settings

• T. Fleming and B. Richardson JID
  2004190666-74
• Some Design Issues in Trials of Microbicides for
  the Prevention of HIV Infection. JID 2004190, pg
  666-674

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Robustness of Data

• Magnitude of the benefit
• Consistency of subgroups
• Competing risk

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Competing RiskDeath 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
• The mortality rate would have to be different
  between the two treatment groups
• The mortality censoring would have to affect the
  probability of VTE differentially in the
  treatment groups

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Competing RiskDeath 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

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Competing RiskDeath 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

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Competing RiskDeath 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

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Competing RiskDeath and Recurrence of VTE

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

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Points of Discussion

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

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Risk/Benefit VTE vs. Major BleedIncidence per
30 Days Exposure
VTE
Major Bleed
Incidence Per 30 Days Exposure
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Risk/Benefit Summary

• 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

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Agenda
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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

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Summary of CLOT Study

• Highly significant (p0.0017) 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

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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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