Docstoc

About Nda - PowerPoint

Document Sample
About Nda - PowerPoint Powered By Docstoc
					Dalteparin (Fragmin)
NDA 20-287 S-035

        FDA Oncologic Drugs Advisory
            Committee Meeting
            September 6, 2006


                                       1
Introduction

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

                                        2
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




                                                     3
Agenda

 Regulatory   Background         Connie Newman, M.D.

 Background    on VTE and        Craig Eagle, M.D.
  Cancer

 CLOT Study                      Agnes Y. Y. Lee, M.D.
   Design
   Results

 Interpretation   and Discussion Craig Eagle, M.D.

 Conclusions                     Craig Eagle, M.D.


                                                          4
Consultants Available to the Committee
Agnes Y. Y. Lee, M.D., MSc, FRCPC             Steven Piantadosi, M.D., Ph.D.
Associate Prof., Medicine,                    Prof. of Oncology
McMaster University                           Director of Biostatistics
Hamilton Health Sciences Henderson            Johns Hopkins Oncology Center
Hospital                                      Baltimore, MD
Hamilton, ON

Mark Levine, M.D., MSc, FRCPC                 Frederick R. Rickles, M.D., FACP
Prof., Departments of Clinical Epidemiology   Prof. of Medicine, Pediatrics and
& Biostatistics, and Medicine, McMaster       Pharmacology and Physiology
University                                    The George Washington University
Henderson Research Centre                     Fellow, Center for Science and Technology
Buffett Taylor Chair in Breast Cancer         Healthcare Division
Research                                      Mitretek Systems, Inc.
McMaster University                           Falls Church, VA
Hamilton, ON




                                                                                          5
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
                                                            6
Approved Dalteparin Indications
US Package Insert
   Prophylaxis of DVT which may lead to PE in;
             undergoing abdominal surgery
     Patients
      (December 22,1994)
     Patientsundergoing 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)

                                                            7
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                                                                    8
Agenda

 Regulatory   Background         Connie Newman, M.D.

 Background    on VTE and        Craig Eagle, M.D.
  Cancer

 CLOT Study                      Agnes Y. Y. Lee, M.D.
   Design
   Results

 Interpretation   and Discussion Craig Eagle, M.D.

 Conclusions                     Craig Eagle, M.D.


                                                          9
Background: VTE & Cancer

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




                                10
VTE is a Common Complication in
Patients with Malignancy

 Associationof 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


                                                      11
Clinical Problem

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




                                                    12
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

                                                    13
Clinical Problem

 Pulmonary   embolism can be fatal




                                      14
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          15
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                 16
Comparison of Warfarin and LMWH

Warfarin Problem                     LMWH Advantages
Reduces the function of
                                     Inhibits activated coagulation factors
coagulation factors including
                                     in particular factor Xa
prothrombin

Difficulty maintaining therapeutic   More predictable anticoagulant
control                              response

Interruption & reversal of OAC       Only interrupted if platelets very low.
for thrombocytopenia and             Much simpler to handle if procedure
procedures                           required

Venous access                        Does not require lab monitoring

Multiple interactions with drugs     No or few interactions with drugs

                                                                               17
Dalteparin Studies for Initial Treatment of
VTE
Comparator              Patients        Patients            Dalteparin dose                Duration
                         Total          Cancer
                                                             4000-7500 IU BID
Heparin + OAC1               56              6                      +                       5-7 days
                                                                   OAC
                                                            100-120 IU/kg BID
Heparin + OAC2              179             23                      +                      5-10 days
                                                                  OAC
                                                                200 IU/kg/d
Heparin +   OAC3            802             70                       +                     5-10 days
                                                                   OAC
Dalteparin
Adjusted dose &             223             22                 100 IU/kg BID               5-10 days
200 IU/kg/d4

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                                                  18
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

                                                            19
Agenda

 Regulatory   Background         Connie Newman, M.D.

 Background    on VTE and        Craig Eagle, M.D.
  Cancer

 CLOT Study                      Agnes Y. Y. Lee, M.D.
   Design
   Results

 Interpretation   and Discussion Craig Eagle, M.D.

 Conclusions                     Craig Eagle, M.D.


                                                          20
CLOT Study Design & Results

          Agnes Y. Y. Lee, M.D.




                                  21
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.      22
Study Design
   Multi-national, multi-center, randomized, open-label
    study
                                    Control Group (Standard):
                                       Dalteparin + OAC
Cancer patients
with proximal DVT,        R
PE or both                             Experimental Group:
                                         Dalteparin alone
   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
                                                                23
Study Treatments
    Control Group

    dalteparin
    200 IU/kg OD


    oral anticoagulant (INR 2.0 to 3.0) x 6 mo


   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
                                                                  24
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               25
Efficacy:
Ascertainment and Adjudication

    Patients contacted     Patients instructed
     every 2 weeks to      to report urgently
   ascertain symptoms      symptoms of VTE
          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
                                                   26
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

                                                              27
Statistical Analysis
        Efficacy Analysis                    Safety Analysis
Recurrent VTE                      Bleeding

  Intention-to-treat population       As-treated population (at least

   (all randomized subjects)            one dose)
                                       Included events up to 48
  Included all events up to 6-
                                        hours after stopping study
   month visit or death                 drug
  Time to first recurrent VTE         Time to first bleed (major and
   event                                any)
  Log-Rank (LR) test (2-sided         LR test (2-sided alpha = 0.05)
   alpha = 0.05)                    Overall survival
                                       ITT population
                                       Included all deaths over 6 and
                                        12 months
                                       LR test (2-sided alpha = 0.05)

                                                                      28
CLOT Study Results




                     29
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
                                                    30
Analysis Populations
                             677 Randomized*


 Efficacy          dalteparin                               OAC
 ITT                n=338                                  n=338
                                                                   3 Subjects
                                                                   not dosed
 Safety
                   n=338                                  n=335
 As Treated

 Completed
                    n=180                                  n=163
 Treatment

* Includes one subject randomized to OAC without having given written
  informed consent                                                              31
Baseline Characteristics
                      Dalteparin      OAC
                        n=338        n=338
Gender
  Female (%)          179 (53.0)    169 (50.0)
  Male (%)            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 (%)        235 (69.5)    230 (68.0)
  PE only (%)          64 (18.9)     65 (19.2)
  PE/DVT (%)           39 (11.5)     43 (12.7)

                                                  32
Baseline Characteristics
                           Dalteparin     OAC
                           n=338 (%)    n=338 (%)
ECOG PS
  0                         80 (23.7)    63 (18.6)
  1                        135 (39.9)   150 (44.4)
  2                        118 (34.9)   122 (36.1)
  3                          5 ( 1.5)     3 ( 0.9)
Solid tumor                298 (88.2)   308 (91.1)
   No evidence              36 (10.7)    33 ( 9.8)
   Localized                39 (11.5)    43 (12.7)
   Metastatic              223 (66.0)   232 (68.6)

Hematological malignancy    40 (11.8)    30 ( 8.9)

                                                     33
Frequency of Follow-Up
                                       Dalteparin       OAC
                                         n=338         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)



                                                                   34
Efficacy Endpoints

 Primary:
   Symptomatic   recurrent DVT and/or PE

 Secondary:
   Symptomatic  DVT, PE or central venous
    thrombosis of upper limb, neck, chest




                                             35
     Efficacy Endpoint:
     Recurrent VTE (ITT Analysis)
                                                                          Dalteparin
                25%
                                                                          OAC
                          Risk Reduction = 52%
                          HR 0.48 (95% CI 0.30, 0.77)
                20%       Log-rank p = 0.0017
Recurrent VTE




                15%



                10%



                5%



                0%
                      0       30      60       90       120   150   180       210

                                        Days Post Randomization
                                                                                    36
Subgroup Analyses
             Favors Dalteparin                Favors OAC
                                                                                        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
*adjusting for factors found to be prognostic for outcome (extent of tumor, type of tumor, smoking status and age)         37
     Secondary Endpoint:
     Recurrent DVT, PE, or CVT
                                                                           Dalteparin
                25%       Risk Reduction = 49%                             OAC
                          HR 0.51 (95% CI 0.32, 0.80)
                20%
                          Log-rank p=0.003
Recurrent VTE




                15%


                10%


                5%


                0%
                      0      30      60      90         120    150   180       210

                                     Days Post Randomization                         38
Safety Endpoints

 Bleeding   (major and any)

 Death

 Adverse    Events




                               39
Safety Endpoint:
Bleeding
                                             Dalteparin     OAC       Log-rank
                                             n=338 (%)    n=335 (%)    p-value

Major bleed                                   19 (5.6)     12 (3.6)     0.28

 Associated with death                           1            0

 Critical site (intracranial, intraspinal,
 intraocular, pericardial, or                    4            3
 retroperitoneal)
 Transfusion of > 2 units of packed
 RBC or drop in hemoglobin of at                14            9
 least 2.0 g/dL

Any bleed                                    46 (13.6)    62 (18.5)     0.05



                                                                                 40
Time to First Adjudicated-positive Major
Bleeding - (As-treated Population)
                                                                                    Dalteparin
                        0.5
                                                                                    OAC
                                  Log-rank p=0.28
                        0.4
Incidence of Bleeding




                        0.3



                        0.2



                        0.1



                        0.0
                              0       30      60         90     120     150   180       210


                                                    Days from Randomization
                                                                                              41
Time to First Adjudicated-positive Bleeding
(Major/Minor) (As-treated Population)
                                                                                    Dalteparin
                        0.5
                                                                                    OAC
                                  Log-rank p=0.05
                        0.4
Incidence of Bleeding




                        0.3



                        0.2



                        0.1



                        0.0
                              0       30      60        90      120     150   180       210

                                                    Days from Randomization
                                                                                              42
Investigator Reported Reasons for
Treatment Discontinuation
                                Dalteparin                OAC
                                  n=338                  n=335
                                  n (%)                  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)
                                                                         43
Overall Survival: ITT Population
Overall population                                                                    Dalteparin (n=338)
           100%
                                                                                      OAC (n=338)

           90%

           80%

           70%

           60%
Survival




           50%

           40%

           30%
                      6-month                             12-month
                      HR = 0.93                           HR = 0.94
           20%        95% CI (0.73, 1.18)                 95% CI (0.77, 1.15)
           10%        Log-rank p= 0.56                    Log-rank p= 0.57
            0%
                  0    30   60   90   120   150   180   210   240   270   300   330    360   390


                                       Days After Randomization
                                                                                                      44
Adjudicated Cause of Death During First
6 Months

                                         Dalteparin                   OAC
                                        n=131 deaths              n=137 deaths
Progressive cancer                             119                        124

Fatal PE*                                         6                           8

Fatal bleed**                                     3                           1

Other                                             3                           4

* 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                     45
Drug-Related Treatment Emergent
Adverse Events ≥3% (As-Treated)
System Organ Class                                            Dalteparin    OAC
(disorders)                Preferred Term                       n=337      n=331
                                                               N     %     N    %

Blood & Lymphatic          Anaemia NOS                         5    1.5    11   3.3
System                     Thrombocytopenia                   15    4.5    7    2.1
General & Administration   Fatigue                             8    2.4    12   3.6
Site Condition             Injection site reaction            34    10.1   5    1.5
                           Alanine aminotransferase          12    3.6    2    0.6
                           Aspartate aminotransferase        11    3.3    3    0.9
Investigations             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
                           Ecchymosis                         29    8.6    9    2.7
tissues

                                                                                      46
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
     of bleeding similar between dalteparin and
 Risk
  OAC therapy
 No  difference in overall mortality between
  dalteparin and OAC therapy


                                                   47
Agenda

 Regulatory   Background         Connie Newman, M.D.

 Background    on VTE and        Craig Eagle, M.D.
  Cancer

 CLOT Study                      Agnes Y. Y. Lee, M.D.
   Design
   Results

 Interpretation   and Discussion Craig Eagle, M.D.

 Conclusions                     Craig Eagle, M.D.


                                                          48
CLOT Study – Interpretation and
Discussion

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




                                  49
Points of Discussion

 Key   characteristics of the CLOT trial design

 On-treatment    mortality analysis

 Robustness     of data

 Risk/Benefit




                                                   50
Key Characteristics of the CLOT Trial
Design

 Open      label study design

 Initial   treatment regimen

 Dalteparin    dosing

6   month treatment duration




                                        51
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)
                                                                    52
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
                                                   53
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



                                                   54
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
                                                      55
CLOT Study: 6 Month Treatment Duration
Rationale

 Potentialadvantages 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



                                                    56
Points of Discussion

 Key   characteristics of the CLOT trial design

 On-treatment    mortality analysis

 Robustness     of data

 Risk/Benefit




                                                   57
                        On-Treatment Mortality Analyses
                                                                                             Dalteparin
                                                                                             OAC
                                     1 day definition                      14 day definition
                        100%
Survival Distribution




                        75%



                        50%



                        25%


                                   Log-rank p-value < 0.001             Log-rank p-value = 0.23
                         0%
                               0      50     100    150       200   0        50      100     150      200

                                                          Analysis time (days)                        58
Mortality Analyses
                                                          On-Treatment            ITT
             6 Months                                        1 day
                                                      Dalteparin    OAC   Dalteparin    OAC

                                   X                     54         14       54         14
                                   X                      4         5         4         5
                                   X                      1         0         1         0
                                   X                      0         2         0         2
                                   X                      0         0        12         34
                                   X                      0         0        42         67
                                   X                      0         0        18         15
Number of Deaths Included in Analysis                    59         21      131         137
  Study drug treatment
X Death
  VTE or CVT
   Discontinuation of study medication due to clinical management
   Discontinuation due to other reasons                                                       59
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
                100%


                80%
     Survival




                60%


                40%


                20%


                 0%
                       0   30   60   90   120   150   180   210   240   270   300   330   360   390

                                          Days After Randomization                                    60
Points of Discussion

 Key   characteristics of the CLOT trial design

 On-treatment    mortality analysis

 Robustness     of data

 Risk/Benefit




                                                   61
Robustness of Data

 Magnitude   of the benefit

 Consistency   of subgroups

 Competing   risk




                               62
     Primary Endpoint: Recurrent VTE
                                                                          Dalteparin
                25%
                                                                          OAC
                          Risk Reduction = 52%
                          HR 0.48 (95% CI 0.30, 0.77)
                20%       Log-rank p= 0.0017
Recurrent VTE




                15%



                10%



                5%



                0%
                      0       30      60       90       120   150   180       210

                                        Days Post Randomization
                                                                                    63
Subgroup Analyses
             Favors Dalteparin                Favors OAC
                                                                                        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
*adjusting for factors found to be prognostic for outcome (extent of tumor, type of tumor, smoking status and age)         64
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   65
Robustness of Data

 Magnitude   of the benefit

 Consistency   of subgroups

 Competing   risk




                               66
Competing Risk:
Death and Recurrence of VTE

 Couldmortality 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

                                                       67
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




                                                           68
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




                                                               69
Competing Risk:
Death and Recurrence of VTE

Mortality Censoring and benefit within the initial
30 days
                      Dalteparin              OAC
Censored              23 (6.8%)             22 (6.5%)

VTEs*                 12 (3.6%)            34 (10.1%)
                            *VTE RR=0.35, p=0.001

 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
                                                        70
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




                                                    71
Points of Discussion

 Key   characteristics of the CLOT trial design

 On-treatment    mortality analysis

 Robustness     of data

 Risk/Benefit




                                                   72
                                 Risk/Benefit: VTE vs. Major Bleed
                                 Incidence per 30 Days Exposure
                                                                                          Fragmin
                                                                                          OAC
                                                VTE                        Major Bleed
                                  0.12                            0.12
Incidence Per 30 Days Exposure




                                  0.10                            0.10

                                  0.08                            0.08

                                  0.06                            0.06

                                  0.04                            0.04

                                  0.02                            0.02

                                  0.00                            0.00
                                         Day   Day    Day Total          Day   Day    Day Total
                                         1-7   8-30   31+                1-7   8-30   31+           73
Risk/Benefit Summary
                                        Dalteparin            OAC
                                         n=338                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
                                                                        74
Agenda

 Regulatory   Background         Connie Newman, M.D.

 Background    on VTE and        Craig Eagle, M.D.
  Cancer

 CLOT Study                      Agnes Y. Y. Lee, M.D.
   Design
   Results

 Interpretation   and Discussion Craig Eagle, M.D.

 Conclusions                     Craig Eagle, M.D.


                                                          75
Conclusion

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




                                 76
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
                                                               77
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

 Buildson previous clinical trial experience with
  dalteparin in VTE

                                                     78
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




                                                      79

				
DOCUMENT INFO
Description: About Nda document sample