1.0

Material Utilized in Review ..........................................................................................

3

1.1           Material from NDA ........................................................................................

3

1.2           Related Reviews .............................................................................................

3

2.0

Background ...................................................................................................................

3

2.1           Indication ........................................................................................................

3

2.2           Related INDs and NDAs ................................................................................

4

2.3           Administrative History ...................................................................................

4

2.4           Proposed Directions for Use ...........................................................................

4

2.5           Foreign Marketing ..........................................................................................

5

3.0

Chemistry ......................................................................................................................

5

4.0

Animal Pharmacology ..................................................................................................

6

5.0

Description of Clinical Data Sources ............................................................................

7

5.1           Primary Development Program ......................................................................

7

                5.1.1        Study Type and Design/Patient Enumeration ..................................

7

                5.1.2        Demographics ..................................................................................

8

                5.1.3        Extent of Exposure (dose/duration) .................................................

9

5.2           Secondary Sources ..........................................................................................

10

                5.2.1        Post-Marketing Experience ..............................................................

10

                5.2.2        Literature ..........................................................................................

10

6.0

Summary of Human Pharmacokinetics ........................................................................

11

7.0

Efficacy Findings ..........................................................................................................

11

7.1           Overview of Studies Pertinent to Efficacy .....................................................

11

7.2           Overview of Studies Pertinent to Efficacy .....................................................

11

                7.2.1        Study 203 .........................................................................................

11

                                7.2.1.1     Investigators and Location .................................................

11

                                7.2.1.2     Study Plan ..........................................................................

12

                                7.2.1.3     Study Conduct and Outcome .............................................

13

                                7.2.1.4     Conclusions ........................................................................

17

                7.2.2        Study 205 .........................................................................................

17

                                7.2.2.1     Investigators and Location .................................................

17

                                7.2.2.2     Study Plan ..........................................................................

17

                                7.2.2.3     Study Conduct and Outcome .............................................

18

                                7.2.2.4     Conclusions ........................................................................

23

                7.2.3        Other Studies ....................................................................................

23

7.3           Summary of Data Pertinent to Important Clinical Issues ...............................

23

                7.3.1        Predictors of Response .....................................................................

23

                7.3.2        Size of Treatment Effect ..................................................................

23

                7.3.3        Choice of Dose .................................................................................

24

                7.3.4        Duration of Treatment ......................................................................

24

7.4           Conclusions Regarding Efficacy Data ............................................................

24

8.0

Safety Findings .............................................................................................................

25

8.1           Methods ..........................................................................................................

25

8.2           Deaths .............................................................................................................

25