CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER;
`22-304
`
`STATISTICAL REVIEWQ S)
`
`

`

`STATISTICAL REVIEW AND EVALUATION
`
`Biometrics Division: VI (HFD-705)
`
`_____~.
`I 22-304
`i MATE—0.:
`'
`
`: SERIAL No.: __ R
`" "ii—OWMTTTW ”—ij
`
`:[DATE RECEIVED BY THE CENTER:
`' March 19, 2W”_________.
`
`iDRUGNAME: ‘
`iTapentadolHydrochloride(CG5503)
`-{
`
`
`- Oral
`_____________.___l
`j DOSAGE FORM:
`_
`
`Moderate to severe acute pain
`.._____
`FINDICATION:
`I
`
`! SPONSOR: *w_—j:0rtho-McNeil-Janssen Phannaceuticals, Inc.
`
`DOCUMENTS REVIEWED:
`.
`i Electronic Copy Dated March 19, 2008
`NAME OF STATISTICAL REVIEWER:
`E Meiyu Shen, Ph.D.
`¥ Atiar Rahman, Ph.D.
`!
`
`% Kathleen Young
`i NAME OF PHARM TOX anmwm:
`\—.
`
`
`
`
`i
`-
`
`W—‘i
`,
`
`Meiyu Shen, Mathematical Statistician
`Atiar Rahman, Mathematical Statistician
`
`Concur:
`
`'
`
`Karl K Lin, Ph.D.
`Team Leader, DBVI
`
`Distribution:
`
`NDA 22-304
`HFD—705/Karl K Lin, PhD.
`OND/ODEII/DMEP, Kathleen A. Young
`
`

`

`Statistical Review of NDA22304
`
`TABLE OF CONTENTS
`
`Background
`
`...... .............................................................................................................. 3
`
`1.
`
`2.
`
`Mouse study (Study TP25I8) ......................................................................................................3
`
`Introduction ................................................................................................................................3
`
`
`Sponsor’s analysis ........................................................................................4
`
`Data Analyzed and Sources ...........................................................................4
`
`Reviewer's analysis (I) - Including All Treatment Groups......
`.....5
`Survival analysis ..................................................................................... 5
`
`..... 8
`Tumor data analysis..
`
`Conclusion .................................................................................................................................................. 8
`
`2.1
`
`2.2
`
`2.3
`
`2.4
`2.4.1
`2.4.2
`2.4.3
`
`2.5
`2.5.1
`2.5.2
`2.5.3
`
`Reviewér's Analysis (II) _— Excluding Dose-Escalation Group ..................................................11
`Survival analysis ............................................................................................................. l 1
`
`Tumor data analysis..
`....... 15
`Conclusion ................................................................................................................................................ 15
`
`Rat study (Study TP2418)..........................................................................
`
`............................ 19
`
`3.1
`
`3.2
`
`3.3
`
`Introduction ...................................................................................................................................19
`
`Sponsor’s analysis .........................................................................................................................20
`
`Data Analyzed and Sources..........................................................................................................20
`
`3.4
`3.4.l
`3.4.2
`3.4.3
`3.4.4
`
`Reviewers' analyses»......................................20
`Survival analysis ..........................................................
`20
`Tumor data analyses Using Peto Method .........
`23
`Tumor Data Analysis Using Poly-3 Method”
`27
`Conclusion ................................................................................................................................................ 32
`
`
`
`Page 2 of 32
`
`

`

`Statistical Review of NDA22304
`
`1. BACKGROUND
`
`CG5503 is for treatment of moderate to severe pain. In this submission (NDA 22304), the sponsor
`submitted one 2-year oral carcinogenicity study of CG5503 in mouse (Study TP2518) and one 2-
`year oral carcinogenicity study of CG5503 in rats (Study TP2418).
`
`Dr. Meiyu Shen is the original statistical reviewer of the carcinogenicity studies of this NDA
`submission. She performed the original analysis of the survival and tumor data of both the mouse
`study and the‘rat study using data of all Six treatment groups in the two studies, and completed a
`drafl statistical review and evaluation report before she took a vacation during the summer.
`
`While Dr. Shen was on vacation and the draft report was waiting for the secondary statistical
`reviewer Karl Lin, Ph.D. to concur, the Pharm/Tox Statistics Team of the Office of Biostatistics
`received an urgent request from Adam M. Wasserman, Ph.D., Supervisory
`Pharmacologist/Toxicologist, Division of Anesthesia, Analgesia and Rheumatology Products, to re-
`analyze the survival and tumor data of the mouse excluding the dose-escalation group. Dr.
`Wasserman and Dr. Kathleen Young, the primary pharm/tox reviewer of this submission, also
`informed the OB Pharm/Tox Statistics Team that they were going to present their reviews at the
`scheduled ECAC meeting on 8/26/2008, and would like to have statistical review results from the
`Team before the meeting.
`
`Because urgent requests from the medical division, Dr. Lin asked Dr. Atiar Rahman of the OB
`Pharm/Tox Statistics Team to perform the re-analysis of the survival and tumor data of the mouse
`study instead of waiting for Dr. Sheri to do that after her vacation. Dr. Rahinan re-analyzed the
`survival and tumor data of the mouse study excluding the dose-escalation group as requested by Dr.
`Wasserman. Dr. Rahman also re—analyzed the survival and tumor data of the rat study merely to
`double check the results of the original analysis.
`'
`
`I
`
`Dr. Atiar Rahman used the poly-3 test in his re-analysis versus the Peto test used in Dr. Shen's
`original analysis. Both tests are survival-adjusted tests. The dose-escalation group of the mouse
`study was excluded (for both males and females) in the re-analysis.
`
`Only the results of the re-analysis of the mouse study and the rat study are added to the original
`analysis in this report. It is noted that the re-analysis also includes pairwise comparisons between
`the combined control and individual treated groups.
`
`' 2. MOUSE STUDY (STUDY TP2518)
`2.1 Introduction
`
`The objective of this study was to determine the effects of CG5503 on the incidence and morphology of
`tumors following oral administration to the mouse for 104 weeks. Three treatment groups of 51 male
`and 51 female mice/group were administered the test article at respective dose levels of 50, 100,
`200 mg free base/kg/day. One treatment group of 60 male and 60 female mice/group were
`administered the test article at respective dose levels of 300 mg free base/kg/day. Two control
`groups of 51 male and 51 female mice/group were administered the placebo.
`
`Page 3 of 32
`
`

`

`Statistical Review of NDA22304
`
`Animal numbers
`
`Main study
`Male
`
`Female
`
`Satellite study
`Male
`
`Female
`
`802-825
`
`Control 1
`Low
`Intermediate (1)
`Intermediate (II)
`
`High
`
`0'
`50
`100
`200‘
`200 (Wks 1-13)
`30003131448)
`200 (Wks 2991)“
`0
`
`1-51
`52-102
`103-153
`154—204
`205.255
`.
`-
`833.34”
`256—306
`
`307-357
`358-408
`409-459
`460-510
`511-561
`..
`,
`-
`844.832.:
`562-612
`
`-
`
`613-624
`625-645
`646-666
`667—690
`
`691-714
`
`724-735
`736-756
`757-777
`778-801
`
`715—723
`
`826—834
`
`# dose escalation animals were administered the increased dose levels at Week 14 and 27 in advance of the main study
`and satellite animals
`
`* as the numb-er of smiving Group 4 males fell to 20 in Week 100, the remaining Group 4 males were remixed OE-
`. dose for the remainder of the study
`** All smiving Group 5 animals were subject to early termination fi'om the study in Week 92, since Group 5 reached a
`level considered insufiicient for the continued viability of this group.
`
`At Week 14, 9 males and 9 females from the high dose group (Group 5, 200 mg/kg/day; designated
`dose escalation animals) were administered CG5503 at 300 mg/kg/day. After 7 days dosing,
`animals were considered to have tolerated thisincrease in dose level and all Group 5 animals were
`dosed at 300 mg/kg/day from Week 15.
`
`Dosing of Group 5 was reduced to 200 mg/kg/day from Week 29 although it was scheduled to
`increase to 400 mg/kg/day at the start of Week 27.
`
`2.2 Sponsor’s analysis
`
`The sponsor presented the mean survival estimate in Figures 1 and 2 of the sponsor’s study report
`and the summary cf survival estimates in Table 4 of the sponsor’3 study report. However, the
`sponsor did not present any statistical analysis for the mice mortality data The sponsor noted that
`over the full duration of the study, mortality1n males dosed at 200 and 200/300/200 mg/kg/day and
`females dosed at 200/300/200 mg/kg/day was significantly higher than in combined control groups.
`
`Body weight was unaffected by treatment at doses up to 200 mg/kg/day. There was a slight
`reduction in body weight gain for Group 5 males between weeks 13-28 when administered ,
`300 mg/kg/day.
`
`Food consumption was unaffected by treatment.
`
`There was a statistically significant increase at the 5% level for liver hepatocellular tumors. in males
`(for overall dose response).
`
`2.3 Data Analyzed and Sources
`
`The sponsor submitted the data in electronic format on March 19, 2008. The data are located in the
`EDR at the following link: \\cdsesub1\n22304\S 00.
`
`Page 4 of 32
`
`

`

`Statistical Review of NDA22304
`
`2.4 Reviewer's analysis (I) - Including All Treatment Groups
`
`Dr. Meiyu Shen independently analyzed the survival data for males and females, separately. She
`also independently analyzed the mice tumor data for males and females, separately using Peto’s
`method.
`
`2.4.1 Survival analysis
`The summaries ofthe mortality data are given in Table 1 for males. The time intervals 0-52, 53-78,
`79-90 and 91—105 weeks were chosen for males. The Kaplan—Meier curves for males are shown in
`Figure 1. Analysis of Dose-Mortality Trend for Male Mice is presented in Table 2. From Figure 1,
`we can see that the survival probability in control group was much higher than that in the dosed
`group over the full duration of the study. The highest dose group in males had the highest mortality
`rate. The analysis of Dose-Mortality trend for males in Table 2 showed a statistically significant
`' dose-related trend among the control and the dosed groups because the p-value is 0.0005 (Cox
`method) and 0.0002 (Kruskal-Wallis tests), respectively, which is much smaller than 0.05.
`
` 0
`
`10
`
`20
`
`EX)
`
`40
`
`50
`
`50
`
`7O
`
`80
`
`90
`
`100
`
`110
`
`CTHO
`8—5—5
`fl —a—a- MEDHI
`
`9—9—9-
`*9 -*-»“*-
`
`LOW
`HIGH
`
`‘6)— 9—9-
`
`MED
`
`Figure 1 Kaplan-Meier Survival functions for Male Mice (including all treatment groups)
`
`The summaries of the mortality data are given in Table 3 for females. The time intervals 0-52, 53-
`78, 79—90 and 91—105 weeks were chosen for females. The Kaplan-Meier curves for females are
`shown in Figure 2. Analysis of Dose-Mortality Trend for Female Mice is presented in Table 4.
`From Figure 2, we can see that the- survival probability in control group is much higher than that in
`the highest dosed groups. The analysis of Dose-Mortality trend for females in Table 4 shows a
`statistically significant dose-related trend among the control and the dosed groups because the p—
`value is 0.0487 (Kruskal-Wallis tests), which is smaller than 0.05.
`
`Page 5 of 32
`
`

`

`Statistical Review of NDA22304
`
`Table 1 Analysis of mortality data for male mice (including all treatment groups)
`
`Anal sis of Mortali
`
`
`
`Table 2 Analysis of Dose-Mortality Trend for Male Mice
`(including all treatment groups)
`
`
`
`
`
`
`
`
`
`
`
`
`Note: This test- is run using Trend and Homogeneity Analyses of Proportions and
`Life Table Data Version 2.1, by Donald G. Thomas, National Cancer Institute
`
`From Tables 1 and 3, it is seen that the females’ mortality rate in the control group was 20% higher
`than. the males’ mortality rate in the control group because the females’ mortality rates in the control
`group by Week 90 were 53.9% and the males’ mortality rate by Week 90 were 32.4% for the
`control. The females’ mortality rate in the control is almost higher than the males’ mortality rate in
`any dosed group by Week 90.
`
`Page 6 of 32
`
`

`

`Statistical Review of NDA22304
`
` O
`
`80
`3'0
`<->— ‘3—9
`
`90
`MED
`
`100
`
`110
`
`20
`
`30
`10
`cmo
`3—5—8-
`fi -A—-ér MEDHI
`
`50
`40
`9—6—9-
`*- -*——>*
`
`60
`LOW
`HIGH
`
`Figure 2 Kaplan-Meier Survival fimctions for Female Mice (including all treatment groups)
`
`Table 3 Analysis of mortality data for female mice (including all treatment groups)
`
`
`
`Page 7 of 32
`
`

`

`Statistical Review of NDA22304
`
`Table 4 Analysis of Dose-Mortality Trend for Female Mice (including all treatment groups)
`
`
`
`
`
`
`
`Kruskal-Wallis
`
`
`2.4.2 Tumor data analysis
`The dose response analyses in incidental tumors and fatal tumors were performed using the Peto
`prevalence method and the Peto death-rate method, respectively. The actual dose levels of treatment
`groups were used as the weights for the trend analysis. The number of tumor bearing animals of
`each tumor type and its p-values for many organs were presented in Tables 5 and 6 for males and
`females, respectively. Multiplicity for the trend testing was adjusted using a significance level of
`0.025 for rare tumors, and 0.005 for common tumors because two species were studied. A tumor
`type with a background rate of 1 percent or less is classified as rare by Haseman; more frequent
`tumors are classified as common.
`
`It is also well known that the approximation results may not be stable and reliable, and tend to
`underestimate the exact p-values when the total numbers of tumor occurrence across treatment
`groups are small. In this situation, the exact permutation trend test should be used to test for the
`positive trend. The exact permutation trend test is a generalization of the Fisher’s exact test.
`
`From Table 5, it is seen that the p-value (asymptotic method) of the trend test for the rare tumor SK
`(Sarcoma-NOS) in skin subcutis for males is 0.0214 (<0.025). From Table 6, it is seen that the p-
`value of the trend test for the rare tumor 0V in ovary (benign granulose cell tumor) for females is
`0.0203 (<0.025). The p-value of the trend test for the rare tumor 0V in ovary (benign luteoma
`tumor) for females is 0.0154 (<0.025). The p-Value of the trend test for the rare tumor SM in
`sternum+marrow (haenangioma tumor) for females is 0.0074 (<0.025).
`
`2.4.3 Conclusion
`
`The analysis of Dose-Mortality trend for males in Table 2 showed a statistically significant dose-
`related trend among the control and the closed groups because the p-value is 0.0005 (Cox method)
`and 0.0002 Kruskal—Wallis tests), respectively, which is much smaller than 0.05.
`
`The analysis of Dose-Mortality trend for females in Table 4 shows a statistically significant dose-
`related trend among the control and the dosed groups because the p-value is 0.0487 (Kruskal—Wallis
`tests), which is smaller than 0.05 .
`
`The mortality rate in the 200/3 00/200 mg/kg/day group is much higher than the control for both
`females and males although the 300 mg/kg/day was dosed for 15 weeks (from Week 14 to 28) and
`switched back to 200 mg/kg/day for the rest 64 weeks (from Week 29 to 92).
`
`From Tables 1 and 3, it is seen that the females’ mortality rate in the control group was 20% higher
`than the males’ mortality rate in the control group because the females’ mortality rates in the control
`
`’ Page 8 of 32
`
`

`

`Statistical Review of NDA22304
`
`group by Week 90 were 53.9% and the males’ mortality rate by Week 90 were 32.4% for the
`control.
`
`From Table 5, it is seen that the p—value (asymptotic method) of the trend test for the rare tumor SK
`(Sarcoma-NOS) in skin subcutis for males is 0.0214 (<0.025). From Table 6, it is seen that the p-
`value of the trend test for the rare tumor 0V in ovary (benign granulose cell tumor) for females is
`0.0203 (<0.025). The p-value of the trend test for the rare tumor 0V in ovary (benign luteoma
`tumor) for females is 0.0154 (<0.025). The p-value of the trend test for the rare tumor SM in
`sternum+marrow (haenangioma tumor) for females is 0.0074 (<0.025).
`
`Table 5 Report on Test for Positive Linear Dose-Tumor Trends in Male Mice (including all
`
`treatment groups)
`
`
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`Page 9 of 32
`
`

`

`Statistical Review in" NDA22304
`
`
`
`
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`
`
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`Note: The check mark t~:-\’.indicates statistically significant test results, based on the decision ruleof FDA.CDER.Divisions of Biometrics.
`
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`
`'
`
`,
`
`Table 6 Report on Test for Positive Linear Dose-Tumor Trends in Female Mice (including all
`
`treatment groups)
`
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`Page 10 of 32
`
`

`

`Statistical Review of NDA22304
`
`«W
`
`
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`MMsmmsuacuns
`.
`' L {JAREWQMAM ,
`i
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`Note: The check mark Citziindlcates statistically significant test results, based on the decision rule of FDA.CDER.Divisions of Biometrics.
`
`2.5 Reviewer's Analysis (II) — Excluding Dose-Escalation Group
`Dr. Atiar Rahman independently analyzed the survival data for males and females, separately He
`also independently analyzed the mice tumor data for males and females, separately using the poly-3
`method excluding the dose-escalation group.
`
`2.5.1 Survival analysis
`The summaries of the mortality data are given in Table 1R for males. The "time intervals 0-52, 53-
`78, 79-91, 92—104, and 105-105 weeks were chosen for males. The Kaplan-Meier curves for males
`are shown in Figure 1R. Analysis of Dose-Mortality Trend for Male Mice is presented in Table 2R.
`The analysis of Dose-Mortality trend for males in Table 2R shows that the dose-related trend is
`statistically significant.
`
`APPEARS nus my
`DH one:will
`
`Page 11 of 32
`
`

`

`Statistical Review of NDA22304
`
`10
`
`20
`
` O
`
`30
`
`' 40
`
`50
`
`60
`
`1'0
`
`80
`
`90
`
`100
`
`110
`
`E—E—B- emu
`
`S—e—-—9— LOW
`
`+6—0-
`
`MED
`
`fi-fl—fi
`
`HIGH
`
`Figure 1R Kaplan—Meier Survival functions for Male Mice (Excluding Dose-Escalation Group)
`
`Table 1R Analysis of mortality data for male mice (excluding dose—escalation group)
`
`Analysis of Mortality Data for Male Mice by Treatment and Time
`
`Analysis of Mortality
`0-52
`
`No. Risk No. Died No. Alive Pct Survival Pct Mortality
`102
`7
`95
`93.1
`6.9
`
`CTRO
`
`53-78
`
`79-91
`
`92-104
`
`95
`
`79
`
`69
`
`FINALKILL105-105 59
`
`51
`
`16
`
`1o
`
`10
`
`59
`
`3
`
`79
`
`69
`
`59
`
`0
`
`48
`
`77.5
`
`67.6
`
`57.8
`
`94.1
`
`22.5
`
`32.4
`
`42.2
`
`5.9
`
`0-52
`
`53-78
`
`7991
`
`48
`
`42
`
`35
`92-104 ,
`FINALKILL105-105 24
`
`0-52
`
`53-78
`79-91
`
`92-104
`
`-
`
`51
`
`44
`38
`
`31
`
`Low
`
`MED
`
`FINALKILL105-105 20
`
`HIGH
`
`0-52
`
`51
`
`6
`
`7
`
`11
`24
`
`7
`
`6
`7
`
`11
`
`' 20
`
`9
`
`42
`
`35
`
`24
`0
`
`, 44
`
`38
`31
`
`20
`
`0
`
`42
`
`'
`
`82.4
`
`68.6
`
`47.1
`
`86.3
`
`74.5
`60.8
`
`39.2
`
`17.6
`
`31.4
`
`52.9
`
`13.7
`
`25.5
`39.2
`
`60.8
`
`82.4
`
`' 17.6
`
`Page 12 0132
`
`

`

`Statistical Review of NDA22304
`
`Analysis of Mortality
`53-78
`
`No. Risk No. Died No. Alive Pct Survival Pct Mortality
`42
`6
`36
`70.6
`29.4
`
`79-91
`
`92-104
`
`36
`
`23
`
`FINALKILL105-105 20
`
`13
`
`3
`
`20
`
`23
`
`20
`
`0
`
`45.1
`
`39.2
`
`54.9
`
`60.8
`
`Table 2R Analysis of Dose—Mortality Trend for Male Mice
`(Excluding Dose—Escalation Group)
`
`Analysis of Dose-Mortality Trend for Male Mice
`
`Method
`
`Cox
`
`Kruskal-Wallis
`
`Statistics P-Value Statistics P-Value
`
`T‘m‘LAthed Trend TeSt0.5467
`Depart from Trend
`
`0.7608 0.3088
`
`0.8569
`
`Dose-Mortality Trend
`
`6.6580
`
`0.0099 6.7061
`
`0.0096
`
`0.0714
`0.0657 7.0149
`7.2046
`Homogeneity
`Note: This test is run using Trend and Homogeneity Analyses of Proportions and
`Life Table Data Version 2.1, by Donald G. Thomas, National Cancer Institute
`
`The summaries of the mortality data are given in Table 3R for females. The time intervals 0—52, 53—
`78, 79-91, 92-104, and 105-105 weeks were chosen for females. The Kaplan—Meier curves for
`females are shown in Figure 2R. Analysis of Dose-Mortality Trend for Female Mice is presented in
`Table 4R. The analysis of Dose-Mortality trend for females in Table 4R shows that the dose-related
`trend in survival is not statistically significant.
`
`APPEARS nus WAY
`ON ORIGTNAL
`
`Page 13 of 32
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`

`Statistical Review of NDA22304
`
` O
`
`40
`
`50
`
`60
`
`70
`
`80
`
`90
`
`1m
`
`110
`
`10
`
`20
`
`3)
`
`E-B—E- cmo
`
`6-6—-9
`
`LOW
`
`+e~o MED
`
`ar—firfiflr
`
`HIGH
`
`Figure 2R Kaplan—Meier Survival functions for Female Mice (Excluding Dose-Escalation Group)
`
`Table 3R Analysis of mortality data for female mice (excluding dose-escalation group)
`
`Analysis of Mortality Data for Female Mice by Treatment and, Time
`Analysis of Mortality
`No. Risk No. Died No. Alive Pct Survival Pct Mortality
`0-52
`102
`11
`- 91
`89.2
`10.8
`
`CTRO
`
`53—78
`
`79-91
`
`92-104
`
`91
`
`70
`
`45
`
`FINALKILL105-105 30
`
`'
`
`0-52
`
`53-78
`
`51
`
`46
`
`21
`
`25
`
`15
`
`30
`
`5
`
`8
`
`70
`
`45
`
`30
`
`o
`
`46
`
`38
`
`,
`
`68.6
`
`44.1
`
`29.4
`
`90.2
`
`74.5
`
`31.4
`
`55.9
`
`70.6
`
`9.8
`
`25.5
`
`39.2
`
`LOW
`
`79-91
`
`92-104
`
`38
`
`31
`
`FINALKILL105-105 17
`
`0-52
`
`53-78
`
`79-91
`
`92-104
`
`51
`
`47
`
`33
`
`26-
`
`FINALKILLIOS-IOS 21
`
`0-52
`
`53-78
`79-91
`
`51
`
`46
`36
`
`MED
`
`HIGH
`
`’
`
`7
`
`14
`
`17
`
`4
`
`14
`
`7
`
`5
`
`21
`
`5
`
`10
`8
`
`31
`
`17
`
`0
`
`47
`
`‘ 33
`
`26
`
`21
`
`0
`
`46
`
`36
`28
`
`‘
`
`Page 14 of 32
`
`60.8
`
`33.3
`
`92.2
`
`64.7
`
`51.0
`
`41.2
`
`90.2
`
`70.6
`54.9
`
`66.7
`
`7.8
`
`35.3
`
`49.0
`
`58.8
`
`9.8
`
`29.4
`45.1
`
`

`

`Statistical Review of NDA22304
`
`Analysis of Mortality
`92-104
`
`No. Risk No. Died No. Alive Pct Survival Pct Mortality
`28
`11
`17
`33.3
`66.7
`
`FINALKILL105-105 17
`
`17
`
`0
`
`Table 4R Analysis of Dose-Mortality Trend for Female Mice (Excluding Dose-Escalation Group)
`
`Method
`
`Cox
`
`Kruskal-Wallis
`
`Statistics P-Value Statistics P-Value
`
`Tlme‘AdJ“Sted Trend Te“ 1.4793
`Depart from Trend
`
`0.4773
`
`1.7024
`
`0.4269
`
`Dose-Mortality Trend
`
`0.5821
`
`0.4455 0.4733
`
`0.4915
`
`Homogeneity
`
`2.0614
`
`0.5598 2.1757
`
`0.5367
`
`2.5.2 Tumor data analysis
`.The dose response analyses and pairwise comparisons between the combined control group and
`individual treated groups were performed using the poly-3 method. The actual dose levels of
`treatment groups were used as the weights for the trend analysis. The number of tumor bearing
`animals cf each tumor type and its p-values for many organs were presented in Tables SR and 6R
`for males and females, respectively. Multiplicity for the trend testing was adjusted using a
`significance level of 0.025 for rare tumors, and 0.005 for common tumors because two species were
`studied. A tumor type with a background rate of 1 percent or less is classified as rare by Haseman;
`more frequent tumors are classified as common.
`
`Results from Tables SR and 6R show that there is no statistically significant positive trend or
`pairwise increase in incidence in all tumors tested in males and females of mice and rats.
`
`2 5.3 Conclusion
`
`When all treatment groups were included, the Dose-Mortality trends1n both male and female mice
`were statistically significant.
`
`When the dose-escalation group was excluded from the survival data analysis, the dose-mortality
`trend in male mice was statistically significant, but the dose-mortality trend in female mice was not
`statistically significant.
`
`Results of analysis of tumor data of the mouse study 'show that there is no statistically significant
`positive trend and pairwise increase between the combined control and individual treated groups in
`incidencein all tumor types tested1n male and females mice.
`
`Page 15 of 32
`
`

`

`Statistical Review of NDA22304
`
`Table 5R Report on Test for Positive Linear Dose—Tumor Trends in Maie Mice (Excluding Dose-
`Escalation Group)
`
`NDA 22-304
`Dose Response Relationship Test and Pairwise Comparisons
`Using P01 y—3 test
`Ma'le Mice
`
`200 mg
`100 mg
`50 mg
`0 mg
`P_ya1ue P_va1ue
`P_value P_ya1ue
`High
`Med
`Law
`cont
`C vs. M C vs. H
`Dos Resp c vs. L
`N=51
`N=51
`N=51
`N=102
`Tumor Name
`Organ Name
`fffffffffffffffffffffffifffififflfffffffffffffffffiffffffffffffffffffifffffflfffffifffiffifffffffffifffffflffff
`
`ADRENAL
`
`BONE
`
`BRAIN
`
`BENIGN PHAEOCHROMOWTOMA
`SUBCAPSULAR CELL ADENOMA
`
`OSTEOMA
`
`MALIG‘JANT MENINGIOMA
`
`CONNECI’IVE TISS HISTIDLYTIC SARCOMA
`
`DUODENUM
`
`OSTEOSARCOMA
`
`0
`S
`
`0
`
`1
`
`0
`
`0
`
`1
`
`0
`2
`
`0
`
`0
`
`1
`
`0
`
`0
`
`1
`2
`
`1
`
`0
`
`0
`
`1
`
`0
`
`0
`1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0.366
`0.695
`
`0 . 366
`
`.
`0.436
`
`.
`
`0.313
`0.330
`
`0 . 313
`
`.
`0.571
`
`0 . 576
`
`0. 333
`
`0 . 310
`
`O. 291
`
`0. 366
`
`0.336
`
`0 . 370
`
`.
`
`0 . 319
`
`0.576
`
`0.333
`
`0.310
`
`0.291
`
`FOOT/LEG
`
`SQUAMOUS CELL PAPILLOMA
`
`2
`HAEMOLYMFHORETI GRANULOCYTIC LEUKAEMIA
`MALIGNANT LYMPHOMA - LYMP 0
`MALIGMNT LYMPHDMA - PLED 8
`MALIW LYMPHOMA-LYMPHO 0
`
`HARDERIAN GLAND ADENOMA
`
`KIDNEY
`
`LIVER
`
`TUBULAR CELL ADENOMA
`
`HAEMANGIOMA
`HAWNGIOSARCOMA
`HEPATOCELLULAR ADENOMA
`HEPATOCELLULAR CARCINOMA
`HISTIOCYTIC SARCOMA
`
`LUNG
`
`BRONCHIOLO-ALVEOLAR ADENO
`BRONCHIOLO-ALVEOLAR CARCI
`
`MUSCLE
`
`RHABDOMYOSARCOMA
`
`0
`
`0
`
`4
`1
`9
`2
`1
`
`20
`7
`
`0
`
`0
`1
`7
`0
`
`Z
`
`0
`
`0
`1
`4
`0
`0
`
`11
`Z
`
`0
`
`0
`0
`4
`2
`
`0
`
`1
`
`2
`0
`7
`0
`0
`
`7
`Z
`
`l
`
`0
`1
`0
`0
`
`0
`
`0
`
`1
`1 '
`5
`4
`1
`
`12
`2
`
`0
`
`0.819
`0.172
`0.937
`0.356
`
`. 0.554
`0.336
`0.195
`.
`
`0.433
`
`0.111
`
`0.366
`
`.
`
`0. 537
`0.377
`0.215
`0.021
`0.354
`
`0.232
`0.659
`
`0 . 366
`
`0 . 811
`0.561
`0.448
`0.558
`0.333
`
`0.466
`0.630
`
`.
`
`0.522
`.
`0.553
`0.103
`
`0.313
`
`0 .612
`0.313
`0 .182
`0.525
`0.310
`
`0.657
`0.569
`
`0 . 313
`
`0.495
`0.294
`0.941
`
`0 .460
`0.503
`0.382
`0.063
`0.499
`
`0.212
`0.517
`
`APPEARS THIS WAY
`0N 0R|G|NAL
`
`Page 16 of 32
`
`

`

`Statistical Review of NDA22304
`
`.
`NDA 22.304
`Dose Response Re1ationsh‘i p Test and Pa1' rwise Comparisons
`Using Po1y—3 test (Excluding Dose-Escalation Group)
`
`Ma] e M1' ce
`
`100 mg
`50 mg
`0 mg
`200 mg
`Med
`Law
`Cont
`P_Va1ue P_va1ue P_va‘lue P_va'lue
`High
`N=51
`N=51
`N=102. N=Sl
`Organ Name
`Dos Resp Cvs. L Cvs. M Cvs. H
`ffffffffffffffffffffffiffffffffffiffif.ffifffffffffffffffffffffffffffifff.ffffffffffffiffffffiffiffffiffiffffffff
`
`Tumor Name
`
`0.
`
`579
`
`0.336
`
`0.313
`
`0.
`
`294
`
`0000
`
`.579
`
`.579
`.576
`.054
`.366
`
`.364
`
`.366
`
`.824
`
`.294
`
`.294
`.291
`.078
`
`0.313
`
`0.313
`0.310
`0.525
`0.313
`
`0.336
`
`0.336
`0.333
`’ 0.265
`
`0.342
`
`0.336
`
`0.561
`
`0.529
`
`0 o
`
`woo
`
`o
`
`o
`
`o
`o
`2
`o
`
`1
`
`1
`
`o
`
`o
`
`o
`
`o
`o
`1
`1
`
`0
`
`o
`
`o
`
`911111va
`
`ADENOMA
`
`PROSTATE
`
`ADENOCARCINOMA'
`
`1
`
`1
`
`SKIN + suacuus NALIGNANT nanous HISTIOC 1
`OSTEOSARCOMA
`1
`SARCOMA - NOS
`1
`squmous CELL PAPILLOMA
`o
`
`SPINAL COLUMN
`
`, OSTEOS'ARCOMA
`
`SPLEEN
`
`HAEMANGIOMA
`
`o
`
`o
`
`STERNUM + MARRO
`
`HAEMANGIOMA
`
`sTbMACH
`
`TAIL
`
`' TEsus
`
`THYROID
`
`TONGUE
`
`2
`
`o
`o
`
`o
`0
`
`ADENOMA
`squmous CELL PAPILLOMA
`
`HAEMANGIOSARCOMA
`SARCOMA - Nos
`
`INTERSTITIAL CELL ADENOMA 1
`11er TESTIS ADENOMA
`o
`
`FOLLICULAR CELL ADENOMA
`
`squamous CELL PAPILLOMA
`
`z
`
`1
`
`1
`0
`
`o
`1
`
`1
`o
`
`o
`
`o
`
`o
`
`o
`1
`
`o
`o
`
`1
`
`o
`
`o
`
`o
`
`0.336
`
`0.336
`
`0.561
`
`0.313
`
`0.313
`0.313
`
`0.558
`
`0.525
`
`0.336
`
`0.313
`
`.366
`.366
`
`.175
`.366
`
`.13l
`.366
`
`.822
`
`.579
`
`.175
`
`.503
`
`.294
`
`.206
`
`.499
`
`.294
`
`.294
`
`URINARY BLADDER
`
`TRANSITIONAL CELL PAPILLO 0
`
`APPEARS THIS WAY
`'ON ORIGINAL
`
`Page 17 of32 ‘
`
`

`

`Statistical Review of NDA22304
`
`NDA 22.304
`Dose Response Relationship Test and Pairwise Comparisons
`Using Po1y—3 test (Excluding Dose-Escalation Group)
`
`Maie Mice
`
`(Tumor types with Some P_Va1ues <é0.05)
`0 mg
`50 mg
`100 mg
`200 mg
`P_va‘l ue
`P_va1ue
`P_Va'l ue
`P_Va] ue
`Cont
`Low
`Med
`Hi gh
`c vs. M C vs. H
`Dos Resp c vs. L
`N=102
`N=51
`N=51
`N=Sl
`Tumor Name
`organ Name
`UffffifffffffffffffHffffffffIfffffffffffffffffffffiffffiffffffflfffffiIffffffffffff.ffffffifffffffffffffffffff
`
`LIVER
`
`HEPATOCELLULAR CARCINOMA
`
`2
`
`0
`
`0
`
`4
`
`0.021
`
`0.558
`
`0.525
`
`0.063
`
`Table 6 Report on Test for Positive Linear Dose-Tumor Trends in Female Mice (Excluding Dose-
`Escalation Group)
`
`an:
`
`NDA 22-304
`Dose Response Re‘l ati onship Test and Pairwise Comparisons
`Using P01 y-3 test
`Femaie Mice
`50 mg
`100 mg
`200 mg
`0 mg
`P_Va'l ue
`P_Va'l ue
`P__Va'l ue
`P_Va1 ue
`Law
`Med"
`Hi gh
`Cont
`Dos Resp c vs. L C vs. M C vs. H
`N=51
`N=51
`N=51
`N=102
`Tumor Name
`Organ Name
`ffffffffffffffiffi.ffffffffffffffififffffffffffffffIf!fffff.fff.fffHfff.ffffiffffiffiffffffffifffifffffffffffffiff
`
`ADRENAL
`
`sour;
`
`suscstuuuz CELL ADENOMA
`
`051mm
`
`FEMUR + MARROW
`
`OSTEOMA
`
`z
`
`2
`
`1
`
`FOOT/LEG
`
`0
`FIBROMA
`INFLAMM MYOFIBROBLAST. TU 0
`
`1
`
`1
`
`0
`
`0
`
`o
`0
`
`o
`
`0
`
`0
`
`1
`
`'
`
`0
`
`0
`
`0
`
`0
`1
`
`0
`
`2
`11
`0
`
`0.709
`
`0.597
`
`0.271
`
`0.572
`
`0.859 .
`
`0.602 - 0.577
`
`0.577
`
`0.622
`
`0.367
`
`0.347
`
`0.347
`
`0.206
`0.402
`
`0.493
`0.436
`0.552
`0.816
`0.618
`
`.
`0.367
`
`0.367
`0.597
`0.313
`0.477
`0.354
`
`.
`
`0.354
`
`0.585
`0.572
`0.285
`0.681
`0.344
`
`0.347
`0.271
`0.347
`0.708
`0.344
`
`HAEMOLVMPHORETI GRANULOCYTIC LEUKAEMIA
`Hrsnoorric SARCOMA
`1
`MALIGNANT LYMPHOMA — LYMP
`MALIGNANT LYMPHOMA - PLEO 1s
`MALIGNANT LYMPHOMA-LYMPHO
`1
`
`HARDERIAN GLAND ADENOCARCINOMA
`
`0
`
`1
`o
`2
`
`HAEMANGIOMA
`HEPATOCELLULAR ADENOMA
`HISTIOCYTIC SARCOMA
`
`BRONCHIOLO-ALVEOLAR ADEND 10
`BRONCHIOLO-ALVEOLAR cmcx 4
`
`LIVER
`
`'
`
`LUNG
`
`1
`0
`2
`7
`0
`
`0
`
`0
`0
`1
`
`6
`4
`
`1
`
`1
`
`1
`0
`0
`
`0
`1
`0
`7
`0
`
`1
`
`0
`0
`0
`
`7
`1
`
`1
`
`o
`
`1
`0
`1
`
`o
`
`0
`1
`0
`
`7
`0
`
`3
`
`o
`
`o
`0
`2
`
`0.206
`
`0 .622
`0.402
`0.713
`
`0.293
`0.524
`
`.
`
`.
`
`0. 367
`0.367
`0.602
`
`0.421'
`0.842
`
`0. 347
`.
`0.276
`
`0.491
`0.288
`
`0.354
`
`0 .347
`.
`0.577
`
`0.349
`0.577
`
`0.774
`
`0.501
`
`0.563
`
`0.577
`
`0.406
`
`0.121
`0.622
`0.805
`
`.
`
`0.354 -
`
`.
`0.367
`0.379
`
`0.347
`0.347
`0.821
`
`0.347
`0.347
`0.563
`
`MAMMARY GLAND
`
`menocmcmoun
`
`ORAL own-v
`
`osteosmcom
`
`OVARY
`
`334ch LUTEOMA
`BENIGN THECOMA
`CYSTADENOMA
`
`4
`
`0
`
`0
`1
`4
`
`Page 18 of 32
`
`

`

`Statistical Review of NDA22304
`
`_
`NDA 22_304
`Dose Response Relationship Test and Pa1rw1'se comparisons
`using Po1y-3 test (Excluding Dose-Escalation Group)
`
`Femal e M'i ce
`
`200 mg
`100 mg
`so mg
`0 mg
`P_Va'| ue
`P_Val ue
`P__Val ue
`P_Va1ue
`Hi gh
`Med
`Low
`Cont
`C vs. H
`c vs. L C vs. M
`Dos Resp
`N=51
`N=51
`N=51
`N=102
`Tumor Name
`organ Name
`.ffffffffiffffIf1!”!foffffffffffififfffffffiffffffffffffffffffffffff!fIf!ffflffHffffffffffffffffifffiIfffiff
`
`PANCRFAS
`
`ISLET CELL ADENOMA
`
`PITUITARY
`
`ADENOMA
`
`sxru + suacu-rrs
`
`BENIGN HAIR FOLLICLE TUMO
`55mm Hrsrmcv‘rom
`SQUAMOUS CELL CARCINOMA
`
`SPLEEN
`
`HAEMANGIOMA
`
`510mm
`
`TAIL
`
`UTERUS
`
`VAGINA
`
`ADENOCARCINOMA '
`ADBJOMA
`squmous CELL PAPILLOMA
`
`SARCOMA — NOS
`
`ADENOCARCINOMA
`HAEMANCIOMA
`HAEMANGIos'ARconA
`HISTIOCYHC SARCOMA
`HISTIOCYTDMA
`LEIOMYOMA
`LEIOMYOSARmMA
`STROMAL POLYP
`STROMAL SARCOMA
`
`HAEMANGIOSARCOMA
`STROMAL POLYP
`STROMAL SARCOMA
`
`1
`
`5
`
`0
`o
`1
`
`o
`
`o
`1
`0
`
`0
`
`1
`2
`0
`6
`1
`4
`1
`6
`0
`
`0
`1
`o
`
`0
`
`4
`
`1
`o
`0
`
`1
`
`o
`1
`1
`
`0
`
`0
`0
`1
`0
`0
`0
`1
`4
`0
`
`Z
`0
`
`_
`
`1
`
`2
`
`0
`1
`0
`
`1
`
`1
`0
`0
`
`0
`
`0
`1
`o
`3
`0
`3
`0
`3
`1
`
`0
`0
`1
`
`1
`
`2
`
`0
`0
`0
`
`0
`
`o
`0
`0
`
`1
`
`1
`2
`o
`2
`0
`1
`0
`1
`1
`
`1
`0
`0
`
`0.312
`
`0.367
`
`0.577
`
`0.577
`
`0.653
`
`0.424
`
`0.470
`
`0.470
`
`0.402
`0.406
`0.622
`
`0.367
`.
`0.367
`
`.
`0.354
`0.347
`
`,
`0.347
`
`0. 491
`
`0 . 367
`
`0. 347
`
`0.406
`0.691
`0.402
`
`0.201
`
`- 0.410
`0.246
`0.402
`0.594
`0.622
`0.567
`0.692
`0.834
`0.124
`
`0 . 206
`0.712
`0.402
`
`0.354
`0.347
`
`.
`0.347
`
`.
`0.610
`0.367
`
`.
`
`.
`
`0.367
`0.602
`a . 367
`0.939
`0.367
`0.842
`0.602
`0.534
`.
`
`.
`0.313
`.
`
`0.347
`0.285
`.
`0.390
`0.347
`0.470
`0.347
`0.363
`0.347
`
`.
`0.347
`0.347
`
`0.347
`
`0.585
`0.445
`.
`0.579
`0.347
`0.563
`0.347
`0.759
`0.354
`
`0 . 3 54
`0.347
`
`3. RAT STUDY (STUDY TP2418)
`Introduction
`
`3.1
`
`The objective of this study was to evaluate the carcinogenic potential of CG5503 following daily oral
`administration in SPF Wistar rats at dose levels of 10, 50, 125 or 250 mg/kg body weight/day for at
`lease 104 consecutive weeks. Two control groups received identical feed devoid of test item. The
`groups comprised 50 animals per sex for oncogenicity evaluation and were sacrificed after 104
`weeks of treatment (allocation A). Additional 10 rats per sex and group were used for the
`determination of plasma drug concentrations at weeks 4, 13 and 26 (allocation B). After the last
`blood sampling in week 26, these animals were killed and discarded without further examinations.
`Thus a total of 360 males and 360 females were assigned to this study.
`
`Page 19 of 32
`
`

`

`Statistical Review of NDA22304
`
`
`
`
`
`Assigned number of animals per dose
`
`
`
`B animals
`2111131313
`A animals
`
`
`Plasma level
`Oncogenicity
`
`
`
`determination
`'
`evaluation
`
`
`Inn—_—
`III-__—
`“___—
`
`Total number of Number ofallocation
`
`Number of allocation
`
`_
`
`
`
`* = The dose levels refer to the hydrochloride salt of CG5503, M = male; F = ferrule
`
`3.2 Sponsor’s analysis
`The sponsor presented the mean survival estimate in Figures 1 and 2 of the sponsor’s study report
`and the summary of survival estimates in Table 10 of the sponsor’s study report. However, the
`sponsor did not present any statistical analysis for the rate mortality data.
`
`The hepatocellular hypertrophy at 125 and 250 mg/kg/day in males and females were statistically
`significant (p<0.0005). This finding was considered to be test item-related. The follicular cell
`hypertrophy and focal follicular cell hyperplasia in the thyroid gland in females at 250 mg/kg/day
`showed a positive trend with p-values of 0.0010 and 0.0007, respectively. These findings are
`considered to be caused by the liver cell hypertrophy and the consequently enhanced liver enzyme
`activities. The type, incidence, and severity of all other non-neoplastic changes in this study are
`considered to be incidental as they are common in rats of this strain and age.
`
`’ 3.3 Data Analyzed and Sources
`The sponsor submitted the data in electronic format on March 18, 2008. The data are located in the
`EDR at the following