(cid:15003)(cid:15036)(cid:15047)(cid:15032)(cid:15049)(cid:15051)(cid:15044)(cid:15036)(cid:15045)(cid:15051) (cid:15046)(cid:15037) (cid:15007)(cid:15036)(cid:15032)(cid:15043)(cid:15051)(cid:15039) (cid:15032)(cid:15045)(cid:15035) (cid:15007)(cid:15052)(cid:15044)(cid:15032)(cid:15045) (cid:15018)(cid:15036)(cid:15049)(cid:15053)(cid:15040)(cid:15034)(cid:15036)(cid:15050)
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`S TAT I S T I C A L R E V I E W A N D E VA L U AT I O N
`CARCINOGENICITY STUDIES
`
`NDA:
`Drug Name:
`Indications:
`Applicants:
`
`204063
`BG00012 (Dimethyl Fumarate) delayed action capsule
`Multiple Sclerosis
`Sponsor: Biogen Idec, Inc.
` 14 Cambridge Center, Cambridge, MA 02142
`
`(b) (4)
`
`Date(s):
`
`Submitted: 27 February 2012
`To Reviewer: 30 July 2012
`Standard
`Review Priority:
`Division 6
`Biometrics Division:
`Steve Thomson
`Statistical Reviewer:
`Concurring Reviewers: Karl Lin, Ph.D.
`Medical Division:
`Neurology Products
`Toxicologist Team:
`Melissa Banks-Muckenfuss, Ph.D.
`Project Manager:
`Nicole Bradley, Pharm.D.
`Keywords: Bayesian analysis, Carcinogenicity, Cox regresson, Kaplan-Meier product limit,
`Survival analysis, Trend test
`
`
`Reference ID: 3207500
`
`Page 1 of 79
`
`Biogen Exhibit 2375
`Coalition v. Biogen
`IPR2015-01993
`
`

`

`NDA 2034063 BG00012 (Dimethyl Fumarate) Biogen Idec, Inc.
`
`
`Table of Contents
`1. EXECUTIVE SUMMARY ....................................................................................................................................3
`1.1. CONCLUSIONS AND RECOMMENDATIONS .......................................................................................................3
`1.2. BRIEF OVERVIEW OF THE STUDIES ....................................................................................................................11
`1.3. STATISTICAL ISSUES AND FINDINGS ..................................................................................................................11
`1.3.1. Statistical Issues.........................................................................................................................................11
`1.3.2. Statistical Findings ....................................................................................................................................17
`2. INTRODUCTION .................................................................................................................................................17
`2.1. OVERVIEW.........................................................................................................................................................17
`2.2. DATA SOURCES .................................................................................................................................................17
`3. STATISTICAL EVALUATION ..........................................................................................................................17
`3.1. EVALUATION OF EFFICACY................................................................................................................................17
`3.2. EVALUATION OF SAFETY ...................................................................................................................................17
`4. FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ................................................................................36
`5. SUMMARY AND CONCLUSIONS ...................................................................................................................36
`5.1. STATISTICAL ISSUES AND COLLECTIVE EVIDENCE ............................................................................................36
`5.2. CONCLUSIONS AND RECOMMENDATIONS ..........................................................................................................36
`APPENDICES............................................................................................................................................................37
`APPENDIX 1. FDA SURVIVAL ANALYSIS..................................................................................................................37
`APPENDIX 2. FDA POLY-K TUMORIGENICITY ANALYSIS .........................................................................................42
`APPENDIX 3. BAYESIAN TUMORIGENICITY ANALYSIS IN RATS ................................................................................66
`APPENDIX 4. REFERENCES........................................................................................................................................70
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3207500
`
`2
`
`Page 2 of 79
`
`

`

`NDA 2034063 BG00012 (Dimethyl Fumarate) Biogen Idec, Inc.
`
`1. EXECUTIVE SUMMARY
`(b) (4)
`
`Reports and data from two studies, in rats and mice, were provided.
` The study report and data
`for the rat study were originally submitted with IND 73061 from the same Sponsor. The results
`of the FDA analysis of the rat study are summarized in the statistical carcinogenicity review
`dated 22 April 2008. Although the current analysis of the rat study is slightly different, only the
`new mouse study contains completely new results.
`
`According to the mouse report provided by the Sponsors: “The purpose of this study was
`to evaluate the potential carcinogenicity of BG00012 following once daily oral gavage to CD-1
`mice for at least 104 weeks and toxicokinetics following once daily oral gavage for 180 days.”
`(page 18 of report) The objective of the rat report is expressed similarly. Each study included
`five treatment groups, as described below.
`
`1.1. Conclusions and Recommendations
`The Sponsor describes the drug vehicle as hydroxypropylmethylcellulose (HPMC) or
`hypromellose (3,500-5,600 cps), 0.8% w/v in reverse osmosis deionized water. For each study,
`in each gender, there are five treatment groups. Animals were dosed once daily by oral gavage.
`Gross aspects of the study designs for the main study animals are summarized in Tables 1 and 2
`below:
`Table 1. Design of Rat Study (75 animals per main study group/gender)
`Dosing
`Dose
`BG00012
`Treatment
`Vehicle
`Concent
`Volume
`Dosage
` Group
`or Test
`rationa
`(mL/kg)
`(mg/kg/day)
`Article
`HPMCa
` 0
` 10
` 0
`1. Vehicle
`BG00012
` 25
` 10
` 2.5
`2. Low
`BG00012
` 50
` 10
` 5
`3. Medium
` 100
`4. Med-High b BG00012
` 10
` 10
`5. High b
`BG00012
` 150
` 10
` 15
`a Hydroxypropylmethylcellulose or Hypromellose (3,500-5,600 cps), 0.8% w/v in reverse osmosis deionized water.
`b Due to mortality, the High dose group (150 mg/kg/day, Group 5) males were terminated during Week 86 and the
`Medium-High (100 mg/kg/day,Group 4) males were terminated during Week 88.
`
`Table 2. Design of Mouse Study (75 animals per main study group/gender)
`Treatment
`Vehicle
`BG00012
`Dose
`Dosing
` Group
`or Test
`Dosage
`Volume
`Concent
`rationa
`Article
`(mg/kg/day)
`(mL/kg)
`1. Vehicle a HPMC
` 0
` 10
` 0
`2. Low
`BG00012
` 25
` 10
` 2.5
`3. Medium
`BG00012
` 75
` 10
` 7.5
` 200
`4. Med-High BG00012
` 10
` 20
`5. High
`BG00012
` 600/400 b
` 10
` 60/40 b
`a Hydroxypropylmethylcellulose or Hypromellose (3,500-5,600 cps), 0.8% w/v in reverse osmosis deionized water.
`b Due to mortality observed in the high-dose group, beginning on Day 9,.the dose level for Group 5 was decreased
`from 600 mg/kg/day to 400 mg/kg/day (40 mg/mL) . For tests it is treated as dosage at 400 mg/kg/day.
`
`
`
`3
`
`Reference ID: 3207500
`
`Page 3 of 79
`
`

`

`NDA 2034063 BG00012 (Dimethyl Fumarate) Biogen Idec, Inc.
`
`
`More detailed descriptions of the studies are provided in Section 3.2.1 and 3.2.2 below.
`In this report the vehicle group is sometimes referred to as the “HPMC” or “control group” while
`the other dose groups are referred to as “actual dose groups”, and, purposes of assessing trend,
`the Vehicle, Low, Medium, Medium-High, and High dose groups (i.e., Groups 1-5) as “treated
`groups.” Simple summary life tables in mortality are presented in the report in these sections of
`this report. Also, because early very high mortality in the mice study, on day 9 dosage was
`reduced from 600 mg/kg/day to 400 mg/kg/day. On all tests used in the FDA analysis it is
`treated as the 400 mg/kg/day.
`
`In Appendix 1, Figures A.1.1 and A.1.2 for rats display Kaplan-Meier estimated survival
`curves for each study group for each gender. Two sets of plots are displayed for mice. Figures
`A.1.3 and A.1.4 for mice display the Kaplan-Meier estimated survival curves for gender using
`the original data while Figures A.1.5 and A.1.6 display the corresponding plots deleting those
`animals that died before day 9, because of initial high mortality. Results of tests on survival in
`rats and mice are summarized below:
`
`Table 3. Statistical Significances of Tests of Homogeneity and Trend in Survival in the Rat
`Study
`Hypothesis Tested
`
`Males a Females
`Log rank Wilcoxon Log rank Wilcoxon
` < 0.0001
` < 0.0001
` 0.4421
` 0.2737
`Rat Homogeneity over Groups 1-5
` < 0.0001
` < 0.0001
` 0.2904
` 0.1602
` Homogeneity over Groups 1-4
` 0.0292
` 0.0153
` 0.2090
` 0.1594
` Homogeneity over Groups 1-3
` < 0.0001
` < 0.0001
` 0.3427
` 0.2033
` No trend over Groups 1-5
` < 0.0001
` < 0.0001
` 0.1345
` 0.0389
` No trend over Groups 1-4
` 0.0169
` 0.0119
` 0.1386
` 0.0734
` No trend over Groups 1-3
` < 0.0001
` < 0.0001
` 0.4943
` 0.3229
` No Difference Between Groups 1 vs 5
` < 0.0001
` < 0.0001
` 0.2503
` 0.0931
` No Difference Between Groups 1 vs 4
` 0.0180
` 0.0142
` 0.1205
` 0.0613
` No Difference Between Groups 1 vs 3
`a Due to mortality, the High dose group (150 mg/kg/day, Group 5) males were terminated during Week 86 and the
`Medium-High (100 mg/kg/day,Group 4) males were terminated during Week 88.
`
`From Figure A.1.1, in male rats, the HPMC vehicle and Low dose group are largely
`intertwined, with the highest survival, while the Medium dose group has the next highest
`survival, and the Medium-High and High dose groups having the lowest but quite close survival
`over the study period. Note these groups were sacrificed early due to low survival, but in the
`analysis such deaths are considered as censored times, not deaths. This is sufficient to cause
`significant tests of lack of homogeneity, no trend, and no difference between the highest doses
`and vehicle in groups 1-4 and groups 1-5 (all 12 p < 0.0001, usually much less than the 0.0001
`level). Even the seperation of the Medium dose group from the Vehicle and Low dose is
`sufficient to result in consistently statistically significant results (all six p (cid:148) 0.0292). The
`situation in female rats is quite different. From Figure A.1.2, in female rats, although the HPMC
`vehicle seems to have slightly highest survival, the survival curves of the other four dose groups
`are generally quite close and are largely intertwined. While this is not strong evidence of no
`
`
`
`4
`
`Reference ID: 3207500
`
`Page 4 of 79
`
`

`

`NDA 2034063 BG00012 (Dimethyl Fumarate) Biogen Idec, Inc.
`
`differences, it is evidence of no strong differences when comparing all five groups plus the High
`dose to HPMC (all six p (cid:149) 0.2033). Results of the tests using treatment subgroups 1-4 and 1-3
`are primarily included to match those for male rats. Note that the Wilcoxon test is more sensitive
`to early differences in survival and the corresponding test of lack of trend is barely statistically
`significant at the usual level (i.e., Wilcoxon p = 0.0389), but this conclusion is not supported by
`the Logrank test ( p = 0.1386).
`
`Table 4. Statistical Significances of Tests of Homogeneity and Trend in Survival in the
`Mouse Study
`Hypothesis Tested
`
`Males Females
`Log rank Wilcoxon Log rank Wilcoxon
`Mouse Homogeneity over Groups 1-5 a
` < 0.0001 < 0.0001
` < 0.0001
` < 0.0001
` 0.1115
` 0.3129
` 0.4603
` 0.5208
` Homogeneity over Groups 1-4
` No trend over Groups 1-5 a
` < 0.0001 < 0.0001
` < 0.0001
` < 0.0001
` 0.1119
` 0.3181
` 0.1847
` 0.2348
` No trend over Groups 1-4
` No Difference Between Groups 1 vs 5a
` < 0.0001 < 0.0001
` < 0.0001
` < 0.0001
` 0.4876
` 0.7711
` 0.1099
` 0.1322
` No Difference Between Groups 1 vs 4
`a Printed P-value bounds are identical whether one conditions on survival to day 9 or not.
`
`Figures A.1.3 and A.1.4, in Appendix 1, display the gender specific survival curves over
`the five dose groups in mice. Note that in both genders the High dose group is clearly separated
`from the remaining dose groups. This is sufficient to result in the highly statistically significant
`tests of homogeneity, lack of trend, and no difference between the High dose and the vehicle
`dose group (for each gender all six p < 0.0001). One might speculate that the separation of the
`High dose from the other dose groups may be due solely to the early deaths in the High dose
`group, reflected in the initial drop in the Kaplan-meier curve apparent in the figures. Figures
`A.1.5 and A.1.6 in the appendix display the survival curves over the five dose groups
`conditional upon animals surviving to at least until day 9. Even with this criterion, the High dose
`remains seperated from the remaining dose groups. While the actual values of the significance
`levels for the tests of homogeneity and trend over groups 1-5, and the pairwise comparison
`between the High dose and vehicle are larger (and thus less statistically significant), the printed
`values remain the same (i.e., all tests still have all six p < 0.0001).
`
`In both sets of plots, for both genders, the survival curves for the dose groups 1-4 are
`more or less closely intertwined, but with much higher survival than that in the High dose group.
`This is consistent with the tests of survival completely deleting the High dose group, i.e., none of
`the tests of homogeneity, lack of trend, and no difference between the next highest dose and the
`Vehicle dose group were particularly statistically significant, at least at the usual 0.05 level
`(Males: all six p (cid:149) 0.1115, Females all six p (cid:149) 0.1009). This suggests that differences in survival
`are largely due to differences in the High dose from the remaining dose groups.
`
`Of course in a carcinogenicity study, primary interest is on the occurrence of cancers.
`The statistical analysis of tumors compares tumor incidence over dose groups. Complete tumor
`
`
`
`5
`
`Reference ID: 3207500
`
`Page 5 of 79
`
`

`

`NDA 2034063 BG00012 (Dimethyl Fumarate) Biogen Idec, Inc.
`
`incidence tables for each organ listed by the Sponsor in the submitted data sets and those
`combined by this reviewer are provided in Tables A.2.3 through A.2.6 in Appendix 3. For each
`species by gender by organ the number of animals analyzed and used in the statistical tests is
`presented first. The tumor incidence for each organ is presented next, with the significance
`levels of the tests of trend, and the results of pairwise tests between the high, medium, and low
`dose groups. These statistical tests are supposed to be conditioned on the animals actually
`evaluated, ignoring those not analyzed. In other words, animals not analyzed are treated as being
`not at risk.
`
`To adjust for the multiplicity of tests the so-called Haseman-Lin-Rahman rules discussed
`in Section 1.3.1.5, below, are often applied. That is, when testing for lack of trend in
`carcinogencity over dose and no difference between the highest dose group with a control group
`using Peto or poly-k tests, to control the overall Type I error rate to roughly 10% for a standard
`two species, two sex study, one compares the unadjusted significance level of the trend test to
`0.005 for common tumors (incidence > 1%) and 0.025 for rare tumors, and the pairwise test to
`0.01 for common tumors and 0.05 for rare tumors. As also discussed in section 1.3.1.5,
``employing these adjustments for other than the overall trend and the comparison between the
`High dose group and vehicle can be expected to increase the overall type I error rate to some
`value above the nominal rough 10% level, possibly considerably higher than this nominal rate.
`
`The following tables, Tables 5-8, display those organ tumor combinations that had at
`least one comparison statistically significant at the “usual” 0.05 level (but not adjusted for
`multiplicity). . As discussed in section 1.3.1.3 below, the adjusted number at risk seems to be a
`more appropriate denominator than the actual number evaluated when assessing tumor rates.
`
`Table 5. Potentially Statistically Significant Neoplasms in Male Rats
` Incidence Significance Levels
`organ Hi vs MedHi Med vs Low
` tumor Veh Low Med MedHi High Trend Veh vs Veh Veh vs Veh
`BRAIN
` # Evaluated 73 75 75 75 74
` Adjusted # at risk 49.5 48.6 40.3 25.3 23.1
` CEREBRUM-GRANULAR CELL TMR 0 0 0 0 2 .0149 .0990 . . .
`KIDNEYS
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 49.6 48.6 40.7 25.9 25.2
` RENAL TUBULE- ADENOMA 0 0 1 1 4 .0006 .0110 .3378 .4494 .
`LIVER
` # Evaluated 75 74 75 75 75
` Adjusted # at risk 50.1 49.9 42.2 25.3 22.2
` Hepato. Adenoma/Carcinoma 2 8 5 0 0 .9542 1 1 .1520 .0426
`PARATHYROID
` # Evaluated 68 64 70 71 70
` Adjusted # at risk 44.5 42.8 38.7 23.8 21.5
` ADENOMA 0 0 1 0 2 .0251 .1010 . .4634 .
` Adjusted # at risk 44.5 42.8 38.7 23.8 22.3
` Adenoma, any 0 0 1 0 3 .0049 .0337 . .4634 .
`
`
`
`6
`
`Reference ID: 3207500
`
`Page 6 of 79
`
`

`

`NDA 2034063 BG00012 (Dimethyl Fumarate) Biogen Idec, Inc.
`
`Table 5. (cont.) Potentially Statistically Significant Neoplasms in Male Rats
` Incidence Significance Levels
`organ Hi vs MedHi Med vs Low
` tumor Veh Low Med MedHi High Trend Veh vs Veh Veh vs Veh
`SKIN
` # Evaluated 75 74 75 74 75
` Adjusted # at risk 50.8 51.2 41.4 28.7 27.4
` KERATOACANTHOMA 8 8 9 7 9 .0256 .0736 .2494 .3236 .6237
` Adjusted # at risk 49.6 48.9 40.3 24.7 23.6
` SUBCUT TISS.-FIBROSARCOMA 0 1 0 0 2 .0357 .0990 . . .4948
` Adjusted # at risk 51.2 52.1 42.1 30.9 29.7
` Sq.Cell Pap./Carc./Kerato. 11 11 10 10 12 .0136 .0532 1825 .4950 .6147
`STOMACH
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 49.6 49.2 50.1 60.0 61.3
` NONGLAND.- SQUAMOUS CELL 0 5 18 51 58 <.0001 <.0001 <.0001 <.0001 .0281
` CARCINOMA
` Adjusted # at risk 49.6 53.5 51.4 55.7 58.4
` NONGLAND.- SQ. CELL PAP. 0 22 24 46 49 <.0001 <.0001 <.0001 <.0001 <.0001
` Adjusted # at risk 49.6 53.5 55.3 70.9 71.1
` Nongland.Sq.Cell Pap./Carc. 0 22 34 68 70 <.0001 <.0001 <.0001 <.0001 <.0001
`TESTES
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 50.3 49.0 41.4 30.2 32.8
` INTERSTITIAL CELL- ADENOMA 3 3 2 9 17 <.0001 <.0001 .0053 .7514 .6415
` Adjusted # at risk 49.6 48.6 40.3 25.3 23.5
` INTERSTITIAL CELL- ADENOMA, 0 0 0 0 2 .0149 .0990 . . .
` BILATERAL
` Adjusted # at risk 50.3 49.0 41.4 30.2 34.0
` Intersit. Adenoma, any 3 3 2 9 19 <.0001 <.0001 .0053 .7514 .6415
`
`In male rats, even adjusting for multiplicity (please see Section 1.3.1.4), the tests of no
`trend and no differences in all pairwise comparisons of the four treated groups to HPMC vehicle
`in nonglandular squamous cell papilloma and pooled papilloma and carcinoma were all highly
`statistical significant (all p<0.0001, with both trend < 0.025 and pairwise tests < 0.05 since the
`tumors are categorized as rare). The same holds for nonglandular squamous cell carcinoma
`except that the comparison between the low dose group and vehickle was just statistically
`significant ( p = 0.0281 < 0.05). The tests of trend and pairwise differences between the high
`dose and vehicle in interstial cell adenoma of the testes were both highly statistically significant
`(p < 0.0001 < 0.005 and 0.1, respectively, since the tumor would be categorized as common).
`Accepting the increase in probable error from including other tests, the pairwise comparison
`between the medium dose group and vehicle would also be classified as statistically significant
`(p = 0.0053 < 0.01). Since adding the interstial cell carcinoma only affects incidence in the high
`dose group, the tests for pooled interstitial cell adenoma and carcinoma are, at least to the printed
`significance levels, identical to those for carcinoma are identical to those for interstial cell
`adenoma alone. In this organ, the simple test of trend in interstial cell bilateral adenoma was
`also statistically significant (p = 0.0149 < 0.025), though not extremely. The test of trend in
`renal tubule adenoma of the kidneys was also statistically significant ( p = 0.0006 < 0.025), as
`were the tests of granular cell tumor of the brain ( p = 0.0149 < 0.025) and the test of pooled
`adenomas of the parathyroid ( p = 0.0049 < 0.025). The test of trend in simple adenoma of the
`
`
`
`7
`
`Reference ID: 3207500
`
`Page 7 of 79
`
`

`

`NDA 2034063 BG00012 (Dimethyl Fumarate) Biogen Idec, Inc.
`
`parathyroid was close to statistical significance (p= 0.0251 > 0.025). No other test achieved the
`multiplicity adjusted levels of statistical significance.
`
`Table 6. Potentially Statistically Significant Neoplasms in Female Rats
` Incidence Significance Levels
`organ Hi vs MedHi Med vs Low
` tumor Veh Low Med MedHi High Trend Veh vs Veh Veh vs Veh
`CAVITY, ABDOMINAL
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 54.8 53.2 48.7 48.1 51.9
` HISTIOCYTIC SARCOMA 0 0 0 0 2 .0397 .2335 . . .
`KIDNEYS
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 54.8 53.2 48.7 48.1 51.9
` RENAL TUBULE-CARCINOMA 0 0 0 2 4 .0015 .0523 .2190 . .
` Adjusted # at risk 54.9 53.2 48.7 48.1 52.4
` Renam Tub. Adenoma/Carc. 1 0 0 2 5 .0033 .0942 .4555 1 1
`MAMMARY GLAND
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 57.8 56.6 52.7 50.3 56.8
` CARCINOMA 10 13 13 8 19 .0688 .0372 .6800 .2364 .3036
`STOMACH
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 54.8 53.2 49.6 56.6 65.8
` NONGLANDULAR-SQUAMOUS 0 1 4 30 48 <.0001 <.0001 <.0001 .0479 .4953
` CELL CARCINOMA
` Adjusted # at risk 54.8 55.0 53.7 56.4 61.2
` NONGLANDULAR- SQUAMOUS 0 11 21 31 24 <.0001 <.0001 <.0001 <.0001 .0003
` CELL PAPILLOMA
` Adjusted # at risk 54.8 55.0 54.3 61.1 69.3
` Nongland. Sq, Pap./Carc. 0 11 23 48 58 <.0001 <.0001 <.0001 <.0001 .0003
`VAGINA
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 54.8 53.2 48.7 48.1 52.2
` Endo. Stromal polyp/sarcoma 0 0 0 1 2 .0314 .2383 .4706 . .
`
`Results in female rats are rather similar. In female rats, the tests of trend and all pairwise
`comparisons between the high, medium high, and medium dose groups with vehicle in
`nonglandular squamous cell papilloma and pooled papilloma and carcinoma were all highly
`statistical significant (all p < 0.0001, with both trend < 0.025 and pairwise tests < 0.05) even
`adjusting for multiplicity. For both of these the comparison between the low dose and vehicle
`was also statistically significant (for both tumors, p = 0.0003 < 0.05). These results also hold for
`the tests of trend and pairwise comparisons between the high and medium high dose groups in
`nonglandular squamous cell carcinoma (p < 0.0001, with both trend < 0.025 and pairwise tests <
`0.05). The comparison between the medium dose and vehicle was barely statistically significant
`( p = 0.0479 < 0.05). The test of trend in renal tubule carcinoma of the kidneys was also
`statistically significant ( p = 0.0015 < 0.025), as was the test of pooled adenoma and carcinoma
`(p = 0.0033 < 0.005). Again, no other test achieved the multiplicity adjusted levels of statistical
`significance, although several were somewhat close.
`
` A
`
` Bayesian analysis of carcinogenicity in rats, as originally presented in the review for
`IND 73061, is given in Appendix 3. This Bayesian analysis is also generally consistent with the
`
`8
`
`Reference ID: 3207500
`
`Page 8 of 79
`
`

`

`NDA 2034063 BG00012 (Dimethyl Fumarate) Biogen Idec, Inc.
`
`analysis above. Although it is hardly surprising given the incidence, in both male and female rats
`the posterior probability that there is no effect of increasing dose on nonglandular squamous cell
`papilloma and carcinoma are both essentially zero to a number of decimal places. In females, the
`posterior probabilities of no differences between the high dose group and controls in these
`tumors is similar, as well as for nonglandular squamous cell carcinoma in males. In males the
`posterior probability that there is no difference between nonglandular squamous cell papilloma is
`actually 0.0002 (so the estimated probability that there is difference is about 1 - 0.0002 =
`0.9998), i.e., almost certainly. In male rats the estimated posterior probability that there is no
`trend in interstitial cell adenoma in the testes is also 0.0 to a number of decimal places, while the
`corresponding probability that there is no difference between the high dose group and control is
`0.091 (so the estimated probability of a difference is 1 - 0.091 = 0.909). In male rats the
`estimated posterior probability that there is no trend in renal tubule adenoma in the kidneys is
`essentially 0.086 (so the probability there is a difference in 1 - 0.086 = 0.914), while in female
`rats the estimated posterior probability that there is no trend in renal tubule carcinoma in the
`kidneys is essentially 0.0074 (with 1- 0.0074 = 0.9926). More details are included in the
`appendix.
`
`Results in mice are given below:
`
`Table 7. Potentially Statistically Significant Neoplasms in Male Mice
` Incidence Significance Levels
`organ Hi vs MedHi Med vs Low
` tumor Veh Low Med MedHi High Trend Veh vs Veh Veh vs Veh
`KIDNEY
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 47.5 52.1 50.6 48.7 22.1
` Adenoma 1 2 0 5 3 .0074 .0922 .1067 1 .5382
` Adjusted # at risk 47.5 52.1 50.7 49.3 22.8
` Adenoma/Carcinoma 1 2 2 8 5 .0003 .0109 .0179 .5234 .5382
` Adjusted # at risk 47.5 52.1 50.7 47.7 22.0
` Carcinoma 0 0 2 4 3 .0015 .0265 .0585 .2631 .
`LUNG WITH BRONCHI
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 50.0 53.9 52.5 51.4 23.2
` Bronchiolo-Alveolar 6 6 5 11 5 .0411 .2292 .1541 .7598 .6607
` Adenocarcinoma
`STOMACH
` # Evaluated 74 75 75 75 75
` Adjusted # at risk 47.5 52.1 50.6 47.1 23.0
` Leiomyosarcoma 0 0 0 0 3 .0010 .0324 . . .
` Adjusted # at risk 47.5 52.5 51.1 50.0 30.5
` Papilloma 0 1 3 12 14 <.0001 <.0001 .0002 .1369 .5253
` Adjusted # at risk 47.5 52.4 50.6 47.7 22.3
` Squamous Cell Carcinoma 0 1 0 2 6 <.0001 .0006 .2473 . .5253
`As with rats, in male mice, the test of trend and pairwise comparisons between the High
`dose group with HPMC Vehicle in papilloma of the stomach was highly statistical significant
`(both p < 0.0001, with trend < 0.025 and pairwise test < 0.05) even adjusting for multiplicity.
`The pairwise test between the Medium High dose and vehicle was also statistically significant ( p
`= 0.0002 < 0.05). The tests of trend and pairwise comparison of the High dose to vehicle in
`
`
`
`9
`
`Reference ID: 3207500
`
`Page 9 of 79
`
`

`

`NDA 2034063 BG00012 (Dimethyl Fumarate) Biogen Idec, Inc.
`
`terms of squamous cell carcinoma of the stomach were also statistically significant (p < 0.0001 <
`0.025 and p = 0.0006 < 0.05, respectively), as were the tests of Leiomysarcoma (p < 0.0010 <
`0.025 and p = 0.0324 < 0.05, respectively). In the kidneys the tests of trend in carcinoma and
`pooled carcinoma and adenoma were also statistically significant ( p = 0.0015 < 0.025 and
`0.0003 < 0.005, respectively). Again, although a couple of tests were close, no other test
`achieved the multiplicity adjusted levels of statistical significance.
`Table 8. Potentially Statistically Significant Neoplasms in Female Mice
` Incidence Significance Levels
`organ Hi vs MedHi Med vs Low
` tumor Veh Low Med MedHi High Trend Veh vs Veh Veh vs Veh
`HEMOLYMPHORETICULAR
` # Evaluated 23 18 20 19 12
` Adjusted # at risk 15.7 12.4 14.6 10.3 6.0
` Leukemia 1 0 0 0 2 .0269 .1404 1 1 1
`KIDNEY
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 56.6 52.9 52.1 51.8 29.1
` Adenoma 0 0 0 2 4 .0002 .0117 .2248 . .
` Adjusted # at risk 56.6 52.9 52.1 51.8 29.1
` Adenoma/Carcinoma 0 0 0 2 4 .0002 .0117 .2248 . .
`LUNG WITH BRONCHI
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 58.6 56.9 54.6 55.8 31.8
` Bronchiolo-Alv. Adenoma 12 14 9 20 10 .0372 .1714 .0503 .7839 .3725
`STOMACH
` # Evaluated 75 75 74 75 75
` Adjusted # at risk 56.6 52.9 52.0 51.8 28.2
` Fibrosarcoma 0 0 0 0 2 .0134 .1084 . . .
` Adjusted # at risk 56.6 52.9 52.0 51.8 29.9
` Leiomyoma/Leiomysarcoma 0 0 0 0 3 .0016 .0370 . . .
` Adjusted # at risk 56.6 52.9 52.0 51.8 29.9
` Leiomyosarcoma 0 0 0 0 3 .0016 .0370 . . .
` Adjusted # at risk 56.6 52.9 52.6 53.4 37.0
` Papilloma 1 0 3 6 16 <.0001 <.0001 .0483 .2815 1
` Adjusted # at risk 56.6 53.2 52.2 52.7 33.1
` Squamous Cell Carcinoma 0 1 1 5 12 <.0001 <.0001 .0233 .4815 .4862
`UTERUS
` # Evaluated 75 75 75 75 75
` Adjusted # at risk 57.4 56.3 55.1 54.4 30.3
` Endometrial Stromal Polyp 6 9 14 11 8 .0597 .0529 .1197 .0340 .2776
`
`
`As with rats, results in female mice are similar to those in male mice. The tests of trend
`and pairwise comparison between the high dose group with vehicle in squamous cell carcinoma
`of the stomach was highly statistical significant (both p < 0.0001, with trend < 0.025 and
`pairwise test < 0.05) even adjusting for multiplicity. Results are similar for papilloma of the
`stomach with a significant test of trend (p < 0.0001 < 0.005) a