CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`206439Orig1s000
`
`STATISTICAL REVIEW(S)
`
`
`
`
`
`
`
`

`

`STATISTICAL REVIEW AND EVALUATION
`
`Biometrics Division: VI
`
`206439
`October 17, 2014
`
`NDA NO.:
`DATE RECEIVED BY ONDQA:
`DRUG NAME:
`Namzaric
`GENERIC NAME
`Memantine HCl ER/Donepezil Capsules
`Tablet
`DOSAGE FORM:
`14 mg 10 mg, 28 mg / 10 mg
`STRENGTH
`Treatment of moderate to severe dementia of the
`INDICATION:
`Alzheimer’s type.
`SPONSOR:
`Forest Laboratories, Inc.
`October 27, 2014
`REVIEW FINISHED:
`NAME OF STATISTICAL REVIEWER: Xiaoyu (Cassie) Dong, Ph.D.
`
` ____________________________________
`
`
` Reviewer: Xiaoyu Dong, Mathematical Statistician, CDER/OTS/OB/DB VI
`
`
`Concur: ______________________
`
` Meiyu Shen, TL, Mathematical Statistician, CDER/OTS/OB/DB VI
`
`
`
`NDA 206439
`Distribution:
`CDER/OTS/OB/DB VI/ Yi Tsong
`CDER/OTS/OB/DB VI/ Meiyu Shen
`CDER/OTS/OB/ Lillian Patrician
`CDER/ONDQA/Pei-I Chu
`CDER/ONDQA/ Okpo Eradiri
`CDER/ONDQA/ Teshara G, BOUIE
`
`Reference ID: 3648813
`
`

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`NDA 206439: Stability Analysis of Dissolution Data
`
`TABLE OF CONTENTS
`
`I. EXECUTIVE SUMMARY..................................................................................................... 4
`II.
`INTRODUCTION............................................................................................................................. 4
`III.
`FDA STAT REVIEWER’S ANALYSES ................................................................................... 5
`
`Reference ID: 3648813
`
`2
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`

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`NDA 206439: Stability Analysis of Dissolution Data
`
`List of Figures
`
`Figure 1 : Stability Plots of Average 1-Hour Dissolution at 14 mg/ 10 mg Strength from FDA
`Statistical Reviewer’s Analysis (the dash lines are the 95% one-sided confidence interval of
`the mean response, the solid line is the mean response from regression analysis; the red
`straight line is the FDA’s proposed specification of
`%)..................................................... 6
`Figure 2 : Stability Plots of Average 1-Hour Dissolution at 28 mg/ 10 mg Strength from FDA
`Statistical Reviewer’s Analysis (the dash lines are the 95% one-sided confidence interval of
`the mean response, the solid line is the mean response from regression analysis; the red
`straight line is the FDA’s proposed specification of
`%)..................................................... 8
`Figure 3 : Stability Plots of Average 4-Hour Dissolution at 14 mg/ 10 mg Strength from FDA
`Statistical Reviewer’s Analysis (the dash curves are the 95% two-sided confidence interval of
`the mean response, the solid line is the mean response from regression analysis; the red
`straight lines are the FDA’s proposed specification of
`%........................................... 9
`Figure 4 : Stability Plots of Average 4-Hour Dissolution at 28 mg/ 10 mg Strength from FDA
`Statistical Reviewer’s Analysis (the dash curves are the 95% two-sided confidence interval of
`the mean response, the solid line is the mean response from regression analysis; the red
`%......................................... 12
`straight lines are the FDA’s proposed specification of
`Figure 5 : Stability Plots of Average 8-Hour Dissolution at 14 mg/ 10 mg Strength from FDA
`Statistical Reviewer’s Analysis (the dash curves are the 95% two-sided confidence interval of
`the mean response, the solid line is the mean response from regression analysis; the red
`straight lines are the FDA’s proposed specification of
`%......................................... 15
`Figure 6 : Stability Plots of Average 8-Hour Dissolution at 28 mg/ 10 mg Strength from FDA
`Statistical Reviewer’s Analysis (the dash curves are the 95% two-sided confidence interval of
`the mean response, the solid line is the mean response from regression analysis; the red
`straight lines are the FDA’s proposed specification of
`%......................................... 18
`Figure 7 : Stability Plots of Average 12-Hour Dissolution at 14 mg/ 10 mg Strength from FDA
`Statistical Reviewer’s Analysis (the dash curves are the 95% one-sided confidence interval of
`the mean response, the solid line is the mean response from regression analysis; the red
`straight line is the FDA’s proposed specification of NLT %............................................... 21
`Figure 8 : Stability Plots of Average 12-Hour Dissolution at 28 mg/ 10 mg Strength from FDA
`Statistical Reviewer’s Analysis (the dash curves are the 95% one-sided confidence interval of
`the mean response, the solid line is the mean response from regression analysis; the red
`straight line is the FDA’s proposed specification of NLT %............................................... 22
`
`Reference ID: 3648813
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`(b)
`(4)
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`(b) (4)
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`

`

`NDA 206439: Stability Analysis of Dissolution Data
`
`I.
`
`EXECUTIVE SUMMARY
`
`We performed statistical analysis of 12 months long-term dissolution stability data at 1h, 4h, 8h,
`and 12h for Memantine HCl ER
`manufactured by Forest Research for the strength of 14 mg
`/ 10 mg and 28 mg/10 mg.
`
`The results are summarized in Table 1.As it shows, the shelf life for each strength is not able to be
`established because most of the observations at 4h and 8h are out of the specification proposed by
`FDA. More specifically, the dissolution results at 4h and 8h are in general too high compared to
`the upper limit of the acceptance criteria. Revision and finalization of the specifications may be
`needed for this combined drug product.
`
`Please see section III for detailed stability analysis results.
`
`Table 1 - FDA Statistics Reviewer’s Estimated Shelf Life for each Strength using Long-term
`Dissolution Stability Data and FDA’s Proposed Specification
`8h
`Strength
`1h
`4h
`Most observations are out of the
`14 mg / 10 mg
`18 months
`upper limit of the proposed
`28 mg/10 mg
`18 months
`acceptance criteria
`
`12h
`18 months
`18 months
`
`II.
`
`INTRODUCTION
`
`The sponsor submitted the long-term stability data of dissolution testing up to 12 months for the
`following batches as listed in Table 2. The product of each batch was packaged in bottle
`configurations of 30 counts and 90 counts as shown in Table 3.
`
`Table 2: Available Long-Term Stability Data
`
`Reference ID: 3648813
`
`4
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`(b) (4)
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`

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`NDA 206439: Stability Analysis of Dissolution Data
`
`Table 3—1.ND-\ Reg'ntration Batches - Container Closure Svsmn
`
`Table 3: Package Configurations
`
`Capsule
`Count
`
`Strength
`(mg)
`
`GOCOHDPE’BOTIIEWWI-11TH]
`(I!) (4)
`
`(It)(4)
`
`SSMM("IUWHITE'CAP
`
`Ww
`
`(I!) (4)
`
`SI'IEOCCIHDPE‘BO‘I'IIE’WTIITE
`
`I
`(”"0 ”M‘mmmfimp
`
`‘
`
`(m4)
`
`w...
`
`(mo were obtained at 1h, 4h, 8h, and 12h for
`The dissolution testing results for Memantine ER
`each batch and each configuration at the long-term storage condition. The FDA’s proposed
`
`specifications are listed below in Table 4.
`
`Table 4 - FDA Proposed Acceptance Criteria for Dissolution Testing at Each Time Point
`In
`4h
`8h
`121:
`"’"" %
`W" %
`"’"° %
`NLT 23%
`
`Acce tance Criteria
`
`III.
`
`FDA STAT REVIEWER’S ANALYSES
`
`We performed statistical analysis of 12 months long-term dissolution stability data at 1h, 4b, 8b,
`and 12h for Memantine HCl ER (5x4) manufactured by Forest Research for the strength of 14 mg
`/ 10 mg and 28 mg/ 10 mg. The results are summarized as below.
`
`0 For 1hr average dissolution data, the estimated shelf life using 12-months long term data is
`18 months with an acceptance criterion of NMT 8%;
`
`o For 4hr average dissolution data, the estimated shelf life using 12-months long term data
`cannot be obtained with acceptance criteria of
`(”(0% because most of the data points
`
`are out of upper limit of the specification. In addition, the data of three batches at each
`
`strength cannot be pooled due to significant batch effect.
`
`0 For 8hr average dissolution data, the estimated shelf life using lZ-months long term data
`cannot be obtained with acceptance criteria of
`o)(o%_ %, because most of the data
`points are out of upper limit of the specification. In addition, the data of three batches at
`
`each strength cannot be pooled due to significant batch effect.
`
`Reference ID: 3648813
`
`

`

`NDA 206439: Stability Analysis of Dissolution Data
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`0 For 12 hr average dissolution data, the estimated shelf life using 12-months long term data
`is 18 months with an acceptance criterion of NLT¢)(4)%;
`
`The stability plots of 1h, 4h, 8h, and 12h dissolution data from three batches listed in Table 2 are
`
`provided below. In those plots, red straight lines are the FDA proposed acceptance criteria; the
`dashed cmves are the 95% confident limits. The estimated shelf life would be the shortest intersect
`
`of the dashed line (95% confidence limits) with the limits of the acceptance criteria.
`
`Figure 1 : Stability Plots of Average l-Hour Dissolution at 14 mg] 10 mg Strength from FDA Statistical
`
`Reviewer’s Analysis (the dash lines are the 95% one-sided confidence interval of the mean response, the
`
`solid line is the mean response from regression analysis;
`specification of (”(0%)
`
`the red straight line is the FDA’s proposed
`
` .
`
`(5X4)
`
`.
`.
`.
`.
`.
`.
`: Stability Analysns of Dissolution at 1 hour (%) at long term
`conditions
`
`STREN GTII=1 4mg/10mg COENT=1200€ 9060unt
`
`(mo
`
`Mcmantmc ER
`
`25
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`20
`
`15
`
`10
`
`5
`
`0
`
`oO
`
`
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`21
`
`24
`
`Time in Mouth
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`
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`BATCH - - - - BN00023907 - - - ‘ BN00023908 - - - - BNOOOZ3909
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`l6 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
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`Reference ID: 364881 3
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`

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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`XIAOYU DONG
`10/27/2014
`
`MEIYU SHEN
`10/27/2014
`
`Reference ID: 3648813
`
`