CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`204063Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`
`ADDENDUM TO BIOPHARMACEUTICS REVIEW
`Office of New Drug Quality Assessment
`
`
`NDA 204063
`
`February 27, 2012
`
`Division of Neurology
`Products
`
`Applicant:
`Trade Name:
`
`Biogen Inc.
`
`
`
`
`Application No.:
`
`Submission Date:
`
`Division:
`
`Generic Name:
`
`Indication:
`
`Formulation/
`strengths
`
`
`Reviewer: Elsbeth Chikhale, PhD
`
`Acting Team Leader: Tapash
`Ghosh, PhD
`
`Acting Supervisor:
`Richard Lostritto, PhD
`Date
`February 29, 1012
`Assigned:
`Date of
`Addendum
`to Review:
`Type of Submission: 505(b)(1)
`Original New Drug Application
`
`February 12, 2013
`
`Dimethyl fumarate (DMF)
`Also referred to as BG00012
`
`Treatment of Multiple
`Sclerosis
`
`delayed
`release capsules/ 120 mg and
`240 mg
`Oral
`
`Route of
`Administration
`
`ADDENDUM TO ORIGINAL BIOPHARMACEUTICS REVIEW DATED 11/19/12:
`
`The original Biopharmaceutics review by Elsbeth Chikhale, Ph.D., dated 11/19/12 included the
`following recommended language for the action letter:
`
`If approved, the AP letter should include the following two comments:
`• We have not made a BCS classification determination for your drug, since the data
`provided in the NDA are inconclusive with regards to the drug’s permeability.
`
` •
`
` We are reminding you of your commitment to collect 20 minute (buffer stage) dissolution
`data for all stability samples of all commercial batches to be released post approval for
`one year in order to evaluate the possibility of tightening the buffer stage dissolution
`acceptance criterion to Q=
` at 20 minutes and to submit the data in a prior approval
`supplement (PAS) one year after approval for our review.
`
`
`During an ONDQA internal discussion, it was decided that the above comments (with minor
`revisions) will be sent to the Applicant by ONDQA in a separate communication.
`
`
`
`Reference ID: 3260436
`
`1
`
`(b) (4)
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`(b) (4)
`
`(b) (4)
`
`

`

`RECOMMENDATION :
`
`It is recommended that ONDQA conveys the following comments to the Applicant in an separate
`communication after the action letter is issued:
`
`
`(cid:190) We would like to remind you of your commitment to collect 20 minute (buffer stage)
`dissolution data for all stability samples of all commercial batches to be released post
`approval for one year and to submit these data to FDA as a prior approval supplement
`(PAS) 15 months after approval in order to determine if the buffer stage acceptance
`criterion can be tightened to Q=
` at 20 minutes.
`
`
`
`
`(cid:190) We would like to inform you that FDA did not make a determination on the BCS
`classification of your drug (dimethyl fumarate) at this point, because the provided
`permeability data for your drug are inconclusive.
`
`
`
`From the Biopharmaceutics perspective the overall recommendation included in the original
`Biopharmaceutics Review dated 11/19/12 for this NDA remains the same.
`
`
`From the Biopharmaceutics perspective, NDA 204063 for dimethyl fumarate delayed
`release capsules (120 mg/capsule and 240 mg/capsule) is recommended for APPROVAL.
`
`
`
`
`Elsbeth Chikhale, Ph.D. Tapash Ghosh, Ph.D.
`Biopharmaceutics Reviewer Acting Biopharmaceutics Team Leader
`Office of New Drug Quality Assessment Office of New Drug Quality Assessment
`
`cc: SPope, RLostritto
`
`
`
`
`
`Reference ID: 3260436
`
`2
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ELSBETH G CHIKHALE
`02/12/2013
`
`TAPASH K GHOSH
`02/12/2013
`
`Reference ID: 3260436
`
`

`

`BIOPHARMACEUTICS REVIEW
`Office of New Drug Quality Assessment
`
`NDA 204063
`Reviewer: Elsbeth Chikhale, PhD
`
`Application No.:
`
`Submission Date:
`
`Division:
`
`February 27, 2012
`
`Division of Neurology
`Products
`
`Applicant:
`Trade Name:
`
`Biogen Inc.
`
`
`Acting Team Leader: Tapash
`Ghosh, PhD
`
`Acting Supervisor:
`Richard Lostritto, PhD
`Date
`February 29, 1012
`Assigned:
`Date of
`November 19, 2012
`Review:
`Type of Submission: 505(b)(1)
`Original New Drug Application
`
`Generic Name:
`Indication:
`
`Formulation/
`strengths
`
`Dimethyl fumarate (DMF)
`Also referred to as BG00012
`
`Treatment of Multiple
`Sclerosis
`
`delayed
`release capsules/ 120 mg and
`240 mg
`Oral
`
`Route of
`Administration
`SUBMISSION:
` delayed release capsule indicated
`This 505(b)(1) New Drug Application is for an
`for the treatment of Multiple Sclerosis (MS). The pharmacological properties of BG00012 are
`proposed to be mediated through activation of the nuclear factor (erythroid-derived 2)-like 2
`(NFE2L2 or Nrf2) antioxidant response pathway, which is the primary cellular defense system for
`responding to a variety of potentially toxic stimuli. DMF is rapidly and completely hydrolyzed to
`its active metabolite mono-methyl fumarate (MMF) by esterases present in the GI tract, in the gut
`wall and in blood before DMF reaches the systemic circulation. The drug product was
`formulated as
` a size 0 hard gelatin capsule. The
`design of the drug product formulation was based on the desired gastro-resistant properties and on
`the physico-chemical properties of the drug substance. The goal was to develop a delayed release
`formulation that prevents release of the active ingredient in the gastric environment while
`allowing for rapid release of the active ingredient in the intestine region. A formulation
`consisting of a capsule
` was pursued because such systems
`are designed to achieve the targeted delivery profile
`
`
`
`Reference ID: 3218542
`
`1
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`

`

`BIOPHARMACEUTICS INFORMATION:
`
`The Biopharmaceutics review for this NDA will be focused on the evaluation and acceptability of
`l) the proposed dissolution methodology, 2) dissolution acceptance criteria, 3) the in vitro alcohol
`dose dumping method and data, and 4) solubility and dissolution data to support the BCS
`
`Reference
`
`Amount
`per
`capsule
`(mg)
`
`Amount
`per
`capsule
`(mg)
`
`lntemal specification
`USP-NF. Ph. Eula, JP
`
`USP-NF. Ph. Eur., JP
`
`USP-NF. Ph. Eur, JP
`
`USP-NF. Ph. Eula. JP
`
`USP-NF, Ph. Eur. JP
`
`USP-NF, Ph. EUL, JP
`
`
`
`Co
`
`osition of the
`
`Process
`Step
`
`Ingredient
`
`Dimethyl fumarate
`Croscarmellose sodium
`
`Microcrystalline
`cellulose
`
`Magnesium steamtc '
`Talc
`
`Colloidal silicon dioxide
`
`Methacrylic acid
`copolymer, Type A 2
`
`Tricthyl citrate
`
`Mcthacrylic acid
`copolymer dispersion 1
`
`Polysorbatc 80
`
`Sodium lauryl sulfate
`
`.lllllll
`
`Triethyl citrate
`
`USP-NF. Ph. Eur.. JP
`USP-NF. Phi Eur.
`
`||||||Il||
`
`USP-NF, Ph. Eur., JP
`
`USP-NF. Ph. Eur.
`USP-NF. Ph. Eur.
`
`USP-NF, Ph. Eur., JP
`
`USP-NF, Ph. Eur.. JP
`USP-NF. Ph. Eur.
`
`USP-NF, Ph. Eur.
`Subtotal
`
`DISSOLUTION NIETHOD:
`
`'Ihe prop_osed dissolution method utilizes a two stage approach:
`USP Apparatus I[ (paddle)
`Temperature: 37 °C
`Rotation speed: 100 rpm
`Acid stage for 2 hours: Dissolution medium: 500 mL 0.1 N HCl
`Buffer stage after 2 hours: Dissolution medium: 500 mL pH 6.8 phosphate buffer
`
`The dissolution method development was submitted and reviewed under IND 73,061, which is
`summarized as follows:
`
`8/26/11: Sponsor and FDA met, a dissolution method development report was requested by FDA
`
`Reference ID: 3218542
`
`

`

`9/16/11: Dissolution method development report was submitted to the IND, proposed method has
`pH 6.8 medium for the buffer stage, the proposed rotation speed is 100 rpm
`11/29/11: Dissolution method development report was reviewed by Houda Mahayni, Ph.D.
`(DARRTS)
`12/16/11: Comments from the review by Houda Maha
`s nsor ARRTS). It was suggested to try
`
`‘, Ph.D. were communicated to the
`for bufler stage with a rotation speed
`
`12/29/11: S nsor res nded to the comments. S nsor
`. Also at
`
`rovided data and claims that-
`inco
`lete dissolution occurs after 60
`
`).
`minutes
`1/25/12: Review of res use by Houda Mahayni, Ph.D (in DARRTS). The review acknowledges
`
`thew andagrees totheuse oftheproposeddissolutionmethod(usingpH
`
`er stage at 100 rpm) and states that the acceptance criteria will be
`e
`6.8 or
`reviewed during the NDA review. The review states that in the NDA, in addition to the
`in vitro dose dumping study data for the 120 mg capsules, the in vitro dose dumping
`data for the 240 mg capsules should also be provided.
`1/25/12: The comments from Dr. Houda Mahayni’s review were e-mailed to the sponsor.
`
`
`
`The dissolution method validation report is provided in the NDA, and the following 3 tables
`summarize the results:
`
`Table 9:
`
`Summary of Dissolution Validation (Acid Stage. 0.1 N HCl)
`
`Specificity
`
`Linearity
`
`Analytc signal matches reference
`R Z 1‘75
`
`Match to reference
`RMHF DMF = 10-00
`
`Correlation coefficient, r 2 0.99
`Coefficient of variation, V“ S 5 %
`No tendency in the plot of the residuals
`
`r = 1.00
`Vx0 = 0.2 %
`No tendency
`
`:t 20 of specification limits 1: 0% - 45 %
`
`0 % - 5| "/0 (0.05-
`6.09 Ing'lOOinl)
`
`Robustness:
`
`Stability of the analysis
`solutions
`
`Time interval with less than 2 % decrease
`
`27 hours
`
`Specification limits: The average allowable release of dimethyl ftunarale is
`individual results-is allowed
`
`. f label content. however
`
`Reference ID: 321 8542
`
`

`

`decrease Table 11:
`
`Robustness:
`
`Stability of the
`analysis solutions
`
`Validation
`Parameters
`
`Accuracy:
`
`Add Stage
`
`Requirements
`
`Mean recovery R = 100 :1: 5 "/o
`Across a range from 0.8 - 26.6 "/o'
`
`Buffer Stage
`
`Mean recovery R : 100:5 "/o
`Across a range from 29 - 102 °o ‘
`
`
`
`Table 10: Summary of Dissolution Validation (Buffer Stage. pH 6.8 Phosphate Buffer)
`
`Validation
`Parameters
`
`Requirements
`
`Specificity
`
`Resolution R_\ 1. 75
`
`Rm” imr =.10 ()3
`
`Linearity
`
`Correlation coefficient r> 0 99
`
`=1 00((19999)
`
`Cocfficrent of variation. V“. E 5 "/o
`No tendency in the plot ofthc residuals
`
`Vxn= 0.3 /o
`No tendency
`
`Range is based on results for Linearity
`
`22 "o - l 1 l %
`
`Time interval with less than 2 %
`
`140 hours
`
`R ant-rs min:100 A .R alter: m~= 99 %
`(Rccmcr) mm. : 93 “/01
`(Recovery: 7 = 102 "in
`(Recoverymn: —102°2.)
`
`R after 5 mm : 98 0/0 . R arm 45 mm : 97 %
`(Recovery 39% = 96 “/0)
`(Recovery (,5 .0 = 97 %)
`(RCCOVCB'mgon = 97 %)
`
`Repeatability
`
`(Buffer Stage)
`
`Intermediate
`precision
`
`RSDr S 10.0 %
`
`RSDr = 4.6 %
`
`RSDIP S 10.0 %
`
`RSD“, = 4.9 %
`
`(Buffer Stage)
`Percentage oflabel claim " " = 120 mg
`
`Evaluation of the dissolution method and dissolution method validation:
`
`The proposed dissolution method was reviewed under IND 73,061 and found acceptable.
`Based on the provided validation report, the dissolution method has been appropriately validated.
`
`
`
`Reference ID: 321 8542
`
`

`

`DISSOLUTION ACCEPTANCE CRITERIA:
`
`1 10
`
`100
`
`'LDIssolved
`
`90
`
`80
`
`7O
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`O
`
`0
`
`50
`
`100
`
`Time (min)
`
`150
`
`.
`
`The to sed dissolution acc
`tance criteria are:
`“Complies with USP <711> for delayed release dosage forms, with Q =- in 30 minutes.”
`
`The Applicant states that the 30 minute criterion has been determined to be most appropriate time
`point based on the dissolution data for the dru
`roduct with rapid release profile at pH 6.8 bufler
`stage and that the acceptance criterion Q =
`is supported by the historical batch analysis data.
`
`Evaluation of the ro osed dissolution acc
`
`tance criteria:
`
`For the acid stage, the proposed acceptance criteria at 2 hours per USP <711> (copied below) for
`dela ed release dosa e forms are acce table.
`
`Averageoflhe 12 units (A1+A2)isnot
`morethm1096 dasolvedfind no 'ndivid—
`
`Averageoflhe 24 urits (A1 +A2+Aa)is
`not more than 10% (issolved,and no in—
`dividud unit isgreater than 25% dis-
`
`Additional dissolution data were needed to evaluate the acceptance criterion for the bufi'er stage,
`therefore, the following comment/information request was sent to the Applicant on 7/27/12:
`
`In order to evaluate the proposed dissolution acceptance criteria, provide dissolution profile
`data (individual, mean, SD, figures) for the pivotal clinical batches and the primary
`stability/registration batches. For the stability batches, provide the dissolution profile data
`at release and upon storage during the stability study.
`
`The Applicant responded in an amendment dated 8/10/12:
`“Dissolution profile data is availablefor the I20mg and 240mg registration batches. The data
`supports the dissolution acceptance criteria. All dissolution profile resultsfor both 120mg and
`o
`240m stren ' th re '
`' tration batches exhibit similar dissolution Iro les with a mean 0 < 10%
`
`Reference ID: 3218542
`
`

`

`dissolved after 2 hours in the acid stage and a mean of> 90% dissolved within thefirst 10
`minutes in the bufi'er stage. Based on the consistent and comparable dissolution profile results
`between strengths and between registration batches the initial registration batchfor each
`strength arepresented as representative batches. Dissolution profile data on the I20mgpivotal
`clinical batches and the primary validation batches is not available. Pro Ie testin was initially
`not conductedfor the 120mg registration batches
`prior to
`the 18 month timepoint. Profile testing was added to theprotocol and initiated at the 18 month
`timepoint and will continue through the remainder ofthe study. Profile data is providedfor the
`available 18 and 24 month timepoints. A summary ofthe available dissolution profile data
`(individual, mean, SD, figures)for representative 120mg and 240mgprimary stability /
`registration batches is provided in Table I and Table 2, respectively. The dissolution profile data
`supports theproposed specification ofQ- at 30 minutes. ”
`
`
`
`Buffer sta_e after 2 hours E
`This recommendation was communicated to the Applicant in an e—mail dated 10/1 5/12. The
`Q n licant initial] acce .ted the recommendation as is e-mail dated 10/16/12 , but then chan ed
`
`Reference ID: 3218542
`
`Evaluation of resmnse and provided dissolution profile/stabilitg data:
`A representative example of a buffer stage dissolution profile for drug product (registration batch)
`stored at room temperature for up to 24 months is:
`
`As stated in the Applicant’s response, the provided dissolution data indicate that both 120mg and
`240mg strength registration batches exhibit similar dissolution profiles with a mean of < 10%
`dissolved after 2 hours in the acid stage and a mean of > 90% dissolved within the first 10
`minutes in the bufl'er stage.
`Based on the provided data, the acceptance criterion for the bufl'er stage should be
`_htened to Q =
`at 20 minutes:
`
`Proposed dissolution
`acce .tance criterion:
`
`Recommended dissolution
`acce tance criterion:
`
`exceeds 10% dissolved.
`
`exceeds 10% dissolved.
`
`Stage 2 (n=6): Average of the 12 units
`isnotmonethan10%dissolved,andno
`individual unit is greater than 25%
`dissolved.
`
`Stage 2 (n=6): Average ofthe 12 units
`isnotmorethan10%dissolved,andno
`individual unit is greater than 25%
`dissolved.
`
`Stage 3 (n=12): Average of the 24 units
`isnotmorethan 10% dissolved, andno
`individual unit is greater than 25%
`dissolved.
`
`Stage 3 (n=12): Average ofthe 24 units
`isnotmorethan 10% dissolved,andno
`individual unit is greater than 25%
`
`

`

`their response as follows (e-mail dated 10/30/12):
` at 20 min
`“Biogen Idec agrees with the FDA’s recommended acceptance criterion of Q=
`based on the development phase data. However, there is only limited data available on
`commercial batches at the 20 min time point since a 30 min time point was used to release
`batches intended for commercial use as required by the current specification. Therefore, we
`propose that testing at the 20 min time point be performed under a testing protocol post approval
`on 30 batches in order to assess data on commercial product to ensure that the Q=
` at 20 min
`acceptance criterion is supported. It is Biogen Idec’s expectation that the data will show that the
`FDA recommended acceptance criterion is appropriate but we would like to base the decision on
`a commercial batch dataset. Biogen Idec commits to this as a post approval commitment and will
`submit the data and the revised specification, if appropriate, in the Annual Report.”
`FDA responded by e-mail on 11/2/12 as follows:
` at 30 minutes on an
`“We agree that the Applicant can change the acceptance criterion to Q=
`interim basis for one year. During this period, they need to collect dissolution data both at 20 and
`30 minutes for all stability samples of all commercial batches to be released post approval. They
`need to submit these data for the Agency's evaluation to justify the Agency's recommendation to
`tighten the dissolution acceptance criterion to Q=
`at 20 minutes in a PAS after one
`year. The Applicant should submit a revised specification sheet and a revised stability protocol.”
`The Applicant responded as follows (e-mail dated 11/6/12):
`“We appreciate very much the FDA’s response on dissolution proposal. Biogen Idec agrees with
`the FDA’s recommendation to change the acceptance criterion to Q=
` at 30 minutes post
`approval. We will collect dissolution data both at 20 and 30 minutes on commercial batches
`manufactured post approval and submit the data in a prior approval supplement after one
`year. As requested, Biogen Idec will amend the application with the revised dissolution
`specification and stability protocol by COB 11/9/2012.”
`FDA responded as follows (e-mail dated 11/6/12):
` at 30 minutes pre-
`“We like to clarify that you should change the acceptance criterion to Q=
`approval, and then, based on additional data, tighten to Q=
` at 20 minutes if deemed
`appropriate, post-approval after one year.”
`The Applicant responded as follows (e-mail dated 11/7/12):
`“Thank you for the clarification on dissolution proposal. Biogen Idec agrees with the FDA’s
`recommendation to change the acceptance criterion to Q=
` at 30 minutes pre-
`approval. However, due to the already-completed manufacturing activities for commercial
`launch and the additional activities necessary to implement this change retrospectively, we kindly
`propose that this criterion be applied pre-approval to all commercial batches manufactured from
`the date of your acceptance of this response. We also commit to apply this change to all ongoing
`and future stability studies upon acceptance of this proposal by the Agency. The drug product
`batches already manufactured and released against the originally filed criterion (Q=
` at 30
`min) will be deemed acceptable for commercial use. The revised criterion will be applied for
`these batches on stability moving forward. As requested, Biogen Idec will amend the application
`with the revised dissolution specification and post-approval stability protocol within 3 business
`days of FDA’s acceptance of this response. Furthermore, a post approval supplement will be
` at 20 min data after one year of the NDA approval.”
`submitted with Q
`FDA responded as follows (e-mail dated 11/9/12):
`“Distribution of drug product batches that do not meet the approved drug product specifications
`is not acceptable. All commercial, to-be-marketed batches need to meet the acceptance criterion
`
`
`
`Reference ID: 3218542
`
`7
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`

` at 30 minutes. However, if you have batches that do not meet this acceptance
`of Q=
`criterion at stage 1, you can retest those batches according to stage 2 and/or stage 3 testing.”
`
`On 11/14/12, the Applicant submitted revised drug product specifications, including a buffer
`stage dissolution acceptance criterion of Q=
` at 30 minutes, and a revised stability protocol
`with a buffer stage dissolution acceptance criterion of Q=
`at 30 minutes and with a footnote
`stating that 20 minute dissolution data will be collected for information only.
`
`Evaluation of response:
`at 30 minutes, with a commitment to
`The buffer stage dissolution acceptance criterion of Q=
`collect and submit (as PAS) buffer stage dissolution data at 20 minutes for one year at release and
`on stability for all commercial batches is acceptable, based on the fast dissolution observed in the
`buffer stage, and based on previous regulatory actions, where the Agency has allowed other
`Applicants to collect additional dissolution data on their commercial batches for one year. The
`possibility of tightening the buffer stage dissolution acceptance criterion to Q=
`at 20 minutes
`will be evaluated when the PAS is reviewed. A reminder of the Applicant’s commitment to study
`Q=
`at 20 minutes should be noted in the AP letter if the NDA is approved. This commitment
`is not intended to be an official post marketing commitment (PMC).
`
` IN VITRO ALCOHOL DOSE DUMPING:
`The Applicant conducted an in vitro dose dumping study using 3 batches of 120 mg strength drug
`product in 0.1 N HCl (acid stage) containing 0, 5%, 20%, and 40% ethanol. Representative
`dissolution data and profiles for drug product batch 43664 are shown here: (Similar results were
`obtained for the other two drug product batches (batch 43665 and 43666))
`
`
`
`
`
`Reference ID: 3218542
`
`
`
`8
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`

`Evaluation: These dissolution data indicate that alcohol dose dumping is occurring in vitro.
`The OCP reviewer (Jagan Parepally, Ph.D.) was informed by e-mail on 7/16/12, in order to alert
`him of the possibility of in vivo alcohol induced dose dumping based on the provided in vitro
`data. This issue should be further addresses by the OCP reviewer by either request and/or review
`of additional in vivo alcohol dose dumping studies, or by drug product labeling. The e-mail from
`the Biopharmaceutics reviewer (this reviewer) to the OCP reviewer (Jagan Parepally, Ph.D.)
`stated: “I am sending this e-mail to let you know that the in vitro alcohol dose dumping study for
`this drug product indicates that dose dumping occurs in vitro. I understand that this issue can be
`addressed by additional in vivo alcohol dose dumping studies, or by drug product labeling.”
`According to communications with the OCP reviewer, Dr. Parepally (see also his review dated
`11/18/12), it was determined that there is no need for an in vivo alcohol dose dumping study or
`any labeling statements with regards to alcohol use.
`
`BCS CLASSIFICATION:
`Although no specific claims were made based on the BCS class, the Applicant stated in the
`original NDA that dimethyl fumarate is a BCS class 1 drug. The CMC lead made the following
`information request, which was sent to the Applicant on 5/8/12:
`You state in Module 3.2.S.1.3 that dimethyl fumarate is classified as BCS classification I.
`Provide data to support this classification or identify the location of the data in the NDA
`submission.
`
`The Applicant responded in an amendment dated 6/8/12:
`As per the guidance by the FDA, there are three criteria for determining the BCS class of a drug
`substance (FDA Guidance for Industry, Waiver of In Vivo Bioavailability and Bioequivalence
`Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics
`Classification System, August 2000).
`For BCS class I, the following criteria need to be met:
`• Solubility – the highest dose strength should be soluble in less than 250 mL or less in
` aqueous media from pH range pH 1-7.5.
`• Permeability – the drug substance should be permeable in in vitro assay or have
` greater than 90% absorption in humans based on the radiolabeled mass balance study.
`• Dissolution – the IR drug product should rapidly dissolve when no less than 85% is
` released in 30 min.
`The Applicant provided solubility, permeability, human absorption, and dissolution data for
`dimethyl fumarate.
`
`Evaluation of response:
`Biopharmaceutics, ONDQA (this reviewer): The provided dissolution and solubility data indicate
`that DMF has a high solubility over the pH range and exhibits a rapid dissolution.
`Clinical Pharmacology, OCP: The permeability data were reviewed by Jagan Parepally, Ph.D.
`from OCP, and his review of the permeability data (e-mailed to the Biopharmaceutics ONDQA
`reviewer on 9/26/12) concluded that the current available data are inconclusive and DMF cannot
`be considered as a highly permeable drug (see also his review dated 11/18/12) . Since the
`Applicant did not make any claim based on the BCS class, the inability to classify this drug as a
`BCS 1 will not affect the approval of this NDA. If approved, the AP letter should include a
`comment to that effect.
`
`
`
`Reference ID: 3218542
`
`9
`
`

`

`RECOMMENDATION:
`(cid:190) The applicant’s dissolution methodology, as summarized below is acceptable by the
`Agency:
`USP Apparatus II (paddle)
`Temperature: 37 °C
`Rotation speed: 100 rpm
`Acid stage for 2 hours: Dissolution medium: 500 mL 0.1 N HCl
`Buffer stage after 2 hours: Dissolution medium: 500 mL pH 6.8 phosphate buffer
`(cid:190) Based on the dissolution data provided, agreement was reached on the following (interim)
`dissolution specification:
`
`
`
`
`
`Recommended dissolution
`Proposed dissolution
`acceptance criterion:
`acceptance criterion:
`USP <711> for delayed release dosage
`USP <711> for delayed release dosage
`forms:
`forms:
`Stage 1 (n=6): No individual value
`Stage 1 (n=6): No individual value
`exceeds 10% dissolved.
`exceeds 10% dissolved.
`Stage 2 (n=6): Average of the 12 units
`Stage 2 (n=6): Average of the 12 units
`is not more than 10% dissolved, and no
`is not more than 10% dissolved, and no
`individual unit is greater than 25%
`individual unit is greater than 25%
`dissolved.
`dissolved.
`Stage 3 (n=12): Average of the 24 units
`Stage 3 (n=12): Average of the 24 units
`is not more than 10% dissolved, and no
`is not more than 10% dissolved, and no
`individual unit is greater than 25%
`individual unit is greater than 25%
`dissolved.
`dissolved
`Buffer stage (after 2 hours)
`Q=
`at 30 minutes
`Q=
` at 30 minutes
`The Applicant committed to collect dissolution data at 20 minutes and submit these data
`to FDA as a PAS one year after approval in order to determine if the buffer stage
`acceptance criterion can be tightened to Q=
`at 20 minutes.
`
`(cid:190) Although alcohol dose dumping was shown to occur in vitro, it was determined by the
`OCP reviewer that there is no need for an in vivo alcohol dose dumping study or any
`labeling statements with regards to alcohol use.
`
`(cid:190) No determination will be made on the BCS classification of dimethyl fumarate at this
`point.
`
`Acid stage (2 hours)
`
`
`From the Biopharmaceutics perspective, NDA 204063 for dimethyl fumarate delayed release
`capsules (120 mg/capsule and 240 mg/capsule) is recommended for APPROVAL. If approved,
`the AP letter should include the following two comments:
`• We have not made a BCS classification determination for your drug, since the data
`provided in the NDA are inconclusive with regards to the drug’s permeability.
`• We are reminding you of your commitment to collect 20 minute (buffer stage) dissolution
`data for all stability samples of all commercial batches to be released post approval for
`one year in order to evaluate the possibility of tightening the buffer stage dissolution
`acceptance criterion to Q=
` at 20 minutes and to submit the data in a prior approval
`supplement (PAS) one year after approval for our review.
`
`
`The commitment in the second comment is not intended to be an official post marketing
`commitment (PMC).
`
`
`
`Reference ID: 3218542
`
`10
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Elsbeth Chikhale, Ph.D. Tapash Ghosh, Ph.D.
`Biopharmaceutics Reviewer Acting Biopharmaceutics Team Leader
`Office of New Drug Quality Assessment Office of New Drug Quality Assessment
`
`
`
`
`Reference ID: 3218542
`
`11
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ELSBETH G CHIKHALE
`11/19/2012
`
`TAPASH K GHOSH
`11/19/2012
`
`Reference ID: 3218542
`
`

`

`NDA:
`
`204063
`
`CLINICAL PHARMACOLOGY REVIEW
`
`Brand Name:
`Generic Name:
`Dosage Form & Strength:
`
`mo
`Dimethyl Fumarate (BGOOOlg?
`w Gelatin Capsule (120 and 240
`
`Indication:
`
`mg)
`Treatment Ofpatients with relapsing multiple sclerosis
`
`(mo
`
`Applicant:
`Submission:
`Submission Date:
`
`Biogen Idec
`505(b)(1), Stande
`2/27/2012
`
`OND-l/Division Of Neurology Drug Products
`0ND Division:
`Office Of Clinical Pharmacology /DCP-l
`OCP Divisions:
`Jagan Mohan Parepally, Ph.D.,
`Primary Reviewer:
`Xinning Yang, Ph.D.
`Acting Team Leader:
`The OCP Office level briefing was held on November 13th, 2012.
`
`TABLE OF CONTENTS
`
`1. EXECUTIVE SUMMARY ..................................................................................................................................... 2
`
`1.1 RECOMMENDATION ............................................................................................................................................. 2
`1.2 PHASE IV COMMITMENT ..................................................................................................................................... 2
`1.3 SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS FINDINGS ............................. 2
`
`2. QUESTION BASED REVIEW .............................................................................................................................. 6
`
`2.1 GENERAL ATI'RIBUTES ........................................................................................................................................ 6
`2.2 GENERAL CLINICAL PHARMACOLOGY................................................................................................................. 6
`2.3 INTRINSIC FACTORS ........................................................................................................................................... 14
`2.4 EXTRINSIC FACTORS .......................................................................................................................................... 15
`2.5 GENERAL BIOPHARMACEUTICS ......................................................................................................................... 17
`2.6 ANALYTICAL SECTION ....................................................................................................................................... 21
`
`3. DETAILED LABELING RECOMMENDATIONS ........................................................................................... 23
`
`4. APPENDICES ....................................................................................................................................................... 25
`
`4.1 INDIVIDUAL STUDY REVIEWS ............................................................................................................................ 25
`4.2 OCP FILING/REVIEW FORM ............................................................................................................................... 89
`
`Reference ID: 321 8383
`
`1
`
`

`

`1.
`
`Executive Summary
`
`”m(dimethyl fumarate, BGOOOIZ) for the treatment
`The sponsor is seeking approval of
`ofpatients with relapsing multiple sclerosis OVIS)
`(hm)
`It is proposed that dimethyl
`filmarate (DMF) acts through activating the nuclear factor (erythroid—derived 2)-like 2 (Nrf2)
`transcriptional pathway, reducing inflammatory responses in both peripheral and central cells,
`and promoting cytoprotection of central nervous system cells. The proposed dosing regimen is
`starting at 120 mg twice a day and after 7 days increased to a recommended dose of 240 mg
`twice a day orally.
`
`To support the approval of the application, one Phase 2 and two pivotal efficacy studies and
`one extension study were conducted to evaluate the efficacy and long-term safety of DMF in
`MS subjects. Clinical pharmacology program consists of single- and multiple-dose studies
`evaluating pharmacokinetics (PK) of mono-methyl fiimarate OVINIF), the active metabolite of
`DMF. DMF is not detectable in systemic circulation, since it is rapidly hydrolyzed to MMF by
`esterases present in gastroenteral (GI) tract, gut wall and blood. The dose proportionality,
`effects of food and potential for drug-drug interactions were studied based on plasma
`concentrations of MMF. The proposed dosing regimen is supported by a dose-response
`relationship from a Phase 2 dose ranging