CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`203752Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`
`
`
`
`

`

`Cross—Discipline Team Leader (CDTL) Review
`
`
`Date
`October 12, 2012
`
`From
`
`Shelle R. Slau ter, M.D., Ph.D.
`
`Cross-Discipline Team Leader Review
`
`203752
`
`Ori - inal
`Noven Pharmaceuticals, Inc.
`
`December 29, 2011
`
`October 29, 2012
`
`MINIVELLE ETS/17B- estradiol (E2)
`
`Transdermal estradiol system an“) 0.0375, 0.050, 0.075
`and 0.1 mg/day applied twice weekly
`Treatment of Moderate to Severe Vasomotor Symptoms
`Due to Meno
`
`A roval is recommended.
`
`
`
`NDA/BLA #
`
`Sun lement#
`
`T 1 n e of Submission
`A licant
`
`Date of Submission
`
`PDUFA Goal Date
`
`Proprietary Name /
`Established (USAN) names
`Dosage forms / Strength
`
`Proposed Indication(s)
`
`Reference ID: 3207733
`
`

`

`Cross Discipline Team Leader Review
`
`1. Introduction
`
`With this 505(b)(1) original NDA submission, the Sponsor is seeking approval for a new
`l7B—estradiol 032) transdermal system (ETS), lVIINIVELLEm, which contains the same
`active ingredient as the previously approved products VivelleQ (NDA 020323) and
`Vivelle®-Dot (020538) manufactured by Noven but marketed by Novartis. M“)
`The
`
`MINIVELLE ETS NDA has a right of cross-reference to both the Vivelle ETS and Vivelle-
`Dot ETS NDAs. Compared to the Vivelle ETS and Vivelle-Dot ETS, MINIVELLE is a
`revised ETS with a smaller active surface area (See Table 1), but with the same
`multipolymeric adhesive platform. The MINIVELLE ETS contains the active component,
`E2, in a multi—polymeric adhesive and is designed to release E2 continuously to intact skin.
`M“) dosage strengths are sought for the MINIVELLE ETS, to provide nominal doses of
`”(4), 0.0375, 0.050, 0.075 and 0.1 mg per day, which corresponds to an active surface
`area of “’"", 2.48, 3.30, 4.95 and 6.6cm2.
`
`Table 1.
`
`Size and Dosage Strengths of the Vivelle ETS, Vivelle-Dot ETS and
`MINIVELLE ETS (Sponsor originally proposed name was
`M“)
`
`Strength
`
`Vivelle
`
`Vivelle-Dot
`
`Active Surface Area/Patch Size
`
`,
`
`,
`
`0.075 mgrday
`
`0.1 mgfday
`
`22 cm2
`
`29 cm2
`
`7.5 cm2
`
`10 cm2
`
`Estradiol Content per Unit
`
`0.0375 mgi’day
`
`0.05 mgr’day
`
`0.075 mgfday
`
`0.1 mglday
`
`4.33 mg
`
`6.57 mg
`
`8.66 mg
`
`0.585 mg
`
`0.78 mg
`
`1.17 mg
`
`1.56 mg
`
`(b) (4)
`
`mm)
`
`4.95 cm2
`
`6.60 cm2
`
`mm
`
`0.62 mg
`
`0.83 mg
`
`1.24 mg
`
`1.65 mg
`
`No new clinical data was submitted in support of the IVIINIVELLE ETS. The
`establishment of safety and efficacy of the MINIVELLE ETS is sought via bridging to the
`
`Page 2 of 17
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`Cross Discipline Team Leader Review
`
`findings of the Vivelle ETS by evaluation for bioequivalence (BE) supported by data
`submitted to the NDA. The Vivelle ETS is available in
` five dosage strengths
` with the Vivelle ETS having larger surface areas, as
`
`noted above.
`
`The Vivelle ETS, Vivelle-Dot ETS, and MINIVELLE ETS all have the same indication (or
`proposed indication in the case of MINIVELLE), treatment of moderate-to-severe
`vasomotor symptoms due to menopause. Both the Vivelle ETS and Vivelle-Dot ETS are
`approved for the prevention of osteoporosis at the 0.025 mg per day dosage strength. As
`noted previously, approval for the MINIVELLE ETS is sought on the basis of BE to the
`Vivelle ETS. The Sponsor has not sought an indication for the prevention of osteoporosis.
`
`There were no controversial issues associated with the review of this NDA. Based on the
`information submitted comprehensive reviews were performed by the review disciplines of
`Chemistry/Biopharmaceutics, Clinical Pharmacology and Clinical. These reviews, as well
`as the abbreviated reviews from Preclinical Pharmacology and Statistics, are summarized.
`2. Background
`NDA 020323 for the Vivelle ETS was Approved on October 28, 1994 for the “treatment of
`moderate to severe vasomotor symptoms associated with menopause”. Approved doses of
`Vivelle ETS for vasomotor symptoms are 0.0375mg, 0.05 mg, 0.075mg, and 0.1mg per
`day. Statistically significant improvement versus placebo in both the frequency and the
`severity, the co-primary endpoints, for the 0.0375 mg dosage strength was not reached until
`the 6th week of treatment. This dosage strength was approved with the restrictive language
`that, “women taking the 0.0375 dosage may experience a delay in the onset of efficacy.” In
`order to remove this restrictive language, the Sponsor agreed to conduct a Phase 4 study
`that would define the percentage of patients who received relief of vasomotor symptoms at
`the lowest dose (0.0375 mg/day). The results of that Phase 4 study were submitted to the
`Agency on April 30, 1999 in Supplement 021 to NDA 020323. The results demonstrated
`that for the study group receiving the 0.0375 mg per day dosage strength of the Vivelle
`ETS, a statistically significant improvement (reduction) vs. the group receiving placebo for
`both the frequency and severity of hot flushes at Weeks 4 and 12. The sample size was
`sufficient to detect a mean difference of greater than or equal to 2.0 hot flushes per day (the
`clinically meaningful threshold) in the reduction of frequency for the Vivelle ETS vs.
`placebo. Supplement 021 to remove the restrictive language (regarding delayed onset of
`efficacy) with the 0.0375 mg per day dose of the Vivelle ETS was approved on February
`25, 2000. On August 16, 2000, NDA 020323/Supplement 23 and NDA 021-167 were
`Approved for the 0.025 mg per day dosage strength of the Vivelle ETS for the indication of
`prevention of postmenopausal osteoporosis in at-risk patients. Noven discontinued the
`manufacture of the Vivelle ETS in 2006.
`
`NDA 020538 for the Vivelle-Dot ETS, in the same dosage strengths as those approved to
`that date for the Vivelle ETS, was Approved on July 31, 1996. Approval of the Vivelle-Dot
`ETS was based on the demonstration of bioequivalence to the Vivelle ETS. On January 18,
`2001, Novartis submitted NDA 020538/Supplement-014 to remove the restrictive language
`for the 0.0375 mg per day dose of the Vivelle-Dot ETS. NDA 020538/Supplement 14 was
`
`Page 3 of 17
`
`Reference ID: 3207733
`
`3
`
`(b) (4)
`
`(b) (4)
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`

`

`Cross Discipline Team Leader Review
`
`Approved on May 03, 2002. NDA 020538/Supplement 015 adding the prevention of
`postmenopausal osteoporosis indication in at-risk patients for the 0.025 mg per day dosage
`strength of the Vivelle-Dot ETS was also Approved on May 03, 2002.
`
`There are many estrogen-alone products, oral (7 originator drug products), transdermal (8
`originator drug products), topical (5 originator drug products) and vaginal creams, rings or
`tablets (5 originator drug products), which have been previously approved for the treatment
`of moderate to severe vasomotor symptoms due to menopause.
`
`A pre-IND meeting (PIND 076647) was held between the Division of Reproductive and
`Urologic Products (DRUP) and Noven Pharmaceuticals on September 11, 2007 to discuss
`the developmental plan for the MINIVELLE ETS. DRUP made the following major
`recommendations:
`• No preclinical studies were necessary if the patch and matrix and the impurities and
`degradation products of the MINIVELLE ETS were qualitatively and quantitatively
`similar to the Vivelle ETS and Vivelle-Dot ETS
`• A pivotal, single dose, two-way crossover, bioequivalence study comparing the
`highest strength of the Vivelle ETS (not Vivelle-Dot ETS) to the highest strength of
`the MINIVELLE ETS would provide support for approval of the MINIVELLE
`ETS. The Division stated the following with regards to assessment for
`bioequivalence:
`(cid:131) The Vivelle ETS should be used as the reference in the study since the clinical
`trials were conducted with the Vivelle ETS. The Vivelle ETS, at the 0.1 and
`0.05 mg per day dosage strengths, was still commercially available at the time
`of the meeting
`(cid:131) BE should be based on both baseline corrected and uncorrected relevant
`pharmacokinetic parameters
`(cid:131) The BE requirement for the lower strengths of the MINIVELLE ETS could be
`waived based on information:
`- BE at the highest dose strength
`- Proportionally similar composition (active and inactive ingredients) to
`the strength of the product for which the same manufacturer had
`conducted the in vivo BE study
`- Comparable in-vitro dissolution profiles of the MINIVELLE ETS
`- Dose proportionality of the MINIVELLE over the dose range of 0.025 to
`0.1 mg per day
`• A separate single-dose, crossover study with at least three dosage strengths of the
`MINIVELLE ETS should be conducted to determine the dose proportionality of the
`MINIVELLE ETS
`• The dermal characteristics (i.e., adhesive properties, skin irritation, and discomfort)
`of the MINIVELLE ETS should be evaluated in the BE and dose proportionality
`studies.
`
`On March 18, 2011, DRUP reiterated to Noven Pharmaceuticals that they should conduct a
`dose proportionality study and advised them on the study design. DRUP further advised
`that measurement of E2 and estrone (E1) would be sufficient. DRUP also indicated that a
`
`Page 4 of 17
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`Reference ID: 3207733
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`4
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`Cross Discipline Team Leader Review
`
`full 24-hour baseline measurement of both E2 and E1 concentrations should be performed
`and a standardized adhesion scale should be used to assess adhesion of the MINIVELLE
`
`ETS. Both recommendations were incorporated by the Sponsor into their final protocol.
`
`The MINIVELLE ETS for the treatment of moderate to severe vasomotor symptoms due to
`menopause was submitted on December 29, 2011. The application was administratively
`filed on February 27, 2011. DRUP issued a 74-day “no filing issues identified” letter on
`March 09, 2012.
`
`3. CMCIBiopharmaceuticleevice
`
`The drug substance, E2, is a white to practically white crystal or powder, chemically
`described as estra- 1, 3, 5 (10)-triene-3, 17B-diol, with a melting point of l73—179°C. It has
`an empirical formula of C13H24O2 and a molecular weight of 272.38. The drug substance
`will be manufactured and packaged at
`mar The applicant
`references DMF mm for all relevant information pertaining to the manufacture, control
`and release of the drug substance. DNIF mm was most recently reviewed and deemed
`adequate on May 24, 2011. No changes to the DMF have been made since the 2011 review
`and, therefore, DNIF mm is considered adequate to support NDA 203752.
`
`The drug product, IvIlNTVELLE ETS, contains E2 in a multipolymeric adhesive. The
`system is designed to release E2, the active pharmaceutical product (API), continuously
`upon application to intact skin. The MlNIVELLE ETS is comprised of three layers.
`Proceeding from the visible surface toward the surface attached to the skin, these layers
`are: 1) a flexible backing fihn; 2) an adhesive formulation containing E2, acrylic adhesive,
`silicone adhesive, oleyl alcohol (0A), Povidone-
`m4) and dipropylene glycol OJPG);
`and 3) a polyester release liner that is attached to the adhesive surface and must be removed
`before the patch can be used.
`
`In addition to the API E2, the drug-in—adhesive matrix contains
`
`excipients:
`
`(I!) (4)
`
`(I!) (4)
`
`The MINIVELLE ETS is circular in shape and translucent to slightly opaque white. It is
`manufactured at Noven Pharmaceuticals in Miami, FL. Two additional facilities have been
`listed for raw material and finished product microbial testing all of which are domestic. It
`was noted during review, that the maximum storage time for the raw material
`(m4)
`is
`(mm from the date of manufacture. Use within
`M“) prevents the impurity
`(law) from rising above USP acceptance criterion of
`M“) The quality of the drug
`product is controlled by tests for appearance, assay, content uniformity, identification,
`adhesion, drug release, impurities, cold flow, pouch seal integrity and microbial limits.
`Each carton will contain eight transdermal systems of a single strength. A 24 month
`expiration date has been granted (based on 12 months of provided stability data for Vivelle-
`Dot). The container “Closure System Development of the Drug Product” information
`presented in the application is adequate.
`
`Page 5 of 17
`
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`

`

`Cross Discipline Team Leader Review
`
`Inspections of all manufactluing sites were requested through EES. The recommendation
`from the Office of Compliance (made August 15, 2012) is ACCEPTABLE for the drug
`product manufacturing and testing sites.
`
`In the PLR formatting of the labeling submitted with the application, there were errors inmm
`
`. The labeling
`errors were identified in the 74—day filing memorandum. All outstanding errors in the
`CMC section of Prescriber Information were adequately addressed in Amendments dated,
`September 12 and November 02, 2011.
`
`The identifying label on the ETS includes the tradename and the strength of each system.
`The backing print is a random print with qualified ink. Given the small size of the ETS and
`the low intensity of the print, the Agency made the recommendations (IR letter dated July
`19. 2012) to improve the readability of the identifying information by 1.) using a
`darker/more distinguishable ink color than the currently proposed
`"4) 2.
`decreasing the number of rows printed per unit and 3.) Remove the M“) from
`if a tradename is not to be used. Noven responded and stated that they will launch the
`commercial product utilizing a
`mu) (newly proposed ink), while completing
`their qualification and stability work of this more distinguishable ink. The Applicant
`confirmed that they do not intend to switch between the “
`M“) and
`because of concern for potential patient confusion. The Sponsor also provided a
`justification supporting that it was not possible to decrease the number of rows of wording
`printed per unit. This justification was acceptable.
`
`(am;
`
`0) (4)
`
`Per the 0NDQA Chemistry reviewer, the NDA is recommended for Approval from a CMC
`perspective.
`
`The Biopharmaceutics review was focused on:
`
`1. The evaluation and acceptability of the data supporting the proposed in vitro drug
`release methodology and acceptance criteria.
`
`2. The biowaiver request for the lower strengths of the MINIVELLE ETS.
`
`Regarding the biowaiver request, the Biopharmaceutics review notes that the in vitro drug
`release profile of each of the lower strengths of the MINIVELLE ETS (0.025, 0.0375,
`0.050, and 0.075 mg per day) was compared to. the drug release profile of the highest
`strength (0.1mg per day). The release profiles are similar in shape and meet the criteria for
`similarity (f l and t2 factors). Per the Biopharmaceutics reviewer, the results from the BE
`study and similarity t2 test support Noven’s request for a bioavailability (BA)/BE waiver
`for the proposed lower strengths of MINIVELLE and, therefore, the biowaiver is granted.
`
`Page 6 of 17
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`

`Cross Discipline Team Leader Review
`
`Regarding the in vitro drug release method and acceptance criteria, agreement on the
`following was reached.
`
`0 The following drug release method and acceptance criteria are acceptable on an
`interim basis
`
`Apparatus
`
`Cylinder Medium
`Speed
`
`Acceptance Criteria
`
`Volume USP
`
`Apparatus 6
`
`Water at
`32°C
`
`M (4)
`:
`6 hr: W"
`18 hr: TBD (report value)
`24 hr:
`"M"
`mm; 0.05 mg/24 hr and
`0.075 mg/24 hr. 0.1 mg/24 hr 36 hr: TBD (report Value)
`
`Refer to USP <724> for
`
`Ll/L2/L2 testing
`
`0 The Applicant will collect drug release profile data for the additional 18 and 36
`hours time-points for the registration batches starting at the next scheduled stability
`time-point and for the upcoming validation batches. The extension of the collection
`period to 36 hrs will ensure that 2 (m4) of drug can be consistently achieved
`(It) (4)
`
`will result
`0 The Applicant will investigate whether an
`in a higher release rate with > M") of drug being released in a shorter sampling
`period, without loosing the discriminating ability
`
`0 The drug release data collected during the first year from approval date will be used
`for the setting of the final acceptance criteria
`
`0 The collected data and a proposal for the final drug release method and acceptance
`criteria should be submitted to FDA within fifteen months of the approval date,
`under a prior approval supplement (PAS) to the NDA
`
`0 Upon review of the data provided in the PAS, the drug release methodology and
`acceptance criteria for MINIVELLE ETS will be finalized.
`
`In submission SDN-012, dated September 17, 2012, Noven confirmed the following
`commitments:
`
`0
`
`In the IR Response dated July 31, 2012 Noven agreed to add drug release sampling
`timepoints at 18 and 36 hours. The response states, “We agree to collect 18 and 36
`hour data starting at the next stability timepoint and for the upcoming validation
`batches.” Noven finther agreed to collect dissolution data including the 18 and 36
`hr timepoints for 12 months. Noven agreed that by the end of 15 months, they will
`submit the dissolution data, proposed acceptance criteria, and justification as a post-
`approval supplement.
`
`0 Noven committed to evaluating the release rate method recommended by the
`Agency in its IR letter dated, July 12, 2012. The recommended methodology
`consists of
`(mm The results
`
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`

`Cross Discipline Team Leader Review
`
`of this evaluation will also be included in the post approval supplement planned for
`submission in 15 months.
`
`The Biopharmaceutics reviewer found the agreements on the part of Noven
`Pharmaceuticals to be acceptable and recommends that the MINIVELLE ETS receive
`approval.
`4. Nonclinical Pharmacology/Toxicology
`In the September 11, 2007 preIND meeting with Noven Pharmaceuticals, the Agency
`agreed that no additional preclinical studies for the MINIVELLE ETS were necessary to
`support marketing. This decision was based on the following:
`
`1. The MINIVELLE ETS patch and matrix materials are the same and the impurities
`and degradation products are reported qualitatively and quantitatively similar to the
`Vivelle ETS and Vivelle-Dot ETS. The manufacturing process for the Vivelle-Dot
`ETS and MINIVELLE ETS is represented by the Sponsor to be very similar.
`
`2. Preclinical studies have shown that the Vivelle-Dot ETS is neither a primary skin
`irritant nor a dermal sensitizer.
`
`3. The nonclinical pharmacology, pharmacokinetics, and toxicology of 17β-estradiol
`delivered via an estradiol transdermal system are well characterized as summarized
`in the current Package Inserts for the Vivelle ETS and Vivelle-Dot ETS.
`
`Based on the results of the preclinical studies with the Vivelle ETS demonstrating lack of
`skin irritation in the rabbit and delayed sensitization in guinea pig in addition to the safety
`profile of the Vivelle ETS in clinical trials, Pharmacology/Toxicology recommends
`approval of NDA 203752 for the MINIVELLE ETS for treatment of moderate to severe
`vasomotor symptoms associated with menopause.
`5. Clinical Pharmacology/Biopharmaceutics
`The Sponsor submitted four Clinical Pharmacology studies including a BE study (Study
`N28-004) and a dose-proportionality study (Study N28-005). The BE and dose
`proportionality studies used the to-be-marketed (TBM) formulation. The other two studies
`submitted to the NDA, Studies N28-001 and N28-003, used previous formulations and
`were submitted as supportive information. The Office of Clinical Pharmacology (OCP)
`reviewed the BE and dose proportionality studies conducted with the TBM formulation.
`The reader is referred to the review of Dr. Chongwoo Yu, OCP, dated August 16, 2012
`for a comprehensive review of the BE and dose proportionality studies. The two studies
`submitted as supportive were not reviewed as they were not conducted with the to-be-
`marketed formulation and not considered relevant by OCP.
`
`The pivotal BE study, Study N28-004, was conducted with the highest strength of the
`MINIVELLE ETS developed [1.65 mg E2 in a 6.6 cm2 estradiol transdermal system (ETS)
`with nominal delivery dose of 0.1 mg per day) compared to the Vivelle ETS (8.66 mg E2
`in a 29 cm2 ETS with nominal delivery dose of 0.1mg per day). A biowaiver was sought
`
`Page 8 of 17
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`Reference ID: 3207733
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`

`Cross Discipline Team Leader Review
`
`for the lower dosage strengths. Study N28-004 was an open-label, single center, single
`dose, randomized, 2-way crossover study conducted under a fed state (after standardized
`breakfast) in 100 healthy nonsmoking postmenopausal women 40 to 65 years of age. The
`inclusion and exclusion criteria for entrance into the study were standard for a
`pharmacokinetic study in healthy women and were acceptable. In two treatment periods,
`at 8am (± 10 min) on Day 1 and Day 22 (cross over) of the study, each subject received
`Treatment A (test), a single MINIVELLE ETS applied for 84 hours of treatment, and then
`Treatment B (reference), a single Vivelle ETS applied for 84, according to the
`randomization schedule. There was a 17.5 day washout period between the removal of the
`Treatment A ETS on day 4 (84 hours after application of the first patch on Study Day 1)
`and the application of the Treatment B ETS on Study Day 22. While on treatment,
`subjects were allowed to shower, but not to completely immerse themselves in a bath.
`Subjects were prohibited from using any soap, body lotion, oil, or cream at or around the
`application site. The application site was not rubbed or disturbed for the period of time
`inclusive of application to 72 hours following removal. Blood sampling was performed at
`24, 22, 20, 18, 16, 12, 10, 8, 4, and 0.5 hours before ETS application, and 2, 4, 8, 12, 24,
`36, 48, 60, 72, 84, 86, 88, 90, 92, 96, 102, 108, and 120 hours post-dose in each treatment
`period. ETS were evaluated multiple times for evidence of adhesion to the site of
`application and discomfort at that site. Application sites were also assessed for adhesive
`residue remaining on the skin immediately after ETS removal. An assessment for skin
`irritation was made prior to ETS application and multiple times after removal of the
`transdermal system.
`
`Ninety-nine (99) subjects were randomized and received both treatments. Two subjects
`did not complete both treatments [Subject 004-01-029 had detachment prior to the 24 hour
`post dose assessment of Treatment A and Subject 004-01-048 withdrew her consent prior
`to Treatment B (see Section 8 Safety of this review for an explanation)]. These two
`subjects were removed from the analysis. An additional subject (Subject 004-01-063) was
`excluded from the analysis because of an abnormally high concentration of E2 at baseline.
`The OCP reviewer excluded a fourth subject (Subject 004-01-015) for this same reason
`Serum samples were analyzed for E2, unconjugated E1, and total E1. PK analysis was
`performed on all three analytes. E2 was analyzed with and without baseline correction (for
`endogenous E2). However, as the goal is to compare the exposure of E2 by the
`contribution of the drug products, the baseline corrected E2 PK parameters were selected
`for the BE analysis. The clinical team agrees that the baseline corrected PK parameters are
`more appropriate for the BE analysis. The reader is referred to Dr. Yu’s review for a
`discussion of the E2 baseline correction. The following PK parameters were calculated for
`baseline uncorrected E2, baseline corrected E2, unconjugated E1, and total E1:
`• Cmax:
`the maximum serum concentration observed
`• AUC84:
`the area under the serum concentration-time profile; calculated from
`time 0 to 84 hour (wear time)
`• AUClast:
`the area under the serum concentration-time profile; calculated from
`time 0 to the last measurable concentration by the linear trapezoidal rule (120 hours
`post-dose
`• AUCinf:
`infinity
`
`the area under the serum concentration-time profile extrapolated to
`
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`

`Cross Discipline Team Leader Review
`
`Tm:
`
`the time of the maximum observed concentration
`
`elimination rate constant (slope of the log concentration vs. time curve
`kc]:
`between 84 and 120 hours)
`fig:
`elimination half-life (1n 2/kel)
`
`0
`
`The average concentration-time profiles for baseline-corrected E2 are presented in Figure
`1.
`
`Figure 1. Average Baseline-Corrected E2 Serum Concentration-Time Profiles
`Following a Single Dose of Treatment A (Test: MINIVELLE ETS) And
`Treatment B (Reference: VIVELLE ETS)
`
`
`
`-I III
`
`II
`
`II
`
`I
`
`I
`
`I
`
`I O C
`
`I H I
`
`I
`
`I
`
`I
`
`II
`
`‘II I
`
`'I'Illo M
`
`Source: OCP review Figure 4, page 10 and Sponsor Figurell—Z Study Report N28—004
`
`The Sponsor’s baseline and uncorrected BE analyses are presented in Table 2.
`
`Table 2. Sponsor’s Baseline Corrected and Uncorrected BE Analyses of E2 (N=97)
`
`—————
`—_Baseline Corrected Anal is
`
`Ratio of LSM‘
`864%
`
`81.0-92.2%
`90% _eometric C '
`Baseline Uncorrected Anal sis
`
`79.5-90.6%
`
`78.9-89.8%
`
`103-116%
`
`80.8-91.1% [ru- 103-115%
`
`Ratio of LSM'
`90% eometric c '
`
`87.0%
`81.9-92.5%
`
`85.8%
`
`[m- 109%
`
`' Calculated using least squares means according to the formula: e “w ' a"
`b 90% geometric confidence interval using ln-transformed data.
`c not reported
`Source: OCP review Table 4, page 10
`
`' "
`
`: X 100.
`
`The OCP reviewer also performed a BB analysis to confirm the Sponsor’s findings.
`Results of that analysis are presented in Table 3.
`
`Page 10 of 17
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`

`Cross Discipline Team Leader Review
`
`Table 3. Reviewer’s Baseline Corrected Analysis of E2 (N=96)
`Cmax
`
`AUC84
`AUC120
`AUCinf
`Ratio of LSMa
`108.8%
`86.1%
`84.5%
`84.5%
`90% geometric CIb
`102.4-115.6%
`80.7-91.7%
`79.2-90.3%
`79.2-90.3%
`a Calculated using least squares means according to the formula: e (MINIVELLE (A) –Vivelle (B)) X 100.
`b 90% geometric confidence interval using ln-transformed data.
`Source: OCP review Table 5, page 10
`
`The OCP Reviewer determined that the 90% geometric CIs are within the acceptable BE
` and Cmax but not for AUC120 and AUCinf. OCP finds the assessment of
`range for AUC84
`AUC84 to be more clinically relevant as the patch was applied for an 84 hour period [the
`approved labeling states that the ETS should be applied every 3 (72 hours) to 4 days (96
`hours). Based on the findings for AUC84 and Cmax, BE at the highest strength of the
`MINIVELLE ETS is declared.
`
`The Sponsor submitted a biowaiver request for the lower dose strengths of 0.025, 0.0375,
`0.050, and 0.075 mg per day. The Sponsor supports the biowaiver request based on:
`• The establishment of BE of the MINIVELLE ETS to the Vivelle ETS at the highest
`strength of 0.1 mg per day
`• Establishment of dose proportionality over the dose range of 0.025-0.1 mg per day
`(see dose proportionality discussion below)
`• Different doses of MINIVELLE are compositionally proportional (see Section 1
`Introduction Table 1 of this review)
`In vitro dissolution profiles of all strengths of the MINIVELLE ETS are
`comparable [(f2 > 50) see Biopharmaceutics discussion under Section 3 CMC,
`Biopharmaceutics and Devices]
`
`•
`
`The Sponsor conducted and submitted a dose proportionality study, Study N28-005, to
`support their request for biowaiver for each of the lower dose strengths of the
`MINIVELLE ETS. The study was a Phase 1, randomized, open-label, single center,
`single-dose, three-way crossover study of 36 healthy nonsmoking postmenopausal women
`40 to 65 years of age. The inclusion and exclusion criteria for entrance into the study were
`consistent with those used in Study N28-004 with the addition of an exclusion criterion for
`the use of antihistamines or topical products within 72 hour of initial dosing in the study.
`The entrance criteria were acceptable. During the three treatment periods, all subjects
`received Treatment A, a single 0.1 mg per day MINIVELLE ETS applied for 84 hours of
`treatment; Treatment B, a single 0.05 mg per day MINIVELLE ETS applied for 84 hours
`of treatment; or Treatment C, a single 0.025 mg per day MINIVELLE ETS applied for 84
`hours of treatment according to the randomization schedule. Subjects received their
`assigned treatment on Day 1, Day 22, and Day 43. There was a minimum 21 day washout
`period between each of the treatment periods. Blood sampling was on Day 0 (for baseline)
`at -24, -22, -20, -18, -16, -12, -10, -8, -4 and -0.5 hours pre-dose prior to period 1 and then
`2, 4, 8, 12, 24, 36, 48, 60, 72, 84, 86, 88, 92, 96, 102, 108, and 120 hours after treatment
`administration in each treatment period.
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`Figures 2 and 3, respectively presents the relationship of the E2 dose with the E2 AUC84 or
`E2 Cmax, respectively.
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`Figure 2. Relationship of dose of E2 and Mean AUC84 Following a Single Dose of the
`MINIVELLE ETS in Postmenopausal Women
`
`Source: OCP review Figure 6, page 12
`
`
`
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`Figure 3. Relationship of the dose of E2 and Mean Cmax Following a Single Dose of
`the MINIVELLE ETS in Postmenopausal Women
`
`
`
`Source: OCP review Figure 7, page 13
`
`The E2 AUC and Cmax increase linearly with increasing E2 dose from 0.025mg per day to
`0.1 mg per day of the MINIVELLE ETS and dose proportionality is established.
`
`Adherence of the MINIVELLE ETS was assessed based on the combined data from the
`BE and dose proportionality studies consisting of 208 total observations. Of the 208
`MINIVELLE observations, approximately 98 % of the observations had an adhesion score
`of 0 (i.e., the skin adhesion rate was greater than or equal to 90 percent) over the 84-hour
`wear period. One subject had a complete detachment during the wear period.
`Approximately 65 percent of the MINIVELLE ETS evaluated in these studies were with
`the 0.1 mg per day (6.6 cm2 active surface area) dose.
`
`Distribution, metabolism, and excretion of E2 from MINIVELLE are expected to be the
`same as those for the Vivelle ETS. The Sponsor is proposing to use the information from
`the Vivelle ETS for their product.
`
`No new DDI studies were conducted with the MINIVELLE ETS. Noven proposes to use
`the information from the Vivelle ETS in the MINIVELLE ETS label.
`
`At the request of OCP and DRUP, the Division of Bioequivalence and GLP Compliance
`(DBGC) conducted audits of the clinical and analytical portion of BE Study N28-004. The
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`audits were conducted at Elite Research Institute, Inc., Miami, Florida and at
`during the period of
`The audits included a thorough examination of study record, facilities, and equipment as
`well as interviews and discussions with the firms’ management and staff. Following the
`inspections at the clinical and analytical sites, no significant objectionable conditions were
`observed and Form 483 was not issued.
`
`(m4)
`
`(b) (4)
`
`The OCP review concludes that the information submitted to support NDA 203752 for the
`MINIVELLE ETS is acceptable provided that a satisfactory agreement is reached
`regarding labeling.
`
`6. Clinical Microbiology
`
`Not applicable to this NDA.
`
`7. Clinical/Statistical - Efficacy
`
`No new Phase 3 trials for efficacy and safety were submitted with this NDA. Efficacy is
`bridged to Vivelle by BB. The reader is referred to NDA 020323 for the discussion of the
`efficacy of the Vivelle ETS. The MOR (Section 6 Review of Efficacy) for MINIVELLE,
`summarizes the Vivelle ETS efficacy data previously submitted in NDA 020323 (for the
`Approval cycles for the Vivelle ETS) from the 12-week Phase 3 efficacy and safety studies,
`1003A, 1003 B and Protocol 036 (Supplement 21). The reader is referred to the MOR for
`this summary discussion of the efficacy of the Vivelle ETS.
`
`8. Safety
`
`No new Phase 3 trials for efficacy and safety were submitted with this NDA. The labeling
`for MINIVELLE ETS will have a Section 6 ADVERSE REACTIONS that will reflect the
`
`clinical trial experience with the Vivelle ETS vs. placebo in the pivotal Phase 3 studies
`(Studies 1003A, 1003B and Protocol 036) presented in NDA 020323 and the postmarketing
`experience with the Vivelle ETS. The MOR review for MINIVELLE summarizes the
`previously reviewed safety profile of the Vivelle ETS derived from the Phase 3 clinical
`trials presented in the Vivelle ETS NDA 020323. The reader is referred to the MOR
`(Section 7 Review of Safety) of this NDA for this summary discussion of the safety profile
`of the Vivelle ETS.
`
`Both the BE study, Study N28—004, and dose proportionality study, Study N28-005, were
`short term studies with total duration of drug exposure between 168 and 252 days. No
`deaths or serious adverse events occurred while on study drug in either study.
`
`In Study N28—004, during the washout period between treatments, one subject (Subject
`004-01-048) experienced first-degree sunburn which resulted in her withdrawal from the
`study prior to