CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`203752Orig1s000
`
`
`SUMMARY REVIEW
`
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`

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`Division Director Review
`
`Summary Review for Regulatory Action
`
`electronic st u u
`
`H lton V. Joffe, M.D., M.M.Sc.
`From
`
`Subject
`Division Director Summary Review
`NDA/BLA #
`NDA 203752
`
`Su lement #
`
`Applicant Name
`Noven Pharmaceuticals, Inc.
`Date of Submission
`December 29, 2012
`
`PDUFA Goal Date
`
`October 29, 2012
`
`Proprietary Name /
`Established
`S ‘
`
`Name
`
`Dosage Forms / Strength
`
`Proposed Indication(s)
`
`Minivelle (Estradiol transdermal system)
`
`Transdermal patch applied twice weekly, delivering
`0.0375, 0.05, 0.075, and 0.1 m
`
`Treatment of moderate to severe vasomotor symptoms
`associated with the meno ause
`
`Action/Recommended Action for Approval
`
`
`
`Material Reviewed/Consulted
`
`0ND Action Packa ' e, includin:
`
`Names of disci 1 line reviewers
`
`Medical Officer Review
`
`Phill Price, M.D.
`
`Statistical Review
`
`Xin Fan- , Ph.D. and Mahboob Sobhan, PhD.
`
`Phannacolo 3 Toxicolo 3 Review
`CMC Review
`
`Krishan Rahe'a, D.V.M, Ph.D. and Alex Jordan, Ph.D.
`Caroline Strasin- er, PhD. and Terrance Ocheltree, Ph.D.
`
`B10 .harmaceutics
`
`Ta ash Ghosh, Ph.D.
`
`Clinical Pharmacoloa Review
`
`Chem 00 Yu, PhD. and M on -Jin Kim, PhannD.
`
`OPDP
`
`081
`
`Melinda McLawhom, Pharm.D., BCPS and Carrie Newcomer, PharmD.
`
`J oti Patel, Ph.D. and Goa Biswas, Ph.D.
`
`CDTL Review
`
`Shelle R. Slau Iter, M.D., Ph.D.
`
`OSE/DIVIEPA
`SEALD
`Division of Medical Policy
`Pro u ams
`
`Walter Fava, R.Ph M S Ed and Zach Oleszczuk, PharmD.
`Abimbola Adebowale, PhD. and Laurie Burke, MD.
`LaShawn Griffiths, RN, MSHS-PH, BSN and Melissa Hulett, RN, BSN,
`MSBA
`
`OND=Ofice ofNew Drugs
`0PDP=0ffice of Prescription Drug Promotion
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division ofMedication Brat Prevention and Analysis
`SEALD=Smdy Endpoints and Labeling Development
`OSI=Oifice of Scientific Investigations
`CDTLPCross—Discipline Team Leader
`
`Page 1 of 7
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`Reference ID: 3209776
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`Division Director Review
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`Signatory Authority Review
`1. Introduction
`
`
`Minivelle is a new transdermal system designed to continuously release 17β-estradiol when
`applied to intact skin. Noven, the applicant, has submitted a 505(b)(1) New Drug Application
`(NDA) seeking approval of Minivelle for the treatment of moderate to severe vasomotor
`symptoms associated with the menopause. This document serves as the decisional
`memorandum for the application.
`2. Background
`
`
`Vivelle (NDA 020323) is an estradiol transdermal system indicated for the treatment of
`moderate to severe vasomotor symptoms associated with the menopause and for the
`prevention of postmenopausal osteoporosis. Phase 3 trials have confirmed the efficacy and
`safety of Vivelle for the treatment of moderate to severe vasomotor symptoms at doses (shown
`as the nominal delivery rate of estradiol per day) of 0.0375 mg/day, 0.05 mg/day, 0.075
`mg/day, and 0.1 mg/day. The 0.025 mg/day dose of Vivelle was approved as the starting dose
`for the prevention of postmenopausal osteoporosis. Efficacy of the 0.025 mg/day dose for the
`treatment of vasomotor symptoms has not been established. Vivelle is still approved but is no
`longer marketed or distributed.
`
`Vivelle-Dot (NDA 020538) is an estradiol transdermal system that was approved based upon
`demonstration of bioequivalence to Vivelle. Vivelle-Dot delivers the same daily dose of
`estradiol as Vivelle but does so from a smaller active surface area. Vivelle-Dot is currently
`marketed for the same indications as Vivelle. Novartis is the holder for both the Vivelle and
`Vivelle-Dot NDAs.
`
`Noven has now developed Minivelle, an estradiol transdermal system that is smaller than
`Vivelle-Dot (Table 1). Noven is seeking an indication only for vasomotor symptoms based
`upon a demonstration of bioequivalence to Vivelle. Noven has a right of reference to both the
`Vivelle and Vivelle-Dot NDAs.
`
`Minivelle is applied twice weekly to the skin of the lower abdomen or buttocks. The proposed
`dosage strengths are
` 0.0375 mg/day, 0.05 mg/day, 0.075 mg/day, and 0.1
`mg/day.
`
`
`Table 1. Patch Size (in cm2) for Vivelle, Vivelle-Dot and Minivelle
`Strength (mg/day)
`Vivelle
`Vivelle-Dot
`Minivelle
`0.025
`7.25
`2.5
`
`0.0375
`11
`3.75
`2.48
`0.05
`14.5
`5.0
`3.30
`0.075
`22
`7.5
`4.95
`0.1
`29
`10
`6.60
`
`
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`Page 2 of 7
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`Reference ID: 3209776
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`(b) (4)
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`(b) (4)
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`Division Director Review
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`3. CMClDevice
`
`The Chemistry/Manufacturing/Controls (CMC) reviewers recommend approval. See the
`review by Dr. Caroline Strasinger for further details. Per Dr. Strasinger, the applicant has
`provided sufficient information to assure the identity, strength, purity and quality of the drug
`product. The drug substance, estradiol, is identical to the drug substance in Vivelle and
`Vivelle-Dot.
`
`mm
`
`The Office of Compliance has issued an “Acceptable” recommendation for the manufacturing
`facilities. The applicant will be granted a 24-month expiration date based on 12 months of
`provided stability data and supporting Vivelle—Dot data.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The nonclinical pharmacology/toxicology reviewers recommend approval based on adequate
`supportive non-clinical pharmacology/toxicology data in the Vivelle and Vivelle—Dot NDAs.
`The Minivelle NDA does not contain new non-clinical phannacology/toxicology data. See the
`review by Dr. Krishan Raheja for further details.
`
`5. Clinical Pharmacologleiopharmaceutics
`
`The applicant submitted results from two clinical pharmacology studies that used the to-be-
`marketed formulation of Minivelle. These studies are summarized briefly below. See the
`clinical pharmacology review by Dr. Chongwoo Yu for fiuther details.
`
`Study N28—004 is the pivotal bioequivalence study. The clinical and analytical sites were
`inspected by the Office of Scientific Investigations and the data were found to be acceptable.
`See the review by Drs. Jyoti Patel and Gopa Biswas for further details. This open-label,
`randomized, cross—over study compared Minivelle to Vivelle in healthy postmenopausal
`women. Each patch was applied for 84 hours (3.5 days) with a washout period of 17.5 days.
`The applicant compared the highest to-be-marketed dose of Minivelle to the highest approved
`dose of Vivelle, both of which nominally deliver 0.1 mg of estradiol per day. A total of 100
`women were randomized.
`
`I agree with the clinical pharmacology reviewers that the tested dose of Minivelle is
`bioequivalent to the tested dose of Vivelle based on the area under the time—concentration
`curve (AUC)g411r and Cmax. For these parameters, the standard bioequivalence criteria (90%
`confidence interval 80—125%) are met regardless of whether the baseline estradiol is corrected
`or uncorrected for endogenous estradiol concentrations (Iable 2). The AUC1201., and AUCinf
`results are qualitatively similar to the results for AUCg4h, although some of the results for
`AUC1201.: and AUCinf do not meet the bioequivalence criteria based on the lower bound of the
`90% confidence intervals (78.9-79.5%, which is below the 80% cutoff). Because Minivelle
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`Reference ID: 3209776
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`Division Director Review
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`and Vivelle were removed after 84 hours, I agree with Dr. Yu that AUC84h is more appropriate
`than AUC120hr or AUCinf for assessing bioequivalence. Ideally, participants in the study should
`have worn the patches for 96 hours (4 days) rather than 84 hours because these patches are
`intended for use up to 4 days.
`
`Table 2. Pivotal bioequivalence study showing estradiol exposures with Minivelle 0.1 mg/day relative to
`estradiol exposures with Vivelle 0.1 mg/day (adapted from Tables 4 and 5 from Dr. Yu’s review)
`AUC84hr
`AUC120hr
`AUCinf
`Cmax
`
`Baseline uncorrected: Applicant (n=97) 87.0 (81.9-92.5)
`85.8 (80.8-91.1)
`Not reported
`109 (103-115)
`Baseline corrected: Applicant (n=97)
`86.4 (81.0-92.2)
`84.9 (79.5-90.6) 84.2 (78.9-89.8) 109 (103-116)
`Baseline corrected: Dr. Yu (n=96)
`86.1 (80.7-91.7)
`84.5 (79.2-90.3) 84.5 (79.2-90.3) 109 (102-116)
`Least square means with ln-transformed 90% geometric confidence intervals
`
`
`Figure 1 shows that the Minivelle and Vivelle pharmacokinetic exposures are most similar
`during the first 2 days of patch wear with larger differences thereafter. This figure shows the
`baseline-corrected estradiol data. The baseline-uncorrected data are similar.
`
`Figure 1. Mean baseline-corrected estradiol concentration-time profiles for Minivelle (A,
`closed circles) and Vivelle (B, open triangles)
`
`
`
`
`The applicant also conducted a dose proportionality study (N28-005) to support a biowaiver
`request for the dosage strengths below 0.1 mg/day. In this open-label, three-way crossover
`study, 36 healthy postmenopausal women were randomized to Minivelle 0.1 mg/day (the
`highest proposed dose), Minivelle 0.05 mg/day and Minivelle 0.025 mg/day
`
` Each patch was worn for 84 hours with a 17.5 day washout period between
`treatments. As discussed by Dr. Yu, this study adequately demonstrated dose-proportionality.
`
`
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`Reference ID: 3209776
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`Division Director Review
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`The applicant has also provided adequate data to show proportional composition and
`comparable in vitro dissolution profiles for all Minivelle strengths. Based on these data, the
`biopharmaceutics reviewers agree to grant the applicant a biowaiver for the lower proposed
`Minivelle doses
` 0.0375 mg/day, 0.05 mg/day, and 0.075 mg/day). See the
`review by Dr. Tapash Ghosh for further details.
`
`
`6. Clinical Microbiology
`
`
`This NDA does not contain clinical microbiology data.
`
`
`7. Clinical/Statistical-Efficacy
`
`
`This NDA does not contain new clinical data beyond the data contained in the clinical
`pharmacology studies. Based on the clinical pharmacology and biopharmaceutics data
`described above, the applicant is able to bridge to the efficacy data from the Vivelle NDA. See
`the clinical review by Dr. Phill Price and the Cross-Discipline Team Leader memorandum by
`Dr. Shelley Slaughter for further details.
`8. Safety
`
`
`Based on the clinical pharmacology and biopharmaceutics data described above, the applicant
`is also able to bridge to the safety data from the Vivelle NDA. Dr. Price and Dr. Slaughter
`summarize the safety data derived from the Minivelle clinical pharmacology studies, including
`skin-related adverse events. I agree with Drs. Price and Slaughter that no new safety concerns
`were identified for Minivelle based on these limited data.
`
`
`9. Advisory Committee Meeting
`
`
`This NDA was not taken to advisory committee.
`10.
`Pediatrics
`
`
`In consultation with the Pediatric Review Committee (PeRC), we determined that this NDA
`does not trigger the Pediatric Research Equity Act (PREA) because it does not provide for a
`new active ingredient, new indication, new dosage form, new dosing regimen or new route of
`administration. We will inform the applicant in the approval letter that this NDA is exempt
`from this requirement.
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`Reference ID: 3209776
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`(b) (4)
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`Division Director Review
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`11.
`
`Other Relevant Regulatory Issues
`
`The Division of Medication Error Prevention and Analysis (DIVIEPA) approved the trade name
`Minivelle within 90 days of today’s action date. See the review by Walter Fava for details.
`
`There are no unresolved regulatory issues.
`
`12.
`
`Labeflng
`
`Upon our request during the review cycle, the applicant has agreed to launch the product using
`a more distinguishable ink
`(mm on the transdennal system than originally proposed.
`The Chemistry reviewers find it acceptable for the applicant to complete their qualification and
`stability work for this ink while it is being used on the marketed product. See Dr. Strasinger’s
`review for further details.
`
`Key aspects of the physician labeling include the following. See the review by Dr. Slaughter
`for additional details.
`
`0 Compliance with the Physician’s Labeling Rule (PLR) format
`0 Class labeling for estrogen-related safety concerns
`0
`
`(I!) (4)
`
`0 Clarifying text that Minivelle is bridged to the efficacy and safety data for Vivelle
`based on clinical pharmacology and biopharmaceutics data and that there are no
`additional clinical data with the Minivelle product
`
`The Division of Medical Policy Programs reviewed the patient labeling (Patient information
`and Instructions for Use) and provided revisions to improve readability. See the review by
`LaShawn Griffiths and Melissa Hulett for details.
`
`DMEPA reviewed the carton and container labeling and provided several revisions to improve
`readability and reduce the likelihood of medication error. See the review by Walter Fava for
`further details.
`
`The Office of Prescription Drug Promotion (OPDP) has reviewed all labeling. Several
`revisions were made to text that appeared inappropriately promotional. See the review by Dr.
`Melinda McLawhom for details.
`
`The Study Endpoints and Labeling Development (SEALD) group conducted a Selected
`Requirements of Prescribing Information (SRPI) review and identified several formatting
`deficiencies. We have incorporated all of their recommendations into the final package insert
`except for the following:
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`Page 6 of 7
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`Division Director Review
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`0
`
`0
`
`SEALD requested that we reduce the length of the Boxed Warning in Highlights from
`22 lines to 20 lines. However, the current text is identical to class labeling that exists in
`approved PLR labels for other hormonal therapies and this text has previously been
`found to be acceptable by SEALD. On further discussion, SEALD accepted this
`rationale and agreed to this exception.
`
`SEALD recommended that we remove the term “Vivelle” from the package insert and
`instead use text such as “another approved transdennal estradiol product”. However, by
`using the term “Vivelle” it is clear to the reader that the comparator data are derived
`fiom Vivelle and not from Vivelle-Dot, which is another approved transdermal
`estradiol product. SEALD deferred the final decision on this issue to the Division.
`Based on the rationale above, we will maintain the term “Vivelle” in the package
`insert.
`
`In summary, all labeling issues have been satisfactorily addressed.
`
`13.
`
`Decision/Actioanisk Benefit Assessment
`
`0 Regulatory Action
`
`Approval.
`
`0 Risk Benefit Assessment
`
`Phase 3 clinical trials have previously established the efficacy and safety of the 0.03 75
`mg/day, 0.05 mg/day, 0.075 mg/day and 0.1 mg/day doses of Vivelle for the treatment
`of moderate to severe vasomotor symptoms due to the menopause. In the current NDA,
`the applicant has successfully bridged Minivelle to the clinical efficacy and safety data
`of Vivelle via clinical pharmacology and biopharmaceutics data. No new safety
`concerns were identified with Minivelle based on the clinical data derived from the
`clinical pharmacology studies.
`W"
`
`0 Recommendation for Postmarketing Risk Evaluation and Iintigation Strategies
`
`None.
`
`0 Recommendation for other Postmarketing Requirements and Commitments
`
`None. The initial biopharmaceutics review requested that several postmarketing
`commitments be established. However, formalized postmarketing commitments were
`no longer requested afler fmther discussions were held between the biophannaceutics
`reviewers and the applicant. See the reviews by Dr. Tapash Ghosh.
`
`Page 7 of 7
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`Reference ID: 3209776
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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/
`----------------------------------------------------
`
`HYLTON V JOFFE
`10/29/2012
`
`Reference ID: 3209776
`
`