CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203752Orig1s000
`
`
`MEDICAL REVIEW(S)
`
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`

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`CLINICAL REVIEW
`
`Application Type NDA
`Application Number 203752
`Priority or Standard Standard
`
`Submit Date December 29, 2012
`Received Date December 29, 2012
`PDUFA Goal Date October 29, 2012
`Division/Office Division of Reproductive and
`Urologic Products
`(DRUP)/Office of Drug
`Evaluation III (0DE III)
`
`Reviewer Name Phill H. Price, M.D.
`Review Completion Date September 24, 2012
`
`Established Name Estradiol transdermal system
`(Proposed) Trade Name Minivelle
`Therapeutic Class Estrogen
`Applicant Noven Pharmaceuticals, Inc.
`
`Formulation Transdermal Patch
`Dosing Regimen 0.0375 mg per day twice
`weekly initially allowing for
`titration upward (0.05 mg,
`0.075 mg, and 0.1 mg of
`estradiol per day if necessary
`depending upon relief of
`
`Reference ID: 3199711
`
`

`

`symptoms
`Indication Treatment of Moderate to
`Severe Vasomotor symptoms
`due to menopause
`Intended Population(s) Healthy Postmenopausal
`Women
`
`
`
`Template Version: March 6, 2009
`
`Reference ID: 3199711
`
`

`

`Clinical Review
`Phill H. Price, M.D.
`NDA 203752
`Minivelle (estradiol transdermal delivery system)
`
`
`2
`
`Table of Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 7
`1.1 Recommendation on Regulatory Action ............................................................. 7
`1.2 Risk Benefit Assessment.................................................................................... 7
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 7
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 7
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 7
`2.1 Product Information ............................................................................................ 8
`2.2 Tables of Currently Available Treatments for Proposed Indications ................... 9
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 11
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 11
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 11
`2.6 Other Relevant Background Information .......................................................... 12
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 12
`3.1 Submission Quality and Integrity ...................................................................... 12
`3.2 Compliance with Good Clinical Practices ......................................................... 13
`3.3 Financial Disclosures........................................................................................ 13
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 13
`4.1 Chemistry Manufacturing and Controls ............................................................ 13
`4.2 Clinical Microbiology......................................................................................... 13
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 14
`4.4 Clinical Pharmacology...................................................................................... 14
`4.4.1 Mechanism of Action.................................................................................. 14
`4.4.2 Pharmacodynamics.................................................................................... 14
`4.4.3 Pharmacokinetics....................................................................................... 14
`PATCH ADHESION...................................................................................................... 36
`SKIN IRRITATION EVALUATION................................................................................ 36
`5.1 Tables of Studies/Clinical Trials ....................................................................... 45
`5.2 Review Strategy ............................................................................................... 47
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 47
`6 REVIEW OF EFFICACY (THIS SECTION WILL PRESENT A HISTORICAL
`SUMMARY OF PREVIOUSLY REVIEWED DATA) ............................................... 47
`Efficacy Summary...................................................................................................... 47
`6.1
`Indication .......................................................................................................... 48
`6.1.1 Methods ..................................................................................................... 48
`6.1.2 Demographics............................................................................................ 48
`6.1.3 Subject Disposition..................................................................................... 48
`
`Reference ID: 3199711
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`3
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`

`

`Clinical Review
`Phill H. Price, M.D.
`NDA 203752
`Minivelle (estradiol transdermal delivery system)
`
`
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 50
`6.1.5 Analysis of Secondary Endpoints(s) .......................................................... 50
`6.1.6 Other Endpoints ......................................................................................... 56
`6.1.7 Subpopulations .......................................................................................... 56
`7 REVIEW OF SAFETY (THIS SECTION WILL PRESENT A HISTORICAL
`SUMMARY OF PREVIOUSLY REVIEWED DATA) ............................................... 57
`Safety Summary ........................................................................................................ 57
`Safety data from Studies 1003A and study 1003B and Protocol 036 will be
`summarized separately. ................................................................................... 57
`7.1 Methods............................................................................................................ 59
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 59
`7.1.2 Categorization of Adverse Events.............................................................. 59
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 59
`7.2 Adequacy of Safety Assessments .................................................................... 59
`7.3 Major Safety Results ........................................................................................ 59
`8 POSTMARKET EXPERIENCE............................................................................... 59
`8.1 Literature Review/References .......................................................................... 59
`8.2 Labeling Recommendations ............................................................................. 59
`8.3 Advisory Committee Meeting............................................................................ 60
`9 APPENDICES ........................................................................................................ 61
`
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`Reference ID: 3199711
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`4
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`

`

`Clinical Review
`Phill H. Price, M.D.
`NDA 203752
`Minivelle (estradiol transdermal delivery system)
`
`
`Table of Tables
`
`Table 1: Estrogen-Alone Products Approved for the Treatment of Moderate to Severe
`Vasomotor Symptoms due to Menopause ...................................................................... 9
`Table 2: System Adhesion Scale .................................................................................. 22
`Table 3: Dermal Reactions............................................................................................ 23
`Table 4: Demographic and Baseline Characteristics..................................................... 28
`Table 5: Mean (CV) Serum PK Parameters for Baseline-Uncorrected Estradiol........... 30
`Table 6: Mean (CV) Serum PK Parameters of Baseline-Corrected Estradiol................ 31
`Table 7: Mean (CV) Serum PK Parameters of Total Estrone ........................................ 32
`Table 8: Statistical Analyses of Uncorrected and Corrected Estradiol PK Parameters . 33
`Table 9: Adverse Events for the Two Treatment Groups .............................................. 34
`Table 10: Summary of Possibly Treatment-Related TEAE, Safety Population.............. 35
`Table 11: Mean (CV%) Serum PK Parameters for Baseline-Uncorrected Estradiol...... 41
`Table 12: Mean (CV%) Serum PK Parameters for Baseline-Corrected Estradiol ......... 41
`Table 13: Mean (CV%) serum PK Parameters for Total Estrone .................................. 42
`Table 14: Mixed Effects Power Models for Cmax, AUCinf, AUClast, and AUC0-84 of
`corrected estradiol used to assess pharmacokinetic dose proportionality..................... 42
`Table 15: Summary of Adverse Events Study N28-005 ................................................ 44
`Table 16: Listing of Clinical Studies .............................................................................. 45
`Table 17: Subject Disposition for Study 1003A ............................................................. 48
`Table 18: Primary Efficacy Analysis Study 1003A......................................................... 50
`Table 19: Mean reduction in the severity of hot flushes/flashes: ................................... 51
`Table 20: the Mean Reduction in Number of Hot Flashes—Study 1003B..................... 52
`Table 21: Distribution of subjects by treatment group (all randomized subjects)........... 54
`Table 22: Change from Baseline in the Mean Number of Hot Flushes for per 24 hours in
`the Last Two Weeks of Cycle 1 (ITT) population........................................................... 55
`Table 23: Change from baseline in the mean number of hot flushes for per 24 hours for
`Cycles 2 and 3 .............................................................................................................. 55
`Table 24: Change from Baseline in Mean Severity of Hot Flushes in Cycles 2 and 3 (ITT
`subjects)........................................................................................................................ 56
`Table 25: Schedule of Activities and Assessments ....................................................... 61
`Table 26: Schedule of Activities and Assessments (Study N28-005)............................ 63
`
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`Reference ID: 3199711
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`

`

`Clinical Review
`Phill H. Price, M.D.
`NDA 203752
`Minivelle (estradiol transdermal delivery system)
`
`
`Table of Figures
`
`Figure 1: Average Baseline Uncorrected Estradiol Concentration-Time Profiles following
`treatment A (Test: Minivelle) and Treatment B (Reference: Vivelle) ............................. 30
`Figure 2: Average Baseline-corrected Estradiol concentration-Time Profiles following
`Treatment A (Test: Minivelle) and Treatment B (Reference: Vivelle) ............................ 31
`
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`Reference ID: 3199711
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`6
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`

`

`Clinical Review
`Phill H. Price, M.D.
`NDA 203752
`Minivelle (estradiol transdermal delivery system)
`
`
`1 Recommendations/Risk Benefit Assessment
`
`Approval of NDA 202752 is recommended. The sponsor has demonstrated
`bioequivalence to Vivelle (transdermal delivery system). Since its approval in 1994
`Vivelle has been shown to be safe and efficacious.
`
`1.1 Recommendation on Regulatory Action
`
`Approval of NDA 202752 is recommended.
`
`1.2 Risk Benefit Assessment
`Since the initial approval of Vivelle® in 1994 and Vivelle-Dot® in 1996 these products
`have had a positive risk-benefit ratio. NDA 202752 is the same product as Vivelle and
`Vivelle-Dot, but is designed to deliver the same amounts of estradiol in a smaller
`transdermal delivery system with similar risk and benefits based upon the pivotal
`bioequivalence Study N28004.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`There is no need for a Risk Evaluation and Mitigation strategy.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`No additional postmarketing action is recommended.
`
`2 Introduction and Regulatory Background
`
`Vivelle (NDA 20-323) was initially approved October 28, 1994. Vivelle has not been
`commercially available since 2006. The doses initially sought for approval were
`0.0375mg, 0.05 mg, 0.075mg, and 0.1mg of estradiol per day. In the initial review cycle
`the 0.075mg and 0.1mg per day doses were shown to demonstrate efficacy at weeks 4
`through week 12. The 0.050mg/day dosage did not demonstrate efficacy at weeks 4
`through 12. The efficacy of the 0.050mg/day dose was accepted based on
`bioequivalence to another estradiol transdermal system. The Vivelle 0.0375mg/day did
`not demonstrate efficacy until the sixth week of treatment. Therefore, the 0.0375mg/day
`dose was approved in October 1994 with restrictive language stating that “women
`taking the 0.035mg/day dosage may experience a delay in the onset of efficacy.” The
`sponsor agreed to 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). A phase 4
`study was conducted under Supplement 021. Supplement 021 addressed the
`sponsor’s original Phase 4 commitment dated March 24, 1994. The study presented in
`
`Reference ID: 3199711
`
`7
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`

`

`Clinical Review
`
`Phill H. Price, M.D.
`NDA 203752
`
`Minivelle (estradiol transdermal delivery system)
`
`Supplement 021 was a randomized, double-blind placebo-controlled trial to evaluate the
`efficacy and safety of the 0.0375mg/day dose of Vivelle; approximately 259 subjects
`were enrolled. The sample size was sufficient to detect a mean difference of 2.0 per
`day in the reduction of total number of hot flushes for Vivelle vs. placebo.
`In cycle 1 the
`mean difference was -3.0 (ITT) and this was maintained through cycles 2 and 3 (-3.21,-
`3.59, p-value <0.001). Severity was also statistically significant different in cycles 2 and
`3. This supplement provided evidence that the lowest dose of Vivelle 0.0375 mg per
`day was statistically significant different from placebo at the end of weeks 4, 8 and 12 in
`the treatment of moderate to severe vasomotor symptoms.
`
`Vivelle-Dot (NDA 20—538) was approved on July 31, 1996 after demonstrating
`bioequivalence to Vivelle. The same restrictive language for the 0.0375mg/day dose
`applied to Vivelle-Dot. This restrictive language was removed after completion of the
`Phase 4 commitment (Supplement 021) on February 25, 2000. Supplement 021
`demonstrated that Vivelle 0.0375 was statistically significant different from placebo at
`the end of weeks 4, 8 and 12.
`In addition, under SO15 Vivelle-Dot was approved for the
`prevention of osteoporosis in 2002.
`
`2.1 Product Information
`
`Noven Pharmaceuticals, Inc is developing Minivelle, a smaller estradiol transdermal
`system (ETS) compared to the marketed Vivelle-Dot (approximately 60% of the size of
`Vivelle-Dot. Minivelle has the same multipolymeric adhesive platform as Vivelle-Dot
`and it releases 17B—estradiol continuously upon application to intact skin, and has a
`target absorption profile similar to that of Vivelle-Dot. Vivelle-Dot is manufactured by
`Noven and marketed by Novartis Pharmaceutical Corporation in five different estradiol
`strengths (0.025 mg/day to 0.1 mg/day) with corresponding active surface areas (2.5
`cm2 to 10 cm2). Minivelle is available in “M" dosage strengths that have been designed
`to deliver the same therapeutic levels of estradiol as Vivelle and Vivelle-Dot, but with a
`smaller active surface area.
`(m4)
`
`17B—estradiol is the primary estrogenic hormone secreted by the human ovary. Loss of
`ovarian estradiol secretion at the onset of menopause or after bilateral oophorectomy is
`associated with vasomotor symptoms (hot flashes and night sweats). Hot flashes are
`recurrent, transient episodes of flushing, perspiration, and a sensation ranging from
`warmth to intense heat on the upper body and face, sometimes followed by chills. Hot
`flashes that occur with perspiration during sleep are termed night sweats. Systemic
`hormone therapy (HT) is considered to be the therapeutic standard for the treatment of
`hot flashes. Treatment of moderate to severe menopause symptoms (including hot
`flashes) is the primary indication for systemic hormone therapy.
`
`Reference ID: 319971 1
`
`

`

`Clinical Review
`Phill H. Price, M.D.
`NDA 203752
`Minivelle (estradiol transdermal delivery system)
`
`
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`Table 1: Estrogen-Alone Products Approved for the Treatment of Moderate to
`Severe Vasomotor Symptoms due to Menopause
`
`Oral Estrogen-Alone Products
` Premarin® (conjugated estrogens) Tablets
`
` Cenestin® (synthetic conjugated estrogens, A)
` Enjuvia® (synthetic conjugated estrogens, B)
`
` Menest® (esterified estrogens)*
` Estrace® (estradiol)
` Femtrace® (estradiol acetate)
` Ogen (estropipate)
`Transdermal Products
` Alora® (estradiol matrix patch)
`
` Climara® (estradiol matrix patch)
`
` Esclim® (estradiol matrix patch)
`
` Menostar® (estradiol matrix patch)
` Vivelle® (estradiol matrix patch)
`
` Vivelle Dot® (estradiol matrix patch)
`
` Various Generics (estradiol matrix patch)
`
` Estraderm® (estradiol reservoir patch)
`
`Topical Products
` EstroGel® 0.06% (estradiol gel)
` Elestrin® (estradiol gel)
`
` Divigel (estradiol gel) 0.1%
`
` Estrasorb® (estradiol topical emulsion)
`
` Evamist® (estradiol transdermal spray)
`
`Vaginal Cream
` Premarin® (conjugated estrogens) Vaginal
` Cream
` Estrace (estradiol) Vaginal Cream
`
`Vaginal Rings
`
`Available Dosage Strengths
`0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, or 1.25 mg
`once daily
`0.625 mg, 0.9 mg, or 1.25 mg once daily
`0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, or 1.25 mg
`once daily
`0.3 mg, 0.625 mg, 1.25 mg, or 2.5 mg once daily
`0.5 mg, 1.0 mg, or 2.0 mg once daily
`0.45 mg, 0.9 mg, or 1.8 mg once daily
`0.625 mg, 1.25 mg, or 2.5 mg once daily
`Available Dosage Strengths
`0.025 mg/day, 0.05 mg/day, 0.075 mg/day, or 0.1
`mg/day; patch applied twice weekly
`0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075
`mg/day, or 0.1 mg/day; patch applied once weekly
`0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075
`mg/day, or 0.1 mg/day; patch applied twice weekly
`0.014 mg/day; patch applied once weekly
`0.05 mg/day or 0.1 mg/day; patch applied twice
`weekly
`0.025 mg/day, 0.0375 mg/day, 0.05 mg/day, 0.075
`mg/day, or 0.1 mg/day; patch applied twice weekly
`0.05 mg/day or 0.1 mg/day; patch applied once or
`twice weekly
`0.05 mg/day or 0.1 mg/day; patch applied twice
`weekly
`Available Dosage Strengths
`0.075 mg/day; 1.25 gram gel applied once daily
`0.52 mg/day or 1.04 mg/day; 0.87 gram or 1.7
`gram applied once daily
`0.25 mg/day, 0.5 mg/day, or 1.0 mg/day; 0.25
`gram, 0.5 gram or 1.0 gram applied once daily
`0.05 mg/day; two 1.74 gram pouch applied once
`daily
`1, 2 or 3 spray(s) 90 mcL containing 1.53 mg
`estradiol applied once daily
`Available Dosage Strengths
`0.5 to 2 grams (0.625 mg per gram) inserted
`intravaginal daily
`2 to 4 grams (0.1 mg per gram) inserted
`intravaginal daily for 1 to 2 weeks, then 1 gram
`inserted intravaginal daily thereafter
`Available Dosage Strengths
`
`Reference ID: 3199711
`
`9
`
`

`

`Clinical Review
`Phill H. Price, M.D.
`NDA 203752
`Minivelle (estradiol transdermal delivery system)
`
` Estring® (estradiol)
`
` Femring® (estradiol acetate)
`
`Vaginal Tablet
` Vagifem® (estradiol hemihydrate)
`
`Release of 7.5 mcg estradiol/day; ring is worn for
`90 days
`Release of 0.05 mg estradiol/day or 0.10 mg
`estradiol/day; ring is worn for 90 days
`Available Dosage Strengths
`10 mcg/day or 25 mcg/day; vaginal tablet is
`inserted twice weekly
`
`
`Table 1: Estrogen-Plus Progestin Products Approved for the Treatment of
`Moderate to Severe Vasomotor Symptoms due to Menopause
`
`Oral Estrogen Plus Progestin Products
` Prempro® (conjugated estrogens [CE] plus
` medroxyprogesterone acetate [MPA])
`
` Premphase® (conjugated estrogens [CE] plus
` medroxyprogesterone acetate [MPA])
`
` femhrt® (ethinyl estradiol [EE] plus norethindrone
` acetate [NETA])
`
` Activella® (estradiol [E2] plus norethindrone
` acetate [NETA])
` Angeliq® (estradiol [E2] plus drospirenone)
`
` Prefest® (estradiol [E2] plus norgestimate)
`
`Available Dosage Strengths
`0.3 mg or 0.45 mg CE/day plus 1.5 mg MPA/day
`taken daily or
`0.625 mg CE/day plus 2.5 mg or 5.0 mg MPA/day
`taken daily
`0.625 mg CE/day taken daily for 14 days, then
`0.625 mg CE plus 5.0 mg MPA/day taken daily on
`days 15-18
`2.5 mcg EE/day plus 0.5 mg NETA/day taken daily
`or
`5 mcg EE/day plus 1.0 mg NETA/day taken daily
`0.5 mg E2/day plus 0.1 mg NETA/day taken daily or
`1 mg E2/day plus 0.5 mg NETA/day taken daily
`1 mg E2/day plus 0.5 mg drospirenone/day taken
`daily
`1 mg E2/day taken daily for 3 days, then 1 mg E2
`plus 0.09 mg norgestimate/day taken daily for 3
`days, repeated continuously
`Transdermal Estrogen Plus Progestin Products Available Dosage Strengths
` CombiPatch (estradiol [E2] plus norethindrone
`0.05 mg E2/day plus 0.14 mg NETA/day; patch
` Acetate [NETA])
`applied twice weekly
`0.05 mg E2/day plus 0.25 mg NETA/day; patch
`applied twice weekly
`0.05 mg E2/day plus 0.015 mg levonorgestrel/day;
`patch applied once weekly
`
` ClimaraPro® (estradiol [E2] plus levonorgestrel)
`
`
`Table 1: Progestin Products Used in Combination with Conjugated Estrogens
`Approved for the Treatment of Moderate to Severe Vasomotor Symptoms due to
`Menopause
`
`Oral Progestogen Tablet or Capsule
` Provera® (medroxyprogesterone acetate [MPA])
`
` Various Generics
`
` Prometrium® (progesterone in peanut oil)
`
`
`
`Available Dosage Strengths
`2.5 mg/day, 5 mg/day or 10 mg/day taken once
`daily for 12 days of each 28-day cycle
`2.5 mg/day, 5 mg/day or 10 mg/day taken once
`daily for 12 days of each 28 day cycle
`100 mg/day or 200 mg/day taken daily for 12 to 14
`days of each 28-day cycle
`
`Reference ID: 3199711
`
`10
`
`

`

`Clinical Review
`
`Phill H. Price, M.D.
`NDA 203752
`
`Minivelle (estradiol transdermal delivery system)
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`Minivelle contains estradiol in a multipolymeric adhesive. The system is designed to
`release 17B-estradiol, the active pharmaceutical product (API), continuously upon
`application to intact skin. Estradiol USP (17(3-estradiol) is a white, crystalline powder,
`chemically described as estra- 1, 3, 5 (10)-triene-3, 17(3-diol. The molecular formula of
`estradiol is C18H2402. The molecular weight is 272.38.
`
`Minivelle is comprised of three layers. Proceeding from the visible surface toward the
`surface attached to the skin, these layers are: 1) a flexible backing film; 2) an adhesive
`formulation containing estradiol, acrylic adhesive, silicone adhesive, oleyl alcohol (OA),
`Povidone-
`"m and dipropylene glycol (DPG); 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 17B—estradiol (E2), the drug-in-adhesive matrix contains
`excipients:
`
`(b) (4)
`
`(b)(4)
`
`Based upon previous experience,
`
`“m"
`
`The 16
`
`formulations were studied in a multivariate factorial (4 by 4) skin permeability study
`.
`.
`(b)(4)
`.
`.
`(coat weight,
`Five formulations were selected and further assessed In
`skin permeability studies versus Vivelle-Dot and Vivelle in multiple skin donors. The
`three formulations with the highest average flux, when compared to Vivelle-Dot and
`Vivelle, were selected for further study.
`
`2.4 Important Safety Issues With Consideration to Related Drugs
`
`Large prospective studies such as the Heart and Estrogen-Progestin Replacement
`Study and the Women’s Health Initiative have assessed the risks associated with the
`use of hormone replacement therapy (HRT). Following the publication of the long-term
`effects of hormone therapy (HT) in these large randomized controlled trials specifically
`regarding the increased risk of breast cancer, coronary heart disease, and venous
`thromboembolism, questions remain regarding of long term benefit/risk profile with the
`use of estrogen products.
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`A pre-IND meeting was held between DRUP and the sponsor on September 11, 2007 to
`discuss the developmental plan for Minivelle. Key recommendations by the Division to
`the sponsor are as follows:
`
`Reference ID: 3199711
`
`1 1
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`

`

`Clinical Review
`
`Phill H. Price, MD.
`NDA 203752
`
`Minivelle (estradiol transdermal delivery system)
`
`0 No preclinical studies were necessary if the patch and matrix and the impurities
`and degradation products of Minivelle were qualitatively and quantitatively similar
`to Vivelle and Vivelle-Dot
`
`o A pivotal, single dose, two-way crossover, bioequivalence study comparing the
`highest strength of Vivelle to the highest strength of Minivelle would provide
`support for approval of Minivelle. The Division stated the following with regards
`to the bioequivalence study:
`-
`Vivelle should be used as the reference in the study since the clinical trials
`were conducted with Vivelle and Vivelle 0.1 and 0.05 mglday ETS were still
`commercially available at the time of the pre-IND meeting
`The bioequivalence requirement for lower strengths of Minivelle would be
`waived based on information of dose proportionality, proportionally similar
`composition, and a comparison of the in-vitro dissolution profiles of Minivelle
`and Vivelle
`
`-
`
`-
`
`Bioequivalence should be based on both baseline corrected and
`uncorrected relevant pharmacokinetic parameters
`
`0 A single-dose, crossover study with at least three strengths of Minivelle should
`be conducted to determine the dose proportionality of Minivelle
`- The dermal characteristics (i.e., adhesive properties, skin irritation, and
`discomfort) of Minivelle should be evaluated in the bioequivalence dose/
`proportionality studies.
`
`On March 18, 2011 the Division sent Noven a written response on the design of the
`dose proportionality study and reiterated the need for a dose proportionality study. The
`Division agreed that measurement of estradiol and estrone would be sufficient.
`In
`addition a full 24-hour baseline measurement of estradiol and estrone concentration and
`
`a standardized adhesion scale should be used to assess adhesion of Minivelle. Both
`
`recommendations were incorporated into the final protocol.
`
`2.6 Other Relevant Background Information
`
`All relevant background information as conveyed in the preceding sections.
`
`3 Ethics and Good Clinical Practices.
`
`3.1 Submission Quality and Integrity
`
`At the request of DRUP and the Division of Clinical Pharmacology III, the Division of
`Bioequivalence and GLP Compliance (DBGC) conducted audits of the clinical and
`analytical portion of the bioequivalence Study N28-004. The audits were conducted at
`Elite Research Institute, Inc., Miami and at
`“m"
`during the period of
`“m. The audits included a thorough
`examination of study record, facilities, and equipment, and interviews and discussions
`
`Reference ID: 3199711
`
`12
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`

`

`Clinical Review
`Phill H. Price, M.D.
`NDA 203752
`Minivelle (estradiol transdermal delivery system)
`
`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.
`
`3.2 Compliance with Good Clinical Practices
`
`This study was conducted in compliance with Good Clinical Practices (GCPs) and ICH
`Guidelines of GCP and was conducted in full compliance with the principles of the
`World Medical Assembly Declaration of Helsinki and its most recent amendments.
`This study received IRB approval prior to commencement. Written informed consent
`for the study was obtained from all subjects before any study-related procedures were
`performed.
`
`
`
`3.3 Financial Disclosures
`
`Form FD 3454, dated December 23, 2011 was signed by Sean Russell, the Associate
`Director, Regulatory Affairs for Noven. Per the applicant, each listed clinical investigator
`disclosed no “proprietary interest in this product or a significant equity in the sponsor” as
`defined in 21 CFR 542(b).
`
`4 Significant Efficacy/Safety Issues Related to Other Review Disciplines
`
`Since the approval of Vivelle and Vivelle-Dot a Black Box Warning has been required
`for all estrogen and estrogen/progestin drug products. Updated information in this Black
`Box Warning relates to information obtained in the Women’s Health Initiative (WHI) and
`the Women’s Health Initiative Memory Study (WHIMS). In addition, the Black Box
`Warning retains information regarding the increased risk of endometrial cancer.
`
`4.1 Chemistry Manufacturing and Controls
`
`The Chemistry and Manufacturing reviews recommended approval of this NDA. During
`the review cycle several clarifications were required to qualify a more distinguishable ink
`to Minivelle. The sponsor will launch their commercial product utilizing
` ink
`and continue to utilize
` ink while completing their qualification and stability
`work of a more distinguishable ink for Minivelle.
`
`4.2 Clinical Microbiology
`
`Microbiology was not consulted for this application.
`
`
`Reference ID: 3199711
`
`13
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`Phill H. Price, M.D.
`NDA 203752
`Minivelle (estradiol transdermal delivery system)
`
`4.3 Preclinical Pharmacology/Toxicology
`
`There are no preclinical/toxicology issues related to this NDA.
`
`4.4 Clinical Pharmacology
`
`4.4.1 Mechanism of Action
`
`Endogenous estrogens are largely responsible for the development and maintenance of
`the female reproductive system and secondary sexual characteristics. Although
`circulating estrogens exist in a dynamic equilibrium of metabolic interconversions,
`estradiol is the principal intracellular human estrogen and is substantially more potent
`than its metabolites estrone and estriol at the receptor level.
`The primary source of estrogen in normally cycling adult women is the ovarian follicle,
`which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the
`menstrual cycle. After menopause, most endogenous estrogen is produced by
`conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral
`tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most
`abundant circulating estrogens in postmenopausal women. The pharmacologic effects
`of ethinyl estradiol are similar to those of endogenous estrogens.
`
`Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To
`date, two estrogen receptors have been identified. These vary in proportion from tissue
`to tissue.
`
`Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing
`hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback
`mechanism. Estrogens act to reduce the elevated levels of these hormones seen in
`postmenopausal women.
`
`4.4.2 Pharmacodynamics
`
`There were no Pharmacodynamic studies conducted with this submission.
`
`4.4.3 Pharmacokinetics
`
` (Minivelle) to Vivelle
`The primary study to support the bioequivalence of
`0.1mg was study protocol N28-004. Subjects were enrolled from February 2, 2011 (first
`subject enrolled) to May 5, 2011 (last subject enrolled). This was a Phase 1, open-
`label, single-center, randomized, single-dose, two-way crossover study in 100 healthy,
`non-smoking postmenopausal women (aged 40 to 65 years, inclusive). Subjects were
`
`Reference ID: 3199711
`
`14
`
`(b) (4)
`
`

`

`Clinical Review
`Phill H. Price, M.D.
`NDA 203752
`Minivelle (estradiol transdermal delivery system)
`
`housed during each treatment period from approximately 36 hours prior to dosing
`through the 120-hour post-dose assessment.
`
`Each subject received a single dose of each of the two treatments. Each transdermal
`system was worn for 84 hours. There was a minimum washout period of at least 14
`days between the 120-hour assessments of treatment one and the administration of the
`second treatment. Eligible subjects reported to the clinic on Day -1 and Day 21 in the
`evening at approximately 1900 hours and subjects were housed during each treatment
`period.
`
`The two treatments included in this study were:
`
`
`• Treatment A (test): one
` ETS patch (1.65 mg/6.6 cm2) applied for 84
`hours. The application was applied to the abdomen below the umbilicus to a
`clean d