♦
`
`SUMMARY OF SAFETY AND EFFECTIVENESS DATA
`
`I.
`
`GENERAL INFORMATION
`
`Device Generic Name:
`
`Injectable Dermal Filler
`
`Device Trade Name:
`
`JUVEDERM™
`
`Applicant's Name and Address:
`
`!named Corporation
`5540 Ekwill Street
`Santa Barbara, California 93 I 11
`
`Date(s) of Panel Recommendation: None
`
`Premarket Approval Application (PMA) Number: P050047
`
`Date ofNotice of Approval to Applicant: June 2, 2006
`
`11.
`
`INDICATIONS FOR USE
`
`JUVEDERM 30, JUVEDERM 24HV and JUVEDERM 30HV are injectable gels
`indicated for injection into the mid to deep dermis for correction of moderate to severe
`facial wrinkles and folds (such as nasolabial folds).
`
`III.
`
`CONTRAINDICATIONS
`
`JUVEDERM is contraindicated for patients with severe allergies manifested by a history
`of anaphylaxis or history or presence of multiple severe allergies.
`
`JUVEDERM contains trace amounts of gram positive bacterial proteins and is
`contraindicated for patients with a history of allergies to such material.
`
`IV. WARNINGS AND PRECAUTIONS
`
`The warnings and precautions can be found in the JUVEDERM labeling.
`
`V.
`
`DEVICE DESCRIPTION
`
`JUVEDERM injectable gel is a sterile, biodegradable, non-pyrogenic, viscoelastic, clear,
`colorless, homogenized gel implant. JUVEDERM consists of crosslinked hyaluronic acid
`(HA) formulated to a concentration of 22-26 mg/mL. suspended in a physiological buffer.
`HA is a naturally occurring polysaccharide of the extracellular matrix in human tissues.
`including skin. The HA in JUV1°DERf\1 is produced by Streptococcus equi bacteria.
`
`The HA used in JUVEDERM has a molecular weight of approximately 2.5 million
`Daltons and is crosslinkcd by adding a minimum amount of BDDE ( 1.4-butanecliol
`
`Page 1
`
`Exhibit 1074
`Prollenium v. Allergan
`
`

`

`!
`
`diglycidyl ether) to form a 3-dimensional HA gel. The chemical stabilizing (crosslinking)
`process does not change the polyanionic character of the polysaccharide chain.
`
`JUVEDERM is available in three formulations (30, 24HV and 30HV) and is supplied in
`pre-filled disposable syringes. Juvederm 30 HV is a more highly crosslinked robust
`formulation, injected using a 27G needle for volumizing and correction of deeper folds
`and wrinkles. Juvederm 24HV is a highly crosslinked formulation that can be injected
`using a 30 G needle for more versatility in contouring and volumizing of facial wrinkles
`and folds. Juvederm 30 is a highly crosslinked formulation, injected using a 27G needle,
`for subtle correction of facial wrinkles and folds. Each syringe contains 0.8 mL of
`JUVEDERM gel implant. The syringe is equipped with a Luer lock adaptor, a plunger rod
`with a latex free stopper, a tip cap and a backstop. Each syringe bears a label with the
`name of the product, lot number, expiration date, volume, and sterility information. Each
`Juvederm filled syringe is packaged in a protective pouch and then placed into a
`cardboard labeled box along with sterile disposable standard 27G and/or 30G sterile
`needles, Directions for Use, and product labels.
`
`VI.
`
`ALTERNATIVE PRACTICES OR PROCEDURES
`
`Treatment of photo-damaged skin, with its associated wrinkling and changes in texture
`and pigmentation, is often accomplished by use of topical creams (e.g. retinoids),
`chemical peeling procedures or laser rcsurl'acing. Deeper wrinkles, folds, scars, and other
`depressed lesions are often treated with surgery (e.g. rhytidectomy), Botox® Cosmetic
`injections, or by implantation of dermal filler substances (e.g. injection of collagen, other
`hyaluronic acid gels, or autologous fat). In these cases, correction of the depression is the
`goal of therapy.
`
`VII. MARKETING HISTORY
`
`Upon CE marking in 2000, Corneal first introduced a family of non-animal hyaluronate
`gel implants in Europe under the trade names of JUVEDERM ® and Hydrafill®. The
`JUVEDERM family ofproduets was later introduced in Canada in 2002.
`
`In 2004, Corneal and !named formed a partnership for the clinical development and
`commercial distribution of JUVEDERM hyaluronate gel implants in Canada, Australia
`and the United States and in Europe under the trade name Hydrafill.
`
`The device has not been withdra,,n J'rum marketing in any country for any reason related
`to the safety or effectiveness of the dc,·icc.
`
`VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH
`
`In a U.S. Investigational Device [~emptions (IDE) study 439 subjects at 11 centers were
`randomized to one of three cohorts (.IUVl~DERM 30. JUVEDER'vl 24HV or
`JUVEDERM 30HV) and received .ll1V(:DERM injections in one side of the face
`(nasolabial fold [NLF]) and injections ut' an injectable bovine collagen (Control) in the
`
`Page 2
`
`

`

`other side of the face. Subjects recorded their observations of treatment responses for
`each side of the face in pre-printed diaries during the first 14 days following each
`treatment. The diaries included check boxes for commonly expected treatment responses,
`e.g. redness, swelling, pain, bruising, and itching, at the injection/application sites. A
`diary was completed for each initial and subsequent "touch up" treatment. It should be
`noted that the study subjects were required to record the presence and level of severity for
`each observed treatment response as "Mild," "Moderate," "Severe," or "None." A
`summary of the maximum severity and duration of the subject observations is presented
`in Tables I through 6 on the following pages.
`
`Injection site responses reported by greater than 1 % but less than 5% of subjects and not noted in
`the following tables were skin peeling and wrinkling in the JUVEDERM 30 cohort; skin peeling
`and dryness in the JUVEDERM 24HV cohort; and skin peeling and tingling in the JUVEDERM
`30HV cohort.
`
`Table 1 - JUVEDERM 30 vs. Control
`Injection Site Responses by Maximum Severity
`Occurring in >5% of Treated Subjects
`(Number/% of Subject NLFs)
`
`TOTALS
`
`JUVEDERM30
`(N.=149 NLFS)
`
`Control"'*
`(N.=149 NLFs)
`
`Severe Mild Modt
`ni %
`n+%
`nt %
`60
`8
`63
`5%
`40%
`42%
`17
`63
`54
`11%
`42%
`36%
`9
`81
`43
`6%
`54%
`29%
`91
`10
`33
`7%
`61%
`22%
`9
`64
`50
`6%
`43%
`34%
`51
`15
`25
`10%
`34%
`17%
`3
`37
`5
`2%
`25%
`3%
`1
`38
`11
`1%
`26%
`7%
`
`Severe
`n+ %
`9
`6%
`15
`10%
`4
`3%
`4
`3%
`8
`5%
`,.,
`..1
`2%
`1
`1%
`,.,
`..1
`2%
`
`Injection Site
`Responses
`
`Firmness
`
`Redness
`
`Swelling
`
`Pain/Tenderness
`
`Lumps/Bumps
`
`Bruising
`
`Discoloration
`
`Itching
`
`JUVEDERM
`Control** Mild Mod+
`30
`n+ (1/o
`n:%
`11! (¼J
`nt¾
`132
`62
`66
`136
`42%
`44%
`91%
`89%
`132
`73
`44
`134
`49%
`30%
`89%
`90%
`128
`65
`58
`132
`86%
`44%
`39%
`89%
`74
`128
`45
`129
`86%
`50%
`30%
`87%
`122
`65
`123
`49
`82%
`44%
`33%
`83%
`79
`27
`91
`49
`53%
`33%
`18%
`61%
`:;c,
`7
`46
`43
`24'½,
`29%
`5%
`31%
`31
`10
`52
`42
`7%
`35%
`28%
`21%
`.
`Number ofsubJect NLFs treated with the respective ,kv1ce
`**A commercially available injectable bovine' c,,llagcn
`t Mod-, .• Moderate
`:Number of subject NLFs with each specific injcclion sik response
`
`Page 3
`
`

`

`Table 2 - JUVEDERM 24HV vs. Control
`Injection Site Responses by Maximum Severity
`Occurring in >5% of Treated Subjects
`(Number/% of Subject NLFs)
`
`TOTALS
`
`.ruVEDERM 24HV
`(N.=146 NLFS)
`
`Control"'*
`(N•=146 NLFs)
`
`Injection Site
`Responses
`
`Redness
`
`Painff enderness
`
`Firmness
`
`Swelling
`
`Lumps/Bumps
`
`Bruising
`
`Itching
`
`Discoloration
`
`JUVEDERM
`24HV
`nt %
`136
`93%
`131
`90%
`129
`88%
`125
`86%
`115
`79%
`86
`59%
`52
`36%
`48
`33%
`
`Control** Mild Modt
`nt %
`n+ %
`n! '1/o
`48
`130
`72
`49%
`33%
`89%
`74
`45
`128
`51%
`88%
`31%
`127
`66
`53
`87%
`45%
`36%
`60
`122
`54
`84%
`41%
`37%
`61
`122
`45
`84%
`42%
`31%
`43
`29
`80
`29'%
`20%
`55%
`53
`5
`42
`36%
`3%
`29'%
`JI
`49
`11
`go' 1/o
`34'%
`21%
`
`Severe Mild Modt
`n+ %
`nt %
`nt %
`16
`69
`45
`11%
`47%
`31%
`12
`87
`34
`8%
`60%
`23%
`60
`lO
`56
`7%
`41%
`38%
`11
`77
`37
`8%
`53%
`25%
`9
`66
`42
`6%
`45%
`29%
`14
`47
`27
`10%
`32%
`18%
`43
`5
`7
`3%
`29%
`5%
`6
`31
`15
`4%
`21%
`10%
`
`Severe
`nt %
`16
`11%
`7
`5%
`l l
`8%
`8
`5%
`14
`10%
`6
`4%
`3
`2%
`3
`2%
`
`. Number ofsubJect NLFs treated with the n.:opect1vc device
`
`**A commercially available injectable bovin~ colbgtcn
`t Mod= Moderate
`tNumber of subject NLFs with each specific injection site response
`
`\\
`
`Page 4
`
`

`

`f
`
`Table 3 - JUVEDERM 30HV vs. Control
`Injection Site Responses by Maximum Severity
`Occurring in >5% of Treated Subjects
`(Number/% of Subject NLFs)
`
`TOTALS
`
`JUVEDERM 30HV
`(N.=144 NLFS)
`
`Control**
`(N.=144 NLFs)
`
`Severe Mild Modt
`n! %
`nl%
`n!%
`7
`71
`42
`5%
`49%
`29%
`15
`86
`32
`10%
`60%
`22%
`15
`62
`51
`l0%
`43%
`35%
`13
`71
`41
`9%
`49%
`28%
`10
`40
`66
`7%
`46%
`28%
`7
`38
`25
`5%
`26%
`17%
`2
`39
`9
`1%
`27%
`6%
`9
`5
`31
`3%
`22%
`6%
`
`Severe
`nt %
`15
`10%
`5
`3%
`9
`6%
`9
`6%
`7
`5%
`6
`4%
`3
`2%
`3
`2%
`
`Injection Site
`Responses
`
`Redness
`
`Pain/f enderness
`
`Finnness
`
`Swelling
`
`Lumps/Bumps
`
`Bruising
`
`Itching
`
`JUVEDERM
`Control** Mild Modt
`30HV
`n! %
`nt%
`n!%
`nt '1/o
`128
`61
`61
`129
`42%
`89%
`42%
`90%
`68
`123
`46
`129
`85%
`47%
`90%
`32%
`122
`59
`127
`53
`41%
`85%
`37%
`88%
`61
`121
`50
`124
`42%
`84%
`35%
`86%
`57
`113
`53
`120
`40%
`78%
`37%
`83%
`47
`69
`33
`87
`33%
`48%
`23%
`60%
`9
`38
`51
`49
`26%
`35%
`6%
`34%
`4--_)
`Discoloration
`15
`29
`49
`30%
`20%
`10%
`34%
`. Number ofsubJect NLFs treated with the rcspeCllvc device
`** A commercially available injectable bovin~ col la gen
`t Mod = Moderate
`!Number of subject NLFs with each specific injection site response
`
`5
`
`,,.
`
`\'L
`
`Page 5
`
`

`

`t
`
`Table 4 - JUVEDERM 30 vs. Control
`Duration of Injection Site Responses
`Occurring in > 5% of Treated Subjects
`(Number/% of Subject NLFs)
`
`Injection Site
`Response
`
`Duration4
`
`Firmness
`
`Redness
`
`Swelling
`
`Pain/Tenderness
`
`Lumps/Bumps
`
`Bruising
`
`Discoloration
`
`Itching
`
`~3
`Days
`40
`27%
`68
`46%
`48
`32%
`73
`49%
`38
`26%
`
`30
`20%
`31
`21%
`23
`15%
`
`.nJVEDERM 30
`(N.=149 NLFs)
`nt¾
`8-14
`Days
`21
`14%
`14
`9%
`28
`19%
`15
`10%
`21
`14%
`24
`16%
`
`4-7
`Days
`26
`17%
`40
`27%
`44
`30%
`36
`24%
`27
`18%
`34
`23%
`8
`5%
`14
`9%
`
`4
`3%
`_,
`'
`2%
`
`>14
`Days
`49
`33%
`12
`8%
`12
`8%
`5
`3%
`37
`25%
`
`3
`2%
`3
`2%
`
`2
`1%
`
`~3
`Days
`34
`23%
`51
`34%
`
`63
`42%
`60
`40%
`16
`11%
`41
`28%
`26
`17%
`24
`16%
`
`Control**
`(N• =149 NLFs)
`flt Ofo
`8-14
`Days
`14
`9%
`14
`9%
`14
`9%
`21
`14%
`21
`14%
`
`4-7
`Days
`28
`19%
`37
`25%
`43
`29%
`39
`26%
`21
`14%
`30
`20%
`11
`7%
`12
`8%
`
`7
`5%
`3
`2%
`9
`6%
`
`>14
`Days
`56
`38%
`
`30
`20%
`8
`5%
`8
`5%
`64
`43%
`
`1
`1%
`3
`2%
`7
`5%
`
`*Number of subject NLFs treated with the respect ivc device
`** A commercially available injectable bovine collagen
`tNumber of subject NLFs with each specific injection site response by maximum duration
`louration refers to number of days from symptom onset until resolution, irrespective of date of
`implantation.
`
`' 'f
`
`Page 6
`
`

`

`T
`
`Table 5 - JUVEDERM 24HV vs. Control
`Duration of Injection Site Responses
`Occurring in > 5% of Treated Subjects
`(Number/% of Subject NLFs)
`
`Injection Site
`Response
`
`Durationt
`
`Redness
`
`Pain/Tenderness
`
`Firmness
`
`Swelling
`
`Lumps/Bumps
`
`Bruising
`
`Itching
`
`Discoloration
`
`JUVEDERM 24HV
`(N.=146 NLFs)
`nt °/4,
`8-14
`Days
`8
`5%
`
`4-7
`Days
`50
`34%
`
`46
`32%
`
`34
`23%
`
`48
`33%
`
`32
`22%
`
`28
`19%
`
`15
`10%
`
`12
`8%
`
`18
`12%
`
`20
`14%
`
`2'.!
`15%
`
`18
`12%
`
`24
`16'½,
`
`7
`5%
`
`q
`3%
`
`>14
`Days
`18
`12%
`
`6
`4%
`
`46
`32%
`
`17
`12%
`
`39
`27%
`
`5
`3%
`
`5
`3%
`
`10
`7%
`
`:9
`Days
`60
`41%
`
`61
`42%
`
`29
`20%
`
`38
`26%
`
`26
`18%
`
`29
`20%
`
`25
`17%
`
`22
`15%
`
`Control**
`(N.=146 NLFs)
`nt %
`8-14
`Days
`10
`7%
`
`4-7
`Days
`46
`32%
`
`53
`36%
`
`28
`19%
`
`38
`26%
`
`18
`12%
`
`27
`18%
`
`17
`12%
`
`9
`6%
`
`14
`10%
`
`20
`14%
`
`20
`14%
`
`19
`13%
`
`10
`7%
`
`4
`3%
`., ..,
`2%
`
`~3
`Days
`46
`32%
`
`49
`34%
`
`25
`17%
`
`54
`37%
`
`16
`11%
`
`35
`24%
`
`21
`14%
`
`26
`18%
`
`>14
`Days
`28
`19%
`
`12
`8%
`
`54
`37%
`
`10
`7%
`
`69
`47%
`
`8
`5%
`
`11
`8%
`
`11
`8%
`
`*Number of subject NLFs treated with the respective device
`**A commercially available injectable bovine collagen
`tNumber of subject N-LFs with each specific injection site response by maximum duration
`touration refers to number of days from symptom onset until resolution, irrespective of date of
`implantation.
`
`7
`
`Page 7
`
`

`

`t
`
`Table 6 - JUVEDERM 30HV vs. Control
`Duration of Injection Site Responses
`Occurring in > 5% of Treated Subjects
`(Number/% of Subject NLFs)
`
`Injection Site
`Response
`
`Duration:
`
`Redness
`
`Pain/Tenderness
`
`Firmness
`
`Swelling
`
`Lumps/Bumps
`
`Bruising
`
`Itching
`
`Discoloration
`
`JUVEDERM 30HV
`(N.=144 NLFs)
`nt %
`8-14
`Days
`10
`7%
`
`4-7
`Days
`43
`30%
`
`37
`26%
`
`29
`20%
`
`49
`34%
`
`24
`17%
`
`31
`22%
`
`9
`6%
`
`11
`8%
`
`25
`17%
`
`18
`13%
`
`21
`15%
`
`19
`13%
`
`22
`15%
`
`6
`4%
`
`4
`3%
`
`_:s:3
`Days
`56
`39%
`
`59
`41%
`
`24
`17%
`
`31
`22%
`
`32
`22%
`
`25
`17%
`
`32
`22%
`
`22
`15%
`
`>14
`Days
`20
`14%
`
`8
`6%
`
`56
`39%
`
`23
`16%
`
`45
`31%
`
`9
`6%
`
`2
`1%
`
`12
`8%
`
`_:s:3
`Days
`53
`37%
`
`55
`38%
`
`28
`19%
`
`53
`37%
`
`15
`10%
`
`26
`18%
`
`24
`17%
`
`27
`19%
`
`Control**
`(N.=144 NLFs)
`nt %
`8-14
`Days
`13
`9%
`
`4-7
`Days
`37
`26%
`
`44
`31%
`
`26
`18%
`
`47
`33%
`
`26
`18%
`
`29
`20%
`
`18
`13%
`
`5
`3%
`
`17
`12%
`
`16
`11%
`
`13
`9%
`
`14
`10%
`
`11
`8%
`
`6
`4%
`
`5
`3%
`
`>14
`Days
`25
`17%
`
`7
`5%
`
`52
`36%
`
`8
`6%
`
`58
`40%
`
`3
`2%
`
`3
`2%
`
`6
`4%
`
`*'Number of subject NLFs treated with the respective device
`0 A commercially available injectable bovine collagen
`tNumber of subject NLFs with each specific injecticm site response by maximum duration
`!Duration refers to number of days from symptom onset until resolution, irrespective of date of
`implantation.
`
`Surveillance Outside the United States
`
`In postmarket surveillance for .IUVE:I)ERM products in countries outside the United
`States, one anaphylaxis reaction has been reported. Reported treatment included
`administration of antihistamine medications with subsequent resolution. Additionally,
`injection site responses (e.g. swelling, redness, infection, tenderness, induration, itching
`at the injection site) have been reported after treatment with JUVEDERM.
`
`8
`
`Page 8
`
`

`

`IX.
`
`SUMMARY OF PRECLINICAL STUDIES
`
`Biocompatibility
`
`The following biocompatibility testing has been conducted:
`
`Test
`Cytotoxicity (Agar Overlay Microplate
`Assay)
`Pyrogenicity (Rabbits)
`
`Bacterial Endotoxin (Kinetic-Chrornogenic
`Test)
`Acute Systemic Toxicity: Direct
`intraperitoneal administration in mice
`
`Subchronic Toxicity (12 weeks): Direct
`intradermal administration in rats
`
`Results
`Non cytotoxic
`
`Non pyrogenic
`
`<20EU/syringe
`
`Non toxic
`
`Non toxic
`
`lntradermal Reactivity: Direct intradermal
`administration in rabbits
`
`Slight irritation
`
`Genotoxicity
`• Bacterial Reverse Mutation (Ames Assay)
`• In Vitro. Chromosomal Aberration Study
`• Mouse Bone Marrow Micronucleus Study
`
`Skin Sensitization: Maximization assay in
`Guinea pigs
`
`• Non mutagenic
`• Non genotoxic
`• Non genotoxic
`
`Non sensitizer
`
`Intradermal Implantation ( 1, 3, 6, and 9
`months): Direct intramuscular administration
`in rabbits
`Muscle Implantation (4 & 12 weeks): Direct Well tolerated
`intramuscular administration in rabbits
`Subcutaneous Implantation (3 and 13 days)
`
`Well tolerated
`
`No chronic inflammation
`
`JUVEDERM passed all biocompatibility testing based on the International Organization
`for Standardization (ISO) 10993-1. The device was sho\\11 to be non-mutagenic by ISO
`genotoxicity requirements. i.e. bacterial 1-c\·erse mutation (Ames assay), in vitro
`chromosomal aberration study. and l1H1llSL' hnne marrow micronucleus study.
`
`!named assessed the potential cancer risk nf n:sidual BODE from lifetime use of
`JUVEDERM dermal fillers. BODE. a matl:'rial used in the manufacturing process of
`
`l)
`
`Page 9
`
`

`

`JUVEDERM, is a sensitizer and has also been found to be a mutagen in Drosophila.' An
`animal study was performed by an independent laboratory to study the carcinogenicity
`potential ofBDDE.2 Based on the results of this study, a cancer risk assessment of the use
`of BDDE as a crosslinking agent was performed. 3 Through applying both a linear
`·
`extrapolation method and a dose-response model (bench mark dose (BMD)), it was
`concluded that the excess cancer risk was minimal. Estimated excess cancer risk ranged
`from 1 x 10·5 to 1 x 10·8 from lifetime exposure to residual BODE.
`
`!named's carcinogenicity risk assessment assumes a worst-case dose of 2 ppm ofresidual
`BDDE present in JUVEDERM. Assuming the worst-case scenario where JUVEDERM
`contains 2 ppm of residual BODE, and the tumorigenic dose that was obtained from the
`CIBA-GEIGY study, the estimated excess cancer risk ranged from 2 x 10'5 to 5 x 10·9
`from lifetime exposure to residual BDDE in the dermal filler. In conclusion, the
`calculated risk of cancer associated with the use of JUVEDERM is minimal.
`
`The preclinical testing and the BODE cancer assessment indicated that JUVEDERM was
`safe to be evaluated in clinical studies.
`
`Chemical and Physical Characterization
`
`All three formulations of JUVEDERM (30, 24HV, and 30HV) hyaluronate gel implants
`have been extensively tested and characterized, through physical and chemical analyses.
`Oxygen derived free radical and enzymatic degradation assays were also performed on
`JUVEDERM gel implants to ensure that they naturally degrade within the body during
`their clinical lifespan.
`
`Based on all the chemical and physical ksting of the raw material sodium hyaluronate
`and the finished JUVEDERM products that have been performed, there was sufficient
`data to demonstrate that JUVEDERM hyaluronate gel implants were appropriate for
`evaluation in clinical studies as dermal fil lcrs.
`
`X.
`
`SUMMARY OF CLINICAL STUDIES
`
`Pivotal Study
`
`The clinical basis for approval for this pre-mnrking application is the outcome of a
`
`1 P. Foureman, J.M. Mason, R. Valencia. and S. 7.inmu:ring, Chemical Mutagenesis Testing in Drosophila,
`Environmental Molecular Mutagencs is 1994: 23 :'i 7-63.
`
`2 CIBA-GEIGY: A Cutaneous Carci11oge11icit_1' S111d1· 11·i1h Alice on the Diglyc1dyl Ether of 1,4-Butane Diol
`with Attachments and Cover Leiter Dated 09i.:'8'87: National Technical Information Service,
`NTIS/OTS0513957
`
`3 U.S. Food and Drug Administration (FDA) Clllccr Risk Assessment, Advisory Panel Briefing
`Information, PMA P020023, (Restyl.inc). HJ0:-i Nln
`{http:llwww.fda.gov/ohrmsldockl.'t ,1/c1L-/03/bric/i11g,' ./ I)(}./ b J _ 02 _ Cancer%20R isk¾20Assessment. htm ,l
`
`J()
`
`Page 10
`
`

`

`!
`
`prospective, randomized Pivotal Clinical Study performed in the United States.
`
`The JUVEDERM clinical trial included a treatment phase with an initial treatment to the
`nasolabial folds and up to two touch-up treatments as appropriate at 2-week intervals.
`The safety and efficacy follow-up phase included assessment at 4-week intervals through
`24-weeks after the last treatment.
`
`Devices
`
`The investigational devices used in the study were three formulations of JUVEDERM
`injectable gel (JUVEDERM 30, JUVEDERM 24HV and JUVEDERM 30HV).
`JUVEDERM is a non-animal, hyaluronic acid-based, lightly crosslinked dermal filler.
`The JUVEDERM products were delivered during the study via a 1.0cc syringe (0.8 mL
`fill volume) and a 30 gauge needle.
`
`The control device was a commercially available collagen implant composed of purified
`bovine dermal collagen cross linked with glutaraldehyde, dispersed in phosphate buffered
`saline and 0.3% lidocaine. The collagen implant is a PMA-approved device indicated for
`the correction of contour deficiencies of soft tissue. The collagen implant was delivered
`during the study via 1.0cc syringe (1.0 ml fill volume) and a 30 gauge needle.
`
`Primary Objectives
`
`The primary objectives of this study were to evaluate the safety and effectiveness of
`JUVEDERM injectable gel compared to a commercially available control device in
`subjects seeking augmentation correction of bilateral, moderate to severe nasolabial folds.
`
`Effectiveness Objective: To evaluate three JUVEDERM implant formulations
`(JUVEDERM 30, JUVEDERM 24HV and .JUVEDERM 30HV) versus control collagen
`implants, first in terms of non-inferiorit\' and second in terms of superiority, in the
`correction of moderate to severe NLFs. Co-primary efficacy analyses compared NLF
`severity scores for each treatment group at Week 12 following the last device treatment.
`Independent Expert Reviewer NLF severity scores were based on live assessments using
`a validated 5-point photographic scale: subjects used a similar 5-point non-photographic
`NLF severity scale.
`
`Safety Objective: To evaluate treatment site responses and adverse events as recorded by
`study subjects and Investigators follo\\'ing treatment with JUVEDERM implants vs.
`control collagen implants. Pre-printed diary forms were to be used by subjects to record
`specific signs and symptoms observed each day during the first 14 days after treatment.
`For each of the 14 days after initial and touch-up treatments subjects were instructed to
`rate each of a list of common treatment responses as "Mild," "Moderate," "Severe," or
`"None." It should be noted that subjects \\ere encouraged to record all signs and
`symptoms in their diaries. The ln\'estigator re\'iewed each subject's diary entries, treated
`the symptoms as appropriate, follm,cd the subject, and captured the symptom as an
`adverse event (AE) with its probable cause. any action taken, and outcome on the
`
`11
`
`Page 11
`
`

`

`appropriate case report forms. Safety was determined by the rate of AEs associated with
`the use of each product.
`
`Secondary Objectives
`
`The secondary study objectives for this study were as follows:
`
`• Evaluation of Independent Expert Reviewer NLF severity scores and subject NLF
`severity scores averaged over the 3 visits nearest Week 12.
`• Evaluation of treatment effect longevity based on Independent Expert Reviewer NLF
`severity scores and subject NLF severity scores from Week 2 through Week 24
`compared with pretreatment.
`• Evaluation of Investigator live NLF severity scores made over the duration of the study.
`• Evaluation of Independent Expert Reviewer live assessments of optimal (full) NLF
`correction at 2 weeks after each treatment and 4 weeks after the last treatment.
`• Evaluation of subject observations of the effects of treatment during the first 14 days
`after each treatment.
`• Evaluation of subject product preference assessments at the end of the study.
`
`Study Design
`
`The clinical study was a prospective, double-blind, randomized, three-armed, within(cid:173)
`subject controlled, multi-center study conducted to evaluate the safety and efficacy of
`JUVEDERM injectable gel implants when used as a dermal filler. The index treatment
`sites chosen for all subjects in this study were the nasolabial folds (NLFs). Eligible
`subjects signed an !RB-approved consent t<ir treatment, underwent a physical
`examination, NLF severity assessment. and facial photography. In addition, women of
`childbearing potential underwent a urine pregnancy test. Blood samples were collected
`prior to treatment and at 4 and 24 weeks a lier the last treatment for routine hematology
`and chemistry; frozen serum samples were retained for antibody titer evaluation.
`
`Subjects were randomized to one of three cohorts (JUVEDERM 30, JUVEDERM 24HV,
`or JUVEDERM 30HV) and underwent treatment with JUVEDERM on one side of the
`face and a commercially available collagen injectable implant on the opposite side to
`achieve optimal correction in both NLFs.
`
`The Investigator administered up to three bilateral treatments (initial treatment and up to
`two touch-ups) approximately 2 weeks apart. The Independent Expert Reviewer (!ER)
`and the subject remained masked to the treatment assignment.
`
`Routine follow-up visits for safety and eflicacy occurred at 3 and 7 days, 2 weeks after
`each treatment, and at 4. 8. 12. 16. ::,o and 2-1 weeks atier the last NLF treatment.
`Standardized facial photography was pert·l\nned at each office visit. The Investigator.
`Independent Expert Reviewer and suh_icct independently evaluated the NLF severity using
`a 5-point (range Oto 4) scale. Subjcc1s rne1111taincd a preprinted diary of their treatment
`responses and severity for 1-1 days at"icr e:1ch treatment. Treatment site responses and
`other adverse events (AEs) were 1mrnitorc·,I throughout the study.
`
`I -'
`
`Page 12
`
`

`

`I
`
`Skin Type and Gender Bias
`
`The majority of subjects enrolled in the clinical study were Caucasian (74.5%), who most
`commonly represent Fitzpatrick skin types I-III. Minority populations, who more
`commonly represent Fitzpatrick skin types IV-VI, comprised 25.5% of the study group.
`The 95% confidence intervals around the Independent Expert Reviewers' mean scores for
`severity of Caucasian and non-Caucasian subjects at 12 and 24 weeks overlapped,
`indicating that there is no bias upward or downward due to skin type.
`
`Women made up a majority of the subjects in the U.S. trial (91.8%). Gender was
`represented as may be expected in the U.S. market.
`
`Subject Enrollment
`
`A total of 439 subjects were randomized and treated with JUVEDERM 30, JUVEDERM
`24HV or JUVEDERM 30HV; 423 (96.4%) completed the 24 week follow-up period.
`
`Study Population Criteria
`
`•
`
`• Be men or women, greater than 30 yems of age;
`• Have 2 fully visible bilateral NLFs. which are approximately symmetrical and have
`reasonable expectation for correction by an intradermal injection procedure, as
`described in the protocol;
`• Have severity scores of2 or 3 on the 5-point photographic NLF severity scale (range
`0 to 4) for both nasolabial folds, as judged by the Investigator;
`• Agree to refrain from undergoing other anti-wrinkle treatments in the nasolabial fold
`areas and around the mouth during the study;
`If female of child-bearing potential (not sterile nor post menopausal for at least I
`year), have a negative urine pregnancy test and agree to use oral contraceptives or
`another medically acceptable form of birth control (2 forms of contraception, e.g.,
`condoms and spermicide) for at least I month prior to treatment and for the duration
`of the study;
`• Be able to understand and comply with the study requirements;
`• Be willing to provide written Informed Consent prior to any study-related procedures
`being performed;
`• Have no history ofhypersensiti,·it, rcetction to or contraindication for treatment with
`bovine collagen;
`• Have not had \'arious aesthetic focial therapies within specified wash-out periods
`prior to study entry;
`• Have no history ofanaphylaxis, rnulti1,lc severe allergies, atopy or allergy to meat,
`lidocaine or hyaluronic acid products , ,r plans to undergo desensitization therapy;
`• Have no active inflammation. infccti,111. cancerous or pre-cancerous lesion or
`unhealed wound in the NLf mea: and
`• Have no history of connective tissue disease (e.g., rheumatoid arthritis, juvenile
`rheumatoid arthritis. sc!erodcnna. S\stcrnic lupus erythematosus).
`
`1 •
`
`r
`
`Page 13
`
`

`

`'
`
`Effectiveness Assessments
`
`Treatment effectiveness was assessed at each follow-up visit. The subject, Investigator
`and Independent Expert Reviewer independently assessed the severity of the subject's
`NLFs at each sp~cified time point. The Independent Expert Reviewer and the subject
`remained masked to treatment randomization throughout the study.
`
`The Independent Expert Reviewer made live assessments of the severity of the subject's
`NLFs using a validated 5-point photographic scale and comparing each NLF to the
`photographic scale and respective descriptions. The scale represents the spectrum ofNLF
`severity from least to most severe (0-4). The subject performed self-assessments using a
`mirror and the numerical and narrative descriptions on the same 5-point NLF severity
`scale but without photographs. The Independent Reviewer and the subject rated the right
`and left NLFs individually and independently from each other and from their baseline
`scores.
`
`Score
`
`Severity Descriptions
`
`4
`
`3
`
`2
`1
`0
`
`Extreme
`
`Severe
`
`Moderate
`Mild
`None
`
`V cry deep wrinkle, redundant fold
`(overlapping skin)
`Deep wrinkle, well-defined edges
`(but not overlapping)
`Moderately deep wrinkle
`Shallow, just perceptible wrinkle
`No wrinkle
`
`Stud);' Demographics
`
`The majority of the subjects in each cohort were Caucasian and female with a median age
`between 48 and 50 years. Sufficient numbers of persons-of-color were enrolled without
`additional recruitment efforts. Table 7 presents subject demographics for the efficacy
`population in each cohort.
`
`1--1
`
`;1\
`
`Page 14
`
`

`

`t
`
`Table 7 - Demographics and Pretreatment
`Characteristics of the Effectiveness Populations
`
`JUVEDERM30
`N=l47t
`
`JUVEDERM 24HV
`N=146t
`
`JUVEDERM 30HV
`N=146t
`
`136
`1 1
`
`93 %
`7%
`
`135
`11
`
`92%
`8%
`
`132
`14
`
`90%
`10%
`
`49
`49
`30--70
`
`50
`50
`31-75
`
`48
`48
`26-74
`
`115
`14
`16
`1
`
`I
`
`78%
`10%
`11%
`1%
`1%
`
`105
`18
`15
`
`7
`I
`
`72%
`12%
`10%
`5%
`I
`
`Demographic
`
`Gender
`[Number/ %1
`Female
`Male
`Age (years)
`Mean
`Median
`Range
`
`Ethnicity
`[Number/%]
`Caucasian
`African American
`Hispanic
`Asian
`Other
`
`107
`17
`20
`
`0
`2
`
`8
`34
`51
`31
`18
`4
`
`73%
`12%
`14%
`0%
`1%
`
`5%
`23%
`35%
`21%
`12%
`3%
`
`2.6
`2.6
`
`6
`39
`48
`34
`15
`5
`
`4%
`
`27%
`
`33%
`
`23%
`10%
`3%
`
`4
`
`34
`55
`24
`24
`5
`
`3%
`23%
`38%
`16%
`16%
`3%
`
`Fitzpatrick Skin
`Phototypc
`JNumber/%]
`I
`II
`III
`IV
`V
`VI
`Mean Baseline
`NLF Severity
`Score*
`JUVEDERM NLF
`2.5
`2.6
`Control** NLF
`2.6
`2.6
`tNumber of randomized subjects in the respectiv,· trca11m:nr group.
`• NLF Severity was ranked on a 5-point scale fi-0111 None (0) to Extreme (4)
`u A commercially available injectable bovine ndlagcn implant
`
`15
`
`r···
`
`Page 15
`
`

`

`•
`
`Masking
`
`Because the control collagen implant is oft:white to creamy in color and JUVEDERM is
`clear, it was not feasible to mask the treating Investigator. However, the Independent
`Expert Reviewer and the subject remained masked throughout the study and were not
`permitted to refer to their own previous assessments, each other's previous or current
`assessments or any of the Investigator's assessments. Subjects wore blindfolds during
`treatment. No one other than the Investigator, S\udy Coordinator and the subject were
`allowed in the examination room during the injection process. The Investigator and Study
`Coordinator were instructed to refrain from commenting on specific product assignments
`in the presence of the subject, Independent Expert Reviewer and other office personnel.
`The subject, Investigator and Independent Expert Reviewer independently assessed the
`severity of the subject's NLFs at each specified time point using the 5-point NLF severity
`scale.
`
`Safety Conclusions
`
`Subjects reported treatment site responses with similar frequency, severity, and duration
`for JUVEDERM and Control. Most treatment site responses were mild or moderate and
`did not require intervention. The majority of events lasted 7 days or less, and treatment(cid:173)
`emergent events not associated with a nasolabial fold were primarily reported as unrelated
`to the treatment. There were no serious adverse events related to JUVEDERM treatment,
`although one clinically significant event (injection site abscess) was deemed to be related
`to Control treatment.
`
`No trends were seen for changes in physical examinations, vital signs and hematology
`and chemistry determinations over the course of the study. For additional information
`regarding reported adverse events see Tables 1-6 above.
`
`Effectiveness Conclusions
`
`In order to establish effectiveness, JUVEDERM was compared to Control in terms of
`non-inferiority and superiority. The primary effectiveness end point for the study was the
`Independent Expert Reviewer NLF severity scores over the post-treatment follow-up
`period. Effectiveness of device treatment was demonstrated by a lowering of the NLF
`severity score. Results based on the Independent Expert Reviewers' assessments ofNLF
`severity are presented in Tables 8-1 0.
`
`16
`
`Page 16
`
`

`

`t
`
`Table 8 - JUV:EDERM 30 vs. Control
`Independent Expert Reviewer's
`NLF Severity Scores
`
`I
`
`n§
`
`147
`146
`133
`
`143
`
`Juvederm 30
`(N*=:147 NLFs)
`NLF
`Improvement
`Severityt
`since
`Baselinet
`-
`l.9
`1.6
`
`2.5
`0.6
`0.9
`
`Control**
`(N*=147 NLFs)
`NLF
`Improvement
`Severityt
`since
`Baselinet
`-
`1.8
`1.0
`
`2.6
`0.7
`1.5
`
`1.4
`
`1.2
`
`2.1
`
`0.5
`
`Baseline
`Week2
`Week
`12
`Week
`24
`• Number of subject NLFs treated with the respective device
`u A commercially available injectable bovine collagen implant
`§ Number of subjects NLFs with data at base 1 i ne and the specified time point
`tMean score
`
`Table 9 - JUVEDERM 24HV vs. Control
`Independent Expert Reviewer's
`NLF Severity Scores
`
`n§
`
`JUVEDERM 241-IV
`(N*=146 NLFs)
`Improvement
`NLF
`Severity