SUMMARY OF SAFETY AND EFFECTIVENESS
`
`
`I.
`
`GENERAL INFORMATION
`
`Device Generic Names:
`
`Injectable Dermal Filler
`
`Device Trade Name:
`
`Cosmetic Tissue Augmentation product (CT A)
`
`Applicant:
`
`Anika Therapeutics, Inc.
`
`236 West Cummings Park
`
`Woburn, MA 01801
`
`
`Premarket Approval (PMA) Application Number: P050033
`
`Date of Panel Recommendation: None
`
`Date of Notice of Approval to the Applicant: December 20, 2006
`
`II.
`
`INDICATIONS FOR USE
`
`CT A is indicated for injection into the mid to deep dermis for the correction of
`moderate to severe facial wrinkles and folds (such as nasolabial folds).
`
`Ill.
`
`CONTRAINDICATIONS
`
`• CT A is contraindicated for patients with severe allergies manifested by a history of
`anaphylaxis or history or presence of multiple severe allergies.
`
`• CTA is composed of hyaluronic acid, lidocaine and may contain trace amounts of
`gram positive bacterial proteins. CT A is contraindicated for patients with a history of
`allergies to such material.
`
`IV. WARNINGS AND PRECAUTIONS
`
`Warnings and precautions can be found in the CTA physician's labeling.
`
`V.
`
`DEVICE DESCRIPTION
`
`CT A is a sterile, nonpyrogenic gel implant, composed of hyaluronan produced by
`Streptococcus equi (bacterial fermentation) that is crosslinked and suspended in a buffer
`solution at a concentration of28 mg/mL. CTA contains 0.3% lidocaine HCI. The
`finished product is provided in a pre-filled glass syringe at a volume of I mL, co­
`packaged with two 30 G. x y, inch hypodermic needles.
`
`P050033
`Page I of 12
`
`

`

`VI.
`
`ALTERNATIVE PRACTICES & PROCEDURES
`
`Alternative therapies for cosmetic tissue augmentation include bovine collagen dermal
`fillers, human collagen dermal fillers, other hyaluronic acid-based dermal fillers, and
`autologous fat transfer. Other treatment options for the treatment of photo-damaged skin
`with its associated wrinkling and changes in texture and pigmentation include topical
`creams (containing e.g. retinoids), chemical peeling procedures or laser resurfacing.
`Deep wrinkles, folds, scars, and other depressed lesions are often treated with surgery
`(e.g. rhytidectomy).
`
`VII. MARKETING HISTORY
`
`CT A is a new product that has not yet been commercialized.
`
`VIII. POTENTIAL ADVERSE EFFECTS ON HEALTH
`
`In a study of 208 patients at I 0 centers, symptoms reported in patient diaries during 14
`days after initial treatment are listed in Table I by intensity of symptoms and Table 2 by
`duration of symptoms. Patients in the study were either injected with CTA in both
`nasolabial folds (NLF) (n=17) or CTA in one NLF and a human collagen dermal filler
`(Control) in the contralateral NLF (n=l91). Eighty-eight percent (88%) of patients
`reported symptoms on both sides of the face following treatment. In most cases,
`symptoms (bruising, redness, swelling, pain, tenderness, itching, nodule formation) were
`of mild to moderate intensity and resolved in 7 days or less. Adverse events were
`reported on the physician case report form. Events occurring in> 2% of the 191
`randomized patients are listed in Table 3. Many of these adverse events represent
`physician reporting of the same data reported by patients in Table I. Local adverse
`events are reported in Table 3 by side of face; because of the "split-face" study design,
`causality of systemic adverse events cannot be assigned.
`
`Table I. Maximum Intensity of Symptoms after Initial Treatment, Patient Diary
`Control
`Control Side
`CTA Side
`CTA Side
`Intensity
`Intensity
`N=208
`Side
`N=191
`Total
`reporting
`symptoms
`N(%)
`94
`(49.2%)
`124
`(64.9%)
`129
`(67.5%)
`63
`133.0%)
`101
`152.9%)
`49
`(25.7%)
`112
`(58.6%)
`
`Total
`report'mg
`symptoms
`N(%)
`131
`(63.0%)
`151
`(72.6%)
`181
`(87.0%)
`108
`151.9%)
`145
`(69.7%)
`83
`139.9%)
`129
`(62.0%)
`
`Bruising
`
`Redness
`
`Swelling
`
`Pain
`
`Tenderness
`
`Itching
`
`Nodule
`formation
`
`P050033
`Page 2 of 12
`
`Unknown
`N(%)
`
`Mild
`N(%)
`
`Mode-
`rate
`N(%)
`
`Severe
`N(%)
`
`Unknown
`N(%)
`
`Mild
`N(%)
`
`7
`(3.3%)
`6
`(2.9%)
`11
`(5.3%)
`6
`(2.9%)
`11
`(5.3%)
`7
`(3.4%)
`11
`(5.3%)
`
`49
`45
`(23.6%)
`(21.6%)
`76
`45
`(35.5%)
`(21.6%)
`78
`31
`(37.5%)
`(14.9%)
`40
`52
`(19.2%)
`(25.0%)
`57
`57
`(27.4%)
`_[27.4%).
`10
`63
`_[30.3%) _l4.8%)
`39
`61
`(18.8%)
`(29.3%)
`
`30
`(14.4%)
`24
`(11.5%)
`61
`(29.3%)
`14
`(6.7%)
`20
`J9.6'Yo)
`3
`(1.4%)
`18
`(8.7%)
`
`4
`(2.1%)
`6
`(3.1%)
`7
`(3.7%)
`2
`11.0%)
`6
`(3.1%)
`2
`(1.0%)
`9
`(4.7%)
`
`58
`(30.4%)
`71
`(37.2%)
`86
`(45.0%)
`51
`(26.7%)
`71
`(37.2%)
`43
`122.5%)
`69
`(36.1%)
`
`Mode-
`rate
`N(%)
`
`26
`(13.6%)
`42
`(22.0%)
`34
`(17.8%)
`9
`(4.7%)
`20
`(10.5%)
`4
`(2.1%)
`32
`(16.8%)
`
`Severe
`N (%)
`
`6
`(3.1%)
`5
`(2.6'Yo)
`2
`(1.0%
`1
`(0.5%)
`4
`(2.1%)
`0
`(0.0%)
`2
`(1.0'/o)_
`
`

`

`.reatment, patient D'1ary
`
`
`Control Side (N-191)
`Number of Days
`4-7
`8-13
`N (%)
`16
`(8.4%)
`13
`(6.8%)
`11
`(5.8%)
`3
`(1.6%)
`7
`(3.7%)
`4
`(2.1%)
`46
`(24.1%)
`
`I .. IT
`f
`T able 2 Duratwn ofSsymptoms a ter mtia
`CTA Side (N 208)
`Number of Days
`4-7
`8-13
`N(%)
`N(%)
`51
`17
`(24.5%)
`(8.2%)
`49
`14
`(23.6%)
`(6.7%)
`77
`19
`(19.9%)
`(37.0%)
`3
`15
`(7.2%)
`(1.6%)
`52
`5
`(25.0%)
`(2.4%)
`13
`5
`(6.3%)
`(2.6%)
`28
`48
`(23.1%)
`(13.5%)
`ccurrmg m >2%0 0 fPaf1ents, PhIYSIC!aD case ReportForm
`ven s 0
`T able 3 Adverse E
`t
`Description of Adverse Event
`CTA Side
`Control Side
`(WHO Preferred Term)
`(N~208)
`(N~I91)
`N (%)
`N (%)
`59 (27.7%)
`37 (19.4%)
`5 (2.1%)
`I (0.5%)
`3 (1.6%)
`4(2.1%)
`4(1.0%)
`6 (3.1%)
`5 (2.6%)
`0 (0.0%)
`17 (8.4%)
`15 (7.9%)
`14 (6.8%)
`5 (2.6%)
`15 (7.3%)
`4 (2.1%)
`2 (1.0%)
`4 (2.1%)
`7 (3.7%)
`I (0.5%)
`
`.
`
`Bruising
`
`Redness
`
`Swelling
`
`Pain
`
`Tenderness
`
`Itching
`
`Nodule
`formation
`
`< 3
`N (%)
`56
`(26.9%)
`79
`(38.0%)
`81
`(38.9%)
`87
`(41.8%)
`83
`(39.9%)
`61
`(29.3%)
`27
`(13.0%)
`
`14+
`N(%)
`7
`(3.7%)
`9
`(4.7%)
`4
`(2.1%)
`3
`(1.6%)
`5
`(2.6%)
`4
`(2.1%)
`26
`(12.5%)
`
`<=3
`
`47
`(24.6%)
`78
`(40.8%)
`87
`(45.5%)
`52
`(27.2%)
`61
`(31.9%)
`35
`(18.3%)
`24
`(12.6%)
`
`25
`(13.1%)
`28
`(14.7%)
`28
`(14.7%)
`5
`(2.6%)
`31
`(16.2%)
`7
`(3.7%)
`24
`(12.6%)
`
`14+
`N(%)
`6
`(3.1%)
`5
`(2.6%)
`3
`(1.6%)
`3
`(1.6%)
`2
`(1.0%)
`3
`(1.6%)
`18
`(9.4%)
`
`Any Adverse Event
`Injection Site Bruising
`Injection Site Discoloration
`Injection Site Erythema
`Injection Site Edema
`Nodule
`Swelling
`Contusion
`Erythema
`Swelling Face
`
`No adverse events related to treatment were observed at the 9 and 12 month follow-up
`visits in the 101 subjects who participated in the extension phase ofthe study
`
`Local adverse events
`Local adverse events were observed by the physician in 59/208 subjects treated with CTA
`in the randomized study. Injection site reactions included bruising and edema. Additional
`non-injection site reactions of nodule formation, swelling, contusion and facial swelling
`account for the majority of adverse events observed. In most cases, symptoms (bruising,
`redness, swelling, pain, tenderness, itching, nodule formation) were of mild to moderate
`intensity and resolved in 7 days or less.
`
`Non-local adverse events
`Non-local adverse events occurred in 34/191 (I 7.8%) of the study subjects. Since each
`patient received both CTA treatment and control, the causality of these events could not
`be identified. Non local adverse events occurring in >2% of the subjects included
`Infections and Infestations occurring in 12 subjects (5.8%) (bronchitis, cystitis,
`diverticulitis, folliculitis, herpes zoster, influenza, onychomycosis, sinusitis, suture line
`infection and upper respiratory infection); Musculoskeletal disorders (2.4%) (arthralgia,
`back pain, osteoporosis, extremity pain); and Nervous System disorders (2.4%)
`(dizziness, headache and sinus headache).
`
`P050033
`Page 3 of 12
`
`\D
`
`

`

`Serious Adverse Events
`Six subjects experienced serious adverse events. One event (i.e., il\iection site cellulitis)
`was judged definitely related to study treatment. The remaining serious adverse events
`(i.e., difficulty breathing, dizziness and chest pain) were not considered related to study
`treatment.
`
`Retreatment Phase
`90 patients enrolled in an open label retreatment extension study 6 months after their final
`treatment to achieve optimal correction. The safety profile observed during the I and 3
`month follow-up was similar to that described above in the pivotal study.
`
`IX.
`
`NONCLINICAL STUDIES
`
`The clinical trial of CT A was conducted using CT A formulated with HA from an avian
`source. Commercial CT A will be formulated with HA from a bacterial fermentation
`source. Nonc!inical studies demonstrated that the CT A formulated with avian sourced
`HA was safe to be evaluated in clinical studies, and that CT A formulated with fermented
`sourced HA is equivalent to CTA used in the clinical trial.
`
`Biocompatibility Testing
`
`Both the avian- and fermentation-derived CT A devices were tested in accordance with
`ISO 10993 "Biological Evaluation of Medical Devices Part 1: Evaluation and Testing"
`for devices in contact with tissue and bone for durations of greater than 30 days and in
`compliance with FDA GLP regulations. Test results are summarized in Table 5.
`
`ISO 10993-3
`
`No evidence of genotoxicity
`
`Table 5. Summary of Anika CTA Biocompatibility Test Results
`ISO Reference
`Test Results
`Test
`Genotoxicity-Bacterial Reverse
`ISO I0993-3
`Test article was nonmutagenic
`Mutation
`Genotoxicity-/n Vitro
`Chromosomal Aberration
`Genotoxicity-Mouse Bone
`Marrow Micronucleus
`Cytotoxicity-Agarose
`Overlay Method
`ISO Maximization Sensitization
`
`ISO I0993-3
`
`ISO 10993-5
`
`ISO 10993-10
`
`Systemic Toxicity
`Rat Chronic Toxicity-13 week,
`subcutaneous implant
`
`ISO I 0993-11
`ISO I0993-11
`
`Implantation Test-Intradermal
`Injection in Guinea Pig
`
`ISO I0993-6
`
`P050033
`Page 4 of 12
`
`No evidence of genotoxicity
`No evidence of cellular toxicity
`No evidence of cell lysis or toxicity
`
`No evidence of delayed contact
`sensitization
`No evidence of systemic toxicity
`Slight irritant following subcutaneous
`implantation; no evidence of systemic
`toxicity, no changes in histopathology,
`hematology values, or clinical chemistry
`of biological significance or related to
`treatment.
`Slight irritant following intradermal
`injection; present at the injection sites
`up to 24 weeks post-injection
`
`

`

`Design Verification Testing
`
`Design verification testing was conducted to compare the avian and fermented HA raw
`materials and finished products and to demonstrate that the two raw materials are
`equivalent, that the change in raw material source did not affect the finished product, and
`that design outputs meet design inputs. The results of the raw material comparison
`testing (Table 6) demonstrated that the HA from the avian source is comparable to the
`HA produced by bacterial fermentation. The design verification testing of finished CT A
`product (Table 7) demonstrated that CTA made from the two HA raw materials (avian
`and fermented) is comparable and that all design outputs for the fermented CTA product
`met design inputs.
`
`Table 6. Comparability Studies for Avian and Bacterial HA
`Resnlt I Conclusion
`Test
`Molecular Weight
`The average MW for three lots of avian (797.8 kD) and
`fermented (930.3 kD) HA were comparable
`(MW)
`Infrared (IR)
`The IR Spectra for avian and bacterial HA are comparable
`spectroscopy
`Nuclear magnetic
`resonance (NMR)
`spectroscopy
`Endotoxin
`
`The NMR Spectra for avian and bacteria HA are identical
`
`All values observed with avian (n=3) and fermented (n=3) lots
`were below the specification of0.03 EU/mg
`All avian (n-3) and fermented (n-3) lots had< 10 cfu/g with
`regard to bacteria and yeast and no detectable pathogens
`The protein concentrations observed in the SDS-PAGE of avian
`and bacterial HA are equivalent
`
`The average A260nm for avian lots (n-3) 0.069 were similar to,
`but less then the average absorbance observed with bacterial
`HA (i.e., 0.125)
`All values observed with avian (n=3) and fermented (n=3) lots
`were less than 80 ppm
`All values observed with avian (n-3) and fermented (n=3) lots
`were less than 20 ppm
`
`Bioburden
`
`Sodium dodecyl
`sulfate polyacrylamide
`gel electrophoresis
`(SDS-PAGE)
`Ultraviolet (UV)
`absorbance
`
`Iron Content
`
`Heavy Metals
`
`P050033
`Page 5 of 12
`
`

`

`Test
`
`Appearance
`
`Sterility
`Endotoxin
`
`Residual solvents
`
`Residual Mercury
`
`Table: 7. Comparison of CT A Final Products Prepared from
`
`Avian HA (n=3 lots) and Bacterial HA (n=3 lots)
`
`Result I Conclusion
`Avian and bacterial-derived CT A were both clear and
`colorless
`All avian and bacterial CT A lots were sterile
`All avian and bacterial CT A lots had endotoxin values <
`0.08 Endotoxin Unitslml
`All lots of avian and bacterial CT A met the
`specifications for residual levels of dimethyl sulfoxide,
`ethanol, acetone and methanol
`All lots of avian and bacterial CTA had values< 0.005
`ppm
`All lots of avian and bacterial CT A met the specification
`of6.2 -7.6
`The average value observed with 3 lots of bacterial CTA
`(i.e., 300 mOsm) met the specification of280- 340
`mOsm
`All lots of avian and bacterial CT A were within the 21 -
`29 mg/ml specification
`The average fragments concentrations were 0.04% for
`bacterial CT A and 0.06% for avian CT A
`The Abszsonm for avian and bacterial CT A were similar
`The average values for resistance to hyaluronidase were
`similar for bacterial (i.e., 86.2%) and avian CTA
`(71.2%)
`Forces between 3-5 lbs were measured for all lots of
`bacterial and avian CT A
`
`pH
`
`Osmolality
`
`Crosslinked HA
`Concentration
`Low Molecular Weight
`Hyaluronic Acid Fragments
`Crosslinker Concentration
`Durability
`
`Extrusion Force
`
`The following additional tests were performed to further characterize the final CT A
`device.
`
`Table 8. Other Preclinical Studies with the Final CTA Product
`Results I Conclusions
`Test
`Lidocaine Bio-Availability
`In vitro testing demonstrated that over 90% of the
`lidocaine elutes from CT A within 2 minutes.
`Stability studies support an expiration date of 15
`months
`
`Shelf-life via tests for:
`Sterility, Visual appearance,
`Endotoxin, Viscoelastic Properties of
`Crosslinked Gel (i.e., Storage
`Modulus G' and Decrease in G' as a
`Function of Time Due to Enzyme
`Digestion), UV Absorbance of the
`Crosslinked HA, pH, Osmolality, H.A
`Concentration (Gravimetric),
`Extrusion Force, HA fragments and
`Lidocaine concentration
`
`P050033
`Page 6 of 12
`
`

`

`X.
`
`CLINICAL STUDIES
`
`The following is a summary of the pivotal study (i.e., "A Randomized, Controlled, Paired
`Double-Blind, Multicenter, and Pivotal Study of Cross-Linked Hyaluronic Acid in the
`Treatment of Dermal Contour Deformities", Study CTA0302). Following this discussion
`is a summary of the re-treatment study "Study CT A0302-l "An Extension to the
`Randomized, Controlled, Paired, Double-Blind Multicenter, Pivotal Study of Cross­
`Linked Hyaluronic Acid (Anika CTA) in the Treatment of Dermal Contour Deformities."
`
`Study Design:
`
`The safety and effectiveness of CTA for the treatment of facial wrinkles and folds was
`evaluated in a prospective, randomized, controlled, paired, double-blinded, multi-center,
`pivotal clinical study. Randomized subjects underwent treatment with CTA in one NLF
`and control implant (a human .collagen dermal filler) in the contralateral (NLF).
`
`Up to three bilateral treatments (i.e., initial treatment and up to 2 touch-up treatments),
`approximately 2 weeks apart, were allowed. At 2 and 4 weeks after each treatment, a
`Blinded Evaluator assessed the level of correction. If correction was less than optimal
`after the first or second treatment, the Investigator re-treated the under-corrected NLFs
`using the same respective treatment materials as in the initial treatment. The blinded
`evaluator and subject remained blinded to the randomized treatment assignment.
`
`Routine follow-up visits for safety and effectiveness occurred at 2 weeks after each
`treatment and at I, 4, 6, 9 and 12 months after the last treatment. The blinded reviewer
`and subject independently evaluated the severity of the subjects NLF using the Lemperle
`Rating Scale (LRS), (i.e., a validated 6-point wrinkle severity scale ranging from 0 =no
`wrinkles to 5= very deep wrinkle, redundant fold).
`
`Study Endpoints
`
`• Effectiveness
`
`The primary effectiveness endpoint was the blinded evaluator's LRS score at 6-months
`following the last touch-up (at which optimal correction was achieved). Secondary
`effectiveness endpoints included: blinded evaluator LRS at 1- and 4-months; subject LRS
`at 1-, 4- and 6-months; proportion of nasolabial folds returning to baseline at 6-months;
`number of treatment sessions and volume of material to obtain optimal correction. The
`primary endpoint, the LRS score, is a 6-point scale. A change in LRS of I was
`considered to be clinically significant. Optimal correction was defined to be the best
`possible cosmetically pleasing result and 100% correction; unlimited touch-ups were
`permitted to achieve optimal correction.
`
`P050033
`Page 7 of 12
`
`

`

`o Safety
`
`Adverse outcomes were evaluated by comparing the incidence and severity of clinical events
`reported in patient diaries during the 14 days after treatment and the adverse events assessed
`during study visits by investigator.
`
`Patient Enrollment
`
`The study enrolled subjects with bilateral NLF with a 3 or4 LRS score. Patients were
`excluded if they had: an allergy to avian products, sensitivity to lidocaine, previous exposure
`to soft tissue augmentation in any area of the face, aesthetic or dermatologic procedures in the
`target area of the face in the past 6 months, (i.e., medium depth or deep chemical peel, facial
`wrinkle therapies (e.g., Accutane and Renova), facial silicone injections, facial surgery
`(facelift), or facial dermabrasion). Laser resurfacing of the face in the last 56 months was
`also an exclusion criterion. In addition, subjects were excluded if they had: HIV/AIDS,
`Hepatitis C, active facial acne lesions or severe acne scarring that might affect NLF
`assessment, active skin diseases or inflammation on or near the NLF (e.g., psoriasis, herpes
`zoster, infection and discoid lupus), or if they received immunosuppressive therapy,
`anticoagulant therapy, chemotherapy or systemic corticosteroids within the last 3 months or a
`history of bleeding disorders or connective tissue disease. Patients were also excluded if they
`were involved in any research with an investigational product or new application of an
`approved product within 30 days of screening. Finally, patient enrollment also required
`cessation of anti-platelet therapy for 7 -I 0 days prior to each treatment and a commitment to
`forgo dermabrasion, laser resurfacing, facial wrinkle therapies, all aesthetic facial surgeries
`and all other soft tissue augmentation for the study duration.
`
`o Patient Accounting
`
`A total of 208 patients were treated at I 0 centers, including 17 "roll-in" patients implanted
`with CTA in both NLF and 191 subjects treated with CTA in one NLF and Control in the
`contralateral NLF (n=l91). Accounting of these patients is presented below in Table 9.
`
`a e 9 I' . Accountmg
`T bl
`attent
`Randomized
`All subjects
`N=191
`N=208
`191
`208
`9 (4.3%)
`6 (3.1 %)
`199 (95.7%)
`185 (96.9%)
`151 (72.6%)
`140 (73.3%)
`90 (43.3%)
`84 (44.0%)
`101 (48.6%)
`
`Eligible/randomized
`Withdrew prior to month 6
`Completed 6 months
`Eligible for re-treatment
`Participated in re-treatment*
`Eligible for extended follow-up study
`(not retreated)
`Subjects at 9 month visit (not retreated)
`Subjects at 12 month visit
`(not retreated)
`*For accountmg ofretreatment patients, see below
`
`90 (43.3%)
`84 (40.4%)
`
`P050033
`Page 8 of 12
`
`Roll-in
`N=17
`17
`3 (17.6%)
`14 (82.4%)
`II (64.7%)
`6 (35.3%)
`
`-­tO
`
`

`

`• Baseline Demographics
`
`The randomized study population (n=191) was composed of 16 men and 175 women between
`the ages of 30 and 77 years of age. The baseline demographics are displayed in Table I 0.
`
`..· ...';'
`
`172 (90.1 %)
`7 (3.7%)
`4 (2.1%)
`8 (4.2%)
`
`.'•
`
`':>)~
`
`.····
`
`~"' 5·<'
`
`iz .
`
`)> C';.
`
`. :.. ..·· . ~·
`
`E£~ ·. ..}~···
`·.. ··•· .') .. ·.. ...
`':',... ,..,..
`
`....
`
`;.:
`
`..·.....
`
`..
`
`T bl 10 S d P
`. Demograplh.tcs
`I
`a e
`tu ly opu atwn
`Demographic
`N(%)
`Total study enrollment (randomized)
`191 (100%)
`Age (mean± standard deviation)
`52.6 ± 8.5
`:'.\:"f' .
`Gender
`Male
`16 (8.4%)
`Female
`175 (91.6%)
`Race
`Caucasian
`Black or African-American
`Asian
`Other
`Ethnicity
`Hispanic or Latino
`Not Hispanic or Latino
`Cigarette Use (Pre-treatment)
`Non-Smoker
`Current Smoker
`Former Smoker
`Sun Exposure (Pre treatment)
`To Natural Sunlight
`Minimal
`Moderate
`High
`To Artificial Sunlight
`None
`Minimal
`Moderate
`High
`
`18 (9.4%)
`173 (90.6%)
`
`90(47.1%)
`37 (19.4%)
`64 (33.5%)
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`59 (30.9%)
`99 (51.8%)
`33 (13.3%)
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`127 (66.5%)
`54 (28.3%)
`10 (5.2%)
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`
`• Ethnic Representation
`
`The majority of patients enrolled in the study were Caucasian (90.1 % ). Minority
`populations comprised 9.9 percent of the study population. While the study did not
`directly record Fitzpatrick skin type as part of the case report forms, on retrospective
`analysis they believe that between 16-18 subjects had skin types between 4-6 on the
`Fitzpatrick scale, (i.e., 7 African Americans, 4 Asian, I Native American, 4 Hispanic and
`2 Non-Hispanic subjects).
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`• Treatment Material Delivered
`
`The mean total volume injected per nasolabial fold for all treatment sessions (initial and
`touch-ups) was 1.2 mL for the CTA side and 1.9 mL for the control. Forty-seven (47)
`CTA sides (24.6%) required one or more touch-ups, whereas 61 (31.9%) of control sides
`required one or more touch-ups. No randomized CT A NLF and two control-treated
`NLFs required three touch ups.
`
`Effectiveness Results
`
`The primary effectiveness results for CT A based on the Blinded Evaluator assessment of
`NLF severity at 6 months are presented in Table 11. The blinded evaluator LRS scores
`demonstrated non-inferiority of CTA to Control.
`
`Table 11. Mean Blinded Evaluator LRS Scores
`
`P-Value
`Control
`CTA
`N
`Timepoint
`0.8733
`Pretreatment
`3.5
`3.5
`191
`0.2586
`Optimal Correction
`188
`1.1
`1.1
`<0.0001 *
`4-Months
`2.7
`2.2
`175
`0.0001 *
`3.0
`2.7
`6-Months
`182
`* p-values are from a paned companson usmg McNemar's test.
`
`Safety Results
`
`• Adverse Events
`
`The reported adverse events are presented in section VIII.
`
`• Antibody Testing
`
`A pre-existing antibody response against CTA was observed in 5/208 (2.4%) subjects and
`18/208 {8.7%) subjects developed a response after CTA injection. 6/18 subjects with
`elevated anti-CT A titers post-treatment experienced adverse events at the injection site
`that were judged related to device administration. This proportion of adverse events is
`similar to that observed in the entire CTA population 59/208 (27.7%). While most
`reactions were mild in severity, one severe case of swelling and one severe case of
`inflammation were reported.
`
`Other Clinical Studies with CT A
`
`• Extension Study and Retreatment
`
`185/191 subjects who completed the 6 month evaluation were eligible to continue in an
`extension phase of the study. All subjects who had a blinded LRS evaluation which
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`worsened by 2 or more points were eligible for CTA retreatment (which was a total of
`140 subjects). 84 of these subjects, plus an additional6 patients from the "roll-in" phase
`of the study underwent retreatment. These subjects were followed for safety for 3
`months following treatment. Please refer to Section VIII (Adverse Events) for a
`discussion of study outcomes.
`
`I 0 I Subjects who opted not to undergo retreatment as well as those who were ineligible
`for retreatment participated in the extended follow-up evaluation through 9 and 12
`months. 90 subjects were followed through 9 months and 84 subjects through 12 months.
`Please refer to Section VIII (Adverse Events) for a discussion of study outcomes.
`
`XI.
`
`CONCLUSIONS DRAWN FROM STUDIES
`
`Based on both blinded evaluator and subject assessments during the CTA0302 clinical
`study, CT A was shown to be effective and non-inferior to an approved human collagen
`dermal filler. Reasonable assurance of safety has also been demonstrated by the short
`duration and generally mild/moderate severity of adverse events observed.
`
`The in vitro and in vivo studies performed to test CT A demonstrate that: I) CT A is
`biocompatible; 2) fermented HA is comparable to avian-derived HA in all tested
`specifications and characteristics; 3) CTA produced using fermented HA is comparable
`to CTA made with avian-derived HA; and 4) the finished CTA product, when
`manufactured in accordance with the approved design outputs, meets all user
`requirements and design inputs.
`
`Therefore it is reasonable to conclude that the benefits of the use of the device for the
`target population outweigh the risks of illness or injury when used as indicated in
`accordance with the direction for use.
`
`XII. PANEL RECOMMENDATION
`
`In accordance with the provisions of section 515c(2) of the act as amended by the Safe
`Medical Devices Act of 1990, this PMA was not referred to the General and Plastic
`Surgery Devices Panel, an FDA advisory committee, for review and recommendation
`because the information in the PMA substantially duplicates information previously
`reviewed by this panel.
`
`XIII. FDA DECISION
`
`FDA issued an approval order on December 20, 2006.
`
`The applicant's manufacturing facility was inspected and was found to be in compliance
`with the Quality System Regulation (21 CFR 820).
`
`To better understand the safety of the device is patient populations that were
`underrepresented in the clinical study, the sponsor was requested to perform an open­
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`label, longitudinal, uncontrolled, Post Approval study in a minimum of I 00 patients with
`Fitzpatrick Skin Types 4, 5 or 6 at I 0 or more U.S. centers. These patients will have
`elected to undergo nasolabial fold treatment with intradermal injection of CT A and will
`be followed for a minimum of 24 weeks to assess pain, tenderness, redness, ecchymosis,
`swelling, itching, mass (nodule I cyst I abscess) formation, dermal pigmentation and
`keloid changes at the site of injection.
`
`XIV. APPROVAL SPECIFICATIONS
`
`Direction for use: See the labeling.
`
`Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings,
`Precautions and Adverse Events in the labeling.
`
`Postapproval Requirements and Restrictions: See approval order
`
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