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`SUMMARY REVIEW MEMO TEMPLATE
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`JANUARY 6, 2010
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`(b)(6)
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`P050047/S005
`JUVEDERM ULTRA XC AND JUVEDERM ULTRA PLUS XC
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` PHD
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`(b)(6)
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`THE RECORD
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`DATE:
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`FROM:
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`SUBJECT:
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`CONTACT:
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`TO:
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`BACKGROUND/ REASON FOR SUPPLEMENT
`P050047/S005 is a 180 Day Supplement for two wrinkle filler devices with
`lidocaine, Juvederm Ultra XC and Juvederm Ultra Plus XC. The 2 devices were
`studied in a clinical trial under G070227. The devices are identical to the approved
`Juvederm Ultra and Juvederm Ultra Plus (P050047) except for the addition of
`lidocaine. The purpose of adding lidocaine to the wrinkle fillers is to reduce pain
`upon injection.
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`REVIEW TEAM
`Table 1 below lists the participants in this review team and the section of the PMA
`that was reviewed:
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`Reviewer
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`Lead Reviewer
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`Role
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`(b)(6)
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`(b)(6)
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`(b)(6)
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`(b)(6)
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`(b)(6)
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`(b)(6)
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`Clinical Reviewer
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`Statistics Reviewer
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`BIMO Reviewer
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`GMP Reviewer
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`Patient Labeling Reviewer
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`Lidocaine/Stability Study Reviewer
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`CDRH/ODE/DGRND/PRSB
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`(b)(6) MD, MPH
`CDRH/ODE/DGRND/PRSB
` PhD
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`CDRH/OSB/DBS
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` PEBA
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` EA/GSD
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`CDRH/OCER/DUPSA/OPPB
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` PhD
`CDER/OPS/ONDQA/DPA I
`Table 1: Review team for P050047/S005
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`Exhibit 1060
`Prollenium v. Allergan
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`INDICATIONS FOR USE
`Juvederm Ultra XC and Juvederm Ultra Plus XC are indicated for injection into the mid
`to deep dermis for correction of moderate to severe facial wrinkles and folds (such as
`nasolabial folds).
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`DEVICE DESCRIPTION
`Juvederm Ultra XC and Juvederm Ultra Plus XC are biodegradable, non-pyrogenic,
`viscoelastic, clear, colorless, homogenized gel implant. They consist of stabilized,
`hyaluronic acid (HA) produced by Streptococcus equi bacteria, formulated to a
`concentration of 24 mg/ml in a physiological buffer, along with 0.3% lidocaine.
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`PRECLINICAL/BENCH
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`Biocompatibility
`Both Juvederm Ultra XC and Juvederm Ultra Plus XC, are considered implantable
`materials, in contact with tissue and bone for greater than 30 days based on ISO 10993-1.
`As such biocompatibility testing was performed on both formulations in conformance to
`Good Laboratory Practices (GLPs) and ISO 10993-1. The final product concentrations
`were tested for: cytotoxicity, dermal sensitization, intradermal/intracutaneous reactivity,
`acute systemic toxicity, pyrogenicity, subchronic toxicity (12 week), genotoxicity
`(bacterial reverse mutation, chromosomal aberration, and micronucleus study), muscle
`implantation (4 week & 12 week), inflammatory response and bacterial endotoxin. Based
`on the results of the biocompatibility testing, the products were found to be
`biocompatible.
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`Stability Data
`Six month stability studies were conducted with each product being stored under long-
`term and intermediate conditions. The lidocaine reveiewer stated that based on the data,
`which show no trend in lidocaine-related degradants, a shelf life of 12 months is
`recommended for each product stored at USP controlled room temperature (25˚C with
`excursions permitted to 15˚C – 30˚C).
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`CLINICAL DATA
`The study was a multicenter, double blinded, randomized, within-subject controlled study
`of the safety and effectiveness of JUVEDERM™ Injectable Gel with Lidocaine
`compared with JUVEDERM Injectable Gel without Lidocaine in Subjects desiring
`correction of their nasolabial folds (NLFs). There were 2 cohorts to this study: (1)
`Juvederm Ultra vs. Juvederm Ultra XC and (2) Juvederm Ultra Plus vs. Juvederm Ultra
`Plus XC. The purpose of the study was to examine the effectiveness of the addition of
`lidocaine in reducing procedural pain (pain during treatment). The duration of the study
`was 2 weeks. Subjects received a single treatment of Juvederm Ultra or Ultra Plus in one
`NLF and Juvederm Ultra Plus XC or Ultra Plus XC in the other NLF. Within 30 minutes
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`after both NLFs were treated, the subjects rated procedural pain on an 11-point scale and
`a 5-point comparative scale. Both the Investigators and subjects rated NLF severity at
`baseline and 2 weeks after treatment using the 5-point NLF severity scale from the
`pivotal study. Subjects utilized an interactive voice response system diary to record
`common treatment site reactions for 14 days.
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`There were 72 subjects enrolled and randomized in the study, including 36 subjects
`enrolled in the Juvederm Ultra cohort and 36 subjects enrolled in the Juvederm Ultra Plus
`cohort. Most of the subjects were women (96%) of Caucasian descent (78%) with
`Fitzpatrick Skin Types II or III (68%). Fitzpatrick Skin Types IV, V, or VI comprised
`28% of treated subjects. The median age at study entry was 53 years. The demographics
`are summarized in table 2 below:
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`Table 2: Demographics of subjects in study
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`The comparative procedure pain score results show that 64% of subjects reported
`Juvederm with lidocaine (referred to as JULIDO) as less painful and 29% of subjects
`reported Juvederm with lidocaine as slightly less painful than Juvederm (referred to as
`JUVDRM). The results are summarized in table 3 below:
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`Table 3: Subject comparison of comparative procedural pain score
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`NLF severity scores for all formulations of Juvederm improved more than 1 point after
`treatment. The results are summarized in table 4 below:
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`Table 4: Assessment of NLF Severity
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`Both Juvederm with lidocaine and Juvederm had similar safety profiles. Tables 5-7
`summarize the adverse events by severity, duration and product, respectively.
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`Table 5: Summary of AE by severity
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`Table 6: Summary of AE by duration
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`Table 7: Summary of AE by product
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`The clinician stated that overall, the safety profile of the Juvederm devices with lidocaine
`is reportedly very similar to the safety profile of the device without lidocaine. She noted
`that many adverse events occurred more often in the study device as compared to the
`control. She noted that although it is not a major issue, this information should be
`included in the labeling. The sponsor included tables for injection site responses by
`maximum severity and a table for duration of injection site responses in their labeling.
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`The statistician stated that there does not appear to be any significant site-by-treatment
`interaction, or significant differences between the proposed device and the control. He
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`states that we can accept the results as showing that Juvederm with lidocaine is
`comparable to Juvederm in terms of safety.
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`SUMMARY OF INTERACTIVE REVIEW/CORRESPONDENCE
`There were three Not Approvable letters issued under this supplement. The outstanding
`issues of the first letter included insufficient stability data, reported adverse events and
`the calculated statistics of the study. The issues of the second and third letters were
`insufficient stability data.
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`The recurring issue with the stability data was that data did not support the proposed shelf
`life. There were degradants produced as a result of storage, that were not adequately
`accounted for in the study. In the response to the third letter, the sponsor provided
`adequate data to account for the degradants and to support a 12 month shelf life.
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`CONCLUSION
`The clinical data showed that both clinically and statistically, Juvederm with lidocaine
`had a similar safety profile as Juvederm. Based on the stability data, all degradants of the
`product were adequately analyzed. Based on review of the quality system and manufacturing
`information section and the quality manual, the manufacturing of the products are adequate.
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`RECOMMENDATION - I recommend that the supplement be Approved.
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`Date
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`Reviewer name
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`Name, Chief, Branch Date
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