General and Plastic Surgery Devices Panel Hylaform P030032 Herbert Lerner, M.D. General and Plastic Surgery Devices Panel November 21, 2003

REVIEWERS FOR FDA Herbert Lerner, MD- Lead and Clinical David Krause, PhD- Pre-clinical Phyllis Silverman, MS- Statistics David Kaplan- Pre-Clinical Peggy Mayo- OC/GMP Linda Godfrey- OC/BIMO Jack McCracken & Mary Lou Pijar- Labeling

Hylaform Pre-Clinical Review David Krause, Ph.D. General and Plastic Surgery Devices Panel November 21, 2003

Pre-Clinical Biocompatibility Testing Hylaform has successfully passed testing for: Irritation: Intracutaneous Toxicity Subcutaneous Implantation Sensitization and Immunogenicity Immunization Subchronic Toxicity Guinea Pig Dermal Sensitization Delayed Contact Sensitization

Pre-Clinical Biocompatibility Testing (Cont.) Cytotoxicity Acute Systemic Toxicity Hemocompatibility Implantation Muscle Implantation (7-days) Muscle Implantation (30-days)

Pre-Clinical Biocompatibility Testing (Cont.) Mutagenicity: Ames Mutagenicity Test Test for Induction of HGPRT Gene Mutation Chromosome Aberrations Test for Morphological Cell Transformation Subchronic Toxicity Subchronic Intraperitoneal Toxicity (2-weeks) Immunization and Subchronic Toxicity

Pre-Clinical Biocompatibility Testing (Cont.) Chronic Toxicity and Carcinogenicity: One-year Subcutaneous Toxicity Study Reproductive Effects Study: Pharmacokinetics: Intradermal Injection of Radiolabeled Hylan B Distribution of Radiolabeled Hylan B Pharmacodynamics: Intradermal & Subcutaneous Injection (6-Mo.)

Pre-Clinical Testing Formaldehyde Question: Hylaform contains less than 2.3 ppm (ug/g) of formaldehyde in a 1 cc injection. Would multiple injections of Hylaform lead to locally elevated levels of formaldehyde? Normal tissue levels of formaldehyde are between 3 and 12 ug/g. Multiple injections over a number of months would not lead to elevated levels of formaldehyde.

Objectives- Clinical To provide a summary of Genzyme’s Hylaform Clinical Study To highlight issues pertaining to the safety and effectiveness of the study device

Hylaform Study Purpose To evaluate the safety and effectiveness of Hylaform viscoelastic gel when used for cosmetic correction of contour deformities of the dermis of the face

Design Prospective, multi-center, randomized, double-blinded, parallel-group study comparing Hylaform and Zyplast in the nasolabial fold during the initial 12 week treatment, and Hylaform and Hylaform Plus during the extended treatment period.

Design The sponsor has not included any efficiency data for the extended treatment phase of the study, and only 4 week safety data for possible immunological responses were presented in the PMA. The sponsor does not seek approval for Hylaform Plus at this time.

Inclusion Criteria Wrinkle Severity Score of 3 or 4 on the six point grading scale Negative skin test to Collagen Test Implant Two fixed facial sites, fully visible nasolabial folds, which were both candidates for correction

Exclusion Criteria Known, prior or present positive skin test to Collagen Test Implant Received prior therapy (dermabrasion, facelift) during previous six months Previous tissue augmentation or other wrinkle/fold therapies within the past six months

Treatment Protocol Initial Phase Screening Collagen skin test x2 Randomization Treatment Can have “touch-up” at 2 weeks

Treatment Procedures Initial Phase Both nasolabial folds treated Photographs taken at all treatment sessions Investigator Wrinkle Assessments “Touch-up” at 2 weeks Follow-up for 12 weeks

Treatment Protocol Repeat Phase- offered to Hylaform patients only Must have finished initial phase Randomization Treatment Hylaform or Hylaform Plus

Treatment Procedures Repeat Phase Hylaform and Hylaform Plus Investigator Assessment Photographs at each follow-up visit Patient global assessment at each visit

Follow-up Protocol Initial Phase- after skin testing and randomization Day 0, Day 3, Week 2,4,8, and 12 If “touch-up” start above from date of procedure

Wrinkle Assessment Scale A validated 6 point reference scale, with reference photographs, that classifies deep facial wrinkles (nasolabial folds) Zero represents no lines/folds 5 represents severe lines/folds

Clinical Endpoints Primary Phase Evaluate the Efficacy (non-inferiority) of Hylaform for the correction of nasolabial folds as compared to Zyplast®. This was done using serial photograpic documentation and blinded IPR scores at week 12 Evaluate the Safety of Hylaform as compared to Zyplast- determined by rates of adverse events associated with the use of each product

Clinical Endpoints Repeat Phase Evaluate the safety of repeat treatment with hylan B gel products In particular, the sponsor added this phase to assess the safety of the device after repeat maintenance doses by determining the presence or absence of an immunologic response by measuring serum hylan B (IgG) antibodies Evaluate the efficacy (non-inferiority) of Hylaform Plus vs. Hylaform for the correction of nasolabial fold contour defects

Demographics Both groups were comparable with respect to Age Male: Female Ethnicity Smoking History Sun Exposure Height/Weight Approx. 80% of the enrolled patients were Caucasian females, with only 3 African-Americans and 16 Hispanics in the Hylaform group.

Patient Accounting- 12 weeks Hylaform Zyplast Pt. Enrolled, Randomized 133 128 Pt. lost to follow-up 10 11 Pt. discontinued due to AE 2 Pt. Evaluated 123/133 117/128 Actual Follow-up 92.4% 91.4%

Baseline Wrinkle Severity Investigator’s Live Assessment- Day 0 Hylaform Zyplast N (nasolabial folds) 266 256 Mean 3.5 3.6 Median SD 0.46 Min/Max (3, 5)

Baseline Wrinkle Severity Independent Panel Review- Day 0 Hylaform Zyplast N (nasolabial folds) 256 252 Mean 2.2 2.3 Median 2.0 2.5 SD 1.02 1.04 Min/Max (0, 5)

Endpoint Wrinkle Severity Investigators Live Assessment- Week 12 Hylaform Zyplast N (nasolabial folds) 260 250 Mean 2.4 2.3 Median 2.5 2.0 SD 0.86 0.93 Min/Max (0, 5) (0, 4)

Endpoint Wrinkle Severity Independent Panel Review- Week 12 Hylaform Zyplast N (nasolabial folds) 246 234 Mean 2.3 2.2 Median 2.0 SD 1.11 1.12 Min/Max (0, 5)

Adverse Events Initial Phase At least 1 AE 117 88 342 112 88 322 Adverse Event Hylaform N=133 Zyplast N=128 n % Events n % Events At least 1 AE 117 88 342 112 88 322 Procedure related 111 84 281 109 85 259 Not procedure-related 39 29 61 43 34 63 Deaths 0 0 0 0 0 0 Discontinued-AE’s 0 0 0 2 2 2 Serious Adverse Events 1 1 1 0 0 0 Severe Adverse Event 3 2 3 7 6 7

Adverse Events Initial Phase- procedure related

Adverse Events Repeat treatment Phase Adverse Event Hylaform N=96 Hylaform Plus N=96 n % Events n % Events At least 1 AE 87 91 269 92 96 286 Procedure related 87 91 267 92 96 283 Not procedure-related 2 2 2 3 3 3 Deaths 0 0 0 0 0 0 Discontinued-AE’s 0 0 0 0 0 0 Serious Adverse Events 1 1 1 1 1 1 Severe Adverse Event 0 0 0 1 1 2

Adverse Events Repeat Treatment Phase – Procedure Related

Immunologic Response Serum IgG levels during Repeat Phase to demonstrate a response to repeat treatments of Hylaform No immunologic response demonstrated (no patients had a 4-fold increase in IgG levels during repeat treatment) .

Duration of Effect Percent returning to IPR baseline- At 2 weeks- 38.2% (control 21.9%) At 4 weeks- 56.1% (control 26.3%) At 8 weeks- 68.9% (control 46.7%) At 12 weeks- 73.3% (control 65.1%)

Patient Assessment of Treatment Group Assignment Hylaform N= 133 Zyplast N=128 36 (27.1) 25 (19.5) 18 (13.5) 31 (24.2) I do not know 76 (57.1) 69 (53.9)

Conclusions Adverse events were similar in both groups The improvement of wrinkle severity at 12 weeks was comparable.

Panel Question-1 21 CFR 860.7(d)(1) states that there is a reasonable assurance that the device is safe when it can be determined that the probable benefits to health from use of the device for its intended uses, when accompanied by adequate instructions for use and warnings against unsafe use, outweigh any probable risks. Considering the data in the PMA, please comment on whether there is a reasonable assurance that the device is safe.

Panel Question-2 21 CFR 860.7(e)(1) states that there is a reasonable assurance that a device is effective when it can be determined, based on valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will produce clinically significant results. Considering the data in the PMA, is there reasonable assurance that the device is effective?

Panel Question-3 Only three African-American patients were enrolled in the Hylaform clinical study. There were 16 Hispanic, 5 Asian and 5 “Others”. If the device is approved, should the sponsor be required to conduct a post-approval study to collect safety data on specific minorities? Is specific labeling needed to address potential use in minorities that may be at a higher risk for adverse clinical outcome, e.g., African Americans?

Panel Question-4 The sponsor proposes the following indications for use: “Hylaform is intended for the correction of soft tissue contour deficiencies, such as wrinkles and acne scars.” Please discuss the adequacy of these indications based on the fact that only nasolabial folds were treated in the PMA.

Panel Question- 5 As shown by Genzyme, the duration of effect of this device is short, and multiple maintenance doses will be needed to maintain the desired cosmetic effects. To assess safety of these repeated doses the sponsor has provided serum hylan B IgG levels for the repeat study population. Clinically, no significant changes in adverse events were noted in this group. Does this data support the safety of the device for repeated use, or do you believe that a post-approval study is needed to address this issue?