Hylaform P030032

Herbert Lerner, M.D.

General and Plastic Surgery Devices PanelNovember 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 PanelNovember 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 ZyplastPt. Enrolled, Randomized 133 128

Pt. lost to follow-up 10 11

Pt. discontinued due to AE 0 2

Pt. Evaluated 123/133 117/128Actual 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 3.5 3.5

SD 0.46 0.46

Min/Max (3, 5) (3, 5)

Baseline Wrinkle Severity Independent Panel Review- Day

0Hylaform

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) (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 2.0

SD 1.11 1.12

Min/Max (0, 5) (0, 5)

Adverse Events Initial Phase

Adverse Event Hylaform N=133 Zyplast N=128 n % Events n % Events

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

Adverse Events Initial Phase- procedure related

Primary System Organ Class/Preffered Term

n (%) Events

n (%) EventsAt least 1 adverse event 111 84 281 109 85 259

General disorders 111 84 274 109 85 258Injection site erythema 84 63 92 86 67 94

Injection site bruising 54 41 59 39 31 39

Injection site swelling 47 35 50 53 41 54

Injection site pain 42 32 44 29 23 32

Injection site pruritus 10 8 12 11 9 11

Hylaform

N = 133

Zyplast

N = 128

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 286Procedure related 87 91 267 92 96 283Not procedure-related 2 2 2 3 3 3Deaths 0 0 0 0 0 0Discontinued-AE’s 0 0 0 0 0 0Serious Adverse Events 1 1 1 1 1 1Severe Adverse Event 0 0 0 1 1 2

Adverse Events Repeat Treatment Phase – Procedure

Related

N (%) E N (%) E

At least 1 adverse event 87 91 269 92 96 286

General disorders 87 91 265 92 96 282

Injection site erythema 72 75 73 70 73 72

Injection site swelling 50 52 50 50 52 50

Injection site pain 49 51 49 54 56 55

Injection site bruising 34 35 34 41 43 41

Injection site nodule 22 23 22 25 26 25

Injection site pruritus 11 12 11 10 10 11

Hylaform Plus Side

N = 96Primary System Organ Class/Preferred Term

Hylaform Side

N = 96

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

Patient Assessment HylaformN= 133

ZyplastN=128

Hylaform 36 (27.1) 25 (19.5)

Zyplast 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?