Hylaform P030032

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Hylaform P030032

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

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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

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Hylaform Pre-Clinical Review

• David Krause, Ph.D.
• General and Plastic Surgery Devices Panel
• November 21, 2003

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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

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Pre-Clinical Biocompatibility Testing (Cont.)

• Cytotoxicity
• Acute Systemic Toxicity
• Hemocompatibility
• Implantation
• Muscle Implantation (7-days)
• Muscle Implantation (30-days)

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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

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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.)

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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.

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Objectives- Clinical

• To provide a summary of Genzymes Hylaform
  Clinical Study
• To highlight issues pertaining to the safety and
  effectiveness of the study device

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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

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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.

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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.

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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

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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

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Treatment Protocol

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

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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

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Treatment Protocol

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

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Treatment Procedures

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

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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

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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

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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

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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

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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.

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Patient Accounting- 12 weeks
Hylaform Zyplast
Pt. Enrolled, Randomized 133 128

Pt. lost to follow-up 10 11

Pt. discontinued due to AE 0 2

Pt. Evaluated 123/133 117/128
Actual Follow-up 92.4 91.4
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Baseline Wrinkle Severity

• Investigators 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)
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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) (0, 5)
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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)
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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)
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Adverse Events

• Initial Phase

Adverse Event Hylaform N133 Zyplast N128 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-AEs 0 0 0 2 2 2 Serious Adverse Events 1 1 1 0 0 0 Severe Adverse Event 3 2 3 7 6 7
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Adverse Events

• Initial Phase- procedure related

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Adverse Events

• Repeat treatment Phase

Adverse Event Hylaform N96 Hylaform Plus N96 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-AEs 0 0 0 0 0 0 Serious Adverse Events 1 1 1 1 1 1 Severe Adverse Event 0 0 0 1 1 2
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Adverse Events

• Repeat Treatment Phase Procedure Related

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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)

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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)

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Patient Assessment of Treatment Group Assignment
Patient Assessment Hylaform N 133 Zyplast N128
Hylaform 36 (27.1) 25 (19.5)
Zyplast 18 (13.5) 31 (24.2)
I do not know 76 (57.1) 69 (53.9)
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Conclusions

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

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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.

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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?

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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?

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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.

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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?