Hylaform p030032
Download
1 / 41

PPT - PowerPoint PPT Presentation


  • 440 Views
  • Updated On :

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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'PPT' - RoyLauris


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Hylaform p030032 l.jpg

Hylaform P030032

Herbert Lerner, M.D.

General and Plastic Surgery Devices Panel

November 21, 2003


Reviewers for fda l.jpg
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 l.jpg

Hylaform Pre-Clinical Review

David Krause, Ph.D.

General and Plastic Surgery Devices Panel

November 21, 2003


Pre clinical biocompatibility testing l.jpg
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 l.jpg
Pre-Clinical Biocompatibility Testing (Cont.)

  • Cytotoxicity

  • Acute Systemic Toxicity

  • Hemocompatibility

  • Implantation

    • Muscle Implantation (7-days)

    • Muscle Implantation (30-days)


Pre clinical biocompatibility testing cont6 l.jpg
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 cont7 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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.


Design12 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
Treatment Protocol

  • Initial Phase

    • Screening

    • Collagen skin test x2

    • Randomization

    • Treatment

      • Can have “touch-up” at 2 weeks


Treatment procedures l.jpg
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 protocol17 l.jpg
Treatment Protocol

  • Repeat Phase- offered to Hylaform patients only

    • Must have finished initial phase

    • Randomization

    • Treatment

      • Hylaform or Hylaform Plus


Treatment procedures18 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 endpoints22 l.jpg
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 l.jpg
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.



Baseline wrinkle severity l.jpg
Baseline Wrinkle Severity

  • Investigator’s Live Assessment- Day 0


Baseline wrinkle severity26 l.jpg
Baseline Wrinkle Severity

  • Independent Panel Review- Day 0


Endpoint wrinkle severity l.jpg
Endpoint Wrinkle Severity

  • Investigators Live Assessment- Week 12


Endpoint wrinkle severity28 l.jpg
Endpoint Wrinkle Severity

  • Independent Panel Review- Week 12


Adverse events l.jpg
Adverse Events

  • Initial Phase


Adverse events30 l.jpg
Adverse Events

  • Initial Phase- procedure related


Adverse events31 l.jpg
Adverse Events

  • Repeat treatment Phase


Adverse events32 l.jpg
Adverse Events

  • Repeat Treatment Phase – Procedure Related


Immunologic response l.jpg
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 l.jpg
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%)



Conclusions l.jpg
Conclusions

  • Adverse events were similar in both groups

  • The improvement of wrinkle severity at 12 weeks was comparable.


Panel question 1 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg
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?


ad