**Summary of Safety and Effectiveness Data**

# I. General Information

> Device Generic Name: Interactive Wound Dressing
>
> Device Trade Name: INTEGRA^®^ Dermal Regeneration Template
>
> Applicant: Integra LifeSciences Corporation
>
> 311 Enterprise Drive
>
> Plainsboro, NJ 08536, USA
>
> PMA Number: P900033
>
> Supplement Number: S008
>
> Date of Notice of Approval: April 19, 2002

# II. Intended Uses/Indications

> INTEGRA^®^ Dermal Regeneration Template is indicated for the
> postexcisional treatment of life-threatening full-thickness or deep
> partial thermal injuries where sufficient autograft is not available
> at the time of excision or not desirable due to the physiological
> condition of the patient. Written requests for a copy of the Summary
> of the Safety and Effectiveness Data for this indication can be sent
> to the Dockets Management Branch (HFA-305), Food and Drug
> Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
>
> INTEGRA^®^ Dermal Regeneration Template is also indicated for the
> repair of scar contractures when other therapies have failed or when
> donor sites for repair are not sufficient or desirable due to the
> physiological condition of the patient.

# III. Device Description

> INTEGRA^®^ Dermal Regeneration Template (INTEGRA template) is a
> bilayer membrane system for skin replacement. The dermal replacement
> layer is made of a three-dimensional porous matrix of fibers of
> cross-linked bovine tendon collagen and a glycosaminoglycan (GAG)
> (chondroitin-6-sulfate) that is manufactured with a controlled
> porosity and defined degradation rate. The temporary epidermal
> substitute layer is made of synthetic polysiloxane (silicone). The
> silicone layer provides immediate wound homeostasis by controlling
> moisture flux from the dermis in a manner comparable to normal skin
> and imparts strength to the INTEGRA template.
>
> The collagen-GAG dermal layer of INTEGRA template functions as a
> biodegradable template that induces organized regeneration of dermal
> tissue ("neodermis") by the body. The pore volume fraction, average
> pore size, and degradation rate of the collagen-GAG dermal layer are
> controlled to enable tissue ingrowth and inhibit wound contraction.
> The dermal portion serves as a template for the infiltration of
> fibroblasts, macrophages, lymphocytes and endothelial cells that form
> a neovascular network. As healing progresses, native collagen is
> deposited by fibroblasts, and the collagen portion of INTEGRA template
> is biodegraded over approximately 30 days. Upon adequate
> vascularization of the dermal layer and availability of donor
> autograft tissue, the temporary silicone layer is removed and a thin,
> meshed layer of epidermal autograft is placed over the "neodermis".
> Cells from the epidermal autograft grow and form a confluent stratum
> corneum, thereby closing the wound reconstituting a functional dermis
> and epidermis.

# IV. Contraindications

> Use of INTEGRA template is contraindicated in those patients with
> known hypersensitivity to bovine collagen or chondroitin materials.
>
> INTEGRA template should not be used on clinically diagnosed infected
> wounds.

V.  **Warnings and Precautions**

> Refer to device labeling for a list of the warnings and precautions.

**VI. Alternative Practices and Procedures**

> Alternative treatments for scar contracture release include the use of
> full- or split-thickness autograft or skin flaps when sufficient donor
> sites are available. Tissue Expanders are also used in an attempt to
> increase the amount of skin available for autografting. In all cases,
> the use of autograft creates a donor wound site.

# 

# VII. Adverse Effects

> **[Reconstructive Surgery Study and Retrospective Contracture
> Reconstruction Survey]{.underline}**
>
> The following adverse events were reported in a Reconstructive Surgery
> Study involving 20 patients with 30 anatomical sites and a
> Retrospective Reconstruction Contracture Survey involving 89 patients
> and 127 anatomic sites.

Table 1: Incidence of Adverse Events in the Reconstructive Contracture
Surgery Study and

Retrospective Contracture Reconstruction Survey

+-------------------------------+-----------------+--------------------+
|                               | *               | **Retrospective**  |
|                               | *Reconstructive |                    |
|                               | Surgery Study** | **Contracture      |
|                               |                 | Reconstruction     |
|                               | **N=30 Sites**  | Survey**           |
|                               |                 |                    |
|                               |                 | **N= 127 sites**   |
+===============================+=================+====================+
| **Adverse event**             | n/N (%)         | n/N (%)            |
+-------------------------------+-----------------+--------------------+
| Infection                     | 0/30 (0.0%)     | 26/127 (20.5%)     |
+-------------------------------+-----------------+--------------------+
| Fluid under Silicone Layer    | 0/30 (0.0%)     | 18/127 (14.2%)     |
+-------------------------------+-----------------+--------------------+
| Partial graft loss (INTEGRA)  | 0/30 (0.0%)     | 2/127 (1.6%)       |
+-------------------------------+-----------------+--------------------+
| Failure to take (INTEGRA)     | 0/30 (0.0%)     | 8/127 (6.3%)       |
+-------------------------------+-----------------+--------------------+
| Shearing/Mechanical shift     | 1/30 (3.3%)     | 6/127 (4.7%)       |
| (loss of INTEGRA)             |                 |                    |
+-------------------------------+-----------------+--------------------+
| Hematoma                      | 5/30 (16.7%)    | 3/127 (2.3%)       |
+-------------------------------+-----------------+--------------------+
| Granulation tissue formation  | 0/30 (0.0%)     | 4/127 (3.1%)       |
+-------------------------------+-----------------+--------------------+
| Delayed Healing               | 0/30 (0.0%)     | 1/127 (0.8%)       |
+-------------------------------+-----------------+--------------------+
| Separation of the Silicone    | 0/30 (0.0%)     | 1/127 (0.8%)       |
| Layer                         |                 |                    |
+-------------------------------+-----------------+--------------------+
| Seroma                        | 0/30 (0.0%)     | 1/127 (0.8%)       |
+-------------------------------+-----------------+--------------------+
| Pruritis                      | 0/30 (0.0%)     | 1/127 (0.8%)       |
+-------------------------------+-----------------+--------------------+
| Epidermal autograft loss      | 2/30 (6.7%)     | 7/127 (5.5%)       |
| \>15%                         |                 |                    |
+-------------------------------+-----------------+--------------------+
| Epidermal autograft loss      | 7/30 (23.3)     | 9/127 (7.1%)       |
| \<15%                         |                 |                    |
+-------------------------------+-----------------+--------------------+

> There was no mortality reported in either the Reconstructive Surgery
> Study or the Retrospective Contracture Reconstruction Survey. There
> were no reports of infection in the Reconstructive Surgery Study. In
> the Retrospective Contracture Reconstruction Survey the overall
> infection rate reported for INTEGRA template-treated wound sites was
> 20.5% (26 of 127 sites). The consequence of infection at Integra
> treated sites included partial and complete INTEGRA template graft
> loss.
>
> Information about the adverse events observed in the treatment of
> patients with life threatening thermal injuries can be found in the
> summary of safety and effectiveness document (SSED) for P900033 and in
> device labeling which is attached.

# 

# VIII. Marketing History

> FDA approved the original PMA for INTEGRA^^ Dermal Regeneration
> Template for the burn indication on March 1, 1996.
>
> INTEGRA^^ Dermal Regeneration Template is approved for marketing for
> burns and reconstructive surgery in the European Union, Argentina,
> Australia, Brazil, Canada, Chile, China, Dominican Republic, El
> Salvador, Hong Kong, Korea, Mexico, New Zealand, Panama, Singapore,
> Taiwan, Thailand and Uruguay.
>
> The device has not been recalled or withdrawn for any reason related
> to the safety or effectiveness of the device.

# IX. Summary of Preclinical Studies

> The testing performed in the original application was adequate to
> support the safety and effectiveness of the device for the treatment
> of patients with life-threatening thermal injuries. A summary of this
> testing can be found in the SSED for P900033.

**X. Clinical Study and Survey for Contracture Reconstruction**

#### 

> The clinical data provided in the original application were sufficient
> to provide a reasonable assurance of safety and effectiveness for the
> treatment of patients with life-threatening thermal injuries.
>
> The following is a summary of the clinical data to support approval
> for the indication of contracture reconstruction.

**A. [Reconstructive Surgery Study]{.underline}**

> [Study Design and Methods]{.underline} - This study was a prospective,
> non-randomized assessment of the use of INTEGRA^®^ Dermal Regeneration
> Template for the reconstructive surgery of scars and contractures.
> Scars were excised and INTEGRA template was applied to excised wound
> sites. Following formation of the neodermis, the INTEGRA template
> silicone layer was removed and a thin epidermal autograft applied. A
> 4-mm punch biopsy was performed weekly on the first 10 patients in the
> series prior to removal of the INTEGRA template silicone layer. A 4-mm
> punch biopsy was performed on all patients before removal of the
> silicone layer and at monthly intervals for as long as two years.
> Biopsy specimens were preserved, paraffin sections prepared, and
> evaluated.
>
> [Study Endpoints]{.underline} - Postoperative function and cosmesis
> were compared with the pre-operative status. An independent review
> panel assessed the patients using a modified Vancouver Burn Scar
> Assessment Scale. Pigmentation, vascularity, pliability and scar
> heights were assessed independently, with increasing score being
> assigned to a greater pathological condition. A score of 0 is normal
> (i.e., no scar) and score of 15 represents the worst scar.
>
> Patients or their parents assessed treatment outcomes at least 3
> months after the second stage of the reconstruction. A visual analog
> scale was used in which a score of 0%=preoperative scar and a score of
> 100%=normal skin with no scar. Parameters evaluated included range of
> motion, softness, appearance, pruritus and dryness of the scar.
>
> [Results]{.underline} - A series of 20 consecutive patients with 30
> scar contracture sites were surgically treated to reconstruct the skin
> following acute burn surgery. The most common reasons for surgery were
> scar contracture release (19) and painful scars (6). The other reasons
> were resurfacing of scars (5), tight scars (4) and donor site (1).
>
> > Independent assessment using the modified Vancouver Burn Scar
> > Assessment Scale showed an average improvement from a total score of
> > 13.3 preoperatively to a score of 9.0 post-operatively.
>
> > For the patient satisfaction assessments, patients/parents reported
> > mean scores of 72% for range of movement, 62% for softness, 59% for
> > appearance, 27% for pruritis and 14% for dryness.
>
> [Results-Histopathology]{.underline} - Serial histologic microscopic
> examinations were performed on preserved (10% formalin and paraffin
> wax) and stained (hematoxylin and eosin) wound biopsies from patients
> treated with INTEGRA Dermal Regeneration Template. These observations
> revealed, in general, four phases of integration. The earliest phase
> is characterized by the accumulation of wound fluid and adherence of
> the matrix to the wound. This is followed by the second phase, which
> is characterized by the accumulation of myofibroblasts in the dermal
> matrix. The third phase is characterized by the migration of
> endothelial cells and the establishment of new blood vessels. The
> fourth phase starts when the matrix has been populated with
> fibroblasts and new collagen gradually replaces the bovine collagen of
> the Dermal Regeneration Template. The observed histologic phases seen
> with INTEGRA Dermal Regeneration Template are similar to wound-healing
> phases and skin graft "take" seen with standard skin grafting.

## B. [Retrospective Contracture Reconstruction Survey]{.underline}

> These data were collected in a retrospective convenience survey of
> surgeons known to use INTEGRA^®^ Dermal Regeneration Template for
> reconstructive surgery. Information was received from 13 of 19
> physicians surveyed who reported on 89 patients and 127 anatomic
> sites. The demographic profile for the reported patients was: mean age
> 24.8, age range \<1 to 72, gender 52 males and 37 females. Surgeons
> were requested to report on all treated patients regardless of
> outcome. However, it is not known whether the surgeons reported on all
> the patients receiving INTEGRA for contracture reconstruction in their
> practices. The surgeons or their staff completed case report forms
> reporting their experiences, including patient safety information.
> Available data were abstracted from the patients' medical records.
>
> Data were reported for eighty-nine patients with 127 contracture
> revision sites who were treated with INTEGRA template. All the treated
> patients for whom data were reported were trauma victims with
> permanent impairments, disabilities and disfigurements from their
> original injuries. The most common etiology was a thermal injury; 112
> sites (88.8%). Reconstruction occurred from a few months up to 20
> years after the initial injury. Children made up 47.2% of the
> population, 20.2% of the patients were 10 years old or less and 27.0%
> were between 11 and 20 years old.
>
> The anatomical sites requiring reconstruction varied among the
> patients included in the survey. The most common sites were head and
> neck 32 sites (25.2%), upper extremities - 20 sites (15.7%), hand --
> 17 sites (13.4%), lower extremities -- 17 sites (13.4%), and Axilla --
> 15 sites (11.8%). Other sites included: Chest (7.1%), groin/genitalia
> (4.7%), abdomen (3.1%), back (1.6%) and other (0.8%).
>
> Safety information obtained from this survey is reported in Table 1.

# XI. Conclusions

> The data presented in this PMA supplement, coupled with the extensive
> safety and effectiveness data and reports of clinical experience
> available on INTEGRA dermal regeneration template for a similar
> indication, provide reasonable assurance of the safety and
> effectiveness of this device. The INTEGRA Dermal Regeneration Template
> provides a reasonable, alternative method for reconstructing
> contractures that have failed standard therapy or are associated with
> physical or logistical factors that preclude the use of a routine
> graft and/or flap procedure.

**XII. Gender Bias**

> No selection bias because of gender was identified during the review
> of the submission and no significant gender differences were noted in
> the clinical studies. The ratio of male to female patient enrollment
> in the studies is reflective of the type and frequency of the wounds
> and their underlying distribution in the general population.

# XIII. Panel Recommendations

> Pursuant to section 515 (c) (2) of the Food, Drug and Cosmetic Act
> (the Act) as amended by the Safe Medical Devices Act of 1990 this PMA
> supplement was not referred to the General and Plastic Surgery Panel
> and FDA advisory panel for review and recommendation. This is because
> the information in this PMA supplement substantially duplicates
> information previously reviewed by this panel.

# XIV. CDRH Decision

> Based upon a review of the data contained in this panel track
> supplement, CDRH determined that the INTEGRA dermal regeneration
> template has been shown to be safe and effective for the indication
> specified in this labeling.
>
> FDA issued an approval order on April 19, 2002

**XV. Approval Specifications**

> Directions for Use: See product labeling.
>
> Hazard to Health from Use of the Device: See Indications,
> Contraindications, Warnings, and Precautions, Adverse Reactions in the
> labeling.
>
> Postapproval Requirement and Restrictions: See the approval order.