Product Approval Information

Summary Basis for Regulatory Action

Date	March 11, 2008
From	Laura Wood, Committee Chair
Subject	Summary Basis for Regulatory Action
BLA # Supplement#	STN 125266/0
Applicant	Baxter Healthcare Corporation
Date of Submission	June 1, 2007
PDUFA Goal Date	March 31, 2008
Proprietary Name / Established (USAN) names	ARTISS / Fibrin Sealant VH S/D 4 (Human)
Dosage forms	Lyophilized or frozen, 2-. 4-. and 10-mL
Proposed Indication(s)	Adhering of autologous skin grafts to surgically prepared wound beds resulting from burns in adult and pediatric populations
Recommended Action:	Approval
Signatory Authority(ies) Action	Basil Golding____________________________ Offices Signatory Authority: □ I concur with the summary review □ I concur with the summary review and include a separate review or addendum to add further analysis □ I do not concur with the summary review and include a separate review or addendum

Material Reviewed/ Consulted List of specific documentation used in compiling SBRA
Clinical Review	Kimberly Lindsey
Statistical Review	Boris Zaslavsky
Pharmacology/ Toxicology Review	Paul Buehler
CMC Review/Facilities	Laura Wood and Joseph D. Doleski
EIR	N/A
Biomonitoring Review	Robert Wesley
Advisory Committee Transcript	N/A
Labeling	Jean Makie

1. Introduction

Baxter Healthcare Corporation has submitted an original BLA application for Fibrin Sealant, VH S/D 4 (Human) [ARTISST], in frozen and lyophilized forms, for the indication to adhere autologous skin grafts to surgically prepared wound beds resulting from burns in adult and pediatric populations. This product is nearly identical to Baxter's previously licensed fibrin sealant (TISSEEL®), the difference being the much lower concentration of thrombin in the new product. The clinical indication is also different, involving the adhesion of skin grafts in burn patients. Therefore, the clinical data were of primary importance in the review of this submission.

2. Background

Fibrin sealing imitates the final steps of blood coagulation with concentrated solutions of fibrinogen and thrombin. Upon mixing of these two biologic components, along with calcium chloride, soluble fibrinogen is transformed into fibrin that reduces bleeding and/or adheres skin grafts to a wound surface. A fibrinolysis inhibitor, i.e., aprotinin (synthetic), precludes premature fibrinolysis, which might cause re-bleeding or detachment of sealed or glued tissue parts. The concentration of thrombin directly influences coagulation properties. Rapid hemostasis and sealing can be achieved with high amounts of thrombin (as in Baxter Healthcare Corporation's approved product, TISSEEL®) resulting in virtually immediate clot formation. Thrombin concentrations of 500 IU/ml are usually used for surgical procedures where hemostasis and sealing have to be as fast as possible. However, in situations when time for additional handling is needed after applying the sealant, low thrombin concentrations (e.g. 4 IU/ml in ARTISS) are of advantage since the clotting time is prolonged. Fibrin sealant offers an alternative to the use of staples or sutures to secure skin grafts. ------------------------------------------------------------------------------------------------------------------------------------
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3. Chemistry, Manufacturing and Controls (CMC) and Facilities

CMC

ARTISS was developed in parallel to TISSEEL Fibrin Sealant, which was approved by FDA on 7 February 2000 (BL 103980). Except for the difference in final thrombin concentration (4 IU/mL vs. 500 IU/mL), the manufacturing process ------------------- -- ----------

The sealer protein (containing fibrinogen) is manufactured from Source Plasma (Human) that has been tested for the presence of a number of infectious agents. The product is purified by --------------------------------------------. It undergoes solvent detergent treatment and vapor heat treatment to inactivate viruses.

The thrombin component is also manufactured from Source Plasma (Human). It is -------- purified by -------------, activation of prothrombin, and ------------ ----------------------------; it undergoes both solvent detergent treatment and vapor heat treatment for viral inactivation.

The synthetic aprotinin is produced by -----------------------------------.

The calcium chloride solution is manufactured by ------------------------------

ARTISS is presented either as a kit containing the two lyophilized biological components with their respective diluents (aprotinin solution for the Sealer Protein and calcium chloride solution for Thrombin), or as two components frozen in pre-filled syringes (Sealer Protein Solution and Thrombin Solution). Both the freeze-dried and frozen forms are supplied as 2 mL, 4 mL or 10 mL (total volume) pack sizes. Excipients in the Sealer Protein Solution include human albumin, tri-sodium citrate, histidine, niacinamide, polysorbate 80 and water for injection. The Thrombin Solution also contains human albumin, sodium chloride and water for injection.

Stability studies are ongoing. The results currently support a 24 month shelf life for the kit when stored at controlled temperatures from 2^oC to 25^oC. The reconstitution studies for the kit components show that the Sealer Protein and the Thrombin are stable for 4 hours after reconstitution when stored at room temperature (2^oC to 25^oC). Results for the frozen components also support a shelf life of 24 months when stored at ≤ -20^oC. After thawing, the components remain stable for 7 days at room temperature (up to 25^oC).

Conformance lot testing has been performed at CBER for thrombin potency in five lots of ARTISS (3 kits and 2 frozen). Potencies were within the required ranges.

Since the concentration of the thrombin component is much lower in ARTISS than in TISSEEL, we consider it advisable to place ARTISS on lot release and to test for thrombin potency. It has been noted with other thrombin products that lower concentration doses are sometimes less stable than those with higher concentrations.

The CMC reviewer (Laura Wood) finds that Baxter has provided sufficient data and information on the chemistry, manufacture and controls to support licensure of ARTISS.

Facilities

All production sites and major equipment are the ----------------------------- -------------------------------------------------------------------------------------------.

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The most recent FDA biennial inspection occurred on ----------------------- and was classified VAI. During that inspection, Baxter was cited for two FDA 483 items related to standard operating procedures for investigating product complaints and adverse reactions. The pre-approval inspections were waived, as these facilities were already --- ------- ------------ ------------ ---------- ---- by James Crim and Nancy Kirschbaum of CBER on --------- ----- ----- and the inspection was classified as VAI.

There are no ongoing or pending investigations or compliance actions with respect to the above facilities or their products. Therefore, the Office of Compliance and Biologics Quality, Division of Case Management does not object to the approval of this submission, according to Marc A. Alston, CSO.

The facilities reviewer (Joseph D. Doleski) considers this submission approvable on the basis of the facilities information provided.

4. Nonclinical Pharmacology/Toxicology

Primary toxicology was carried out in submission # STN 103980/5224, which supported approval of TISSEEL VH S/D with synthetic aprotinin at thrombin concentrations 125x the concentration present in the FS VH S/D 4 [ARTISS] product. Otherwise the TISSEEL VH S/D and FS VH S/D 4 are no different in terms of chemical composition. It is not believed that reduction in thrombin present in FS VH S/D 4 product would lead to toxicology not associated with TISSEEL VH S/D.

Dr. Paul Buehler performed this review and made the following recommendation: STN 125266/0 is approvable from a pharmacology and toxicology perspective.

5. Clinical Pharmacology

No data were provided.

6. Clinical/Statistical-Efficacy

The overall clinical development program for FS 4 IU consisted of 2 studies: a phase 1 /2 study 520001 and a phase 3 study 550201. The first study, 520001 was a phase 1 / 2 multi-center, prospective, randomized, comparative, feasibility study to assess the safety and efficacy of FS 4IU versus staples for wound healing through the facilitation of surgical closure. Study 550201 was a phase 3 multi-centered, prospective, evaluator blinded, randomized study comparing FS 4 IU VH S/D to staples for use in skin graft adherence and wound healing in subjects with burn wounds.

It should be noted that FS 4 IU and FS 4 IU VH S/D are similar products that differ with respect to the additional solvent/ detergent viral inactivation step used during the manufacture of FS 4 IU VH S/D. Furthermore, FS 4IU VH S/D used in clinical study 550201 (pivotal study) was provided in a frozen formulation , whereas the FS 4 IU used in the phase 1 /2 study was presented in a lyophilized form that required reconstitution prior to use. The sponsor plans to provide FS 4 IU VH S/D in both the frozen and lyophilized forms upon approval of the BLA.

The overall design for both studies was similar involving a comparison of the study product (FS 4IU VH S/D or FS 4IU) to the standard of care (staples). Each subject served as his/her own control and received treatment with both study product and staples at separate test sites. The following were eligibility requirements:

• Deep partial thickness or full thickness burn wounds measuring ≤40% total body surface area (TBSA),
• Ages ≥ 6 and ≤ 65 years old (clinical study 520001, subjects in Baxter clinical study 550201 were to be ≤ 65 years old including pediatric subjects of all ages.
• Test sites grafted with autologous sheet skin grafts.
• Test sites had to be either a single wound measuring between 2% and 8% TBSA that could be split into 2 halves or 2 comparable wounds each measuring between 1% and 4% TBSA.

Wound beds of both test sites were prepared prior to treatment assignment. In accordance with the predetermined randomization scheme, study product was to be used to affix skin grafts at one test site (treatment), and staples to affix skin grafts at the other test site (control). Each subject was to serve as his/her own control.

The postoperative follow-up was planned for 1 year in both studies: Baxter clinical study 520001 comprised an initial 3-month follow-up (Day 0 [grafting], Day 1, Day 5, Day 14, Day 21, Day 28, Day 35, Day 49, Day 64, and Day 91 assessments), followed by a long-term cosmetic evaluation through to the Month 12 end-of-study visit (Month 6, Month 9, and Month 12 assessments). Baxter clinical study 550201 comprised an initial assess-ment of the primary efficacy endpoint and the secondary efficacy endpoints measured up to Day 28 (Part A), followed by the long-term cosmetic follow-up that is still ongoing (Part B). The assessments for Baxter clinical study 550201 were scheduled for Day 0 [grafting], Day 1, Day 5, Day 14, Day 28, Month 3, Month 6, Month 9, and Month 12.

The main difference between the 2 studies was the use of a blinded review panel to assess the primary efficacy of endpoint of complete wound closure by Day 28 in Baxter clinical study 550201. A panel of 3 independent experts, blinded with respect to treatment assignment, reviewed photographs of the test sites in a random order and assessed whether complete wound closure had occurred (success) or not (treatment failure). In contrast, all efficacy endpoints in Baxter clinical study 520001 were assessed by the investigator at the time of examination.

Phase 2 Study (520001) "A Study To Evaluate the Safety and Efficacy of Fibrin Sealant with 4 IU/mL Thrombin, Vapor Heated, Solvent Detergent Treated (FS 4IU VH S/D) to Adhere Tissues and Improve Wound Healing" evaluated 40 treated subjects who were analyzed as a single intent-to-treat population (ITT).The study objectives were the following:

• To evaluate the adherence properties of FS 4IU when applied to autologous split-thickness, sheet skin grafts compared with the current standard of care for skin graft fixation (staples);
• To compare graft survival (% area) of wounds affixed with FS 4 IU to those affixed with staples;
• To compare surgical closure for grafts affixed with FS 4 IU to those affixed with staples
;
• To compare areas of questionable viability (% area) for grafts affixed with FS 4IU to those affixed with staples;
• To evaluate hematomas, seromas, and contracture affixed with the use of FS 4 IU and staples;
• To evaluate the effects associated with the staple removal process; and
• To evaluate the overall safety of FS 4IU used in skin grafting surgery.

This study was a multi-center, prospective randomized comparative design in which the safety and efficacy for FS 4IU was assessed for graft adherence and facilitation of surgical closure in subjects with burn wounds requiring autologous , split thickness, sheet skin graft. Subjects had to have burn wounds measuring ≤ 40% of total body surface area (TBSA) that included test areas comprising, a) either a single contiguous wound area (test area) measuring between 2% and 8% TBSA that could be divided into 2 approximate halves, or b) 2 bilateral wounds (each measuring between 1% and 4% TBSA). All test sites were either deep partial thickness or full thickness wounds. Digits, head, genitalia, palms of hands, soles of feet, and face were excluded. According to a predetermined randomization scheme, 1 test site had sheet skin grafts affixed with FS 4IU (treatment) and the other test site had sheet skin grafts affixed with staples (control), allowing each subject to serve as his/her own control.

Baxter clinical study 520001 was composed of 2 study evaluation periods: 1) An initial 3- month follow-up for all subjects; 2) A 9-month extension for all subjects who achieved surgical closure in 1 or both test sites. Postoperative study procedures and assessments for the 3-month follow-up were performed on Days 1, 5, 14, 21, 28, 35, 49, 64, and 91. These assessments included vital signs, planimetry, surgical closure, observations of hematoma and seroma formation, questionable viability, overall graft survival, photography, and the investigators' clinical impressions (categories of pigmentation, vascularity, and pliability). Days 28, 35, 49, and 64 were optional visits for subjects who achieved surgical closure in both of their test sites by Day 21. If surgical closure was not achieved in 1 or both of the test sites on the Day 21 visit, the subject returned for visits on Days 28, 35, 49, and 64 until surgical closure was achieved. Subjects who achieved surgical closure in 1 or both of their test sites within the 3-month follow-up period were eligible to enter the 9-month extension. Subjects continuing in the 9-month extension were evaluated at 6, 9 and 12 months after surgery using photography, the Vancouver Scar Scale, and other scar assessments including keloid formation and hypertrophic scarring. In addition, adverse experiences and concomitant medications were recorded throughout the study.

Each subject had either a single contiguous burn wound area measuring between 2% and 8% TBSA that was divided into 2 approximate halves, or 2 bilateral burn wounds (each measuring between 1% and 4% TBSA). Test sites were selected and labeled (Test Site A and Test Site B) before randomization to FS 4IU or staples. Randomization was based on a predetermined randomization scheme for each study site.

FS 4IU was administered intraoperatively by spray application using the TISSOMAT and Spray set. Only the DUPLOJECT system and Spray Set (connection tube with sterile filter and spray head) device was used for simultaneous spray application of the 2 solutions of the study product. A thin layer of FS 4IU was applied to the wound bed using a painting motion from side to side to achieve coverage. The recommended volume per application was approximately 0.04 to 0.06 mL/cm².

Efficacy was evaluated by the following:

• Investigator's assessment of the adherence of FS 4 IU on Day 0 using a 4-point scale (excellent, good, fair, poor)
• Hematoma and seroma formation (% area) on Day 1
• Number of hematomas and seromas on Day 1
• Questionable viability (% area) on Day 5
• Staple removal measures on Day 5
• Overall graft survival (% area) on Day 14
• Proportion of subjects achieving surgical closure on Day 5
• Time to surgical closure
• Frequency, cumulative frequency, and cumulative percent of subjects with surgical closure at each test site, assessed at each visit
• Investigators' clinical impressions of pigmentation, vascularization, and pliability on Days 5, 14, 21, 28, 35, 49, 64, and 91
• Degree of contracture on Days 5, 14, 21, and 91
• Rate of regrafting
• Vancouver Scar Scale assessments at 6, 9, and 12 months after surgery
• Incidence of keloid formation and hypertrophic scarring

The overall safety of FS 4IU was assessed by the incidence and severity of adverse experiences and changes in vital signs, clinical, and laboratory parameters.

The comparison of paired quantitative efficacy results (within subject) was made using the Wilcoxon signed rank test. The frequency of surgical closure and other categorical outcomes were evaluated using McNemar's test. Safety outcomes were tabulated.

Subject disposition:
A total of 40 subjects were enrolled at 9 of the 12 participating study sites. The number of subjects enrolled at each study site ranged from 2 to 8. All forty subjects were randomized, and 38 of 40 subjects (95%) completed the study through day 21. Thirty one of 40 subjects (77.5%) completed the 3 month follow-up and of those 31 subjects who completed the 3 month follow-up, 30 subjects entered the 9 month extension phase (96.8%). Twenty of the 30 subjects (66.7%) who entered the 9 month extension phase completed this portion of the study.

The following table describes the summary of endpoints:

Results:

• The median percent area of overall graft survival on Day 14 was 100.0% for both sites (p = 0.3525), and the percentage of subjects deemed surgically closed at Day 5 was not statistically different between the groups (p = 0.0703).
• The median time to surgical closure was 5 days for both treatments (p = 0.2383).
• More FS 4 IU-treated sites (N = 37) closed by Day 91 compared to the corresponding stapled sites (N = 32), and the FS 4 IU-treated sites closed sooner than the stapled sites.
• On Day 5, FS 4 IU-treated sites were closed in 61.5% of the subjects, whereas stapled sites were closed in only 46.2% of subjects (p = 0.0703).
• The maximum difference occurred at the Day 28 visit; 80.0% of subjects with FS 4 IU-treated sites closed, whereas only 59.0% of the subjects with stapled sites closed.
• Vancouver Scar Scale assessments of pigmentation, vascularity, pliability, and height, in addition to keloid formation and hypertrophic scarring assessments were completed postoperatively at Month 6, Month 9, and Month 12 by the investigators. There were no apparent statistically significant differences between FS 4 IU-treated sites and stapled sites were found for any of the Vancouver Scar Scale properties (i.e. pigmentation, vascularity, pliability, and height) evaluated at the 6, 9, or 12 month visits. Similarly, there were no statistically significant differences between FS 4 IU treated sites and stapled sites were found for the assessments of keloid formation and hypertrophic scarring evaluated at the 6, 9, or 12 month visits.

Exploratory analyses compared surgical closure on Day 5 for FS 4IU-treated and stapled sites using alternate definitions of surgical closure. When surgical closure was defined in an alternative manner (> 95% graft survival on Day 14 and 0% area of questionable viability on Day 5), surgical closure was achieved in 24/38 (63.2%) FS 4IU-treated sites compared with 17/38 (44.7%) stapled sites (p = 0.0654). Paired analysis of wound closure by Day 28 was also performed. Wound closure by Day 28 was achieved in 31/39 (79.5%) of FS 4 IU-treated sites compared with 23/39 (59.0%) stapled sites.

The phase 3 study, 550201, entitled, "A Study To Evaluate the Safety and Efficacy of Fibrin Sealant with 4IU/mL Thrombin, Vapor Heated, Solvent Detergent Treated (FS 4 IU VH S/D) to Adhere Tissues and Improve Wound Healing" was designed to assess the safety and efficacy of FS 4IU VH S/D for skin graft adherence and wound healing in subjects with deep partial thickness or full thickness burn wounds. The primary efficacy objective was to test non-inferiority of FS 4 IU VH S/D compared to the current standard of care (staples). Evaluation of complete (100%) wound closure by Day 28 should indicate whether the use of FS 4 IU VH S/D in grafting procedures results in non-inferior graft adherence and wound healing when compared to the use of staples.

The study was multi-centered, prospective, evaluator blinded, and randomized to compare FS 4 IU VH S/D to staples. Eligible subjects were required to have deep partial thickness or full thickness burn wounds that could be designated as a test area, and which could be split into 2 comparable test sites. After test site selection, FS 4 IU VH S/D was to be used to affix skin grafts at one test site (treatment), and staples used to affix skin grafts at the other test site (control) in accordance with the predetermined randomization scheme. The postoperative follow-up was planned for 1 year. The day of the skin grafting procedure, when FS 4 IU VH S/D and staples were used, was designated as Day 0. Subjects were required to undergo evaluations and study procedures at Screening and on Day 0, 5, 14, and 28 and Month 3, 6, 9, and 12 visits.

The study was divided into 2 reporting parts: Part A, which includes the primary endpoint analysis, and Part B, a follow-up of cosmetic outcomes through Month 12. Similar to the Phase 1 / 2 study, the main inclusion criteria were:

• Subjects or their legal representatives, who have read, understood and signed a written informed consent.
• Subjects of either sex.
• Female subjects of childbearing potential with a negative urine or serum pregnancy test within 24 hours prior to surgery.
• Subjects who are ≤65 years of age including pediatric subjects of all ages.
• Subjects with total burn wounds measuring ≤ 40% TBSA.
• Subjects with a contiguous deep partial thickness/full thickness wound, between 2% and 8% TBSA or two comparable, bilateral wounds each measuring between 1% and 4% TBSA.
• Wounds designated as test sites require autologous sheet skin grafts with a thickness of 8/1000 of an inch to 16/1000 of an inch
• Subjects who are able, and willing to comply with the procedures required by the protocol

The following were main exclusion criteria:

• Subjects with electrical burns.
• Subjects with chemical burns
• Digits and genitalia are excluded as test sites.
• Subjects with infection at test area/test sites.
• Subjects with test sites previously randomized and treated in this study.
• Subjects with venous or arterial vascular disorder that directly affects a designated test area/test site.
• Subjects with pre-existing hemolytic anemia
• Subjects with diabetes mellitus.
• Subjects with documented history of pathologically or pharmacologically induced immune deficiency.
• Subjects judged to be chronically malnourished.
• Subjects that are judged to have significant pulmonary compromise.
• Subjects receiving systemic corticosteroids within 30 days prior to skin
• grafting (not including inhaled steroids).
• Subjects with known or suspected hypersensitivity to bovine proteins.
• Subjects participating in another clinical trial that is evaluating an unapproved drug or device.

The primary endpoint is complete wound closure by Day 28 after treatment with either FS 4 IU VH S/D or staples as determined by a blinded independent review of the Day 28 photographs. Complete wound closure was defined as total coverage of the wound with a contiguous layer of viable epithelium; areas closing by secondary intention also had to be fully closed. Factors considered during this assessment included color, presence of granulation tissue, and whether or not the entire wound was covered with a contiguous layer of viable epithelium.

Secondary efficacy endpoints included presence of hematoma and seroma formation, complete wound closure prior to day 28 ( i.e. on days 5 and 14 post procedure),and scar maturation based on the Vancouver Scar Scale at months 3, 6, 9 and 12 post procedure.

The primary efficacy analysis was performed on the intent-to-treat population. The intent-to-treat population consisted of all subjects with at least one available primary endpoint assessment. In addition, an efficacy analysis was done on those subjects deemed evaluable per protocol (i.e., met all inclusion/exclusion criteria, randomized and treated correctly, and adhered to study procedures). The primary statistical analysis was used to test non-inferiority of FS 4IU VH S/D compared to staples with respect to complete wound closure at Day 28 after surgery. To assess the non-inferiority of success rate in wound closure with FS 4IU VH S/D as compared to that with staples, a one-sided 97.5% confidence interval for the difference of correlated proportions was calculated. The non-inferiority margin was set at 10%. If the lower limit of the one-sided confidence interval of the difference in closure rate between FS 4IU VH S/D treated and staples sites was above zero, it was considered to have been proven that FS 4IU VH S/D treatment is superior to grafting with staples in terms of statistical significance at the 0.025 alpha level (p < 0.025).

Median, 95% confidence interval of the median and range (or N, proportions and 95% confidence interval) are presented in tables of summary statistics for the secondary endpoints. Secondary endpoints measured by planimetry (% areas of hematoma/ seroma, % area of engraftment, % area of wound closure) were analyzed twice: once without the re-grafted subjects and subjects who received additional staples, and once with the re-grafted sites and sites that received additional staples imputed to a 'worst case' result.

The purpose of the 2 analyses was to investigate the robustness of the endpoints. These variables were to be analyzed by paired t-test or non-parametric signed rank statistics if the data could not be normalized. All subjects receiving FS 4 IU VH S/D were included in the safety analysis. Probability of occurrence and 95% confidence interval of the probability of occurrence of AEs possibly or probably related to FS 4 IU VH S/D was calculated. Occurrence of local AEs is tabulated for FS 4IU VH S/D and staples separately. In agreement with the assessment of the primary efficacy endpoint, a 95% confidence interval was carried out for the difference of local AEs between FS 4 IU VH S/D and the control. The number, proportion and 95% confidence interval of the proportions are presented for categories of local AEs.

Results:

The ITT population consisted of all subjects with at least one available primary endpoint assessment. The wound closure assessment was analyzed as treated. The sponsor defined the per protocol population (PP) as a subset of the ITT population: those meeting all inclusion /exclusion criteria, those who were randomized and treated correctly, no major protocol violations and had available valid assessments of wound closure by day 28 (subjects with completely missing pictures at one site were excluded from the PP population; if more than one reviewer assessed one site as not fully depicted or unassessable, the subject was excluded from the PP population); and those who had no open wound areas or excoriations due to a secondary cause in any test site by Day 28.

A total of 138 subjects were randomized and treated at 13 study sites. The number of subjects randomized at each site ranged from 3 to 22. The protocol defined intent to treat population (ITT) included 127 subjects. Eleven of the 138 randomized subjects were not included in the ITT population for the following reasons: i.) no primary endpoint assessment at both sites (N =1), ii.) Lost to follow-up prior to day 28 visit (N=7) and iii.) Photographs not taken at both test sites on day 28 visit. The sponsor met the primary endpoint and demonstrated that FS VH S/D 4IU is non-inferior to staples for adhering grafts to burn sites.

The following table depicts the summary of the primary endpoint.

Tabular summaries of the secondary endpoints:

Dr. Kimberly Lindsey and Dr. Boris Zaslavsky conclude that the data collected and analyzed during Baxter's clinical study demonstrate that FS VH S/D 4 is safe and efficacious for the attachment of sheet skin grafts in subjects with deep partial thickness or full thickness burn wounds. They recommend approval. Robert Wesley performed a biomonitoring inspection of three clinical sites. Although he listed some deficiencies in his review, he concluded that they did not preclude approval of this BLA.

7. Safety

In the phase 1 /2 study a total of 423 adverse experiences were reported in 40 subjects. Among these, 6 (1.4%) events in 3 subjects were serious and 417 (98.6%) events in 40 subjects were non-serious. There were no deaths. None of the serious adverse experiences were considered by the Investigators or the sponsor to be related to the use of FS 4 IU.

Of the reported adverse experiences, the serious ones, N= 6 (1.4%) were judged by the investigators to be possibly related to the use of FS 4 IU. These events include intestinal perforation (N= 1), post operative infection (N=4), delirium tremens (N=1). The post operative donor site infections required hospitalization in 4 patients.

Five of the 6 were cases of hematoma and seroma in the FS 4IU-treated sites and were reported by a single investigator. By contrast, no other investigators reported hematoma and seroma as study product-related.

There were 417 non serious adverse events: 296 (70%) reported in 37 subjects were rated mild, 116 (27.4%) reported in 26 subjects were rated moderate, and 5 (1.2%) reported in 5 subjects were rated severe. The 5 severe non serious adverse events included 4 incidences of pain at the graft site and 1 incidence of graft loss.

One site reported 5 cases of hematoma and seroma that were regarded as related to study product due to the temporal relationship of the seroma/hematoma to study product administration.

Seventeen types of events (abscess, blister, cellulitis, excoriation, folliculitis, graft complication, graft loss, hematoma, hypertrophic scar, limb injury, muscle cramp, pain, pain in extremity, pruritus, seroma, staphylococcal infection and stitch abscess) were reported to have occurred locally at 1 or both test sites. Among these event types, there was no apparent difference in the frequency of occurrence at FS 4 IU-treated or stapled sites. A total of 75 events were localized to FS 4 IU-treated sites and 92 were localized to stapled sites.

Examination of vital signs, hematology, and clinical chemistry parameters did not reveal safety concerns for FS 4 IU. Adverse experiences reported for FS 4IU-treated sites were typical for the type of injury sustained by subjects with burn wounds requiring skin grafting procedures. Changes in vital signs, hematology and clinical chemistry parameters showed no evidence of toxicity.

Of the 36 test sites 2, (5.6%) FS 4 IU treated sites and 4 (11.1%) stapled sites were regrafted. Regrafting included full or partial regrafting and patch grafting.

In the Phase 3 study there were no deaths in part A of the study. There were 3 incidences of infection and 1 incidence of staphylococcal infection occurring at both the FS 4IU VH S/D test site and the stapled test site (Subject 010005, Subject 040011, Subject 040016, and Subject 100010). There were 4 incidences of skin graft failure occurring at the FS 4IU VH S/D test site (Subject 040011, Subject 040016, Subject 110003, and Subject 160008) and 3 incidences at the stapled site (Subject 040011, Subject 040016, and Subject 110003).

The incidence of adverse events was also tabulated for non test sites. There were 2 incidences of infections (Subject 160005, and Subject 130010), 1 incidence of staphylococcal infection (Subject 010005), 3 incidences of skin graft failure (Subject 040015, Subject 100010, and Subject 160007), 1 incidence of acute respiratory distress (Subject 130017), and 1 incidence of excessive granulation tissue (Subject 060003).

At FS 4IU VH S/D test sites, there were 35 incidences of skin graft failure, 29 incidences of pruritus, 4 incidences of infection, 2 incidences of graft complication, 2 incidences of dermal cyst, 2 incidences of excessive granulation tissue, and a single incidence of each of the following: edema peripheral, excoriation, culture wound, joint contracture, skin maceration, and hematoma. Five of the 35 incidences of skin graft failure, 2 of the 29 incidences of pruritus, and 1 of the 2 incidences of dermal cyst were considered related to FS 4IU VH S/D. A similar incidence of non-serious AEs occurred at stapled test sites, except for a larger incidence of graft complication at the stapled test sites (15 versus 2 incidences in FS 4IU VH S/D test sites). Of the 15 incidences of graft complication at the stapled site, 12 of them were due to retained staples after the Day 5 visit.

There was a higher rate of graft complication in stapled test sites (10.1%) compared with FS 4 IU VH S/D test sites (1.4%). But this was largely due to retained staples at the stapled sites. The rates of skin graft failure were similar between FS 4 IU VH S/D test sites (25.4%) and stapled test sites (23.2%).

8. Advisory Committee Meeting

A meeting was not convened for the following reasons:

• The manufacture of ARTISS^TM is -------- -- --- ----- --- -- - -- -- ---- --- ------ ----- ------- ---- ---- ----------- the final concentration of the thrombin component. Both the fibrinogen and thrombin components are human plasma-derived and undergo vapor heat treatment and solvent/detergent treatment to inactivate viruses. The Aprotinin, which is included as a fibrinolysis inhibitor, is synthesized using an ------------------------.
• Omrix Biopharmaceuticals, Ltd. also manufactures a similar fibrin sealant product, which was licensed in the U.S. in March 2003.
• The mechanisms of action of fibrinogen and thrombin and their role in blood coagulation are well understood.
• From a historical perspective, fibrin sealants were originally developed during World War II to stop bleeding from battle injuries. They have been marketed in Western Europe and Japan since the 1980's and in the United States since 1998.
• Today, fibrin sealants are widely used in surgical settings to control bleeding, seal off hollow body organs and to provide slow release delivery of medications.
• ARTISS^TM was investigated for fixation of split thickness sheet skin grafts in burn patients in a prospective, randomized, controlled, multicenter clinical study. In each of the 138 patients, two comparable test sites were identified. In one test site, the skin graft was fixed with ARTISSTM; in the other test site, the graft was fixed with staples (control). ARTISS^TM proved to be non-inferior to staples with respect to the primary efficacy endpoint, complete wound closure at Day 28 using a one-sided 97.5% confidence interval on the difference in the proportion of test sites successfully treated.
• The most frequent adverse events noted were hematoma and seroma formation, which are common events in skin grafting procedures. There were no statistically significant differences between the stapled group and the ARTISS^TM treated group with respect to hematoma and seroma formations. In the clinical trial, there were a few incidences of non-adherence of the skin grafts and pruritus, which may have been associated with ARTISS^TM. However, these adverse events were also noted in the control (stapled) group and are not uncommon in skin grafting procedures.
• The results of the pivotal safety and efficacy study did not raise any concern related to safety and efficacy.
• Review of information submitted in the BLA for ARTISS^TM did not raise any controversial issues or pose unanswered scientific questions which would have benefited from advisory committee discussion and recommendation.
• There are no current concerns regarding the risk/benefit ratio

9. Pediatrics

The summary of the clinical studies and pediatric rule requirements were presented to the Pediatric Review Committee on January 30, 2008. The recommendations from the panel were that the 0-1 year of age group be waived because there are too few patients in this age group to be studied or that safety and efficacy of ARTISS be extrapolated to this age group. It is the clinical reviewer's recommendation that the 0-1 year of age group be waived. We cannot be certain that the immature coagulation system of an infant would not be adversely affected by application of ARTISS. It is also unlikely that the sponsor will be able to conduct a substantive post marketing study targeting the 0 to 1 year old age group for the burn grafting indication.

Pediatric patients were studied in both the phase 1 / 2 study and the pivotal study. The primary efficacy analysis for pediatric patients is depicted in summary form in the following table:

Overall, the efficacy of FS 4IU VH S/D was demonstrated in subjects < 18 years old; 72.2% of the ≤ 6 years old group (N=18) and 31.6% of the 7-18 years old group (N=19) achieved complete wound closure by Day 28 (ITT).

10. Other Relevant Regulatory Issues

Financial Disclosure
In item 19 of the original BLA submission regarding Certification: Financial Interests and Arrangements of Clinical Investigators, the sponsor has checked the following as true:

"As the sponsor of the submitted studies, I certify that I have not entered into any financial arrangement with the listed clinical investigators whereby the value of compensation to the investigator could be affected by the outcome of the study as defined in 21 CFR 54.2(a). I also certify that each listed clinical investigator required to disclose to the sponsor whether the investigator had a proprietary interest in this product or a significant equity in the sponsor as defined in 21 CFR 54.2(b) did not disclose any such interests. I also certify that no listed investigator was the recipient of significant payments of other sorts as defined in 21 CFR 54.2(f)."

11. Labeling

• The sponsor's proprietary name, ARTISS, was reviewed by the Advertising and Promotional Labeling Branch (APLB) from a promotional and comprehension perspective and was found to be acceptable on January 18, 2008. OBBR concurred.
• Full Prescribing Information (FPI): APLB reviewed the original FPI submitted by the sponsor. Comments from a promotional and comprehension perspective were provided to OBRR on January 29, 2008. OBBR and APLB comments regarding the FPI were faxed to the sponsor on March 4, 2008. A teleconference was held with the sponsor on March 5, 2008. The sponsor subsequently submitted a revised FPI following the teleconference. APLB reviewed the revised FPI on March 6, 2008 and provided additional comments to OBBR for discussion with the sponsor. A fax containing FDA's comments was sent to the sponsor on March 6, 2008 and discussed on a subsequent teleconference held that afternoon. The sponsor accepted all of FDA's remaining comments and recommendations. FDA and the sponsor also agreed that the following statement will be added underneath the proper name in the Highlights section: "Frozen solution and lyophilized powder for solution for topical application." All FPI issues have been adequately resolved to proceed with final approved labeling.
• Carton and immediate container labels submitted in the original application and revised versions submitted on December 20, 2007 were reviewed by APLB from a promotional and comprehension perspective. Comments on them from a promotional and comprehension perspective were provided to OBRR on January 29, 2008 (for original submission) and February 28, 2008 (for revised submission). FDA's comments regarding the sponsor's carton and container labels were faxed to the sponsor on March 4, 2008. A teleconference was held on March 5, 2008 with the sponsor to discuss the issues raised in the Agency's correspondence. The sponsor submitted revised carton and container labeling following the teleconference. APLB reviewed the revised labeling on March 6, 2008. During the March 6, 2008 teleconference, the sponsor accepted all outstanding recommendations. All carton/container labeling issues have been adequately resolved to proceed with final approved labeling.
• Patient labeling/Medication guide: ARTISS will be administered in a surgical setting only. Patient Information is appropriately provided in the Section 17 of the FPI.

12. Recommendations/Risk Benefit Assessment

The committee unanimously recommends approval of this BLA.

There are currently no concerns regarding the risk/benefit ratio.

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