ATRISORB-D FREEFLOW BIOABSORBABLE GUIDED TISSUE REGENERATION (GTR) BARRIER WITH 4% DOXYCYCLINE

{0}------------------------------------------------ K994137 # SEP 1 3 2000 ## 510(k) SUMMARY OF SAFETY AND EFFECTIVENESS ATRISORB®-D FreeFlow™ Bioabsorbable Guided Tissue Regeneration (GTR) Barrier with 4% Doxycycline Amy Taylor December 3, 1999 - 1 General Information Manufacturer: Atrix Laboratories, Inc. 2579 Midpoint Drive Fort Collins, CO 80525 Telephone: (970) 482 - 5868 Fax: (970) 482 - 9735 Regulatory Affairs Manager Contact: Date Prepared: Proprietary Name: Common Name: Classification Name: 510(k) Clearance Number: Predicate Device: ATRISORB®-D FreeFlow™ Bioabsorbable Guided Tissue Regeneration (GTR) Barrier with 4% Doxycycline Bioabsorbable Guided Tissue Regeneration Barrier with Doxycycline Bone Filling Augmentation Material K ATRISORB® Bioabsorbable Guided Tissue Regeneration (GTR) Barrier K955838 and K982865 #### 2 Device Description #### 2.1 Formulation The polymer formulation used in the ATRISORB®-D FreeFlow™ Bioabsorbable Guided Tissue Regeneration (GTR) Barrier with 4% Doxycycline (hereafter referred to as the ATRISORB®-D FreeFlow™ Barrier) exists as a sterile, synthetic flowable polymeric solution. It is mixed with doxycycline hyclate prior to formation to give a 4% doxycycline concentration in the formulation prior to barrier placement. The barrier precipitates to a firm consistency upon contact with water and {1}------------------------------------------------ bioabsorbs over time. The polymer formulation is composed of poly(DL-lactide) (PLA) dissolved in N-methyl-2-pyrrolidone (NMP). #### 2.2 Device One sterile ATRISORB®-D FreeFlow™ Barrier unit consists of: - A large pouch containing a pouched syringe with 715 mg of the . ATRISORB® polymer formulation and a syringe with 35 mg doxycycline hyclate; - . A blunt tip cannula, and; - A product insert containing instructions for use. . The ATRISORB®-D FreeFlow™ Barrier package contains three product units. #### 2.3 Mechanics The ATRISORB®-D FreeFlow™ Barrier functions as a guided tissue regeneration barrier by isolating the regenerative surgical site from the adjacent gingival connective tissue and epithelium. This facilitates population of the surgical site with cells from the periodontal ligament and adjacent alveolar bone that lead to regeneration. The doxycycline hyclate in the barrier serves to reduce bacterial colonization of the barrier and the surgical site. To prepare the barrier, the user couples the two syringes and mixes the contents together by passing the contents between syringes. Then, the user fills the periodontal defect with bone grafting material and applies the ATRISORB®-D FreeFlow™ Barrier directly over the defect area. To precipitate the barrier, the user sprays it with a fine mist of sterile water and then sutures the surgical flap closed over the barrier and site. Once placed, the ATRISORB®-D FreeFlow™ Barrier precludes the migration of epithelial or connective tissue cells through it, while isolating the periodontal compartment and promoting regeneration. The barrier bioabsorbs through hydrolysis over several months. However, the ATRISORB®-D FreeFlow™ Barrier does remain at the site, intact, during the critical period when periodontal regenerative cells are proliferating during the wound-healing cascade from adjacent periodontal sources. #### ਤੇ Intended Use The ATRISORB®-D FreeFlow™ Barrier is intended for use in the surgical treatment of periodontal defects to aid in the regeneration and integration of tissue components in guided tissue regeneration procedures. ATRISORB®-D FreeFlow™ Barrier has been shown to reduce bacterial colonization of the barrier. The indications for the ATRISORB®-D FreeFlow™ Barrier are equivalent to the predicate device, the ATRISORB® GTR Barrier. The difference is the additional {2}------------------------------------------------ indication for reducing the bacterial colonization of the barrier through the incorporation of doxycvcline hyclate to the barrier. #### Summary of Technological Characteristics 4 The ATRISORB®-D FreeFlow™ Barrier is substantially equivalent to the predicate ATRISORB® GTR Barrier (K955838) and a variation of the device (K982865). Both are legally marketed products. The polymer formulation is the same in both the ATRISORB®-D FreeFlow™ Barrier and the ATRISORB® GTR Barrier. The only difference between the ATRISORB®-D FreeFlow™ Barrier and its predicate is the addition of doxycycline hyclate to the polymer formulation prior to barrier formation. The doxycycline is intended to reduce the bacterial colonization of the barrier. #### Summary of In Vitro Studies 5 #### Pyrogenicity 5.1 A Limulus amebocyte lysate test (LAL) estimated the concentration of bacterial endotoxins in an extract of the ATRISORB®-D FreeFlow™ Barrier. The results indicated that the ATRISORB®-D FreeFlow™ Barrier is non-pyrogenic. #### 5.2 Sterilization The ATRISORB®-D FreeFlow™ Barrier is terminally sterilized by Cobalt-60 gamma irradiation. #### In Vitro Characterization of the ATRISORB®-D FreeFlow™ Barrier 5.3 The ATRISORB®-D FreeFlow™ Barrier was characterized in a simulated use test to demonstrate that the molecular weight specification for the ATRISORB®-D FreeFlow™ Barrier is appropriate and to determine the thickness of the directly applied barrier. The molecular weight of the polymer is a key factor in influencing the viscosity and precipitation behavior of the formulation. In the experiment, ATRISORB®-D FreeFlow™ Barrier formulations with four different PLA molecular weights (21, 25, 41, and 64 kiloDaltons) were evaluated for handling properties and barrier thickness. Results were compared to previous data generated for the directly applied version of the predicate ATRISORB® GTR Barrier. All ATRISORB®-D FreeFlow™ Barriers passed the simulated use test criteria, verifying that the ATRISORB®-D FreeFlow™ Barrier molecular weight limit (21 kiloDaltons) is appropriate. Thickness comparisons demonstrated that the average thickness of the ATRISORB®-D FreeFlow™ Barrier (0.474-3.584 mm) is slightly less than the average thickness of the {3}------------------------------------------------ directly applied version of the ATRISORB® GTR Barrier (0.729-3.178 mm). These data support that the ATRISORB®-D FreeFlow™ Barrier is suitable for its intended use. #### 5.4 Irradiation of Doxycycline Hyclate Experiments were performed to demonstrate that gamma irradiation has no detrimental effects on the doxycycline hyclate present in the barrier, as this is how the device is rendered sterile. Investigators detected a color change from bright yellow to a yellow-brown after irradiation. Attempting to determine if the heat of irradiation produced this effect, investigators heated doxycycline hyclate, but observed no color change. Additional doxycycline analysis detected three impurities not present in unirradiated doxycycline hyclate. However, the levels of these impurities were less than 0.1% and, therefore, considered insignificant. Bioassay results also indicated that the potency of doxycycline irradiated at levels of up to 110.9 kGy remained unchanged after irradiation. Further, clinically usable barriers were formed using irradiated doxycycline hyclate. Collectively these results indicate that the use of gamma irradiation at levels up to 39.4 kGy do not significantly alter the chemical structure, potency, and/or the ability of the doxycycline hyclate to be incorporated into clinically acceptable barriers. #### 5.5 In Vitro Release of Doxycycline Atrix has conducted in vitro doxycycline release studies with ATRISORB®-D Barriers containing varying levels of doxycycline (between 1.0% and 10%) formed extraorally in barrier-forming cases. Results demonstrated greater than 90% cumulative release of doxycycline from the barriers into water at 24 hours. #### 5.6 In Vitro Bioactivity Time kill assay and agar diffusion techniques were used to demonstrate that an ATRISORB®-D Barrier with 5% doxycycline exhibited bioactivity against periodontal pathogens in vitro. The growth of both Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis were inhibited when exposed to various sizes of ATRISORB®-D Barriers with 5% doxycycline in these assays. This study supports the in vitro bioactivity of the ATRISORB®-D FreeFlow™ Barrier. #### 6 Summary of In Vivo Implantation Studies Results from two nonclinical studies performed with the ATRISORB®-D FreeFlow™ Barrier in the dog demonstrated no significant tissue irritation. In addition, extensive biocompatibility, implantation and degradation studies performed {4}------------------------------------------------ previously on the predicate ATRISORB® GTR Barrier and ATRISORB®-D Barriers with varying concentrations of doxycycline (between 2.5% and 10%) support that the ATRISORB®-D FreeFlow™ Barrier is safe for its intended use. #### Clinical Performance Data r Atrix performed a six-month clinical study to compare reduction of microorganisms and clinical outcomes following the treatment of Class II furcation defects with either ATRISORB®-D FreeFlow™ Barrier applied directly over decalcified freezedried bone allograft (DFDBA) versus ATRISORB® GTR Barrier applied over DFDBA. It was conducted at three different centers. The study's primary objective was to demonstrate that sites treated with the ATRISORB®-D FreeFlow™ Barrier applied directly over bone graft material had significantly greater microbial reductions than sites treated with the case-formed ATRISORB® GTR Barrier applied over the same graft material. Researchers compared reductions in total anaerobic bacterial counts and specific counts of periodontal pathogens at evaluated timepoints through Week 6 and met the objective. The ATRISORB®-D FreeFlow™ Barrier treatment group demonstrated significantly greater reductions for total anaerobes and counts of P. intermedia/P. nigrescens when compared to the ATRISORB® GTR Barrier control. Reductions approaching significant levels in favor of the ATRISORB®-D FreeFlow™ Barrier were also observed for counts of F. nucleatum. The study's secondary objective was to evaluate efficacy endpoints (change from baseline for the following clinical parameters: horizontal attachment level, vertical attachment level, probing depth, and percent defect closure) at Month 6. These data will be reported later. Finally, levels of doxycycline achieved in the gingival crevicular fluid at surgical sites in all subjects were consistently higher than the minimum inhibitory concentrations of commonly isolated periodontal pathogens. #### 8 Conclusions The claims for the ATRISORB®-D FreeFlow™ Barrier are equivalent to the ATRISORB® GTR Barrier. Additionally, the ATRISORB®-D FreeFlow™ Barrier also claims to reduce bacterial colonization of the barrier. A human clinical trial has demonstrated that the ATRISORB®-D FreeFlow™ Barrier is superior to the predicate ATRISORB® GTR Barrier as an implantable barrier intended to aid in the healing of periodontal defects. In vitro, animal, and clinical studies have demonstrated that the ATRISORB®-D FreeFlow™ Barrier is safe and effective for its stated indications (treatment of periodontal disease and reducing bacterial colonization of the ATRISORB®-D {5}------------------------------------------------ FreeFlow™ Barrier) and is substantially equivalent to the predicate device, the ATRISORB® GTR Barrier. The ATRISORB®-D FreeFlow™ Barrier is non-pyrogenic and biocompatible. The ATRISORB®-D FreeFlow™ Barrier is bioabsorbed, eliminating the need for a second surgical procedure to remove the barrier. {6}------------------------------------------------ Image /page/6/Picture/1 description: The image is a black and white logo for the U.S. Department of Health and Human Services. The logo features a stylized eagle with three stripes forming its body and wing. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" is arranged in a circular fashion around the eagle symbol. The text is in all capital letters and is evenly spaced around the circle. Public Health Service Food and Drug Administration 9200 Corporate Boulevard Rockville MD 20850 # SEP 1 3 2000 Ms. Amy Taylor · Regulatory Affairs Manager Atrix Laboratories, Incorporated 2579 Midpoint Drive 80525-4417 Fort Collins, Colorado Re : K994137 Atrisorb-D FreeFlow Bioabsorbable Guided Trade Name: ade Name. Acribors BCTR) Barrier with 4% Doxycycline Regulatory Class: Unclassified Product Code: LYC 2000 Dated: August 29, August 30, 2000 Received: ### Dear Ms. Taylor: We have reviewed your Section 510(k) notification of intent to we have reviewed your beceien beve and we have determined the market the device fereice.com and indications for device is substancially orgal(tsure) to legally marketed world use stated in the encrobare, co suger prior to May 28, 1976, devices marketed in incor Medical Device Amendments, or to the enactment date or che fissified in accordance with the devices that have been is Food, Drug, and Cosmetic Act (Act). provisions of the rederal rood, arag, asunged to the general rou may, cherefore, marked ont. The general controls controls proviblem of include requirements for annual provisions of the Act meraus requeed manufacturing practice, labeling, and prohibitions against misbranding and adulteration. If your device is classified (see above) into either class II II your device IS crabbliss III (Premarket Approval), it may (Special Concrols) or Stimal controls. Existing major be subject to such addrois device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 895. ਉ rederal Regulations, freic try Particon assumes compliance with subscancially equivalence uring Practice requirements, as set the Current System Regulation (QS) for Medical Devices: General regulation (21 CFR Part 820) and that, through periodic QS inspections, the Food and Drug Chrough periodic go in-Fl verify such assumptions. Failure to Administration (FBF) regulation may result in regulatory comply with enc on. FDA may publish further announcements action: .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Please note: this response to your premarket notification submission does chis response to your provins have under sections 531 not arrest any oblight for devices under the Electronic Chrough 542 or the not al provisions, or other Federal laws or requlations . {7}------------------------------------------------ Page 2 - Ms. Taylor This letter will allow you to begin marketing your device as described in your 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market. If you desire specific advice for your device on our labeling regulation (21 CFR Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4692. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsma/dsmamain.html". Sincerely yours, Timothy A. Ulatowski Director Division of Dental, Infection Control and General Hospital Devices Office of Device Evaluation Center for Devices and Radiological Health Enclosure {8}------------------------------------------------ ### INDICATIONS FOR USE 510(k) Number (if known): Device Name: ATRISORB®-D FreeFlow™ Bioabsorbable Guided Tissue Regeneration (GTR) Barrier with 4% Doxycycline 994137 Indications For Use: ATRISORB®-D FreeFlow™ Barrier is indicated for the surgical treatment of periodontal defects to aid in the regeneration and integration of tissue components in guided tissue regeneration procedures. ATRISORB®-D FreeFlow™ Barrier has been shown to reduce bacterial colonization of the barrier. ## (PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED) Concurrence of CDRH, Office of Device Evaluation (ODE) Prescription Use (Per 2.1 CFR 801.109) ✓ OR Over-The-Counter Use Susan Rumps (Division Sign-Off) Division of Dental, Infection Control, and General Hospital De 510(k) Number _