MOERAE SURGICAL MARKING PEN

{0}------------------------------------------------ #### DE NOVO CLASSIFICATION REQUEST FOR VASOPREP SURGICAL MARKING PEN #### REGULATORY INFORMATION FDA identifies this generic type of device as: Internal Tissue Marker: An internal tissue marker is a prescription use device that is intended for use prior to or during general surgical procedures to demarcate selected sites on internal tissues. NEW REGULATION NUMBER: 878.4670 CLASSIFICATION: II PRODUCT CODE: PDW #### BACKGROUND DEVICE NAME: VASOPREP SURGICAL MARKING PEN SUBMISSION NUMBER: DEN130004 Date of De Novo: May 6, 2013 CONTACT: VASOPREP SURGICAL ROBERT CHIN, PHD - REGULATORY CONSULTANT 55 Madison Avenue, Suite 400 MORRISTOWN, NJ 07960 REQUESTER'S RECOMMENDED CLASSIFICATION: II #### INDICATIONS FOR USE The VasoPrep Surgical Marking Pen is intended for use prior to or during the harvesting and preparation of vein grafts used in bypass surgery. The pen is used to demarcate selected sites and orientation of the graft. #### LIMITATIONS Caution: Federal Law restricts this device to sale by or on the order of a physician. #### WARNINGS - The VasoPrep Surgical Marking Pen should not be used on a non-sterile surface prior to its internal use. - The safety and performance of the VasoPrep Surgical Marking Pen has not been established in patients with a known allergy to FD&C Blue dye #1. {1}------------------------------------------------ - The VasoPrep Surgical Marking Pen has not been tested on any internal tissue except for veins. ## DEVICE DESCRIPTION The VasoPrep Surgical Marking Pen is a single patient use sterile prescription use only marker intended for use on veins prior to or during Coronary-Assisted Bypass Graft (CABG) surgery. The marker (Figure 1) consists of a pen body, barrel, wick and cap with a wide chisel style applicator tip for delivery of ink to mark internal tissue. The formulation is non-toxic as used and is comprised of an ink material (FD&C Blue Dye #1) compounded into a carrier material (i.e., solvent). The wide chisel tip can deliver either a thin line of ink for precise marks or can be rotated 90° to deliver a wide stripe of ink. Image /page/1/Figure/3 description: The image shows the text "Figure 1: VasoPrep Surgical Marking Pen". The text is written in a clear, sans-serif font and is likely a caption or title for an image or diagram. The text indicates that the image or diagram is related to a VasoPrep Surgical Marking Pen and is labeled as Figure 1. Image /page/1/Figure/4 description: The image shows a technical drawing of an object, with two views presented. The top view displays the object's length as 5.3 units, with a section measuring 3 units and a diameter of 0.44 units. The bottom view, labeled "SECTION A-A", provides a cross-sectional perspective, revealing internal components labeled 1, 2, 5, and 6. Figure 1. The device consists of a Body (1); Tip (2); Barrel (3); Cap (4); Ink Storage Wick (5); and Ink (6). # SUMMARY OF NONCLINICAL/BENCH STUDIES ## BIOCOMPATIBILITY/MATERIALS The VasoPrep Surgical Marking Pen is comprised of three main components and are considered to be in direct contact and/or indirect contact with the patient: 1) the ink formulation; 2) the pen barrel; and 3) the wick/wicking material. These materials are well-characterized, used in medical device applications and were tested in accordance with ISO 10993-1 as indicated in Table 1 (below). The results demonstrate the VasoPrep Surgical Marking Pen is biocompatible when used as intended. | Table 1: A summary of the biocompatibility testing conducted | | | | |--------------------------------------------------------------|--------------------------------------------------------------------------|---------------------|---------------| | Test | Purpose | Acceptance Criteria | Results | | Cytotoxicity (b)(4)<br>(b)(4) (ISO 10993-5) | To test and evaluate the cytotoxicity of the marker and ink formulation. | Non-cytotoxic | Non-cytotoxic | {2}------------------------------------------------ | Sensitization -<br>Maximization<br>Method (guinea<br>pig) (ISO 10993-<br>10) | To test and evaluate the<br>potential for the marker and<br>ink formulation to cause<br>delayed contact sensitization. | No evidence of<br>causing delayed<br>dermal contact<br>sensitization | No evidence of<br>causing delayed<br>dermal contact<br>sensitization | |------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------|----------------------------------------------------------------------| | USP Intracutaneous<br>Reactivity (ISO<br>10993-10) | To test and evaluate the<br>potential for the marker and<br>ink formulation to cause<br>local dermal irritant effects. | Nonirritant | Nonirritant | | USP Systemic<br>Toxicity | To test and evaluate the<br>acute system toxicity of the<br>marker and ink formulation. | No indications of<br>systemic toxicity | No indications<br>of systemic<br>toxicity | | Hemocompatibility<br>(In vitro hemolysis) | To test and evaluate the<br>hemocompatibility of the<br>marker and ink formulation. | No significant<br>hemolysis | No significant<br>hemolysis | | Material Mediated<br>Pyrogenicity (ISO<br>10993-9) | To test and evaluate the<br>pyrogenicity of the marker<br>and ink formulation. | Non-pyrogenic | Non-pyrogenic | ## SHELF LIFE / STERILITY / PACKAGING A single-packed marker is packaged in a clear (b)(4) Low Density Polyethylene (LDPE)/opaque coated paper pouch that is heat-sealed with (b)(4) The single-pack marker packaging is a single sterile barrier. The single packs are then bulk-packed in a cardboard shelf carton for distribution of single markers. Shelf cartons are placed in corrugated boxes for shipping. Labels are placed on the paper side of the pouch, on the shelf carton and the shipping container. Shelf-life and packaging integrity studies indicate a packaged, sterilized device will remain functional (i.e., tissue marking ability), non-cytotoxic and maintain a 10° SAL for 1 year. The standards and methods used are located in Table 2, below. | Table 2: A summary of the sterility and packaging testing conducted | | | | |--------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------| | Test | Purpose | Acceptance Criteria | Results | | Sterility Testing<br>(ISO 11137) | To test and evaluate the<br>sterility of the marker and<br>ink formulation. | To ensure (b)(4)<br>gamma radiation<br>sterilization process<br>is an adequate dose.<br>Devices must have a<br>sterility assurance of<br>at least 10-6. | Meets<br>Acceptance<br>Criteria | | Packaging Integrity<br>(ASTM F1886<br>/F1886M; ASTM<br>F1929; ASTM<br>F88/88M) | To test and evaluate the<br>marking ability after<br>undergoing accelerated aging<br>and mechanical stress. | The packaging must<br>pass the Visual Seal<br>Examinations; Dye<br>Leak Test; and Peel<br>Test. | Meets<br>Acceptance<br>Criteria | {3}------------------------------------------------ ## PERFORMANCE TESTING – BENCH Test protocols were developed based on the results of design and clinical risk analyses of the VasoPrep Surgical Marking Pen in its intended indication for use. The original bench testing performed by the sponsor to assess the performance characteristics are summarized in Table 3. | Table 3: A summary of the performance testing conducted | | | | |---------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------| | Test | Purpose | Acceptance Criteria | Results | | Internal Tissue<br>Marking Ability | To test and evaluate device<br>ability to mark human<br>saphenous veins (HSV) | The marker shall<br>provide a visible<br>mark on wet or dry<br>tissue that is 1-3 mm<br>wide and up to 90<br>cm long with a<br>single swipe. The<br>mark shall remain<br>visible on tissue for<br>at least 4 hours. | Meets<br>Acceptance<br>Criteria | | Effect of Dye on<br>Human Vein Tissue | To test and evaluate for<br>patency effects caused by the<br>ink on HSV | Ex-vivo exposure to<br>ink shall have no<br>detrimental effect on<br>the viability, smooth<br>muscle contractility<br>and endothelial-<br>dependent<br>relaxation of human<br>saphenous vein<br>grafts. | Meets<br>Acceptance<br>Criteria | | Effect of Dye on<br>Animal Vein Tissue | Preliminary dosing<br>experiments to test and<br>evaluate demarcation ability<br>of the ink on porcine<br>saphenous veins, at a dose<br>that will have no detrimental<br>effect on further HSV<br>testing. | Application shall<br>demonstrate ink<br>demarcation ability<br>on porcine<br>saphenous veins at<br>an amount that<br>would have no<br>detrimental effect on<br>the viability, smooth<br>muscle contractility<br>and endothelial-<br>dependent<br>relaxation of human<br>saphenous vein<br>grafts | Meets<br>Acceptance<br>Criteria | {4}------------------------------------------------ ## Ability to mark internal tissues Human Saphenous Vein (HSV) segments were painted on the surface with the device and placed in (b)(4) Photographs were taken with a digital camera to monitor the retention of marking on the tissue. Titration curves were generated by measuring maximum absorbance. The marker provided a visible mark on wet or dry tissue that is 1-3 mm wide and up to 90 cm long with a single swipe. The mark remained visible on tissue for at least 4 hours. ## Effect of Dve on Venous Tissue Human Saphenous Vein (HSV) were dissected free of adipose and connective tissues and divided into segments that were either left untreated (as controls) or exposed to dye prior to physiological measurements for 2 hrs. The buffer was changed to a high (b)(4) buffer which depolarizes the smooth muscle leading to contraction of functionally viable smooth muscle. Contractile responses were converted to stress . The rings were (b)(4) normalized (b)(4) To determine endothelial-dependent relaxation, the (b)(4) Maximal contractile responses to (b)(4) (b)(4) were converted to stress and endothelial dependent function were described as the percentage (%) of relaxation of the maximal (b)(4) induced contraction. The VasoPrep Surgical Marking Pen met all design requirements for compatibility and functional use. ## Effect of Dye on Porcine Venous Tissue Dosing of FD&C Blue dye #1 was tested in porcine saphenous vein and (b)(4) was determined to be the optimal dose for color visualization. # Product Stability The objective was to test and evaluate the performance testing on VasoPrep Surgical Marking Pens after gamma sterilization and aging (based on the proposed shelf life). Four sterilized and aged markers were tested according to protocol. The markers were gamma sterilized at the normal specified dose ((b)(4) Two real-time aged markers (the markers were stored at room temperature for at least one vear after being sterilized) were shipped to multiple locations and tested for marking on wet porcine saphenous vein tissue (i.e. demarcation effectiveness) and dry paper (i.e., fluid volume). Cytotoxicity testing (b)(4) was additionally performed on accelerated-aged sterilized ink. The results (as summarized in Table 4) indicate the sterilized aged marking pens functioned as designed and that the ink is non-cytotoxic. {5}------------------------------------------------ | Table 4: Summary of the Product Stability Testing Conducted | | | | |-------------------------------------------------------------|----------------------------|-----------------------|------------| | Test | Purpose | Acceptance Criteria | Results | | Functionality | To test and evaluate the | The marker shall | Meets | | (ASTM F1980) | marking ability after | provide a visible | Acceptance | | | undergoing real time aging | mark on wet or dry | Criteria | | | and shipping stress. | tissue that is 1-3 mm | | | | | wide and up to 90 | | | | | cm long with a | | | | | single swipe. The | | | | | mark shall remain | | | | | visible on tissue for | | | | | at least 4 hours. | | | Cytotoxicity (ASTM | To test and evaluate the | The marker and | Meets | | F1980; ISO 10993- | cytotoxicity of the marker | contents shall be | Acceptance | | ર) | and ink formulation after | non-cytotoxic. | Criteria | | | undergoing accelerated | | | | | aging. | | | ### TOXICOLOGICAL ASSESSMENT Lifetime toxicity/carcinogenicity literature studies pertaining to FD&C Blue #1 dye were provided. The studies examined histology in a significant number of systemicallyrelevant animal tissues. The histology examined was obtained from canine, porcine and murine models for both genders and using different dye dose levels. Several published literature articles have studied acute and/or chronic dosing of the subject dye by oral, subcutaneous and intravenous routes, demonstrating no toxicity and No Adverse Effect Levels (NOAELs) in accepted animal models at doses far in excess of that intended in the application of the Surgical Marking Pen, which is a 0.68 µg/kg onetime exposure for a 70 kg adult. representing 0.00057% of the FDA adult Acceptable Daily Intake (ADI) for FD&C Blue No. 1 of 12.0 mg/kg per day. Data from literature publications analyzing the elimination routes of FD&C Blue No.1 were also provided. Examples of legally marketed devices containing the device dye were also provided, and include sutures, anchors and dural sealants. From these devices and the above-mentioned toxicological assessment, the risk of inadequate metabolic clearance from the body is believed to be minimal at the dose level used (i.e., 0.68 ug/kg). ### LABELING On the packaging label, the sponsor specifies prescription use only, sterility, shelf life, single-use only, not made with natural rubber latex, lot number and product catalogue number. The labeling for the VasoPrep Surgical Marking Pen is consistent with the data and addresses all known hazards and other relevant information that could impact safe and effective use of the device. The labeling satisfies the requirements of CFR 801.109 Prescription devices. {6}------------------------------------------------ ### RISKS TO HEALTH Table 2 below identifies the risks to health that may be associated with use of Internal Tissue Marker and the measures necessary to mitigate these risks. | Table 2 – Identified Risks and Mitigation Measures | | |----------------------------------------------------|------------------------------| | Identified Risk | Mitigation Measures | | Adverse tissue reaction | Biocompatibility Testing | | | Sterilization Testing | | | Shelf Life/Stability Testing | | | Performance Testing | | | Labeling | | Ineffective Marking | Performance Testing | | | Shelf Life/Stability Testing | | | Labeling | | Improper use | Labeling | ### SPECIAL CONTROLS: In combination with the general controls of the FD&C Act, the Internal Tissue Marker is subject to the following special controls: - 1. The device must be demonstrated to be biocompatible. Material names and specific designation numbers must be provided. - 2. Performance testing must demonstrate that the device performs as intended to mark the tissue for which it is indicated. - 3. Performance data must demonstrate the sterility of the device. - 4. Performance data must support the shelf life of the device by demonstrating sterility, package integrity, device functionality, and material stability over the requested shelf life. - 5. Labeling must include: - A warning that the device must not be used on a non-sterile surface prior to use a. internally. - An expiration date / shelf life. b. - Single use only labeling must be labeled directly on the device. C. ### BENEFIT/RISK DETERMINATION No clinical study was provided nor requested nor deemed necessary for the subject device based on the risks. The risks of the device are based on literature review, nonclinical laboratory data and tissue study data collected as described above. The subject surgical marker could provide a lower risk alternative to the present off-label use of other marking pens not intended for internal usage. However, there are potential adverse events that include, but are not limited to; infection, tissue inflammation, and mechanical failure of vessels. {7}------------------------------------------------ The probable benefits of the device are also based on literature review, nonclinical data and tissue study data collected in a study as described above. The benefit of the subject device would be to provide a safer and effective surgical marking pen to reduce the risks associated with the off-label use of existing marking pens, which are not provided sterile nor designed and intended for CABG surgery. . The use of the device on human saphenous veins to maintain vein orientation during the procedure of coronary artery bypass grafting may help avoid twisting or torsion of the vein during the procedure. Twisting or torsion of the vein, if it occurred during CABG surgery (e.g., vein orientation), could impede early graft patency. In conclusion, given the available information above, the data support that for the indication "The VasoPrep Surgical Marking Pen is intended for use prior to or during the harvesting and preparation of vein grafts used in bypass surgery. The pen is used to demarcate selected sites and orientation of the graft", the probable benefits outweigh the probable risks. The device provides benefits and the risks can be mitigated by the use of general and the identified special controls. Presently, there are no available surgical marking pens specifically designed for usage on internal tissues. Marking pens that are currently used off-label have different dye formulations which may have adverse effects on saphenous vein smooth muscle and endothelium. With the use of off-label pens or no pens at all, the patency of grafted vessels can be jeopardized. Patients are typically not aware of the use of surgical marking pens; however the data, for the subject device indicates it to be reasonably safe and effective such that patients undergoing CABG surgery would be willing to take the risk even though it is uncertain that they will achieve the benefit, because if they benefit, the benefit from maintaining vessel patency in a safe manner is substantial. Finally, the risks associated with this device, although potentially serious, should not occur in any clinically significant number for this device, and they would be expected to be lower than those currently accepted for similar treatments due to safer dye formulation. ## CONCLUSION The de novo for the VasoPrep Surgical Marking Pen is granted and the device is classified under the following: Product Code: PDW Device Type: Internal Tissue Marker Class: Class II Regulation: 21 CFR 878.4670