PREVENA 125 and PREVENA PLUS 125 Therapy Units

{0}------------------------------------------------ #### DE NOVO CLASSIFICATION REQUEST FOR PREVENA 125 AND PREVENA PLUS 125 THERAPY UNITS #### REGULATORY INFORMATION FDA identifies this generic type of device as: Negative pressure wound therapy device for reduction of wound complications. A negative pressure wound therapy device for reduction of wound complications is a powered suction pump intended for wound management and reduction of wound complications via application of negative pressure to the wound, which removes fluids, including wound exudate, irrigation fluids, and infectious materials. This device type is intended for use with wound dressings classified under 21 CFR 878.4780. This classification does not include devices intended for organ space wounds. NEW REGULATION NUMBER: 21 CFR 878.4783 CLASSIFICATION: Class II PRODUCT CODE: QFC #### BACKGROUND DEVICE NAME: PREVENA 125 and PREVENA PLUS 125 Therapy Units SUBMISSION NUMBER: DEN180013 DATE OF DE NOVO: March 15, 2018 - KCI USA. Inc. CONTACT: 6203 Farinon Dr. San Antonio, Tx 78249 #### INDICATIONS FOR USE PREVENA 125 and PREVENA PLUS 125 Therapy Units manage the environment of closed surgical incisions and remove fluid away from the surgical incision via the application of -125mmHg continuous negative pressure. When used with legally marketed compatible dressings, PREVENA 125 and PREVENA PLUS 125 Therapy Units are intended to aid in reducing the incidence of seroma and, in patients at high risk for post-operative infections, aid in reducing the incidence of superficial surgical site infection in Class I and Class II wounds. #### LIMITATIONS The sale, distribution, and use of PREVENA 125 and PREVENA PLUS 125 Therapy Units are restricted to prescription use in accordance with 21 CFR 801.109. {1}------------------------------------------------ The device is not intended to treat surgical site infection or seroma. Safety and effectiveness in pediatric population (<22 years old) have not been evaluated. Safety and effectiveness in Class III (Contaminated) and Class IV (Dirty/Infected) wounds have not been demonstrated. Furthermore, Class IV surgical wounds are not expected to be closed primarily, and the subject device should only be used on closed surgical incisions. The device has not been demonstrated to reduce deep incisional and organ space surgical site infections. The device has not been demonstrated to be effective in reducing the incidence of surgical site infection and seroma in all surgical procedures and patient populations; therefore, the device may not be recommended for routine use to reduce surgical site infection and seroma. Please refer to the 'Summary of Clinical Information' section for the specific surgical procedures and patient populations included in the clinical studies. Surgeons should continue to follow the 'Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection'2 and the 'American College of Surgeons and Surgical Infection Society: Surgical Site Infection Guidelines' + for best practices in preventing surgical site infection. # PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS, AND CONTRAINDICATIONS. ### DEVICE DESCRIPTION The PREVENA 125 and PREVENA PLUS 125 Therapy Units ("PREVENA pumps") are singleuse, compact and portable powered suction pumps. The therapy units are packaged with compatible sterile canisters (45 ml for PREVENA 125 or 150 ml for PREVENA PLUS 125) and sterile tubing set. The therapy units can be used with compatible, legally marketed wound dressings classified under 21 CFR 878.4780, such as the PEEL & PLACE dressing and the CUSTOMIZABLE dressing, which, when combined are referred to as the PREVENA Incision Management Systems ("PREVENA systems"). The PREVENA Incision Management Systems deliver a pre-set, continuous negative pressure of 125 mmHz to the incision site. The systems are intended to be applied to incision sites immediately after surgery for a minimum of 2 days up to a maximum of 7 days depending on the surgeon's preference. The therapy units can be used up to 192 hours, after which they will automatically shut off. The subject devices are identical to the currently marketed PREVENA pumps, except for the change in the intended use (reduction in the incidence of wound complications). The PREVENA 125 Therapy Unit was most recently cleared under K161897, and the PREVENA PLUS 125 Therapy Unit was most recently cleared under K173426. There is no change to the user interface, design, mechanisms of operation, and specifications for delivery of negative pressure therapy from the previously marketed PREVENA pumps. {2}------------------------------------------------ | | PREVENA 125 | PREVENA PLUS 125 | |-----------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | Table 1. Device Description | | | | 1x Disposable<br>non-sterile<br>therapy unit<br>(including<br>compatible<br>non-sterile<br>carrying case) | PREVENA 125 Therapy Unit<br><br>Image: PREVENA 125 Therapy Unit | PREVENA PLUS 125 Therapy Unit<br><br>Image: PREVENA PLUS 125 Therapy Unit | | | Powered by 3 "AA" batteries Visual and audible alarms: Leak Canister full Low battery Critical battery System error | Powered by rechargeable lithium battery or power cord Visual and audible alarms: Leak or canister missing Blockage in tubing or canister full Batteries need to be recharged 8 hours of therapy time remain System fault | | 1x Sterile<br>canister | 45 mL canister | 150 mL canister | | 1x Sterile<br>tubing set | PREVENA Tubing Set – single-lumen, integrated tubing set for direct connection to the PREVENA 125 Therapy unit. Comes with PREVENA V.A.C. Connector, which is necessary for connection to a V.A.C. Therapy Unit<br><br>Image: PREVENA V.A.C Connector | SENSAT.R.A.C. Tubing Set – multi-lumen, non-integrated tubing set for direct connection to the PREVENA PLUS 125 Therapy Unit and to a V.A.C. Therapy Unit<br><br>Image: SENSAT.R.A.C. Tubing Set | #### Table 1. Device Description ### SUMMARY OF NONCLINICAL/BENCH STUDIES All non-clinical/bench test data were referenced from the following previously-cleared 510(k) submissions of the device: K100821, K141017, K150006, K153199, K161897, K173426. No new non-clinical/bench testing was provided in the De Novo request. # BIOCOMPATIBILITY/MATERIALS The current De Novo request contains only the PREVENA 125 and PREVENA PLUS 125 therapy units, canisters and tubing sets, which do not have direct patient contact. The therapy units must be used with compatible, legally-marketed wound dressing kits classified under 21 CFR 878.4780. {3}------------------------------------------------ ## SHELF LIFE/STERILITY The PREVENA 125 and PREVENA PLUS 125 therapy units are provided non-sterile. All canisters and tubing sets are sterilized using gamma irradiation to achieve a sterility assurance level (SAL) of 106. The sterilization method was validated per ISO 11137-1:2006 (Sterilization of health care products – Radiation – Part 1: Requirements for development, validation and routine control of sterilization process for medical devices). The shelf life of the canisters and tubing sets was evaluated after accelerated aging equivalent to three years. The packaging was subject to testing per ASTM-F1980 (Standard guide for accelerated aging of sterile barrier systems for medical devices). Aged canisters and tubing sets were also subject to a series of functional testing. including leak test, canister to tubing bond strength test, and tubing to in-line connector bond strength test. The test articles met the acceptance criteria for each test. # ELECTRICAL SAFETY AND ELECTROMAGNETIC COMPATIBILITY The following Electrical Safety and Electromagnetic Compatibility testing has been performed: - AAMI/ANSI ES60601-1:2005 + A1 2012 Medical Electrical Equipment Part ● 1: General requirements for basic safety and essential performance, amendments - IEC 60601-1-2:2014 4th edition Medical Electrical Equipment Part 1-2: . General requirements for basic safety and essential performance - Collateral Standard: Electromagnetic disturbances - Requirements and tests The PREVENA 125 and PREVENA PLUS 125 therapy units passed all relevant portions of the testing. # SOFTWARE All components of the device are controlled/monitored by software, which is responsible for the functionality, user interface, safety checks and performance accuracy. The agency considers the software to be a moderate level of concern (LOC) because inadvertent software errors could result in injury or delayed wound healing to the patient. All elements of software information corresponding to moderate LOC devices as outlined in FDA's guidance document "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices" (issued May 11, 2005) were provided in previous 510(k) submissions (reference K150006 and K173426) and contain sufficient detail to provide reasonable assurance that the software will operate in a manner described in the specifications. {4}------------------------------------------------ ### PERFORMANCE TESTING-BENCH Bench testing was conducted to demonstrate that the PREVENA 125 and PREVENA PLUS 125 therapy units perform as expected under the anticipated conditions of use. This testing included evaluation of key device parameters such as maintenance of negative pressure at the wound site and system alarms. The following bench testing was conducted to demonstrate the device performance characteristics: - . Pressure manifold testing – The device was bench tested in a simulated wound model and under the worst-case scenarios of use (i.e., with substantial but nonalarming fluid leak and air leak). The device can maintain a continuous negative pressure of -125±25 mmHg across the entire compatible wound dressing for the labeled use life of 7 days. - . Exudate removal testing - The device was bench tested in a simulated wound model and under the worst-case scenarios of use (i.e., with substantial but nonalarming fluid leak and air leak). The device can remove simulated wound fluid as intended. - The following system alarms were tested to ensure they function as intended: ● leak, blockage, low battery, 8-hour therapy time remaining, and system fault. ## HUMAN FACTORS/USABILITY TESTING Usability testing was performed to demonstrate that the device design and associated labeling are sufficient to enable intended operation of the device by each intended user populations (i.e., surgeons, operating room nurses, and patients). A list of critical user tasks was identified and prioritized in accordance with potential harm that would or could arise from users inadvertently performing tasks incorrectly or failing to perform the necessary tasks. Intended users were asked to perform the critical tasks under simulated use conditions. The usability data were reviewed in K141017 and found to be acceptable. # SUMMARY OF CLINICAL INFORMATION The requester provided a systematic literature review and associated meta-analyses to support the safety and effectiveness of the PREVENA Incision Management Systems over closed incisions in reducing the incidence of surgical site infections (SSIs) and seromas versus conventional wound dressings. The systematic literature search was performed using PubMed, The Cochrane Library, OVID, EMBASE, ScienceDirect, and alternative resources such as Google searches and QUOSA. Search terms included: ("negative pressure wound therapy" OR "negative pressure" OR "negative pressure therapy" OR "NPWT") AND ("PREVENA" OR "ciNPT" OR "prophylactic NPWT" OR "preventative NPWT" OR "incision management" OR "incisional management" OR "closed incision negative pressure wound therapy" OR "closed incision negative pressure therapy"). {5}------------------------------------------------ Six (6) independent reviewers performed the study selection. Titles of manuscripts and abstracts that met the search criteria were logged and investigated for duplicates. The abstracts and manuscripts were assessed for inclusion and exclusion criteria (Table 2) by a subset of two (2) independent reviewers. When discordance was identified, the two reviewers deliberated until a consensus was reached. | | Inclusion Criteria | Exclusion Criteria | |---|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------| | ● | Abstract or manuscript written in English | ● Meta-analysis studies | | ● | Published or unpublished study | ● Pre-clinical studies (i.e., animal or bench science assessments) | | ● | Studies that compare the use of PREVENA<br>Incision Management Systems using -125 mmHg pressure with legally marketed compatible dressing over closed incisions to conventional wound dressings (e.g., occlusive gauze dressing) | ● Studies on pediatric patients (age <18 years) | | ● | Contained an endpoint/outcome of surgical site infection (SSI), dehiscence, seroma, hematoma, or post-operative pain | ● Studies with less than 10 patients | | ● | Studies that followed the subjects/patients for a minimum of 30 days for the SSI endpoint | ● Veterinary studies | | ● | Studies that followed the subjects/patients for a minimum of 10 days for the seroma endpoint | | | | | | Table 2. Inclusion and exclusion criteria for the systematic literature review | | |--|--|--|--------------------------------------------------------------------------------|--| | | | | | | For abstracts and manuscripts that met all the inclusion criteria and none of the exclusion criteria, they were examined critically to: i) assess whether containing reference of any other articles that meet the inclusion criteria and ii) extract study characteristics by at least two additional independent reviewers. Registered studies at ClinicalTrials.gov were also reviewed using the same search criteria for completed and terminated studies. The Cochrane Collaboration tool was used for assessing risk of bias. A total of 426 studies resulted from the initial search. After 150 duplications were removed, a total of 276 unique studies were assessed for inclusion. An additional 251 articles were excluded based on the pre-specified inclusion criteria (Table 2), which was comprised of 64 review/meta-analysis, 15 pre-clinical studies, 2 pediatric patient populations, 3 veterinary studies, 12 other (protocol, technical report, subsequent study included in the metaanalysis, and comment), and 119 that did not meet all inclusion criteria. Lastly, seven (7) articles identified as retrospective studies were removed to minimize bias and ensure only the highest level of evidence for the meta-analysis. {6}------------------------------------------------ Image /page/6/Figure/0 description: This image is a flow diagram outlining the process of identifying studies for a meta-analysis. The search terms used included variations of "negative pressure wound therapy." The initial search yielded 426 studies, which were then filtered through several stages, including the removal of duplicates, review of titles and abstracts, and application of inclusion criteria, resulting in 27 studies identified for meta-analysis, with 20 ultimately included. Image /page/6/Figure/1 description: The image shows the title of a figure. The title is "Figure 1. Summary of study selection for the meta-analyses". The title is written in a clear, sans-serif font and is centered on the image. Ultimately, twenty (20) prospective studies, including two (2) KCI USA, Inc.-sponsored, unpublished clinical studies from ClinicalTrials.gov, were included in the meta-analyses for SSI and seroma characterization. A total of up to 6,403 evaluable patients were included in these meta-analyses with 1,367 in the PREVENA Incision Management Systems therapy (treatment) group and 5,036 in the conventional wound dressing (control) group. The two (2) KCI USA, Inc.-sponsored, unpublished clinical studies from ClinicalTrials.gov can be summarized as follows: NCT01341444 was a randomized, single center, interventional trial evaluating the safety and effectiveness of PREVENA Incision Management Systems on closed surgical incisions in subjects who had undergone open renal transplant surgery. Subjects were randomized 1:1 to receive either the PREVENA therapy {7}------------------------------------------------ (treatment group) or a silver-impregnated occlusive dressing (control group). The purpose of the study was to compare surgical site complications, which include incisional fluid accumulation, dehiscence, and surgical site infections, between the PREVENA therapy (treatment group) and conventional occlusive dressing (control group). The measurement outcome was the incidence of surgical site complications up to 30 days (+/- 2 days) post renal transplant surgery. Due to enrollment difficulties, KCI decided to terminate the study after enrolling 63 of 88 subjects. There were a total 28 subjects in the treatment group with 0 surgical site infections (0%) and 30 subjects in the control group with 2 surgical site infections (6.7%). Adverse events were reported: 25 subjects in the treatment group reported at least 1 adverse event and 24 subjects in the control group reported at least 1 adverse event. In the treatment group, 11 subjects reported at least 1 serious adverse event, and in the control group, 13 subjects reported at least one serious adverse event. None of the reported adverse events were related to the PREVENA therapy or conventional wound dressings used. NCT02195310 was a randomized, multi-center, open label, interventional trial evaluating the safety and effectiveness of PREVENA Incision Management System (treatment group) on closed sternal midline incisions in patients at high risk for surgical site occurrences to a control group treated with conventional wound dressings, such as gauze with tape, pressure dressing with additional packing and tape, and silverimpregnated dressings. The purpose of the study was to assess the performance of PREVENA Incision Management System versus conventional wound dressings on closed median sternal incisions in subjects undergoing cardiac surgery. The primary endpoint was the incidence of surgical site infections (SSI) within 30 days postoperatively per CDC guidelines21. Five hundred twenty subjects were expected to be randomized 1:1. An interim data review was conducted on 257 subjects (128 PREVENA subjects, 129 control subjects). The conditional power from this analysis was below 60%. Since the calculated SSI rates from the interim data review were outside the ranges of the sample size assumptions, the study was terminated early due to the lack of evidence to support the objectives and assumptions of the study. A final analysis was conducted on 299 subjects; 145 subjects for the PREVENA arm and 154 subjects for the control arm. The incidence rate of SSI in the PREVENA arm was 9.0% (13 subjects) and in the SOC arm was 10.4% (16 subjects). There was a 1.5-fold higher rate of SSI in control subjects with a Body Mass Index (BMI) >35 kg/m². In the treatment group, 6/68 subjects with a BMI >35 kg/m² had an SSI (8.8%) and 10/75 control subiects with a BMI >35 kg/m2 had an SSI (13.3%). Adverse events were reported. See 'Safety' section below for more detail. There were 286 (83.6%) of subjects that experienced at least one adverse event. In the treatment group. 83.8% subjects experienced an adverse event, while 83.4% of the control group subjects experienced an adverse event. There were 18 subjects that experienced a treatment related adverse event. In the treatment group, 16 (9.2%) subjects experienced a treatment related adverse event, while 2 (1.2%) subjects in the control group experienced a treatment related adverse event. There were 118 serious adverse events. In the treatment group. 36.4% of subjects experienced a serious adverse event. while 32.5% of the control subjects experienced a serious adverse event. There were no device-related serious adverse events in either the treatment or control group. {8}------------------------------------------------ # Surgical Site Infection (SSI) Sixteen (16) prospective studies were included in the meta-analyses for SSI, which are summarized in Table 3 below. Nine (9) studies are randomized controlled trials, which are considered level I evidence. The remaining seven (7) studies are considered level II evidence, which include five (5) prospective treatment and historical controls studies and two (2) prospective observational studies that alternated patient assignment into either the treatment or control group (i.e., not randomized). | Study/ Level<br>of Evidence* | Study<br>Design | Surgical<br>Procedure | Subjects' Risk<br>Factors | Study<br>Duration | Incisional<br>Dressings<br>Used | No. of<br>Subjects | Treatment<br>Duration<br>(days) | |--------------------------------|-------------------------------------------|-----------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|------------------------------------------------|--------------------|---------------------------------| | Cantero 20163<br>Level II | Prospective<br>& Historical<br>Controlled | Diverting loop<br>ileostomy<br>reversal | NR | 30 days | PREVENA<br>IMS | 17 | 5-7 | | | | | | | Conventional<br>Wound<br>Dressing | 43 | 1-2, then daily | | DiMuzio 20174<br>Level I | RCT | Elective<br>vascular<br>surgery† | BMI> 30kg/m2,<br>pannus,<br>immunosuppressant | 30 days | PREVENA<br>IMS | 59 | NR | | | | | disorder,<br>reoperation,<br>prosthetic graft,<br>HbA1c>8 | | Standard gauze<br>dressing | 60 | NR | | Grauhan 20136<br>Level II | Prospective<br>Observational | Median<br>sternotomy† | BMI Mean<br>Treatment: 37 kg/m2,<br>Control: 36 kg/m2;<br>Diabetes; COPD;<br>LVEF | 90 days | PREVENA<br>IMS | 75 | 6-7 | | | | | | | Conventional<br>wound<br>dressings | 75 | 1-2 | | Grauhan 20147<br>Level II | Prospective<br>& Historical<br>Controlled | Median<br>sternotomy | NR | 30 days | PREVENA<br>IMS | 237 | 6-7 | | | | | | | Conventional<br>sterile wound<br>tape dressing | 3508 | 1-2 | | Gunatilake<br>20178<br>Level I | RCT | Cesarean<br>delivery | BMI Mean<br>Treatment: 46.3<br>kg/m2, Control: 46.8<br>kg/m2; Diabetes | 42 ± 10<br>days | PREVENA<br>IMS | 39 | 5-7 | | | | | | | Steri-strips,<br>sterile gauze,<br>Tegaderm | 43 | 1-2 | | Lavryk 201610<br>Level II | Prospective<br>Observational | Reoperative<br>colorectal<br>surgery† | Diabetes; Hx of<br>Smoking | 30 days | PREVENA<br>IMS | 55 | 7±2 | | | | | | | Standard gauze<br>dressing | 101 | NR | | Lee AJ 201611<br>Level I | RCT | CABG with<br>harvesting of<br>GSV† | Diabetes; Smoking;<br>COPD; HTN; CHF;<br>LVD; Aortic<br>Stenosis; AF; CVD;<br>Dyslipidemia; CKF;<br>PVD;<br>Hypothyroidism;<br>Arthritis; Gout;<br>Asthma | 42 days | PREVENA<br>IMS | 33 | Up to 7 | | | | | | | Conventional<br>dry dressing | 27 | NR | | Table 3. Characteristics of studies included in the SSI meta-analyses | | | |-----------------------------------------------------------------------|--|--| | | | | {9}------------------------------------------------ | Lee K 201712<br>Level I | RCT | Femoral to<br>distal artery<br>bypass; femoral<br>endarterectomy;<br>femoral artery<br>crossover;<br>other† | BMI Mean<br>Treatment: 29 kg/m2,<br>control: 29 kg/m2;<br>Diabetes; Hx of<br>Smoking/ COPD;<br>CAD; LVD; HTN;<br>CKD;<br>Anticoagulation;<br>Ischemic tissue loss | 30 days<br>and 90<br>days | PREVENA<br>IMS<br>Standard gauze<br>dressing | 53 | First day of<br>discharge up to<br>8 days | |---------------------------------|-------------------------------------------|-------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|-------------------------------------------| | Matatov 201313<br>Level II | Prospective<br>& Historical<br>Controlled | Femoral<br>cutdown for<br>vascular<br>procedures | BMI Mean<br>Treatment: 26 kg/m2,<br>Control: 27 kg/m2;<br>Diabetes; Hx of<br>Smoking/; COPD;<br>CAD; CHF; HTN;<br>renal insufficiency,<br>anemia | 30 days | PREVENA<br>IMS<br>Primapore or<br>Dermabond<br>Adhesive | 41 (52<br>wounds) | 5-7 | | | | | | | | 49 (63<br>wounds) | 3 | | NCT01341444<br>Level I | RCT | Renal<br>transplant† | BMI Mean<br>Treatment: 29.05<br>kg/m2, Control:<br>28.73; Diabetes;<br>Tobacco Use; | 30 days | PREVEANA<br>IMS<br>Standard<br>incisional<br>dressing | 28 | 5 | | | | | | | | 30 | 3 | | NCT02195310<br>Level I | RCT | Median<br>sternotomy<br>(elective<br>cardiac surgery)† | BMI Mean<br>Treatment: 35.64<br>kg/m2, Control:<br>35.27 kg/m2;<br>Diabetes;<br>Immunosuppressant<br>Disorder; Hx of<br>Smoking; Dialysis;<br>Planned Bilateral<br>Mamery Artery;<br>Chronic Lung<br>Disease; CKD;<br>Previous Chest Wall<br>Radiotherapy; Breast<br>Size D Age > 75<br>years; LVEF< 30%; | 30 days | PREVENA<br>IMS<br>Traditional<br>sterile wound<br>dressings<br>(included<br>gauze with<br>tape, pressure<br>dressings<br>and<br>silver<br>impregnated<br>dressings) | 145 | 4-7 | | | | | | | | 154 | 2-3 | | Newman 201714<br>Level I | RCT | Total hip or<br>knee<br>arthroplasty<br>(elective<br>revision)† | Blood thinners other<br>than aspirin<br>postoperatively,<br>BMI≥ 35 kg/m2;<br>PVD; diabetes<br>mellitus; current<br>smoker; hx of prior<br>joint infection;<br>current use of<br>corticosteroids or<br>immunomodulators;<br>hx or current<br>cancer/hematological<br>malignancy;<br>inflammatory<br>arthritis; renal failure<br>or dialysis;<br>malnutrition, liver<br>disease; transplant<br>status: HIV infection | 84 days | PREVENA<br>IMS<br>Silver<br>impregnated<br>occlusive<br>dressing | 80 | ≥2 | | | | | | | | 80 | 7 | | Redfern 201718<br>Level II | Prospective<br>& Historical<br>Controlled | Total hip or<br>knee<br>arthroplasty<br>(elective<br>primary) | BMI Mean<br>Treatment: 30.5 kg/m²; Control: 30.9 kg/m²; Diabetes;<br>HTN; Hx of Cancer/Tumor;<br>Arthritis; Myocardial<br>Infarction/Heart<br>Disease; Tobacco use | 60 days | PREVENA<br>IMS | 192 | 6-8 | | | | | | | Traditional<br>gauze dressing | 400 | Standard | | Ruhstaller<br>201719<br>Level I | RCT | Unscheduled<br>cesarean<br>delivery† | Gestational<br>Diabetes; Tobacco<br>Use; HTN; | 28 days | PREVENA<br>IMS | 67 | 3 | | | | | | | Telfa bandage<br>with gauze and<br>surgical tape | 69 | 1 | | Sabat 201620<br>Level I | RCT | Vascular<br>surgery<br>involving groin<br>incision | NR | 120 days | PREVENA<br>IMS | 30<br>wounds | 5 | | | | | | | Gauze and<br>Tegaderm | 33<br>wounds | NR | | Swift 201522<br>Level II | Prospective<br>& Historical<br>Controlled | Cesarean<br>section† | BMI ≥ 30 kg/m²;<br>Diabetes; Chronic<br>Hypertension;<br>Preeclampsia;<br>HELLP syndrome;<br>rupture of<br>membranes > 4<br>hours;<br>chorioamnionitis,<br>anticoagulation; | 42 days | PREVENA<br>IMS | 110 | 3 | | | | | | | Standard<br>sterile dressing | 209 | NR | {10}------------------------------------------------ *Population or Procedure identified as high-risk for wound complication *Oxford Centre of Evidence-Based Medicine RCT = Randomized Controlled Trial NR= Not Reported IMS= Incision Management System ciNPWT= closed incision Negative Pressure Wound Therapy BMI= Body Mass Index HX= History COPD= Chronic Obstructive Pulmonary Disorder GERD= Gastroesophageal Reflux Disease HTN= Hypertension AF= Atrial Fibrillation CVD= Cardiovascular disease CKF= Chronic kidney failure PVD= Peripheral vascular disease LVD= Left ventricle dysfunction CAD= Coronary artery disease CKD= Chronic kidney disease LVEF= Left ventricle ejection fraction HIV= Human immunodeficiency virus HELLP = Hemolysis, Elevated Liver enzymes, Low Platelet counts Together, the sixteen (16) studies contained 1,264 evaluable patients receiving the PREVENA Incision Management Systems therapy (treatment group) and 4,923 patients receiving conventional wound dressings (control group). The conventional wound dressings used in each study can be found in Table 3 above and range from occlusive gauze dressings to silverimpregnated dressings. The primary endpoint in the studies was the incidence of surgical site infection in the treatment group compared to the control group for at least four weeks following surgery. {11}------------------------------------------------ The treatment effect for each study was summarized using odds ratio (OR), which was calculated using the following formula: OR = AD/BC, where A = the number of subjects with SSI events for the treatment group B = the number of subjects without SSI events for the treatment group - C = the number of subjects with SSI events for the control group D = the number of subjects without SSI events for the control group An OR of less than 1 suggests a favorable effect by the treatment in reducing SSI, whereas an OR greater than 1 suggests a favorable effect by the conventional wound dressings. The 95% confidence interval (95% CI) for the odds ratio is calculated based on the standard error of Log(OR). The individual study effects for SSI are summarized in Figure 2 below. | Study or Subgroup | Treatment | | | | Control | | | Odds Ratio (95% CI) | Odds Ratio (95% CI) | |---------------------|-----------|-------|--------|--|---------|-------|--------|---------------------|---------------------------------------------| | | Events | Total | (%) | | Events | Total | (%) | | | | Cantero 2016 | 0 | 17 | (0.0) | | 9 | 43 | (20.9) | 0.10 (0.01, 1.89) | | | Dimuzio P 2017 | 6 | 59 | (10.2) | | 15 | 60 | (25.0) | 0.34 (0.12, 0.95) | | | Grauhan O 2013 | 3 | 75 | (4.0) | | 12 | 75 | (16.0) | 0.22 (0.06, 0.81) | | | Grauhan O 2014 | 3 | 237 | (1.3) | | 119 | 3508 | (3.4) | 0.37 (0.12, 1.16) | | | Gunatiliake RP 2017 | 1 | 39 | (2.6) | | 4 | 43 | (9.3) | 0.26 (0.03, 2.40) | | | Lavryk O 2016 | 7 | 55 | (12.7) | | 21 | 101 | (20.8) | 0.56 (0.22, 1.40) | | | Lee AJ 2016 | 0 | 27 | (0.0) | | 0 | 17 | (0.0) | Not estimable | | | Lee K 2017 | 6 | 53 | (11.3) | | 9 | 49 | (18.4) | 0.57 (0.19, 1.73) | | | Matatov T 2013 | 3 | 52 | (5.8) | | 19 | 63 | (30.2) | 0.14 (0.04, 0.51) | | | NCT01341444 | 0 | 28 | (0.0) | | 2 | 30 | (6.7) | 0.20 (0.01, 4.35) | | | NCT02195310 | 13 | 145 | (9.0) | | 16 | 154 | (10.4) | 0.85 (0.39, 1.83) | | | Newman JM 2017 | 2 | 80 | (2.5) | | 12 | 80 | (15.0) | 0.15 (0.03, 0.67) | | | Redfern RE 2017 | 2 | 196 | (1.0) | | 14 | 400 | (3.5) | 0.28 (0.06, 1.26) | | | Ruhstaller K 2017 | 2 | 61 | (3.3) | | 4 | 58 | (6.9) | 0.46 (0.08, 2.60) | | | Sabat J 2016 | 2 | 30 | (6.7) | | 7 | 33 | (21.2) | 0.27 (0.05, 1.39) | | | Swift SH 2015 | 3 | 110 | (2.7) | | 24 | 209 | (11.5) | 0.22 (0.06, 0.73) | | | Total | | 1264 | | | | 4923 | | 0.37 (0.27, 0.52) | | | | | | | | | | | | | | | | | | | | | | | 0.01<br>0.1<br>1<br>10<br>100 | | | | | | | | | | | Favours [experimental]<br>Favours [control] | | | | | | | | | | | | Figure 2. Forest plot of meta-analysis studies on surgical site infection (SSI)4 Overall, there is an observable trend supporting a favorable effect by the PREVENA system in reducing the incidence of SSI. The SSI rates ranged from 0% to 30.2% for the control group in the individual studies, and the SSI rates in the treatment group ranged from 0% to 12.7%. However, the benefit of the PREVENA systems varies considerably across different studies. possibly due to many confounding factors such as different surgical procedures and patient risk factors, which are further explored in subgroup analyses below. Additionally, there are many inherent limitations associated with meta-analyses and biases with each individual study, which are discussed in the 'Limitations of the Clinical Evidence' section below. Because of these confounding factors and limitations of the studies, statistical significance cannot be reliably inferred for the treatment effect based on the combined results from the sixteen (16) studies. a One (1) study (Lee AJ 20161) had no events in either the treatment or control group, and an odds ratio cannot be estimated for this study. {12}------------------------------------------------ Subgroup analyses were performed to elucidate potential confounding factors contributing to the heterogeneity in the treatment effect. The subgroup analyses conducted were based on: i) Wound classification, ii) Infection depth (i.e., superficial, deep, organ space), iii) Risk factors for surgical site infection. ### i.Wound classification To analyze the effect of the PREVENA Incision Management Systems on SSI in wounds of different degrees of contamination, a wound classification designation following the Center for Disease Control and Prevention (CDC) guidelines (Table 4) was assigned to each study based on the surgical procedure performed and CDC wound classification definitions. Each study was reviewed, and a CDC wound classification was assigned by two individuals with appropriate medical and clinical trials background. All the same wound types in each study were treated the same unless the publication (e.g., Newman et. al.14) specifically gave guidance that some wounds were more severe in a particular subgroup (e.g., septic revisions). If the publication provided a CDC wound classification, the provided classification was utilized. One study (Lavryk et. al.10) was excluded as only patients with wound classifications of II, III and IV were enrolled and could not be separated into the individual wound classification groups. | Surgical Wound<br>Classification | Definition | |----------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | Class I/Clean | An uninfected operative wound in which no inflammation is encountered and the<br>respiratory, alimentary, genital, or uninfected urinary tract is not entered. In addition,<br>clean wounds are primarily closed and, if necessary, drained with closed drainage.<br>Operative incisional wounds that follow nonpenetrating (blunt) trauma should be<br>included in this category if they meet the criteria. | | Class II/Clean-<br>contaminated | An operative wound in which the respiratory, alimentary, genital, or urinary tracts are<br>entered under controlled conditions and without unusual contamination. Specifically,<br>operations involving the biliary tract, appendix, vagina, and oropharynx are included in<br>this category, provided no evidence of infection or major break in technique is<br>encountered. | | Class III/Contaminated | Open, fresh, accidental wounds. In addition, operations with major breaks in sterile<br>technique (e.g., open cardiac massage) or gross spillage from the gastrointestinal tract,<br>and incisions in which acute, nonpurulent inflammation is encountered are included in<br>this category. | | Class IV/Dirty-infected | Old traumatic wounds with retained devitalized tissue and those that involve existing<br>clinical infection or perforated viscera. This definition suggests that the organisms<br>causing postoperative infection were present in the operative field before the operation. | Table 4. Surgical wound classifications and definitions21 Eleven (11) of the sixteen (16) studies were determined to contain only Class I wounds, and these eleven (11) studies consist of approximately 88% of the total patient population for the overall SSI meta-analysis. The subgroup analysis results of Class I wounds (Figure 3) show a reduction in favor of the PREVENA Incision Management Systems therapy and are consistent with the overall reduction in SSI observed in Figure 2. {13}------------------------------------------------ | | Treatment | | | | Control | | | | Odds Ratio (95% CI) | Odds Ratio (95% CI) | |-------------------|-----------|-------|--------|--|---------|-------|--------|--|---------------------------------------------|---------------------| | Study or Subgroup | Events | Total | (%) | | Events | Total | (%) | | | | | Dimuzio P 2017 | 6 | 59 | (10.2) | | 15 | 60 | (25.0) | | 0.34 (0.12, 0.95) | | | Grauhan O 2013 | 3 | 75 | (4.0) | | 12 | 75 | (16.0) | | 0.22 (0.06, 0.81) | | | Grauhan O 2014 | 3 | 237 | (1.3) | | 119 | 3508 | (3.4) | | 0.37 (0.12, 1.16) | | | Lee AJ 2016 | 0 | 27 | (0.0) | | 0 | 17 | (0.0) | | Not estimable | | | Lee K 2017 | 6 | 53 | (11.3) | | 9 | 49 | (18.4) | | 0.57 (0.19, 1.73) | | | Matatov T 2013 | 3 | 52 | (5.8) | | 19 | 63 | (30.2) | | 0.14 (0.04, 0.51) | | | NCT01341444 | 0 | 28 | (0.0) | | 2 | 30 | (6.7) | | 0.20 (0.01, 4.35) | | | NCT02195310 | 13 | 145 | (9.0) | | 16 | 154 | (10.4) | | 0.85 (0.39, 1.83) | | | Newman JM 2017 | 2 | 80 | (2.5) | | 12 | 80 | (15.0) | | 0.15 (0.03, 0.67) | | | Redfern RE 2017 | 2 | 196 | (1.0) | | 14 | 400 | (3.5) | | 0.28 (0.06, 1.26) | | | Sabat J 2016 | 2 | 30 | (6.7) | | 7 | 33 | (21.2) | | 0.27 (0.05, 1.39) | | | Total | | 982 | | | | 4469 | | | 0.36 (0.24, 0.55) | | | | | | | | | | | | | | | | | | | | | | | | 0.01<br>0.1<br>1<br>10<br>100 | | | | | | | | | | | | Favours [experimental]<br>Favours [control] | | Figure 3. Forest plot of meta-analysis studies on surgical site infection in Class I wounds Three (3) of the sixteen (16) studies were included in the subgroup analysis for Class II wounds, and these three (3) studies consist of approximately 8% of the total patient population for the overall SSI meta-analysis. The subgroup analysis results of Class II wounds (Figure 4) show a reduction in favor of the PREVENA Incision Management Systems therapy and are consistent with the overall reduction in SSI observed in Figure 2. Figure 4. Forest plot of meta-analysis studies on surgical site infection in Class II wounds | Study or Subgroup | Treatment | | | Control | | | Odds Ratio (95% CI) | | |---------------------|-----------|-------|-------|---------|------------------------|--------|---------------------|--------| | | Events | Total | (%) | Events | Total | (%) | | | | Gunatiliake RP 2017 | 1 | 39 | (2.6) | 4 | 43 | (9.3) | 0.26 (0.03, 2.40) | | | Ruhstaller K 2017 | 2 | 61 | (3.3) | 4 | 58 | (6.9) | 0.46 (0.08, 2.60) | | | Swift SH 2015 | 3 | 110 | (2.7) | 24 | 209 | (11.5) | 0.22 (0.06, 0.73) | | | Total | | 210 | | | 310 | | 0.27 (0.11, 0.68) | | | | | | | | | | | | | | | | | | 0.01 | 0.1 | 1 | 10 100 | | | | | | | Favours [experimental] | | Favours [control] | | There was only one (1) study identified as having Class III wounds; therefore, a subgroup analysis for Class III wounds was not performed. In this study, no SSI events were reported for the treatment group (0 out of n=17) and nine (9) SSI events were reported for the control group (9 out of n=43). There were no studies containing Class IV wounds that could be isolated for analysis; therefore, a subgroup analysis was not performed for Class IV wounds. It should be noted that the PREVENA systems are intended to be used only on closed incisions. As Class IV wounds are generally not expected to be surgically closed primarily, the PREVENA systems should not be used on Class IV wounds. ii.Infection depth Surgical site infection (SSI) can be divided into three (3) subgroups: superficial incisional SSI, deep incisional SSI, and organ space SSI'. Superficial incisional SSI is infection that is limited to the skin or subcutaneous tissue of the surgical incision. Deep incisional SSI is infection that has spread to deep soft tissues such as fascial and muscle layers. Organ space SSI is deeper infection that involves any part of the anatomy that was opened or manipulated during the operation'. {14}------------------------------------------------ Five (5) of the sixteen (16) studies selected for SSI meta-analyses included information to stratify patient SSI events into superficial, deep, and organ space infections. Subgroup analyses examining the effect of the PREVENA systems on different SSI locations were conducted based on these five (5) studies. Among the three subgroups, the PREVENA systems demonstrated the greatest benefit in reducing superficial incisional SSIs (Figure 5). The reduction in superficial SSI appears to be greater than the SSI reduction in the overall data (Figure 2). There was little to no benefit of the PREVENA systems in reducing deep incisional SSIs and organ space SSIs when compared to the control group. Figure 5. Forest plot of meta-analysis studies on surgical site infection in superficial incisional SSI | Study or Subgroup | Treatment<br>Events | Treatment<br>Total | Treatment<br>(%) | Control<br>Events | Control<br>Total | Control<br>(%) | Odds Ratio (95% CI) | | | | | | |-------------------|---------------------|--------------------|------------------|-------------------|------------------|----------------|---------------------|--------------------------------|-----|------------------------|----|-----| | Grauhan O 2013 | 1 | 75 | (1.3) | 8 | 75 | (10.7) | 0.11 (0.01, 0.93) | | | | | | | Lavryk O 2016 | 1 | 55 | (1.8) | 12 | 101 | (11.9) | 0.14 (0.02, 1.09) | | | | | | | Matatov T 2013 | 3 | 52 | (5.8) | 10 | 63 | (15.9) | 0.32 (0.08, 1.25) | | | | | | | Newman JM 2017 | 0 | 80 | (0.0) | 3 | 80 | (3.8) | 0.14 (0.01, 2.71) | | | | | | | Redfern RE 2017 | 0 | 196 | (0.0) | 9 | 400 | (2.3) | 0.10 (0.01, 1.81) | | | | | | | Total | | 458 | | | 719 | | 0.19 (0.08, 0.46) | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0.01<br>Favours [experimental] | 0.1 | 1<br>Favours [control] | 10 | 100 | ### iii. Risk factors for surgical site infection Patients having one or more co-morbidities are generally considered to be at higher risk for surgical site complications. High risk patients were defined in the selected studies as having one or more of the following co-morbidities: obesity (body mass index ≥30 kg/m²); diabetes; history of smoking; immune suppression or receiving drugs that can cause immune suppression, such as steroids, chemotherapeutic medications, and/or antimetabolites; malnutrition with a hydrated serum albumin of less than 3.0 grams/deciliter; neutropenia; preeclampsia; patients who have cardiac, pulmonary, liver or renal disease; history of previous surgery or radiation in the treatment area. Subjects' risk factors for each of the sixteen (16) studies are described in Table 3; however, some of the studies contain all comers with only a portion being high-risk patients. Upon further examination, nine (9) studies were determined to contain only high-risk patients. A subgroup analysis was performed on these nine (9) studies (Figure 6). As expected, the incidence of SSI, in both the treatment and control groups, is higher in high-risk patients (5.5% and 12.9%, respectively) compared to the overall study population (4.2% and 5.8%, respectively). Additionally, there appears to be a greater overall percentage reduction in SSI in high risk patients. Thus, while the reduction in SSI, as measured by odds ratio, in high risk patients does not appear to be significantly different than the reduction observed in the overall data (Figure 2), there is a greater clinical benefit of the PREVENA systems in patients at high risk for surgical site infection based on a greater absolute percentage reduction in the incidence of SSI. {15}------------------------------------------------ | Study or Subgroup | Treatment | | | Control | | | Odds Ratio (95% CI) | | |--------------------|-----------|-------|--------|---------|-------|--------|---------------------|---------------------------------------------| | | Events | Total | (%) | Events | Total | (%) | | | | Dimuzio P 2017 | 6 | 59 | (10.2) | 15 | 60 | (25.0) | 0.34 (0.12, 0.95) | | | Grauhan O 2013 | 3 | 75 | (4.0) | 12 | 75 | (16.0) | 0.22 (0.06, 0.81) | | | Gunatilake RP 2017 | 1 | 39 | (2.6) | 4 | 43 | (9.3) | 0.26 (0.03, 2.40) | | | Lee K 2017 | 6 | 53 | (11.3) | 9 | 49 | (18.4) | 0.57 (0.19, 1.73) | | | NCT01341444 | 0 | 28 | (0.0) | 2 | 30 | (6.7) | 0.20 (0.01, 4.35) | | | NCT02195310 | 13 | 145 | (9.0) | 16 | 154 | (10.4) | 0.85 (0.39, 1.83) | | | Newman JM 2017 | 2 | 80 | (2.5) | 12 | 80 | (15.0) | 0.15 (0.03, 0.67) | | | Ruhstaller K 2017 | 2 | 61 | (3.3) | 4 | 58 | (6.9) | 0.46 (0.08, 2.60) | | | Swift SH 2015 | 3 | 110 | (2.7) | 24 | 209 | (11.5) | 0.22 (0.06, 0.73) | | | Total | | 650 | | | 758 | | 0.40 (0.27, 0.62) | | | | | | | | | | | | | | | | | | | | | 0.01<br>0.1<br>1<br>10<br>100 | | | | | | | | | | Favours [experimental]<br>Favours [control] | Figure 6. Forest plot of meta-analysis studies on surgical site infection in high risk patients Together, the subgroup analyses on wound classification, infection depth, and patient risk factors for surgical site infection serve as the basis for granting the following Indications for Use: PREVENA 125 and PREVENA PLUS 125 Therapy Units manage the environment of closed surgical incisions and remove fluid away from the surgical incision via the application of -125mmHg continuous negative pressure. When used with legally marketed compatible dressings, PREVENA 125 and PREVENA PLUS 125 Therapy Units are intended to aid in reducing the incidence of seroma and, in patients at high risk for post-operative infections, aid in reducing the incidence of superficial surgical site infection in Class I and Class II wounds. Additional subgroup analyses for surgical site infection were performed based on surgical procedure risk factor, combination of surgical procedure and patient risk factors, and incision location. While the results from these subgroup analyses were reviewed, they did not serve as the basis for granting this De Novo request. ### Seroma Seven (7) prospective studies were included in the meta-analysis for seroma, which are summarized in Table 5 below. Five (5) studies are randomized controlled trials, which are level I evidence. The remaining two (2) studies are considered level II evidence, which include one (1) prospective treatment and historical controls study and one (1) prospective observational study that alternated patient assignment into either the treatment or control group (i.e., not randomized). | Study/ Level of<br>Evidence* | Study<br>Design | Surgical<br>Procedure | Subjects' Risk<br>Factors | Study<br>Duration | Incisional<br>Dressings Used | No. of<br>Subjects | Treatment<br>Duration<br>(days) | |--------------------------------|-------------------------------------------|-----------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------|-------------------|----------------------------------------------------------|--------------------|---------------------------------| | Ferrando 20175<br>Level II | Prospective<br>Observational | Breast conserving<br>surgery,<br>oncoplastic<br>surgery, tissue<br>sparing, simple<br>mastectomies† | BMI mean<br>Treatment: 27<br>kg/m²; Control: 29.5<br>kg/m²; Diabetes; Hx<br>of Smoking; HTN;<br>Use of<br>Corticosteroids;<br>Artery and Liver | 1 year | PREVENA PLUSTM<br>CUSTOMIZABLE<br>TM | 17 (25<br>wounds) | 7 | | | | | | | Steri-strip skin<br>adhesive closure | 20 (22<br>wounds) | 14 | | | | | Disease;<br>Chemotherapy;<br>Radiation; Previous<br>Surgery; Invasive<br>surgery | | | | | | Gunatilake 20178<br>Level I | RCT | Cesarean delivery | BMI Mean<br>Treatment: 46.3 kg/m2, Control: 46.8 kg/m2; Diabetes | 42 ± 10 days | PREVENA IMS | 39 | 5-7 | | | | | | | Steri-strips, sterile gauze, Tegaderm | 43 | 1-2 | | NCT01341444<br>Level I | RCT | Renal transplant† | BMI Mean<br>Treatment: 29.05 kg/m2, Control:<br>28.73; Diabetes;<br>Tobacco Use; | 30 days | PREVEANA IMS | 28 | 5 | | | | | | | Standard incisional dressing | 30 | 3 | | Pachowsky<br>201215<br>Level I | RCT | Total hip arthroplasty | NR | 10 days | PREVENA IMS | 9 | 5 days | | | | | | | Standard wound dressing | 10 | NR | | Pauser 201616<br>Level I | RCT | Hip hemiarthroplasty† | NR | 10 days | PREVENA IMS | 11 | 5 | | | | | | | Standard wound dressing consisting of dry wound coverage | 10 | NR | | Pleger 201717<br>Level I | RCT | Vascular procedures with access in common femoral artery† | BMI Mean<br>Treatment: 26.7 kg/m2, Control: 27.8 kg/m2; Diabetes; | 30 days | PREVENA IMS | 43 (58 wounds) | 5-7 | | | |…