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.

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.

AI/ML Overview

The provided text describes the regulatory evaluation of the PREVENA 125 and PREVENA PLUS 125 Therapy Units, focusing on clinical evidence from a systematic literature review and meta-analyses rather than a single, dedicated device performance study with specific acceptance criteria that would typically be seen for AI/ML devices. Therefore, a direct table of "acceptance criteria and reported device performance" as one might expect for a diagnostic AI/ML device is not explicitly present in the document.

However, based on the meta-analysis results and the FDA's granted indications for use, we can infer the "acceptance criteria" were met by demonstrating a favorable trend in reducing SSI and seroma, particularly in specific subgroups. The study essentially is the meta-analysis of existing clinical data.

Here's an interpretation of the information provided, structured to address your points, with explanations where direct parallels to AI/ML device criteria are not exact due to the nature of this submission (a device for wound therapy, not an AI/ML diagnostic).

Inferred Acceptance Criteria and Reported Device Performance (Based on Meta-Analysis Conclusion)

While explicit numerical acceptance criteria for a single study were not provided, the FDA's granting of the De Novo request signifies that the overall body of evidence from the meta-analysis met the regulatory standard for demonstrating safety and effectiveness for the specified indications. The "acceptance" was based on a "small but consistent trend" and "greater absolute percentage reduction" in specific high-risk populations.

Acceptance Criterion (Inferred)	Reported Device Performance (as per Meta-Analysis)
Aid in reducing incidence of seroma for closed surgical incisions.	Overall Favorable Trend: Odds Ratio (OR) of 0.31 (95% CI: 0.13, 0.75) for seroma incidence, indicating a reduction with PREVENA compared to control. (7 studies, N=366 treatment, 586 control)
Aid in reducing incidence of superficial surgical site infection (SSI) in Class I and Class II wounds in patients at high risk for post-operative infections.	Superficial SSI Reduction (Class I & II): - For Superficial Incisional SSI (all wounds analyzed for depth): OR of 0.19 (95% CI: 0.08, 0.46), showing a significant reduction. (5 studies) - For Class I wounds: OR of 0.36 (95% CI: 0.24, 0.55) for overall SSI, consistent reduction. (11 studies) - For Class II wounds: OR of 0.27 (95% CI: 0.11, 0.68) for overall SSI, consistent reduction. (3 studies) - For high-risk patients (overall SSI): OR of 0.40 (95% CI: 0.27, 0.62). Greater absolute percentage reduction observed (5.5% in treatment vs. 12.9% in control vs. 4.2% vs. 5.8% in overall). (9 studies)
Device demonstrates acceptable safety profile.	Similar Safety Profile to Conventional Dressings: No significant differences in Adverse Events (AEs) or Serious Adverse Events (SAEs) between PREVENA and control groups in the 3 studies that reported this data. Post-market data (7 years, hundreds of thousands of units shipped) consistent with anticipated AEs (skin irritation, blisters, pain, etc.), and no device-related SAEs.
Non-clinical performance (pressure maintenance, exudate removal, alarms).	Device capable of maintaining -125±25 mmHg, removing simulated wound fluid, and alarms function as intended under worst-case scenarios.
Usability demonstrated.	Usability testing showed intended users can operate the device (reviewed from prior 510(k) K141017).

Study Details:

Sample sizes used for the test set and the data provenance:
- Test Set Sample Size:
  - For SSI meta-analysis: 20 prospective studies, total of up to 6,403 evaluable patients (1,367 in PREVENA group, 5,036 in control group).
  - For Seroma meta-analysis: 7 prospective studies, total of 952 evaluable patients (366 in PREVENA group, 586 in control group).
- Data Provenance: The data comes from a systematic literature review and meta-analyses of published and unpublished prospective clinical studies. The geographic origin of these individual studies is not explicitly stated but implied to be global as it's a literature search. The studies are prospective. Seven articles identified as retrospective were removed to minimize bias.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- Study Selection/Ground Truth Establishment:
  - Study Selection: Six (6) independent reviewers performed the initial study selection. A subset of two (2) independent reviewers assessed abstracts and manuscripts for inclusion/exclusion criteria. When discordance was identified, these two reviewers deliberated until a consensus was reached.
  - Characteristic Extraction: At least two additional independent reviewers extracted study characteristics.
  - Wound Classification (Ground Truth for Subgroup Analysis): CDC wound classification was assigned to each study by "two individuals with appropriate medical and clinical trials background."
- Qualifications: The specific qualifications (e.g., number of years of experience, board certification) of these reviewers/experts are not detailed beyond "independent reviewers" and "individuals with appropriate medical and clinical trials background."
Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- Study Selection: "When discordance was identified, the two reviewers deliberated until a consensus was reached." This suggests a consensus-based adjudication among the two reviewers, rather than a third expert "tie-breaker" (2+1).
- Wound Classification: "a CDC wound classification was assigned by two individuals with appropriate medical and clinical trials background." It is implied a consensus or adjudication method was used if there was disagreement, but not explicitly stated.
If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
- No, an MRMC study was NOT done. This submission is for a medical device (a wound therapy unit), not an AI/ML diagnostic or assistive technology for human readers. The study is a meta-analysis of clinical trials comparing the device to conventional wound dressings. Therefore, the concept of "human readers improving with AI assistance" is not applicable here.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Not applicable. This is a physical wound therapy device, not a standalone algorithm. Its performance is evaluated in a clinical context on patients.
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- The "ground truth" for effectiveness (reduction in SSI and seroma) was the clinical outcomes data reported directly by the individual prospective studies included in the meta-analysis. These outcomes were typically assessed by the clinical investigators of each respective study.
The sample size for the training set:
- Not applicable. This is a device, not an AI/ML model that requires a training set. The "training data" in a broader sense would be all the accumulated medical knowledge and device design iterations that led to the PREVENA system. The studies reviewed form the evidence base for its effectiveness, not a training set for an algorithm.
How the ground truth for the training set was established:
- Not applicable. As stated above, there is no AI/ML training set in this context.

Summary

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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

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.

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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 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.

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	PREVENA 125	PREVENA PLUS 125
Table 1. Device Description
1x Disposablenon-steriletherapy unit(includingcompatiblenon-sterilecarrying case)	PREVENA 125 Therapy UnitImage: PREVENA 125 Therapy Unit	PREVENA PLUS 125 Therapy UnitImage: 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 Sterilecanister	45 mL canister	150 mL canister
1x Steriletubing 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 UnitImage: 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 UnitImage: 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.

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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.

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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").

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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 PREVENAIncision 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.

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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

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(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.

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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/ Levelof Evidence*	StudyDesign	SurgicalProcedure	Subjects' RiskFactors	StudyDuration	IncisionalDressingsUsed	No. ofSubjects	TreatmentDuration(days)
Cantero 20163Level II	Prospective& HistoricalControlled	Diverting loopileostomyreversal	NR	30 days	PREVENAIMS	17	5-7
					ConventionalWoundDressing	43	1-2, then daily
DiMuzio 20174Level I	RCT	Electivevascularsurgery†	BMI> 30kg/m2,pannus,immunosuppressant	30 days	PREVENAIMS	59	NR
			disorder,reoperation,prosthetic graft,HbA1c>8		Standard gauzedressing	60	NR
Grauhan 20136Level II	ProspectiveObservational	Mediansternotomy†	BMI MeanTreatment: 37 kg/m2,Control: 36 kg/m2;Diabetes; COPD;LVEF	90 days	PREVENAIMS	75	6-7
					Conventionalwounddressings	75	1-2
Grauhan 20147Level II	Prospective& HistoricalControlled	Mediansternotomy	NR	30 days	PREVENAIMS	237	6-7
					Conventionalsterile woundtape dressing	3508	1-2
Gunatilake20178Level I	RCT	Cesareandelivery	BMI MeanTreatment: 46.3kg/m2, Control: 46.8kg/m2; Diabetes	42 ± 10days	PREVENAIMS	39	5-7
					Steri-strips,sterile gauze,Tegaderm	43	1-2
Lavryk 201610Level II	ProspectiveObservational	Reoperativecolorectalsurgery†	Diabetes; Hx ofSmoking	30 days	PREVENAIMS	55	7±2
					Standard gauzedressing	101	NR
Lee AJ 201611Level I	RCT	CABG withharvesting ofGSV†	Diabetes; Smoking;COPD; HTN; CHF;LVD; AorticStenosis; AF; CVD;Dyslipidemia; CKF;PVD;Hypothyroidism;Arthritis; Gout;Asthma	42 days	PREVENAIMS	33	Up to 7
					Conventionaldry dressing	27	NR

Table 3. Characteristics of studies included in the SSI meta-analyses

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Lee K 201712Level I	RCT	Femoral todistal arterybypass; femoralendarterectomy;femoral arterycrossover;other†	BMI MeanTreatment: 29 kg/m2,control: 29 kg/m2;Diabetes; Hx ofSmoking/ COPD;CAD; LVD; HTN;CKD;Anticoagulation;Ischemic tissue loss	30 daysand 90days	PREVENAIMSStandard gauzedressing	53	First day ofdischarge up to8 days
Matatov 201313Level II	Prospective& HistoricalControlled	Femoralcutdown forvascularprocedures	BMI MeanTreatment: 26 kg/m2,Control: 27 kg/m2;Diabetes; Hx ofSmoking/; COPD;CAD; CHF; HTN;renal insufficiency,anemia	30 days	PREVENAIMSPrimapore orDermabondAdhesive	41 (52wounds)	5-7
						49 (63wounds)	3
NCT01341444Level I	RCT	Renaltransplant†	BMI MeanTreatment: 29.05kg/m2, Control:28.73; Diabetes;Tobacco Use;	30 days	PREVEANAIMSStandardincisionaldressing	28	5
						30	3
NCT02195310Level I	RCT	Mediansternotomy(electivecardiac surgery)†	BMI MeanTreatment: 35.64kg/m2, Control:35.27 kg/m2;Diabetes;ImmunosuppressantDisorder; Hx ofSmoking; Dialysis;Planned BilateralMamery Artery;Chronic LungDisease; CKD;Previous Chest WallRadiotherapy; BreastSize D Age > 75years; LVEF< 30%;	30 days	PREVENAIMSTraditionalsterile wounddressings(includedgauze withtape, pressuredressingsandsilverimpregnateddressings)	145	4-7
						154	2-3
Newman 201714Level I	RCT	Total hip orkneearthroplasty(electiverevision)†	Blood thinners otherthan aspirinpostoperatively,BMI≥ 35 kg/m2;PVD; diabetesmellitus; currentsmoker; hx of priorjoint infection;current use ofcorticosteroids orimmunomodulators;hx or currentcancer/hematologicalmalignancy;inflammatoryarthritis; renal failureor dialysis;malnutrition, liverdisease; transplantstatus: HIV infection	84 days	PREVENAIMSSilverimpregnatedocclusivedressing	80	≥2
						80	7
Redfern 201718Level II	Prospective& HistoricalControlled	Total hip orkneearthroplasty(electiveprimary)	BMI MeanTreatment: 30.5 kg/m²; Control: 30.9 kg/m²; Diabetes;HTN; Hx of Cancer/Tumor;Arthritis; MyocardialInfarction/HeartDisease; Tobacco use	60 days	PREVENAIMS	192	6-8
					Traditionalgauze dressing	400	Standard
Ruhstaller201719Level I	RCT	Unscheduledcesareandelivery†	GestationalDiabetes; TobaccoUse; HTN;	28 days	PREVENAIMS	67	3
					Telfa bandagewith gauze andsurgical tape	69	1
Sabat 201620Level I	RCT	Vascularsurgeryinvolving groinincision	NR	120 days	PREVENAIMS	30wounds	5
					Gauze andTegaderm	33wounds	NR
Swift 201522Level II	Prospective& HistoricalControlled	Cesareansection†	BMI ≥ 30 kg/m²;Diabetes; ChronicHypertension;Preeclampsia;HELLP syndrome;rupture ofmembranes > 4hours;chorioamnionitis,anticoagulation;	42 days	PREVENAIMS	110	3
					Standardsterile dressing	209	NR

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*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.

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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)

								0.010.1110100
								Favours [experimental]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.

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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 WoundClassification	Definition
Class I/Clean	An uninfected operative wound in which no inflammation is encountered and therespiratory, alimentary, genital, or uninfected urinary tract is not entered. In addition,clean wounds are primarily closed and, if necessary, drained with closed drainage.Operative incisional wounds that follow nonpenetrating (blunt) trauma should beincluded in this category if they meet the criteria.
Class II/Clean-contaminated	An operative wound in which the respiratory, alimentary, genital, or urinary tracts areentered under controlled conditions and without unusual contamination. Specifically,operations involving the biliary tract, appendix, vagina, and oropharynx are included inthis category, provided no evidence of infection or major break in technique isencountered.
Class III/Contaminated	Open, fresh, accidental wounds. In addition, operations with major breaks in steriletechnique (e.g., open cardiac massage) or gross spillage from the gastrointestinal tract,and incisions in which acute, nonpurulent inflammation is encountered are included inthis category.
Class IV/Dirty-infected	Old traumatic wounds with retained devitalized tissue and those that involve existingclinical infection or perforated viscera. This definition suggests that the organismscausing 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.

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	Treatment			Control			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)

							0.010.1110100
							Favours [experimental]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'.

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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	TreatmentEvents	TreatmentTotal	Treatment(%)	ControlEvents	ControlTotal	Control(%)	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)

								0.01Favours [experimental]	0.1	1Favours [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.

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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)

								0.010.1110100
								Favours [experimental]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:

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 ofEvidence*	StudyDesign	SurgicalProcedure	Subjects' RiskFactors	StudyDuration	IncisionalDressings Used	No. ofSubjects	TreatmentDuration(days)
Ferrando 20175Level II	ProspectiveObservational	Breast conservingsurgery,oncoplasticsurgery, tissuesparing, simplemastectomies†	BMI meanTreatment: 27kg/m²; Control: 29.5kg/m²; Diabetes; Hxof Smoking; HTN;Use ofCorticosteroids;Artery and Liver	1 year	PREVENA PLUSTMCUSTOMIZABLETM	17 (25wounds)	7
					Steri-strip skinadhesive closure	20 (22wounds)	14
			Disease;Chemotherapy;Radiation; PreviousSurgery; Invasivesurgery
Gunatilake 20178Level I	RCT	Cesarean delivery	BMI MeanTreatment: 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
NCT01341444Level I	RCT	Renal transplant†	BMI MeanTreatment: 29.05 kg/m2, Control:28.73; Diabetes;Tobacco Use;	30 days	PREVEANA IMS	28	5
					Standard incisional dressing	30	3
Pachowsky201215Level I	RCT	Total hip arthroplasty	NR	10 days	PREVENA IMS	9	5 days
					Standard wound dressing	10	NR
Pauser 201616Level I	RCT	Hip hemiarthroplasty†	NR	10 days	PREVENA IMS	11	5
					Standard wound dressing consisting of dry wound coverage	10	NR
Pleger 201717Level I	RCT	Vascular procedures with access in common femoral artery†	BMI MeanTreatment: 26.7 kg/m2, Control: 27.8 kg/m2; Diabetes;	30 days	PREVENA IMS	43 (58 wounds)	5-7
			HX of Smoking/;COPD; Renal Insufficiency;Malnutrition; Age >50 years;Overweight		Conventional adhesive plaster	57 (71 wounds)	1
Redfern 201718Level II	Prospective &HistoricalControlled	Total hip or knee arthroplasty(elective primary)	BMI MeanTreatment: 30.5 kg/m2, Control: 30.9 kg/m2; Diabetes;	60 days	PREVENA IMS	192	6-8
			HTN; Hx ofCancer/Tumor;Arthritis:MyocardialInfarction/HeartDisease; Tobacco		Traditional gauze dressing	400	Standard

Table 5. Characteristics of studies included in the Seroma meta-analysis

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*Population or Procedure identified as high-risk for wound complication

*Oxford Centre of Evidence-Based Medicine

NR= Not Reported
RCT = Randomized Controlled Trial 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

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Together, the seven (7) studies contained 366 evaluable patients receiving PREVENA Incision Management Systems therapy (treatment group) and 586 patients receiving conventional wound dressings (control group). The conventional wound dressings used in each study can be found in Table 5 above and mostly consist of gauze and occlusive dressings. The primary endpoint in the studies was the incidence of seroma in the treatment group compared to the control group for at least 10 days following surgery.

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 seroma events for the treatment group

B = the number of subjects without seroma events for the treatment group

C = the number of subjects with seroma events for the control group

D = the number of subjects without seroma events for the control group

An OR of less than 1 suggests a favorable effect by the treatment in reducing seroma, whereas an OR greater than 1 suggests a favorable effect by the standard of care in reducing seroma. The 95% confidence interval (95% CI) for the odds ratio is calculated based on the standard error of Log(OR). The individual study effects are summarized in Figure 7 below.

Study or Subgroup	Treatment			Control			Odds Ratio (95% CI)	Odds Ratio (95% CI)
	Events	Total	(%)	Events	Total	(%)
Ferrando PM 2017	1	25	(4.0)	5	22	(22.7)	0.14 (0.02, 1.32)
Gunatiliake RP 2017	1	39	(2.6)	2	43	(4.7)	0.54 (0.05, 6.19)
NCT01341444	3	28	(10.7)	3	30	(10.0)	1.08 (0.20, 5.85)
Pachowsky M 2012	4	9	(44.4)	9	10	(90.0)	0.09 (0.01, 1.03)
Pauser J 2014	4	11	(36.4)	8	10	(80.0)	0.14 (0.02, 1.03)
Pleger SP 2017	0	58	(0.0)	1	71	(1.4)	0.40 (0.02, 10.05)
Redfern RE 2017	0	196	(0.0)	2	400	(0.5)	0.41 (0.02, 8.49)
Total		366			586		0.31 (0.13, 0.75)
								0.010.1110Favours [experimental] Favours [control]

Figure 7. Forest plot of meta-analysis studies for seroma.

Overall, there is an observable trend supporting a favorable effect by the PREVENA systems in reducing the incidence of seroma formation. The seroma rates ranged from 0.5 % to 90 % for the control group in the selected studies, and the seroma rates in the treatment group ranged from 0 % to 44.4 %. However, the benefit of the PREVENA systems in reducing the incidence of seroma formation varies broadly across different studies, possibly due to many confounding factors such as different surgical procedures and patient risk factors. Subgroup analyses for seroma were not conducted as there are only seven (7) studies total and dividing them into subgroups would not result in meaningful analyses. 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

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confounding factors and limitations, statistical significance cannot be reliably inferred for the treatment effect on seroma rates based on the combined results from the seven (7) studies.

Limitations of the Clinical Evidence

There are many inherent limitations to meta-analyses, such as publication bias and selection bias. In addition, surgical site infection (SSI) and seroma are complex post-operative outcomes that have many potential causes. While efforts were made in the study identification and selection process to ameliorate biases by including both published and unpublished studies and only the highest quality studies, not all aspects of each selected meta-analysis study are identical. First, even though only prospective studies were included in the meta-analyses, these studies often had many potential sources of bias. Bias assessment was conducted using the Cochrane guidelines and focused on randomization, allocation concealment, differences in baseline patient and risk characteristics, blinded assessments, loss to follow up, comparing purpose of study to outcomes reported, and when possible, comparing outcomes to those listed on ClinicalTrials.gov, when available. Fourteen (14) of the twenty (20) meta-analysis studies were identified as high-risk for bias (Cantero 20162, DiMuzio 20174, Ferrando 20175, Gunatilake 2017, Lavryk 201610, Lee AJ 201611, Matatov 201313, NCT013471444, Newman 201714, Pleger 201717, Redfern 201718, Sabat 201620, Swift 201522). One (1) study was assessed as low risk for bias (Lee K 201712). Risk for bias was unclear in the remaining five (5) studies due to the lack of information reported in the studies. Second, the unit of the analysis is not consistent in all studies. Some studies used the wound as the unit of analysis and others used the patient as the unit of analysis. As a result, some of the data used in these analyses were based on wounds and some patients contributed more than one (1) wound to the analyses. Third, the timing of the outcome assessments was not consistent across each of the different studies. For example, although all the SSI studies evaluated SSI events for at least four weeks post-surgery, the duration of some of the studies was much longer. Similarly, although all the seroma studies evaluated the incidence of seroma for at least ten days after surgery, the duration of some of the studies was much longer. Fourth, the reported SSI rates in the metaanalysis studies varied broadly across different studies. It should be noted that the following SSI rates based on wound classification and types of SSI (Table 6) have recently been reported based on a retrospective review of the 2011 American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSOIP) database :

30-d postoperative outcomes	Total	Class I	Class II	Class III	Class IV
Surgical Site Infection (SSI)	3.4%	1.8%	4.8%	5.6%	8.5%
Superficial incisional SSI	1.9%	1.2%	2.6%	2.8%	2.7%
Deep incisional SSI	0.6%	0.4%	0.6%	0.8%	1.5%
Organ space SSI	1.1%	0.3%	1.6%	2.2%	4.4%

Table 6. Surgical Site Infection (SSI) rates based on ACS NSOIP database's
----------------------------------------------------------------------------	--	--	--	--	--	--	--

The SSI rates reported in the studies selected for the meta-analysis, even for the control groups, are generally higher than those reported in the literature. Factors contributing to this discrepancy may be surgeon-, procedure-, or patient-dependent, but nevertheless cannot be pinpointed based on the information provided in the studies. Fifth, five (5) of the seven (7) prospective studies included in the meta-analysis for SSI and one (1) prospective study included in the meta-analysis for seroma compared the PREVENA systems to historical

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controls. There have been significant evidence-based changes in patient care to define and reduce the risk for post-operative complications, including surgical site infections. Additionally, surgical site infection reduction measures vary among surgeons, hospitals, and countries. Changes in disease definitions, interventions, and treatment effectiveness over time contribute to non-contemporaneous bias. Results of studies using historical controls should be evaluated with caution.

These limitations should be considered when examining the results from these meta-analyses.

Conclusion

Overall, there appears to be a small but consistent trend supporting the benefit of the PREVENA systems in reducing surgical site infection (SSI) and seroma. However, due to the many limitations of the selected studies in the meta-analyses described above, any statistical inferences based on the combined results of these studies are inherently unreliable. The benefit of the PREVENA systems in reducing SSI and seroma appears to be small in general and varies potentially based on several factors, including wound classification, infection depth, and patient risk factors for post-operative wound complication. Subgroup analyses demonstrated that while the trend observed in the overall data continues to be observed in most subgroup studies, the greatest benefit of the PREVENA system appears to be in reducing superficial SSI in Class I and Class II wounds. Additionally, there is a greater absolute percentage reduction in the incidence of SSI in patients at high risk for post-operative infections, likely because of the higher incidence of SSI in this patient population. Therefore, taken as a whole, the data may not be supportive of routine use of the PREVENA systems for the sole purpose of reducing surgical site infection and seroma; however, as an adjunct therapy to good clinical practice, the PREVENA system has demonstrated 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. 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' 1 for best practices in preventing surgical site infection.

Safety

Adverse events (AEs) and Serious Adverse Events (SAEs) were reported in three (3) of the twenty (20) studies included in the meta-analyses [Gunatilake (Cesarean section) 2017°, NCT01341444 (Renal transplant). NCT02195310 (Sternotomy)). There were no treatment related AEs or SAEs reported in the Cesarean section study (Gunatilake 2017°). In the two studies conducted by KCI (NCT01341444 (Renal transplant), NCT02195310 (Sternotomy)), there were no SAEs, and the twenty one (21) reported AEs related or possibly related to the device including pain (5), blisters (4), dehiscence (4), draining/wound secretion (2), erythema (2), skin irritation (2), ecchymosis (1), and hematoma (1), which are known adverse events that may be seen with the use of the device on surgical incisions.

No significant differences were reported in AEs or SAEs between the PREVENA systems (treatment group) and conventional wound dressings (control group). No adverse device events, serious adverse device events, or device failures were reported. These results suggest that the

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PREVENA systems have a similar safety profile as conventional wound dressing for closed surgical incisions.

Post Market Data

PREVENA 125 and PREVENA PLUS 125 Therapy Units first received 510(k) clearance in 2010 and have been legally marketed globally. Since 2010, there have been (b) (4) units shipped with (b) (4) complaints. The complaint total includes data from both "Non-Harm" and "Alleging Harm" complaints. Post market surveillance data, from Medical Device Reporting (MDR) and Manufacturer and User Facility Device (MAUDE) databases, have been reviewed against the device risk profile and have been determined to be within acceptable limits. Additionally, the post market reports are consistent with the adverse events reported in the metaanalysis studies.

Although Medical Device Reporting (MDR) is a valuable source of information, this passive surveillance system has limitations, including the potential submission of incomplete, inaccurate, untimely, unverified, or biased data. In addition, the incidence or prevalence of an event cannot be determined from this reporting system alone due to potential under-reporting of events and lack of information about frequency of device use. MDR data alone cannot be used to establish rates of events, evaluate a change in event rates over time, or compare event rates between devices. The number of reports cannot be interpreted or used in isolation to reach conclusions about the existence, severity, or frequency of problems associated with devices.

Pediatric Extrapolation

In this De Novo request, existing clinical data were not leveraged to support the use of the device in a pediatric population.

LABELING

Device labeling includes a clinician guide and patient labeling. The clinician guide includes a description of the sterile and non-sterile device components, instructions for use, relevant clinical evidence, electromagnetic compatibility information, shelf life, and device disposal instructions.

Patient labeling includes instructions for use and information regarding when the treating physician should be contacted.

RISKS TO HEALTH

The table below identifies the risks to health that may be associated with use of a negative pressure wound therapy system for reduction of wound complications and the measures necessary to mitigate these risks.

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Identified Risks to Health	Mitigation Measures
Adverse tissue reaction	Biocompatibility evaluation
Infection	Sterilization validation
	Shelf life testing
	Labeling
Electrical shock orelectromagnetic interferencewith other devices	Electromagnetic compatibility testing
	Electrical safety testing
	Labeling
Damage to underlying tissue(e.g., wound maceration,uncontrolled bleeding) due to	Clinical data
	Non-clinical performance testing
	Usability testing
	Shelf life testing
	Software verification, validation, and hazard analysis
Mechanical failure Software malfunction Use error	Labeling
Increase in wound complicationsdue to use error	Clinical data
	Usability testing
	Labeling

Table 7. Identified Risks to Health and Mitigation Measures

SPECIAL CONTROLS

In combination with the general controls of the FD&C Act, the negative pressure wound therapy system for reduction of wound complications is subject to the following special controls:

(1) Clinical data must demonstrate that the device performs as intended under anticipated conditions of use and evaluate the following:
- (a) Wound complication rates; and
- (b) All adverse events.
(2) The patient-contacting components of the device must be demonstrated to be biocompatible.
(3) Performance data must demonstrate the sterility of the patient-contacting components of the device.
(4) Performance data must support the shelf life of the device by demonstrating continued sterility, package integrity, and device functionality over the labeled shelf life.
(5) Usability testing must demonstrate that intended users can correctly use the device, based solely on reading the instructions for use.
(6) Non-clinical performance data must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be tested in a worst-case scenario for the intended use life:
- (a) Ability to maintain pressure levels at the wound site under a worst-case scenario for the intended use life:

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(b) Fluid removal rate consistent with the wound types specified in the indications for use; and
(c) Timely triggering of all alarms.
(7) Performance data must demonstrate the electrical safety and electromagnetic compatibility (EMC) of the device.
(8) Software verification, validation, and hazard analysis must be performed.
(9) Labeling must include the following:
- (a) Instructions for use;
- (b) A summary of the device technical specifications, including pressure settings, modes (e.g., continuous or intermittent), alarms, and safety features;
- (c) Compatible components and devices;
- (d) A summary of the clinical evidence for the indications for use;
- (e) A shelf life for sterile components; and
- (f) Use life and intended use environments.
(10) For devices intended for use outside of a healthcare facility, patient labeling must include the following:
- (a) Information on how to operate the device and its components and the typical course of treatment:
- (b) Information on when to contact a healthcare professional; and
- (c) Use life.

BENEFIT/RISK DETERMINATION

Risks

The risks of the device are based on nonclinical laboratory studies, data collected in clinical studies, and post-market surveillance data described above. Adverse events (AEs) and Serious Adverse Events (SAEs) were reported in three (3) of the twenty (20) studies included in the meta-analyses (Gunatilake (Cesarean section) 20178, NCT01341444 (Renal transplant), NCT02195310 (Sternotomy)). There were no treatment related AEs or SAEs reported in the Cesarean section study (Gunatilake 20178). In the two studies conducted by KCI USA, Inc. (NCT01341444 (Renal transplant), NCT02195310 (Sternotomy)), there were no SAEs, and the twenty-one (21) reported AEs related or possibly related to the device included skin irritation. blisters, erythema, ecchymosis, pain, drainage, hematoma, and dehiscence, which are known adverse events that are anticipated with the use of the device on surgical incisions. Post-market surveillance (PMS) data of seven years also demonstrate the safety of the PREVENA systems. Overall, the risk of the PREVENA systems is low when used on closed surgical incisions. The risks associated with the PREVENA systems have been appropriately mitigated using the identified special controls. Device labeling will help ensure that the end users clearly understand the system description, indications, contraindications, warnings, and instructions for use.

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Benefits

The probable benefits of the device are based on nonclinical laboratory studies and clinical evidence based on meta-analyses described above. The proposed intended use is supported by a meta-analysis from twenty (20) clinical studies, seven (7) years of post-market surveillance (PMS) data, and preclinical testing: all of which contribute to a favorable benefit risk profile. Overall, the collective clinical evidence demonstrates a small but consistent trend supporting the benefit of the PREVENA systems in reducing surgical site infection (SSI) and seroma. However, due to the many limitations of the selected studies in the meta-analyses, any statistical inferences based on the combined results of these studies are inherently unreliable. The benefit of the PREVENA systems in reducing the incidence of SSI and seroma appears to be small in general and varies potentially based on several factors, including wound classification, infection depth, and patient risk factors for post-operative wound complication. Subgroup analyses demonstrated that while the trend observed in the overall data continues to be observed in most subgroup studies, the greatest benefit of the PREVENA system appears to be in reducing superficial SSI in Class I and Class II wounds. Additionally, there is a greater absolute percentage reduction in the incidence of SSI in patients at high risk for post-operative infections, likely because of the higher incidence of SSI in this patient population. The data, however, do not support the use of the PREVENA systems in reducing surgical site infection and seroma for all surgical procedures and patient populations. Therefore, taken as a whole, the data may not be supportive of routine use of the PREVENA systems for the sole purpose of reducing surgical site infection and seroma; however, as an adjunct therapy to good clinical practice, the PREVENA system has demonstrated to aid in reducing the incidence of seroma and, in patients at high risk for postoperative infections, aid in reducing the incidence of superficial surgical site infection in Class I and Class II wounds. 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.

Patient Perspectives

This submission did not include specific information on patient perspectives for this device.

Benefit/Risk Conclusion

In conclusion, given the available information above, for the following indication statement:

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 .

The probable benefits outweigh the probable risks for the PREVENA systems. The device provides benefits and the risk can be mitigated using general controls and the identified special controls.

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CONCLUSION

The De Novo request for the PREVENA 125 and PREVENA PLUS 125 Therapy Units is granted, and the device is classified under the following:

Product Code: QFC Device Type: Negative pressure wound therapy device for reduction of wound complications Class: II

Regulation: 21 CFR 878.4783

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References

1. Ban, K. A., Minei, J. P., Laronga, C., Harbrecht, B. G., Jensen, E. H., Fry, D. E., . . . Duane, T. M. (2017). American College of Surgeons and Surgical Infection Society: Surgical Site Infection Guidelines, 2016 Update. Journal of the American College of Surgeons,224(1), 59-74. doi:10.1016/j.jamcollsurg.2016.10.029
1. Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection, 2017. JAMA Surg. 2017;152(8):784-791. doi:10.1001/jamasurg.2017.0904
1. Cantero R, Rubio-Perez I, Leon Metal. Negative-Pressure Therapy to Reduce the Risk of Wound Infection Following Diverting Loop Ileostomy Reversal: An Initial Study. Adv Skin Wound Care 2016;29:114-118. doi:10.1097/01.ASW.0000480458.60005.34.
1. DiMuzio P, Staley C, Reiter D et al. RS06: A Randomized Study Evaluating Negative-Pressure Therapy to Decrease Vascular Groin Wound Complications. J Vasc Surg 2017;65:133S.
1. Ferrando, P. M., Ala, A., Bussone, R., Bergamasco, L., Perinetti, F. A., & Malan, F. (2018). Closed incision negative pressure therapy in oncological breast surgery: comparison with standard care dressings. Plastic and Reconstructive Surgery Global Open, 6(6).
1. Grauhan O, Navasardyan A, Hofmann M, Muller P, Stein J, Hetzer R. Prevention of poststernotomy wound infections in obese patients by negative pressure wound therapy. J Thorac Cardiovasc Surg 2013;145:1387-1392.
1. Grauhan, O., Navasardyan, A., Tutkun, B., Hennig, F., Müller, P., Hummel, M., & Hetzer, R. (2014). Effect of surgical incision management on wound infections in a poststernotomy patient population. International wound journal, 11(s1), 6-9.
1. Gunatilake, R. P., Swamy, G. K., Brancazio, L. R., Smrtka, M. P., Thompson, J. L., Gilner, J. B., ... & Heine, R. P. (2017). Closed-incision negative-pressure therapy in obese patients undergoing cesarean delivery: a randomized controlled trial. American Journal of Perinatology Reports, 7(03), e151-e157.
1. Ju, M. H., Cohen, M. E., Bilimoria, K. Y., Latus, M. S., Scholl, L. M., Schwab, B. J., Hall, B. L. (2014). Effect of Wound Classification on Risk Adjustment in American College of Surgeons NSQIP. Journal of the American College of Surgeons,219(3). doi:10.1016/j.jamcollsurg.2014.04.009
1. Lavryk O, Ashburn J, Liska D et al. Incisional negative pressure wound therapy reduces surgical site infections in complex colorectal surgery patients. Dis Colon Rectum 2016;59:e380. doi:1 0.1 097/01 .dcr.0000482708.50838.af.

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1. Lee AJ, Sheppard CE, KentWD, Mewhort H, Sikdar KC, Fedak PW. Safety and efficacy of prophylactic negative pressure wound therapy following open saphenous vein harvest in cardiac surgery: a feasibility study. Interactive Cardiovascular and Thoracic Surgery 2017;24:324-328. doi:1 0.1 093/icvts/ivw400.
1. Lee, K., Murphy, P. B., Ingves, M. V., Duncan, A., DeRose, G., Dubois, L., ... & Power, A. (2017). Randomized clinical trial of negative pressure wound therapy for high-risk groin wounds in lower extremity revascularization. Journal of vascular surgery, 66(6), 1814-1819.
1. Matatov T, Reddy KN, Doucet LD, Zhao CX, Zhang WW. Experience with a new negative pressure incision management system in prevention of groin wound infection in vascular surgery patients. J Vasc Surg 2013;57:791-795.
1. Newman, J. M., Siqueira, M. B., Klika, A. K., Molloy, R. M., Barsoum, W. K., & Higuera, C. A. (2019). Use of Closed Incisional Negative Pressure Wound Therapy After Revision Total Hip and Knee Arthroplasty in Patients at High Risk for Infection: A Prospective, Randomized Clinical Trial. The Journal of arthroplasty, 34(3), 554-559.
1. Pachowsky, M., Gusinde, J., Klein, A., Lehrl, S., Schulz-Drost, S., Schlechtweg, P., ... & Brem, M. H. (2012). Negative pressure wound therapy to prevent seromas and treat surgical incisions after total hip arthroplasty. International orthopaedics, 36(4), 719-722.
1. Pauser, J., Nordmeyer, M., Biber, R., Jantsch, J., Kopschina, C., Bail, H. J., & Brem, M. H. (2016). Incisional negative pressure wound therapy after hemiarthroplasty for femoral neck fractures-reduction of wound complications. International wound journal, 13(5), 663-667.
1. Pleger, S. P., Nink, N., Elzien, M., Kunold, A., Koshty, A., & Böning, A. (2018). Reduction of groin wound complications in vascular surgery patients using closed incision negative pressure therapy (ciNPT): a prospective, randomised, single-institution study. International wound iournal. 15(1), 75-83.
1. Redfern RE, Cameron-Ruetz C, O'Drobinak S, Chen J, Beer KJ. Closed incision negative pressure therapy effects on postoperative infection and surgical site complication after total hip and knee arthroplasty. J Arthroplasty 2017;32:3333-3339.
1. Ruhstaller, K., Downes, K. L., Chandrasekaran, S., Srinivas, S., & Durnwald, C. (2017). Prophylactic wound vacuum therapy after cesarean section to prevent wound complications in the obese population: a randomized controlled trial (the ProVac study). American journal of perinatology, 34(11), 1125-1130.
1. Sabat J. Tyagi S. Srouji A et al. IP123- Prophylactic Negative-Pressure Therapy for Femoral Incision in Vascular Surgery: Preliminary Results of a Prospective, Randomized Trial. (Presented at the 2016 Vascular Annual Meeting, June 8-11, 2016, National Harbor, MD). [abstract]. J Vasc Surg 2016;63:94S-95S.

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1. "Surgical Site Infection (SSI) Event." Surgical Site Infection (SSI) Event, 2019, www.cdc.gov/nhsn/PDFs/pscManual/9pscSSIcurrent.pdf?agree=yes&next=Accept.%20Up dated%20January%202019.
1. Swift SH, Zimmerman MB, Hardy-Fairbanks AJ. Effect of single-use negative pressure wound therapy on postcesarean infections and wound complications for high-risk patients. J Reprod Med 2015;60:21 1-218.

Regulation Number and Section

§ 878.4783 Negative pressure wound therapy device for reduction of wound complications.

(a)
Identification. 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 § 878.4780. This classification does not include devices intended for organ space wounds.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Clinical data must demonstrate that the device performs as intended under anticipated conditions of use and evaluate the following:
(i) Wound complication rates; and
(ii) All adverse events.
(2) The patient-contacting components of the device must be demonstrated to be biocompatible.
(3) Performance data must demonstrate the sterility of the patient-contacting components of the device.
(4) Performance data must support the shelf life of the device by demonstrating continued sterility, package integrity, and device functionality over the labeled shelf life.
(5) Usability testing must demonstrate that intended users can correctly use the device, based solely on reading the instructions for use.
(6) Non-clinical performance data must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be tested in a worst-case scenario for the intended use life:
(i) Ability to maintain pressure levels at the wound site under a worst-case scenario for the intended use life;
(ii) Fluid removal rate consistent with the wound types specified in the indications for use; and
(iii) Timely triggering of all alarms.
(7) Performance data must demonstrate the electrical safety and electromagnetic compatibility (EMC) of the device.
(8) Software verification, validation, and hazard analysis must be performed.
(9) Labeling must include the following:
(i) Instructions for use;
(ii) A summary of the device technical specifications, including pressure settings, modes (
e.g., continuous or intermittent), alarms, and safety features;(iii) Compatible components and devices;
(iv) A summary of the clinical evidence for the indications for use;
(v) A shelf life for sterile components; and
(vi) Use life and intended use environments.
(10) For devices intended for use outside of a healthcare facility, patient labeling must include the following:
(i) Information on how to operate the device and its components and the typical course of treatment;
(ii) Information on when to contact a healthcare professional; and
(iii) Use life.