XSTAT is a hemostatic device for the control of bleeding from junctional wounds in the groin or axilla not amenable to tourniquet application in adults and adolescents.

XSTAT is a temporary device for use up to four (4) hours until surgical care is acquired. XSTAT is intended for use in the battlefield.

Device Description

XSTAT consists of three sterile, syringe-style applicators containing compressed cellulose sponges with an absorbant animal-derived coating. The applicators facilitate fast delivery of the sponges into bleeding wounds. The black, telescoping handle is pulled away from the barrel of the applicator to prepare for sponge deployment. The tip of the applicator is placed into the wound track as close as possible to the source of bleeding before pushing the handle to deploy the sponges. Trained emergency responders may apply up to three applicators of sponges into junctional wounds in the groin or axilla as needed to completely pack the wound.

Each applicator houses 92 non-absorbable, expandable sponges for a total of 276 sponges per device (see Figure 1). Each sponge absorbs 3 ml of blood and a single applicator is therefore capable of absorbing approximately 300 ml. The sponges rapidly expand in length (see Figure 2) upon contact with blood or fluid to fill the wound cavity and thereby provide a physical barrier and pressure that facilitate formation of a clot. Once hemostasis is achieved, a standard occlusive dressing is applied before transporting the patient to a medical facility where surgery is performed to definitively repair the wound. The sponges are intended for temporary use up to four hours until surgical care is acquired. All sponges must be removed from wounds manually and/or with forceps by a surgeon with the capability and equipment for achieving proximal and distal vascular control. For easy detection via x-ray, one face of each tablet contains radiopaque filaments in an "x" pattern (see Figure 2). To confirm removal of all sponges and any applicator tips, a radiograph is required prior to wound closure with imaging in more than one plane recommended.

AI/ML Overview

The provided document describes the acceptance criteria and the studies conducted to demonstrate that the XSTAT device meets these criteria. The studies are primarily non-clinical (bench testing) and animal studies, along with human factors testing. There is no mention of a multi-reader multi-case (MRMC) comparative effectiveness study or standalone algorithm performance, as the device is a physical medical device, not an AI/software.

Here's a breakdown of the requested information based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

This information is drawn from various tables and sections of the document. Due to the extensive and varied nature of the acceptance criteria and results (including qualitative descriptions), this table will summarize key findings from the "Biocompatibility," "Stability/Sterility," and "Performance Testing - Bench" sections. Specific quantitative acceptance criteria are often marked as "(b)(4) Trade Secret/CCI" in the original document, so general "PASS" results are reported where specific numbers are not publicly available.

Category	Acceptance Criteria Description (from document)	Reported Device Performance (from document)
Biocompatibility	Cytotoxicity, Sensitization, Acute Systemic Toxicity, Hemocompatibility (PASS)	Applicator: PASS for all.Sponge: PASS for Cytotoxicity, Sensitization, Acute Systemic Toxicity, Hemocompatibility. (Note: Sponge failed irritation test in polar solvent, found to be a moderate irritant, but considered acceptable due to mitigation and benefit).
Stability/Sterility	Sterility (SAL 10⁻⁶), Endotoxin (PASS < 8.50 EU/device), Package integrity, Shelf-life (6 months)	Sterility: Sterilized by gamma radiation to SAL 10⁻⁶ (ISO 11137).Endotoxin: Applicator PASS (< 8.50 EU/device). Sponge "Inhibition and enhancement validation was not performed," and pyrogenic response observed (mitigated by labeling).Package Integrity: Bubble Emission Integrity (PASS), Seal Peel Strength (PASS).Shelf Life: 6 months, demonstrated through real-time and accelerated aging, with Applicator Deployment Force and Sponge Expansion Rate PASS.
Performance (Bench)	Absorption capacity, Extent of swelling, Mechanical properties, Expansion force/pressure, Radiopacity, Deployment/applicator functionality (various specific criteria, many trade secret)	Absorption Capacity & Extent of Swelling: (b)(4) Trade Secret/CCI.Mechanical Properties: Sponges exhibit stress relaxation, buffering pressure. Single and multi-sponge force curves tested.Expansion Force/Pressure: Gel Wound Simulator: highest pressure 200 mm Hg, relaxed to 150 mm Hg after 40 seconds. Cadaver: 44 mm Hg, increased to 84 mm Hg with ace bandage.Radiopacity: Average optical densities: background = 0.86 ± 0.02, subject device = 0.70 ± 0.01. Significantly different (P = < 0.001) with 95% confidence.Applicator Functionality: All mechanical tests (retraction, deployment, handle failure, lateral load, locking mechanism failure) PASS at various temperatures (high, low, room) and after immersion.
Performance (Animal - Femoral Arter)	Control bleeding (0 min bleeding time), Post-Treatment Blood Loss (low), Survival (100%), Wound Packing Time (low), Radiopacity (no retained sponges), Retrieval (no material adhered/retained).	Bleeding Time: 0 MinutesPost-Treatment Blood Loss: 21.7 (17.5) mLSurvival Time: 6.0 (0.0) hours (100% survival)Wound Packing Time: 1.1 (0.3) minutesRadiopacity/Retrieval: No sponges identified in fluoroscopic images or at necropsy. Neither test nor control material adhered or retained.
Performance (Animal - Subclavian Artery)	Hemostasis at 4 min & 60 min, Survival at 60 min, Low bleeding time & post-TBL, Radiopacity (no retained sponges), Retrieval (no material adhered/retained).	Hemostasis at 4 min: 7 / 8 (87.5%)Hemostasis at 60 min: 7 / 8 (87.5%)Animal Survival at 60 min: 8 / 8 (100%)Bleeding Time: 7.9 (21.1) minutesPost-TBL: 331.5 (818.9) mLRadiopacity/Retrieval: Not explicitly stated for this study, but general animal study objective was to confirm retrieval. Failure in one animal due to applicator tip breaking off (mitigated with glue).
Human Factors (Deployment)	Ability of medics/EMS to understand and execute instructions, deploy device in under 90 seconds.	100% of participants passed device usage criteria, deploying XSTAT in under 90 seconds (mean: 50.1(12.6) sec). User comments led to labeling revisions.
Human Factors (Retrieval)	Surgeons' ability to understand/execute removal instructions, clarity of labeling, ease of removal.	4 of 4 surgeons indicated labeling was clear and completed all steps without assistance. Median scores for clarity on necessity/steps of removal and effective order of steps were 4.5 ("Very Good"). Ease of removal median score was 3.5 ("Acceptable"). User comments led to labeling revisions.

2. Sample Size Used for the Test Set and the Data Provenance

Non-clinical/Bench Studies: Sample sizes are not explicitly stated for individual bench tests (e.g., number of sponges tested for absorption, mechanical properties), only "series of non-clinical performance testing."
Animal Studies:
- Swine Femoral Artery Study: 20 animals (10 with XSTAT, 10 with control article).
- Swine Subclavian Artery Study: 8 animals.
- Data Provenance: Prospective animal studies conducted in swine models. Specific country of origin is not explicitly stated but implies a controlled laboratory setting (e.g., USAISR standard femoral animal injury model).
Human Factors Studies:
- Device Deployment Human Factors Study: 10 subjects (military medics or civilian EMS).
- Sponge Retrieval Human Factors Study: 4 surgeons.
- Data Provenance: Prospective human factors studies. Conducted on simulated casualties (mannequins for deployment) and cadavers (for retrieval).

3. Number of Experts Used to Establish the Ground Truth for the Test Set and the Qualifications of Those Experts

Non-clinical/Bench Studies: Ground truth established through standardized test methods (e.g., ISO, ASTM standards) and direct measurement of physical properties. Implies expertise in material science and engineering for analysis.
Animal Studies: The "ground truth" for success (e.g., control of bleeding, survival, no retained sponges) was established by direct observation during the study and post-mortem evaluation. The studies were GLP (Good Laboratory Practice), implying trained personnel, but specific numbers and qualifications of individual experts are not provided for assessing outcomes beyond "surgeon" or researchers.
Human Factors Studies:
- Deployment: Ground truth for successful deployment was defined by objective criteria (e.g., "deploying XSTAT in under 90 seconds"). The testers/observers would be considered the "experts" in evaluating performance against these criteria.
- Retrieval: The 4 surgeons involved acted as the "experts" whose judgment (e.g., "Labeling clear on use of XSTAT device (Yes / No)", "Ease of removal of sponges, median*") constituted the data for evaluating the "ground truth" of ease of use and clarity. Their qualification is "civilian or military surgeon with no prior experience with XSTAT prior to the study."

4. Adjudication Method for the Test Set

Non-clinical/Bench Studies: Adjudication is inherent in the standardized test methods and criteria.
Animal Studies: Not explicitly described, but GLP studies typically involve clear protocols and independent verification or blinding to ensure objective assessment of endpoints. For example, blinding of the "Surgeon and device applicator" to test material identity was used in the femoral artery study to minimize bias.
Human Factors Studies: The studies involved direct observation and self-reporting/feedback from the participants (medics/EMS for deployment, surgeons for retrieval) against pre-defined criteria. No formal additional adjudication method (like 2+1 or 3+1 consensus) is explicitly mentioned beyond the direct observation and the participants' feedback.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done

No, an MRMC comparative effectiveness study was not done. The XSTAT device is a physical hemostatic sponge, not an AI or imaging diagnostic tool that would typically undergo such a study.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was Done

Not applicable, as XSTAT is a physical medical device, not an algorithm.

7. The Type of Ground Truth Used

Non-clinical/Bench Studies: Ground truth was established through direct physical measurements and observations against engineering specifications and relevant international standards (e.g., ISO, ASTM).
Animal Studies: Ground truth was established through direct observation of physiological responses (e.g., bleeding cessation, survival), post-mortem examination (e.g., for retained materials, tissue damage), and medical measurements (e.g., blood loss, pressure).
Human Factors Studies: Ground truth was established through observing user performance against predefined tasks and collecting user feedback on the device and labeling effectiveness.

8. The Sample Size for the Training Set

The document describes pre-market testing for a physical device, not an AI/ML algorithm that would typically have a "training set." Therefore, there is no explicit "training set" sample size in the context of AI. The animal studies conducted "early in the device development process to inform device design changes" could be seen as an iterative development and "training" phase for the physical device and its use, but not in the algorithmic sense.

9. How the Ground Truth for the Training Set Was Established

As there is no "training set" in the context of an AI/ML algorithm, this question is not directly applicable. If interpreting "training set" broadly as data used to refine the device or instructions:

Early animal studies and potentially early bench testing iterations provided feedback that led to design changes and labeling refinements. The ground truth in these early stages would be similar to the final test sets: direct observation, physical measurements, and physiological outcomes. For example, the subclavian artery study noted a failure due to an applicator tip breaking off, which led to a design change (securing tips with glue). The human factors studies also directly led to labeling revisions.

Summary

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DE NOVO CLASSIFICATION REQUEST FOR XSTAT

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Non-absorbable, expandable, hemostatic sponge for temporary internal use: A nonabsorbable, expandable, hemostatic sponge for temporary internal use is a prescription device intended to be placed temporarily into junctional, non-compressible wounds, which are not amenable to tourniquet use, to control bleeding until surgical care is acquired. The sponges expand upon contact with blood to fill the wound cavity and provide a physical barrier and pressure that facilitates formation of a clot. The device consists of sterile, non-absorbable, radiopaque, compressed sponges and may include an applicator to facilitate delivery into a wound.

NEW REGULATION NUMBER: 21 CFR 878.4452

CLASSIFICATION: II

PRODUCT CODE: PGZ

BACKGROUND

DEVICE NAME: XSTAT

SUBMISSION NUMBER: K130218

DATE OF DE NOVO: JANUARY 28, 2013

CONTACT: REVMEDX, INC. % John Smith, M. D., Ph. D., Regulatory consultant HOGAN LOVELLS US, LLC 555 13TH STREET NW WASHINGTON, DISTRICT OF COLUMBIA 20004

REQUESTER'S RECOMMENDED CLASSIFICATION: II

INDICATIONS FOR USE

XSTAT is a hemostatic device for the control of bleeding from junctional wounds in the groin or axilla not amenable to tourniquet application in adults and adolescents.

XSTAT is a temporary device for use up to four (4) hours until surgical care is acquired. XSTAT is intended for use in the battlefield.

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XSTAT is NOT indicated for use in: the thorax; the pleural cavity; the mediastinum; the abdomen; the retroperitoneal space; the sacral space above the inguinal ligament; or tissues above the clavicle.

LIMITATIONS

The sale, distribution, and use of XSTAT are restricted to prescription use in accordance with 21 CFR 801.109.

Limitations on device use are also achieved through the following statements included in the Instructions for Use:

"For use by trained emergency responders"

"DO NOT attempt to remove sponges from wound. Sponges must be removed intraoperatively by surgeon with the capability and equipment for achieving proximal and distal vascular control."

"Assess patient for peripheral circulation and document presence of distal pulse on included casualty card. WARNING: Vascular compression greater than four hours is not recommended due to concerns related to limb ischemia."

"WARNING: Triangular segments of the applicator tip may break away from applicator during treatment. If this occurs, do not attempt to retrieve it from the wound. Record number of separated applicator tips on casualty card."

"XSTAT has not been tested for use in extremity wounds that are amenable to tourniquet application"

"XSTAT use in conjunction with tourniquet application has not been assessed for use in extremity wounds that are amenable to tourniquet application"

"Prior to wound closure, obtain plane x-ray, optimally in more than one projection. The presence of retained sponges may be easily missed on radiographic images. Thoroughly examine x-ray for radiopaque x-pattern of sponges and any triangular segments of the applicator tip that may be inadvertently retained in the wound cavity."

"If sponges or applicator tip segments are identified via x-ray, carefully re-examine wound cavity and remove them. Perform and review second x-ray to confirm complete sponge and applicator tip segment removal."

"The XSTAT elicited a mild pyrogenic response in biocompatibility tests. Monitor patient for rise in temperature, chills, hypotension, and septic shock."

"Inhibition and enhancement validation was not performed for the LAL method to confirm that the device itself does not bind and/or block detection of endotoxin."

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"Contains material derived from shellfish"

PLEASE REFER TO THE LABELING FOR A MORE COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.

DEVICE DESCRIPTION

Image /page/2/Picture/5 description: The image shows three syringes filled with white tablets, a white card with red text, and a black bag with a white label. The syringes are clear with black plungers and are filled with small, white, cylindrical tablets. The white card has red text that says "XSTAT" and "ATTN TREATMENT FACILITY." The black bag has a white label that also says "XSTAT" and includes instructions for use.

Figure 1: Photograph of one device, which consists of compressed sponges housed in a syringe-style applicator. One device consists of three applicators.

Image /page/2/Picture/7 description: The image shows two white cylindrical objects next to a ruler. The ruler is labeled with both centimeters and inches. The centimeter side of the ruler goes from 1 to 7, and the inches side goes from 1 to 2. The text on the ruler says "Cat. No. 09-016".

compressed and fully expanded sponges. Radiopaque filaments are attached to one end of each sponge in an "x" pattern.

SUMMARY OF NONCLINICAL/BENCH STUDIES

The sponsor conducted a series of non-clinical performance testing to demonstrate that XSTAT

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would perform as anticipated for its intended use population.

BIOCOMPATIBILITY/MATERIALS

XSTAT is comprised of two main components, the XSTAT sponge and the applicator. As summarized in Table 1, these components were subjected to biocompatibility testing as recommended for a limited duration, blood contacting externally communicating device.

Biocompatibility Test	Standard	Applicator Result	Sponge Result
Cytotoxicity (MEM Elution)	ISO 10993-5:2009	PASS	PASS
Sensitization (Guinea PigMaximization)	ISO 10993-10:2010	PASS	PASS
Irritation (IntracutaneousReactivity Test)	ISO 10993-10:2010	PASS	Sponge passed testing innon-polar solvent, butfailed in polar solvent andthus was found to be amoderate irritant in polarsolvent.
Acute Systemic Toxicity	ISO 10993-11:2006	PASS	PASS
Hemocompatibility (HemolysisAssay - Extract Method)	ASTM F756-08	PASS	PASS

Table 1: Summary of Biocompatibility Tests

Material characteristics including specifications for raw materials used in the device were assessed to support safety under anticipated conditions of use. XSTAT contains a raw material derived from an animal source. For the animal derived component, manufacturing information, material specifications, and literature were provided to support the adequacy of viral inactivation and verify that the risk for immunogenicity reactions is low.

STABILITY/STERILITY

XSTAT is labeled with a shelf life of 6 months based on testing of devices exposed to real time and accelerated aging conditions. Devices were stored on a shelf at room temperature for real-time aging with average temperature and relative humidity of 23°C and 29%. respectively (see Table 2). Devices exposed to accelerated aging conditions of 50°C for 25 days represent an equivalent of six months (ASTM F1980-07) (see Table 3). Samples were also evaluated using in vitro tests for applicator deployment force, sponge expansion rate, and package integrity (see Table 4) and met all product stability acceptance criteria.

Table 2: Real Time Aging Summary (6 months)

Test	Criteria	Result
Applicator Deployment Force	(b)(4) Trade Secret/CCI	PASS
Sponge Expansion Rate	(b)(4) Trade Secret/CCI	PASS

Table 3: Accelerated Aging Summary (25 days, equivalent to 6 months)

Test	Criteria	Result
Applicator Deployment Force	(b)(4) Trade Secret/CCI	PASS
Sponge Expansion Rate	(b)(4) Trade Secret/CCI	PASS

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(b)(4) Trade Secret/CCI

Table 4: Packaging Testing on XSTAT

Test	Acceptance Criteria	Baseline Results	6 Months Real Time Aged Results
Bubble Emission Integrity(ASTM F2096)	0 fail locations. There must be no leaks.	PASS	PASS
Seal Peel Strength(ASTM F88)	All seals must have seal strength ≥ 1 lb/in	PASS	PASS

XSTAT is sterilized by gamma radiation to ensure a sterility assurance level of 10° according to ISO 11137. The device is not intended for re-sterilization or reuse. Based on the testing provided as described in Table 5, the subject device may elicit a pyrogenic response. To mitigate this risk, the labeling and training materials advise monitoring the patient for rise in temperature, chills, hypotension, and septic shock. Recommended device use is limited to no more than one device (3 total applicators of sponges) serving as a temporary wound packing for no longer than 4 hours. The risk of a possible pyrogenic response is acceptable considering the mitigations for the risk and the potential benefit of controlling bleeding that is otherwise non-compressible.

Table 5: Summary of Endotoxin and Pyrogenicity Tests

Test	Standard	Applicator Result	Sponge Result
Endotoxin (Limulus AmebocyteLysate, LAL)	USP <85>, USP <161>	PASS (< 8.50 EU/device)	Inhibition and enhancement validation was notperformed for the LAL method to confirm thatthe device itself does not bind and/or blockdetection of endotoxin.
Pyrogen (Materials MediatedRabbit Pyrogen Test)	USP <151>	PASS	Pyrogenic responseobserved

PERFORMANCE TESTING - BENCH

Bench testing demonstrated that the device performs as expected under anticipated conditions of use. Testing to verify the properties and performance of the sponges included measuring the absorption capacity, extent of swelling, expansion force/pressure, mechanical properties, and radiopacity (see Tables 6 and 7). To verify ease of use and the structural integrity of the applicator, mechanical testing measured deployment forces for dry applicators as well as those immersed in liquid for 30 seconds (see Tables 8 and 9).

Table 6: Product Acceptance Criteria

	Criteria Description	Characteristic	Acceptance Criteria
XSTATSampleTesting	MinispongeCompression	(b)(4) Trade Secret/CCI	(b)(4) Trade Secret/CCC
	MinispongeExpansion
	Functional ApplicatorTest

Table 7: Performance Data for Sponges

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Test	Results
Absorption CapacityExtent of Swelling	(b)(4) Trade Secret/CCI
(b)(4) Trade Secret/CCI
Mechanical Properties	Single and Multiple Sponge Force Curves: Force measured as a function of theextent of swelling for single sponges and multiple sponges expanding in the samedirection. Within a wound, the pellets will not all expand in exactly the samedirection and there will inherently be void space between the sponges. The voidspace will in essence buffer the pressure by providing some room for pelletexpansion.Load Relaxation: The sponges exhibit stress relaxation, i.e. a time-dependentdecrease in force under constant compression. Stress relaxation will help to reducethe pressure in a packed wound.
Expansion Force/Pressure	Gel Wound Simulator: Testing in a wound simulator consisting of a cavity createdin a gel indicated that pressures are different at different locations within a packedwound. The highest pressure observed for a model wound packed with XSTATwas 200 mm Hg, which relaxed to 150 mm Hg after 40 seconds.Cadaver: Cadaver experiments with model junctional wounds verified that thepressure inside a wound packed with XSTAT does not appear to be any higherthan that for a wound packed with gauze. The equilibrium pressure after packingwith XSTAT was 44 mm Hg and increased to 84 mm Hg after wrapping thewound with an ace bandage. Moving the limbs caused changes in the volume ofthe wound and therefore changes in the pressure.
Radiopacity (ASTM F640)	Average optical densities: background = $0.86 \pm 0.02$ , subject device = $0.70 \pm 0.01$With 95 percent confidence (a < 0.05), the image background and subject deviceOD were significantly different (P =< 0.001).

Table 8: Mechanical Testing of Applicator

Scenario-based loading condition	Criteria	Rationale for criteria	RESULTS in LBS (st dev)
			@ -18°C	@ 21°C	@ 43°C
Max force required to retract theapplicator handle in high temp, lowtemp, and room temp conditions	(b)(4) Trade Secret/CCI	Ensures that the design provides aneasy one-handed engagement of theapplicator by a combat medic using atwo-finger-pull with low exertion.	Pass	Pass	Pass
Max force required to deploy theapplicator in high temp, low temp,and room temp conditions.	(b)(4) Trade Secret/CCI	Ensures that the design provides aneasy one-handed deployment of theapplicator by a combat medic usingpalm contact and low exertion.	Pass	Pass	Pass
Min force required to generatehandle failure in high temp, lowtemp, and room temp conditions	(b)(4) Trade Secret/CCI	Ensures that the design providessafe and effective performance whenengaged by a combat medic using aone-handed, two-finger pull with highexertion.	Pass	Pass	Pass
Min lateral load the applicator bodycan withstand at the weakest portion(distal end) in high temp, low temp,and room temp conditions	(b)(4) Trade Secret/CCI	Ensures that the design providessafe and effective performance whenexposed to lateral loading equivalentto 2x the weight of a typical combatmedic aid bag (25 lbs).	Pass	Pass	Pass
Min force required to generatefailure of the locking mechanism inhigh temp, low temp, and roomtemp conditions.	(b)(4) Trade Secret/CCI	Ensures that the design providessafe and effective performance whendeployed with one hand (palmcontact) by a combat medic usinghigh exertion.	Pass	Pass	Pass

Table 9: Mechanical Testing of Applicator After Immersion in Fluid

Test	Result
Deployment force after 30 sec of immersion in fluid	PASS

PERFORMANCE TESTING - ANIMAL

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Three animal studies using XSTAT in swine demonstrated reasonably safe and effective use by verifying that the device controls bleeding, does not promote adverse local or systemic effects, and can be completely removed the wound. Studies to assess control of bleeding from swine femoral and subclavian arteries are described in Tables 10 and 11. An additional animal subclavian artery study was submitted within a separate device master file to which the sponsor had a letter of authorization to further support device performance. The animal studies confirmed device performance characteristics including deployment, control of bleeding, radiopacity, and retrieval as well as the impact of device use on the animals in terms of local and systemic effects.

Name of Study	GLP Evaluation of XSTAT Device in a Swine Femoral Model
Study Description	GLP animal study to demonstrate the performance of the XSTAT devicecompared to a control article, using the United States Army Institute ofSurgical Research ("USAISR") standard femoral animal injury1,2
Number of Animals	Ten (10) animals were treated with the XSTAT deviceTen (10) animals were treated with the control article.
Inclusion / Exclusion	Inclusion: Animal breed: Landrace cross swine Weight at procedure: 55 - 65 kg Age at procedure: appropriate to weight Exclusion criteria included inappropriate vessel anatomy, persistently lowMAP (<55 mmHg) prior to femoral artery injury, and significant bloodloss (>300 mL) because of surgical complication or error before femoralartery injury.
Study Procedure	All Wounds Prior to Randomization An incision was created (3.5 cm long) through the skin and subcutaneoustissues in the groin area directly over the right femoral artery and anapproximately 3 cm section of femoral artery was exposed. The femoral artery was covered with a small piece of gauze and bathedwith 2% lidocaine HCl solution to relax the vasospasm and dilate theartery to ≥ 5 mm outer diameter Non-traumatic vessel loops were placed proximally and distally on thefemoral artery. Using a 6.0 mm vascular punch, an arteriotomy was created. The vessel loops were released, injury start time was recorded and thevessel was allowed to bleed freely for 45 seconds before the Test(XSTAT) or Control Article was applied. The vessel loops were allowed to remain in the wound to facilitatehemorrhage control during test material removal. Surgeon and device applicator were blinded to the identity of test materialprior to application. Randomization was accomplished by picking a sealed envelope thatcontained the name of the test material. The contents of the envelope wererevealed in the surgery suite during the 45 second free bleed period. Wounds Randomized to XSTAT XSTAT applied as per product label immediately following the 45-secondfree bleed. XSTAT applied as quickly as possible and as many as necessary until thebleeding has stopped, or until the 5 minute limit, whichever was sooner. If room within the wound allowed, plain gauze (i.e., S-Rolled Gauze) waspacked on top of the XSTAT-filled wound
Results	Cloth bandage used to secure XSTAT/Plain Gauze device within the wound. Manual compression was permitted if bleeding persisted following application of the device. Wounds Randomized to Control Article Immediately following the 45-second free bleed up to 5 minutes was allowed to apply control article(s) by packing device completely into wound track using enough control article to fill the wound and contact all bleeding surfaces. More than one device may be required. If room within the wound allowed, plain gauze (i.e., S-Rolled Gauze) was packed on top of the control article. Cloth bandage used to secure control article within the wound. Manual pressure applied for 3 minutes. Post-Randomization Care Resuscitation began 5 minutes post-injury (i.e., free bleed start time) by infusing approximately 500 ml of Hextend® fluid at a target rate of 33 mL/min through the jugular vein. Resuscitation was continued, if necessary, with pre-warmed lactated Ringer's solution (LRS) infused at a target rate of 100 mL/minute, to maintain the mean arterial pressure (MAP) to at least 65 mmHg. Following the 6-hour observation period, the Test or Control Article was removed from the wound site and the animal euthanized. XSTAT sponges were removed from the wound site manually as well as with surgical forceps. Control article(s) were pulled out of the wound manually. Following sponge removal and euthanasia, the wound site was imaged using a portable fluoroscopy unit. No sponges were identified in the fluoroscopic images or at necropsy.
	Endpoints	XSTAT
	1: Bleeding Time, mean: Duration of bleeding (visible blood shed from the wound site) occurring at any time immediately following test material application until exsanguination or end of the 6 hour observation period.	0 Minutes
	2: Post-Treatment Blood Loss, mean (stdev): Amount of blood shed from the wound cavity during the time period following the 45 second free bleed until exsanguination or end of the 6 hour observation period.	21.7 (17.5) mL

Table 10: Swine Femoral Artery Study

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	Pressure (MAP), mean
	(stdev): Mean arterial
	pressure recorded just
	prior to exsanguination
	or end of the 6 hour
	observation period.
	4: Survival Time,
	mean (stdev): Time
	period immediately
	following the 45
	second free bleed
	during which vital
	signs are; MAP	6.0 (0.0) hours	6.0 (0.0) hours
	>20mmHg and PCO2
	>15 mmHg to
	exsanguination or end
	of the 6 hour
	observation period.
	5: Percentage
	Survival: Percentage of
	animals surviving to
	the end of the study
	observation period (6	100%	100%
	hours) for a given
	treatment, where
	survival was defined as
	the MAP >20 mmHg
	and PCO2 >15 mmHg.
	6: Wound Packing
	Time, mean (stdev)	1.1 (0.3) minutes	4.6 (0.5) minutes
	7: Wound
	Compression Time	0 minutes	3 minutes

			The presence or absence of distal limb ischemia was not assessed in this study.
	There was no postmortem evidence of blood tracking beneath the skin.
	Mean XSTAT removal time 10.5 ± 3.4 minutes.

Device Removal	Mean control article removal time 2 ± 0.8 minutes.Neither test nor control article material adhered to the wound or were found to

	be retained in the wound at necropsy.

'Kheirabadi BS, Arnaud F, McCarron R et al. Development of a Standard Swine Hemorrhage Model for Efficacy Assessment of Topical Hemostatic Agents. J of Trauma. 2011;71:S139-S146. "Littlejohn LF, Devlin JJ, Kircher SS, et al. Comparison of Celox-A, ChitoFlex, WoundStat, and Combat Gauze Hemostatic Agents Versus Standard Gauze Dressing in Control of Hemorrhage in a Swine Model of Penetrating Trauma. Acad Emerg Med. 2011;18:340-350. Acheson, E.M., et al. Comparison of Hemorrhage Control Agents Applied to Lethal Extremity Arterial Hemorrhages in Swine. J of Trauma. 2005;59:865-875.

Table 11: Swine Subclavian Artery Study
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Name of Study	Evaluation of XSTAT Device in a Swine Subclavian Model
Study Description	Animal study to demonstrate the performance of the XSTAT device in a swine subclavian injury
Number of Animals	8
Inclusion / Exclusion	Inclusion: Animal breed: Landrace cross swine

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	Weight at procedure: 55 - 65 kg Age at procedure: appropriate to weight
	Exclusion criteria included inappropriate vessel anatomy, persistently lowMAP (<65 mmHg) prior to femoral artery injury.
	Animal anesthetized and 4.5-cm incision was created to access the subclavian artery and vein Subclavian artery and vein transected After 30-second free bleeding, the wound cavity was filled with the XSTAT sponges with no external pressure. Resuscitative fluids were administered to the animal as needed to support a mean arterial blood pressure of 60 mmHg. No additional wound care was provided during the 1-hour observation period. Following the 1-hour observation period, the XSTAT sponges were removed from the wound site and the animal euthanized.
Study Procedure
	Endpoint	XSTAT
	1: Animals with hemostasis at 4 min after device application.	7 / 8 (87.5%)
	2: Animals with hemostasis at 60 min after device application	7 / 8 (87.5%)
	3: Animal Survival at 60 min where survival was defined as the MAP > 20 mmHg and PCO2 > 15 mmHg.	8 / 8 (100%)
	4: Bleeding Time, mean (StDev) Duration of bleeding occurring at any time immediately following material application until study termination	7.9 (21.1)
Results	5: Post-TBL, mean (stdev) Amount of blood shed from the wound cavity during the time following the 45 second free bleed until study termination	331.5 (818.9)
	The failure to achieve hemostasis in one of the animals was due to an applicator tip breaking off and falling into the wound. The location of the tip in the wound created a small gap (1 cm) that prevented sponges from accessing the point of bleeding. As a result, applicator tips are now secured with glue

PERFORMANCE TESTING – HUMAN FACTORS

Human factors testing and analysis validated that the device design and labeling are sufficient for appropriate use by emergency responders deploying the device as well as surgeons retrieving the device from wounds (see Tables 12 and 13). Human factors assessments were used to modify the labeling to promote reasonably safe and effective use of XSTAT.

Table 12: Device Deployment Human Factors Study

Name of Study	User Evaluation of XSTAT Device and Applicator Use
Study Description	A user evaluation (human factors) was completed to determine the ability ofmedics and civilian EMS to understand and execute instructions for usingXSTAT and applying XSTAT on a simulated casualty.
Number of subjects	10

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Inclusion / Exclusion	Military medic or civilian EMS with no prior knowledge or experience ofusing XSTAT device prior to the study
Study Procedure	A medical-mannequin torso served as a wound model. The wound track—located in the upper thigh region approximately 5 cm distal to the iliac artery—had a diameter of 3 cm and a length of 8 cm and was pre-filled with 150-200 mL of saline. Participants were tested in a low-light environment. Participants were evaluated on the time needed to ready the device for use, as well as the time necessary to deploy the appropriate amount of material to stop bleeding. All participants passed the device usage criteria which involved opening the package, cocking the applicator, applying the applicator into the wound, applying the correct number of applicators, and deploying XSTAT in under 90 seconds (mean (stdev): 50.1(12.6) sec.). The study did not assess a user's ability to properly diagnose a severely bleeding junctional wound in the groin or axilla not amenable to tourniquet application.
Results	Participant	Time (sec)	User Comments	Actions Taken
	1	45
	2	31	Add detail on pulling/locking applicator	Revised instruction on pulling/cocking application handle
	3	47	Add detail on preclinical data	Added detailed information on preclinical testing to product insert
	4	70
	5	43	Explain importance of direct pressure	Added detailed instructions regarding application of direct pressure and bandage
	6	71
	7	53
	8	47
	9	54	Add detail on pulling/locking applicator	Revised instruction on pulling/cocking application handle.

Table 13: Sponge Retrieval Human Factors Study
Name of Study / CitedPublication	User evaluation of XSTAT device removal
Study Description	A user evaluation was completed to assess the ability of surgeons tounderstand and execute instructions for removing XSTAT sponges fromhuman cadaver wounds.
Number	4 surgeons; 1 cadaver; 2 wounds, 2 tests/wound.
Inclusion / Exclusion	Inclusion: civilian or military surgeon with no prior experience with XSTATprior to the study.
Study Procedure	Junctional wounds were made in each shoulder of the cadaver.●Saline solution was circulated through cadaver's vasculature to simulate●blood flow.Following application of 2 XSTAT devices into the shoulder wounds.●

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	each surgeon was handed draft instructions for use and instructed to treatthe wound.
	Endpoint	Result
Endpoints/Results	1. Labeling clear on use of XSTAT device (Yes / No)	4 of 4 surgeons indicated 'Yes'
	2. Completed all steps in IFU without assistance (Yes / No)	4 of 4 surgeons completed
	3. IFU conveys necessity of removal of sponges, median*	4.5
	4. IFU conveys steps to assure removal, median*	4.5
	5. Effective order of removal steps, median*	4.5
	6. Ease of removal of sponges, median*	3.5
	* Scale: 1 = Poor, 2 = Fair, 3 = Acceptable, 4 = Good, 5 = Very Good
	User Comments/Actions Taken	Comment
Add reminder that all sponges must be removed before wound closure.		Package label and casualty card contain explicit instructions for surgical sponge removal
	Note approximate number of sponges per applicator on the package.	Package updated to include number of sponges per applicator

LABELING

Labeling has been provided which includes the instructions for use and an appropriate prescription statement as required by 21 CFR 801.109.

The labeling includes the following information:

directions for use for deployment by emergency responders and retrieval by surgeons; ●
warnings, cautions, and limitations needed for safe use of the device;
information on how the device operates and the typical course of treatment;
detailed summary of the in vivo and human factors testing pertinent to use of the device;
appropriate imaging information to ensure complete retrieval of device;
an expiration date/shelf life.

RISKS TO HEALTH

Table 14 below identifies the risks to health that may be associated with use of non-absorbable, expandable, hemostatic sponge for temporary internal use and the measures necessary to mitigate these risks.

Identified Risk	Mitigation Method
Failure to Stop Bleeding or Recurrence of Bleeding	Non-Clinical Performance DataIn Vivo Performance DataStability Assessment
	Labeling
Obstruction of Vital Organs	Labeling
	Human Factors Testing
	Labeling
Embolization	In Vivo Performance Data
Collateral Tissue Damage (e.g., paralysis, nerve damage, tissue necrosis)	In Vivo Performance Data
	Labeling
Adverse Tissue and Allergic Reactions	Material Characterization
	Biocompatibility
	In Vivo Performance Data
	Labeling
Infection (e.g., cellulitis, Toxic Shock Syndrome, sepsis)	Sterility Testing
	Stability Assessment
Reoperation Due to Material Retained in Body	Non-Clinical Performance Data
	In Vivo Performance Data
	Human Factors Testing
	Labeling
Sponge Deployment Failure	Non-Clinical Performance Data
	In Vivo Performance Data
	Stability Assessment
	Human Factors Testing
	Labeling
Improper Application Technique or Use Error	Human Factors Testing
	Labeling

Table 14: Identified Risks to Health and Mitigation Measures

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SPECIAL CONTROLS :

In combination with the general controls of the Food, Drug & Cosmetic Act, the Non-

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absorbable, expandable, hemostatic sponge for temporary internal use is subject to the following special controls:

1. Performance data must demonstrate the biocompatibility of patient-contacting components.
1. Performance data must demonstrate the sterility of patient-contacting components including endotoxin and pyrogenicity assessments.
1. Performance data must support device stability by demonstrating continued sterility of the patient-contacting components of the device, package integrity, and device functionality over the requested shelf life.
1. Assessment of material characteristics must be sufficient to support safety under anticipated conditions of use. Assessments must include the following:
- A. Material specifications
- B. Immunogenicity
- C. Viral inactivation for animal-derived materials
1. Non-clinical performance data must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be tested:
- A. Absorption capacity
- B. Extent of swelling
- C. Mechanical properties
- D. Expansion force/pressure
- E. Radiopacity
- F. Deployment/applicator functionality
1. In vivo performance data must demonstrate safe and effective use by verifying that the device performs as intended under anticipated conditions of use. Appropriate analysis/testing must demonstrate that the product: controls bleeding, does not promote adverse local or systemic effects, and can be completely removed from the wound. The following performance characteristics must be tested:
- A. Deployment
- B. Control of bleeding
- C. Radiopacity
- D. Retrieval
- E. Assessment of local and systemic effects
1. Human factors testing and analysis must validate that the device design and labeling are sufficient for appropriate use by emergency responders deploying the device as well as surgeons retrieving the device from wounds.
1. Labeling must include:
- A. Specific instructions for deployment by emergency responders and retrieval by surgeons.
- B. Warnings, cautions, and limitations needed for safe use of the device
- C. Information on how the device operates and the typical course of treatment
- D. A detailed summary of the in vivo and human factors testing pertinent to use of the device
- E. Appropriate imaging information to ensure complete retrieval of device
- F. An expiration date/shelf life

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BENEFIT/RISK DETERMINATION

The risks of the XSTAT device are based on nonclinical laboratory and animal studies. The likelihood for each of the listed risks have not been quantified but are expected to be extremely low given the steps taken through the bench testing, animal testing, labeling and training that has been performed to mitigate each of the listed XSTAT device risks. The risks associated with use of the device include the following: failure to stop bleeding or recurrence of bleeding, obstruction of vital organs, embolization, collateral tissue damage, adverse tissue and allergic reactions, infection, reoperation due to material retained in body, sponge deployment failure, and improper application technique or use error.

All of the above listed serious adverse events may also result in non-serious adverse events depending on location of adverse event effect and extent of adverse event effect. As an effect of major hemorrhage, even with adequate resuscitation, significant blood loss could lead to hypothermia, coagulopathy, acidosis and late mortality through the development of sepsis and multiple organ failure. The probability of a harmful event is unknown due to the variable nature of the injury and associated injury, the need for rapid response using the device, the variations in the battlefield circumstances, and variations in the level of experience with the device and junctional injuries by the treating medic. However the risk of these adverse events is unknown but considered to be acceptable considering the benefits of device use to reduce hemorrhage associated with non-compressible, junctional bleeding in the battlefield. Signs or symptoms of many of the listed adverse events may be reversed by removing the device from the wound. The harmful events may or may not be reversible. The harmful events may be mitigated with rapid hemorrhage control and transfer to a definitive treatment facility where the device can be removed.

The probable benefits of the XSTAT device are also based on nonclinical laboratory and animal studies. Early control of bleeding is of high value to both patients and can reduce the secondary effects of severe hemorrhage which include hypothermia, coagulopathy and late development of sepsis and multiple-organ system failure.

Due to an inability to perform a study involving patients with junctional bleeding secondary to battlefield injury. the studies performed were conducted in animal testing offered the advantages of reproducible testing in a standard wound, careful monitoring of device use and animal condition, standardization of resuscitation efforts, and standard post-mortem evaluation. The animal testing performed did not elucidate how benefits may vary across subpopulations. However due to the increased incidence of junctional injury in the military population and the reduced assess to definitive emergency medical care access in the battlefield, it is expected that the benefits far outweigh the risks for XSTAT device use in the military population requiring emergency treatment for junctional bleeding in the battlefield. The benefit risk profile for the civilian population-where the incidence of junctional bleeding is much less and the access to definitive emergency medical treatment is faster-is less clear.

Additional factors to be considered in determining probable risks and benefits for the XSTAT device include: the limitations of the animal study designs, clinical expertise required to use the

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device, and lack of alternative treatments. The animal testing performed was conducted in a limited number of animals with axillary junctional bleeding and groin junctional bleeding but consistently demonstrated that the device can be packed in junctional wounds created in the axilla and groin to reduce hemorrhage. The animal testing was performed using a standard swine junctional bleeding model: however, the model was not adjusted to show device effect and limitations in most severe circumstances of bleeding accompanied by hemodilution or severe coagulopathy. The animal testing was performed in a controlled setting and standard junctional bleeding was created using a live animal testing was performed both early in the device development process to inform device design changes and subsequent additional testing on the standard junctional bleeding live animal model was performed with the near final versions of the XSTAT device to demonstrate proof of concept. The testing was not statistically powered but demonstrated a trend of rapid device deployment with comparable treatment effects as control and required no manual compression. The sponsor has performed human factors testing to assess device deployment and has developed a script with key images for an instructional video. This instructional material has been carefully reviewed and appears to mitigate potential use error associated with device use and early recognition of potential adverse events associated with device use. The human factors testing demonstrated that users could apply the device to a junctional bleeding site in a mock setting. These risk mitigations have been carefully reviewed and appear to be acceptable.

In conclusion, given the available information above, the data support that for the temporary control of bleeding for non-compressible wounds in the groin and axilla, the probable benefits outweigh the probable risks for the XSTAT. Sufficient evidence has been provided to establish special controls that can adequately mitigate the risks to health for the use of XSTAT for its intended patient population. The probable benefits outweigh the probable risks for battlefield device use since junctional bleeding is more frequently encountered in the battlefield and because there are few options for obtaining hemorrhage control in austere battlefield settings where definitive healthcare facility access is limited. There is an urgent need for devices that can reduce hemorrhage from non-compressible groin and axillary junctional bleeding. Many of the listed adverse events may be reversed with expeditious treatment using the device and transfer of the patient to a facility capable of offering definitive treatment of the injury. The device provides substantial benefits and the risks can be mitigated by the use of general and identified special controls.

CONCLUSION

The de novo for the XSTAT is granted and the device is classified under the following:

Product Code: PGZ Device Type: Non-absorbable, expandable, hemostatic sponge for temporary internal use Class: II Regulation: 21 CFR 878.4452

Regulation Number and Section

§ 878.4452 Nonabsorbable expandable hemostatic sponge for temporary internal use.

(a)
Identification. A nonabsorbable expandable hemostatic sponge for temporary internal use is a prescription device intended to be placed temporarily into junctional, non-compressible wounds, which are not amenable to tourniquet use, to control bleeding until surgical care is acquired. The sponges expand upon contact with blood to fill the wound cavity and provide a physical barrier and pressure that facilitates formation of a clot. The device consists of sterile, nonabsorbable radiopaque compressed sponges and may include an applicator to facilitate delivery into a wound.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Performance data must demonstrate the biocompatibility of patient-contacting components.
(2) Performance data must demonstrate the sterility of patient-contacting components including endotoxin and pyrogenicity assessments.
(3) Performance data must support device stability by demonstrating continued sterility of the patient-contacting components of the device, package integrity, and device functionality over the requested shelf life.
(4) Assessment of material characteristics must be sufficient to support safety under anticipated conditions of use. Assessments must include the following:
(i) Material specifications.
(ii) Immunogenicity.
(iii) Viral inactivation for animal-derived materials.
(5) Non-clinical performance data must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be tested:
(i) Absorption capacity.
(ii) Extent of swelling.
(iii) Mechanical properties.
(iv) Expansion force/pressure.
(v) Radiopacity.
(vi) Deployment/applicator functionality.
(6) In vivo performance data must demonstrate safe and effective use by verifying that the device performs as intended under anticipated conditions of use. Appropriate analysis/testing must demonstrate that the product: Controls bleeding, does not promote adverse local or systemic effects, and can be completely removed from the wound. The following performance characteristics must be tested:
(i) Deployment.
(ii) Control of bleeding.
(iii) Radiopacity.
(iv) Retrieval.
(v) Assessment of local and systemic effects.
(7) Human factors testing and analysis must validate that the device design and labeling are sufficient for appropriate use by emergency responders deploying the device as well as surgeons retrieving the device from wounds.
(8) Labeling must include:
(i) Specific instructions for deployment by emergency responders and retrieval by surgeons.
(ii) Warnings, cautions, and limitations needed for safe use of the device.
(iii) Information on how the device operates and the typical course of treatment.
(iv) A detailed summary of the in vivo and human factors testing pertinent to use of the device.
(v) Appropriate imaging information to ensure complete retrieval of device.
(vi) An expiration date/shelf life.