As part of the INDIGO Aspiration System, the INDIGO Aspiration Catheters and Separators are indicated for the removal of fresh, soft emboli and thrombi from vessels of the peripheral arterial and venous systems, and for the treatment of pulmonary embolism.

INDIGO Aspiration Tubing:

As part of the INDIGO Aspiration System, the INDIGO Sterile Aspiration Tubing is indicated to connect the INDIGO Aspiration Catheters to the Penumbra Aspiration Pump.

Penumbra Aspiration Pump:

The Penumbra Aspiration Pump is indicated as a vacuum source for Penumbra Aspiration Systems.

Device Description

The INDIGO® Aspiration System is comprised of several devices:

INDIGO Aspiration Catheter ●
Penumbra Aspiration Pump
INDIGO Aspiration Pump Canister ●
INDIGO Aspiration Tubing ●
INDIGO Separator™ ●

The INDIGO Aspiration System is designed to remove thrombus from the vasculature using mechanical aspiration. The INDIGO Aspiration Catheter targets aspiration from the pump directly to the thrombus. The INDIGO Separator may be used to clear the lumen of the INDIGO Aspiration Catheter should it become blocked with thrombus. The INDIGO Aspiration Catheter is introduced through a guide catheter or vascular sheath and into the peripheral vasculature and guided over a guidewire to the site of the primary occlusion. The INDIGO Aspiration Catheter is used with the Penumbra Aspiration Pump to aspirate thrombus from an occluded vessel. As needed, an INDIGO Separator may be deployed from the INDIGO Aspiration Catheter to assist with thrombus removal. The INDIGO Separator is advanced and retracted through the INDIGO Aspiration Catheter at the proximal margin of the primary occlusion to facilitate clearing of the thrombus from the INDIGO Aspiration Catheter tip. The devices are visible under fluoroscopy. For the aspiration source, the INDIGO Aspiration Catheter is used in conjunction with the Penumbra Aspiration Pump, which is connected using the INDIGO Aspiration Tubing and the INDIGO Aspiration Pump Canister. The INDIGO Aspiration Catheter may be provided with a steam shaping mandrel, rotating hemostasis valve, and introducer. The INDIGO Separator may be provided with an introducer and torque device.

AI/ML Overview

The provided text describes the 510(k) summary for the Penumbra Indigo Aspiration System. The core of this submission is to demonstrate substantial equivalence to a predicate device, with an expanded indication for the treatment of pulmonary embolism.

Here's an analysis of the acceptance criteria and the study that proves the device meets those criteria, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria	Reported Device Performance
Primary Efficacy Endpoint: Lower limit of the 95% confidence interval (CI) of the change in RV/LV ratio from baseline to 48 hours for acute PE patients (assessed by CTA) must be > 0.20 (indicating reduction in right ventricular dilation).	Absolute reduction in RV/LV ratio of 0.42 ± 0.25 (95% CI 0.37, 0.46). The lower limit of the 95% CI (0.37) is > 0.20. (26.9% reduction, p<0.0001)
Primary Safety Endpoint: 48-hour rate of major adverse events (composite of device-related death, major bleeding, and device-related SAEs including clinical deterioration, pulmonary vascular injury, and cardiac injury) should not be equal to 40%.	The 48-hour rate of major adverse events was 1.7% (95% CI 0.0%, 4.0%), p<0.0001. This is significantly lower than 40%.

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

Sample Size:
- ITT (Intent-To-Treat) analysis population: 119 subjects
- mITT (Modified ITT) population (primary for efficacy): 110 subjects (excluded subjects who received adjunctive treatments or thrombolytics intra-procedure through 48 hours post-procedure).
- Safety endpoints: Evaluated based on the ITT population (119 subjects).
Data Provenance: The Penumbra EXTRACT-PE trial was a prospective, multicenter, single-arm trial conducted at 22 centers in the U.S.

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

The document states: "An independent imaging core lab and a clinical events committee (CEC) reviewed safety endpoints data." It does not specify the exact number of experts or their detailed qualifications (e.g., "radiologist with 10 years of experience"). However, the involvement of an "independent imaging core lab" implies that imaging specialists (e.g., radiologists) were involved in assessing the imaging data for the RV/LV ratio, and a "clinical events committee" suggests physicians or clinical experts were involved in assessing safety events.

4. Adjudication Method for the Test Set

The document mentions an "independent imaging core lab" and a "clinical events committee (CEC)" reviewed endpoints data. This implies a form of expert review and consensus, but the specific adjudication method (e.g., 2+1, 3+1) is not explicitly stated.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, an MRMC comparative effectiveness study was not done. The EXTRACT-PE trial was a single-arm trial, evaluating the device's performance without direct comparison to human readers or another treatment arm within the study design (though it established substantial equivalence to a predicate device based on its performance). Therefore, an effect size of how much human readers improve with AI vs. without AI assistance is not applicable here, as this device itself is a mechanical aspiration system, not an AI-assisted diagnostic tool.

6. Standalone (Algorithm Only Without Human-in-the-Loop Performance) Study

Yes, in a sense. The "device performance" in this context refers to the Indigo Aspiration System as a standalone therapeutic device. The clinical trial evaluated the device's ability to achieve specific physiological outcomes (RV/LV ratio reduction) and safety outcomes when used by clinicians. Since it's a therapeutic device for mechanical thrombectomy, its performance is its standalone performance in treating patients. There isn't an "algorithm" being evaluated in the AI sense; rather, the mechanical system's efficacy is being assessed.

7. Type of Ground Truth Used

The ground truth for efficacy (reduction in RV/LV ratio) was established by CTA (Computed Tomography Angiography) images assessed by an independent imaging core laboratory.
The ground truth for safety (major adverse events) was established by clinical evaluation and review by a clinical events committee (CEC). This would incorporate clinical diagnoses, patient outcomes, and potentially imaging findings.

8. Sample Size for the Training Set

Not applicable / Not explicitly stated for this submission. The Indigo Aspiration System is a mechanical medical device, not an AI/ML algorithm that requires a "training set" in the computational sense. The device's design and functionality are based on engineering principles and prior validated devices. The clinical study (EXTRACT-PE) served as a validation study for the expanded indication.

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

Not applicable. As explained above, this device does not involve an AI/ML algorithm that requires a "training set" with established ground truth. The development and validation of this mechanical device rely on engineering design, bench testing, animal studies, and then human clinical trials to demonstrate safety and efficacy. The prior versions of the device (predicate and reference devices) would have undergone similar developmental and validation processes.

Summary

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December 20, 2019

Penumbra, Inc. Teri Nguyen Regulatory Affairs Specialist II One Penumbra Place Alameda, California 94502

Re: K192833

Trade/Device Name: Indigo Aspiration System Regulation Number: 21 CFR 870.5150 Regulation Name: Embolectomy Catheter Regulatory Class: Class II Product Code: QEW Dated: November 27, 2019 Received: November 29, 2019

Dear Teri Nguyen:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's

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requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

For

Gregory O'Connell Assistant Director DHT2C: Division of Coronary and Peripheral Intervention Devices OHT2: Office of Cardiovascular Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K192833

Device Name

Indigo Aspiration System

Indications for Use (Describe)

INDIGO Aspiration Catheters and Separators:

INDIGO Aspiration Tubing:

As part of the INDIGO Aspiration System, the INDIGO Sterile Aspiration Tubing is indicated to connect the INDIGO Aspiration Catheters to the Penumbra Aspiration Pump.

Penumbra Aspiration Pump:

The Penumbra Aspiration Pump is indicated as a vacuum source for Penumbra Aspiration Systems.

Type of Use (Select one or both, as applicable)

X Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

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1 510(k) Summary

(as required by 21 CFR 807.92)

Pursuant to Section 12, Part (a)(i)(3A) of the Safe Medical Devices Act of 1990, Penumbra, Inc. is providing the summary of Substantial Equivalence for the Indigo® Aspiration System.

1.1 Sponsor/Applicant Name and Address

Penumbra, Inc. One Penumbra Place Alameda, CA 94502 USA

1.2 Sponsor Contact Information

Teri Nguyen Regulatory Affairs Specialist II Phone: (510) 995-2012 FAX: (510) 217-6414 Email: tnguyen2@penumbrainc.com

1.3 Date of Preparation of 510(k) Summary

December 19, 2019

1.4 Device Trade or Proprietary Name

Indigo® Aspiration System

1.5 Device Classification

Regulatory Class: II Classification Panel: Cardiovascular Classification Name: Catheter, Embolectomy Regulation Number: 21 CFR §870.5150 Product Code: QEW

1.6 Predicate and Reference Devices

510(k) Number/Clearance Date	Name of Device	Name of Manufacture
Predicate Device
K142870 cleared on May 26, 2015	Penumbra EmbolectomyAspiration System (INDIGOAspiration System)	Penumbra, Inc.One Penumbra PlaceAlameda, CA 94502 USA
Reference Device
K180939 cleared on May 03, 2018	INDIGO AspirationSystem	Penumbra, Inc.One Penumbra PlaceAlameda, CA 94502 USA
K180466 cleared on May 19, 2018	FlowTriever Retrieval/AspirationSystem	Inari Medical, Inc.9272 Jeronimo RoadSuite 124Irvine, CA 92618 USA

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1.7 Predicate Comparison

System Name	Predicate Device	Reference Device		Subject Device¹
510(k) No.	K142870	K180939	K180466	K192833
Classification		Class II, DXE		Class II, QEW
Indication forUse	The PenumbraEmbolectomy AspirationSystem (INDIGO™Aspiration System) isintended for the removal offresh, soft emboli andthrombi from vessels of theperipheral arterial andvenous systems.Not for use in the coronariesor the neurovasculature.	INDIGO Aspiration Cathetersand Separators:As part of the INDIGOAspiration System, theINDIGO Aspiration Cathetersand Separators are indicatedfor the removal of fresh, softemboli and thrombi fromvessels of the peripheralarterial and venous systems.INDIGO Aspiration Tubing:As part of the INDIGOAspiration System, theINDIGO Sterile AspirationTubing is indicated to connectthe INDIGO AspirationCatheters to the PenumbraAspiration Pump.Penumbra Aspiration Pump:The Penumbra AspirationPump is indicated as avacuum source for thePenumbra AspirationSystems.	The FlowTrieverRetrieval/Aspiration Systemconsists of the FlowTrieverCatheter, Aspiration GuideCatheter, and RetractionAspirator. The FlowTrieverRetrieval/Aspiration System isindicated for:• The non-surgical removal ofemboli and thrombi from bloodvessels.• Injection, infusion, and/oraspiration of contrast media andother fluids into or from a bloodvessel.The FlowTrieverRetrieval/Aspiration System isintended for use in the peripheralvasculature and for the treatmentof pulmonary embolism.	INDIGO Aspiration Cathetersand Separators:As part of the INDIGOAspiration System, the INDIGOAspiration Catheters andSeparators are indicated for theremoval of fresh, soft emboli andthrombi from vessels of theperipheral arterial and venoussystems, and for the treatment ofpulmonary embolism.INDIGO Aspiration Tubing:As part of the INDIGOAspiration System, the INDIGOSterile Aspiration Tubing isindicated to connect the INDIGOAspiration Catheters to thePenumbra Aspiration Pump.Penumbra Aspiration Pump:The Penumbra Aspiration Pumpis indicated as a vacuum sourcefor the Penumbra AspirationSystems.

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	Predicate Device	Subject Device1
Packaging,Materials &Configurations	Commonly utilized for interventional devices	SAME
Aspiration Source	Penumbra Aspiration Pump	SAME
Sterilization	EO	SAME
Shelf-Life	36 Months	SAME
Use	Single use, disposable	SAME

1The Indigo System Aspiration Catheters, Separators, Tubing and Penumbra Aspiration Pumps are unchanged and remain identical to those currently cleared in Section 1.6.

1.8 Device Description

The INDIGO® Aspiration System is comprised of several devices:

INDIGO Aspiration Catheter ●
Penumbra Aspiration Pump
INDIGO Aspiration Pump Canister ●
INDIGO Aspiration Tubing ●
INDIGO Separator™ ●

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provided with a steam shaping mandrel, rotating hemostasis valve, and introducer. The INDIGO Separator may be provided with an introducer and torque device.

1.9 Indications for Use

INDIGO Aspiration Catheters and Separators:

INDIGO Aspiration Tubing:

As part of the INDIGO Aspiration System, the INDIGO Sterile Aspiration Tubing is indicated to connect the INDIGO Aspiration Catheters to the Penumbra Aspiration Pump.

Penumbra Aspiration Pump:

The Penumbra Aspiration Pump is indicated as a vacuum source for Penumbra Aspiration Systems.

1.10 Summary of Non-Clinical Data

The subject and predicate Indigo System devices are identical. Therefore, previous device performance data regarding substantial equivalence described below remain unchanged.

1.10.1 Biocompatibility

The subject and predicate Indigo System sterile devices are identical. There are no changes to the previously provided biocompatibility data of the Indigo System sterile device materials, which were reviewed and cleared under the premarket notifications listed in 1.6. No additional biocompatibility testing is required or was performed for the Indigo System sterile devices.

The subject and predicate Indigo System devices are categorized and tested as a limited exposure (<24 hours), externally communicating device with circulating blood contact in

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accordance with EN ISO 10993-1, USP standards, and FDA Good Laboratory Practices (GLP). Biocompatiblity test results demonstrate biological safety per BS EN ISO 10993 and USP requirements.

1.10.2 Design Verification (Bench-top Testing)

The subject and predicate Indigo System devices are identical. There are no changes to the previously provided bench-top data of the devices, which were reviewed and cleared under the premarket notifications listed in 1.6. No additional bench-top testing is required or was performed for these devices.

1.10.3 Design Validation - Animal Study

The subject and predicate Indigo System devices are identical. There are no changes to the previously provided animal testing data of the devices, which were reviewed and cleared under the premarket notifications listed in 1.6. No additional animal testing is required or was performed for these devices.

1.10.4 Performance Data - Clinical

1.10.4.1 Introduction

The Penumbra EXTRACT-PE trial was a prospective, multicenter, single arm trial to determine the safety and efficacy of the Indigo Aspiration System for mechanical thrombectomy in subjects with acute pulmonary embolism (PE).

1.10.4.2 Study Design

The Penumbra EXTRACT-PE trial was a prospective, multicenter, single arm trial. The trial enrolled 119 subjects at 22 centers in the U.S. An independent imaging core lab and a clinical events committee (CEC) reviewed safety endpoints data.

1.10.4.3 Methods

The study procedure was initiated in 119 subjects and completed in 118 subjects; one subject had the procedure aborted prior to aspiration. Conscious sedation was

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used in 97.5% of subjects and 78.2% had a right femoral access site. The median procedure time was 66 min; IQR [46.0, 94.0]. The median time from the first Indigo device insertion to the last Indigo device removal was 37 minutes; IQR [23.5, 60.0]. The median ICU stay was 1.0 day [1.0, 2.0].

The treatment included the following pulmonary embolism locations:

Treatment Location	All Subjects (N=119)
Main PA with Unilateral	0.8% (1/119)
Main PA with Bilateral	23.5% (28/119)
Unilateral Only	5.9% (7/119)
Bilateral Only	69.7% (83/119)

1.10.4.4 Study Results

There were 119 subjects that were enrolled and included in the Intent-To-Treat (ITT) analysis population. The Modified ITT (mITT) population was a subset of the ITT population and was the primary population for all efficacy parameters. The mITT population excluded subjects who received adjunctive treatments or thrombolytics intra-procedure through 48 hours post-procedure for the purpose of reducing clot burden in the pulmonary artery. There were 110 subjects in the mITT population. Safety endpoints are evaluated based on ITT population.

There were 110 patients who completed the study 30 day follow-up, 3 patients died, 1 withdrew from the study, and 5 were lost to follow-up.

The primary efficacy endpoint was the reduction in RV/LV ratio from baseline to 48 hours assessed by CTA and evaluated by independent core laboratory. The lower limit of the 95% confidence interval (CI) of the change in RV/LV ratio at 48 hours was >0.20. The primary efficacy endpoint was met with absolute reduction in RV/LV ratio of 0.42±0.25 (95%CI 0.37, 0.46), representing a 26.9% reduction (p<0.0001). The primary safety endpoint was major adverse events, a composite of device-related death, major bleeding, and device-related SAEs (defined as clinical deterioration, pulmonary vascular injury, and cardiac Injury) within 48 hours. The safety hypothesis stated that the 48-hour rate of major

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adverse events would not equal 40%. The primary safety endpoint was met and the rate was 1.7% (95% CI 0.0%, 4.0%), p<0.0001).

1.10.4.5 Conclusion

The EXTRACT-PE trial demonstrated that the Indigo Aspiration System showed substantially equivalent safety and effectiveness outcomes for acute PE. The primary efficacy and safety endpoints were met.

1.10.5 Shelf Life

The subject and predicate Indigo System are identical. There are no changes to the previously provided shelf-life data for the devices, which were reviewed and cleared under premarket notifications listed in 1.6. No additional stability testing is required or was performed for the Indigo System sterile devices.

1.10.6 Sterilization

The subject and predicate Indigo System sterile devices are identical and utilize the same Ethylene Oxide (EO) gas exposure sterilization method in accordance with BS EN ISO 11135. There are no changes to the previously provided sterilization data of the devices, which were reviewed and cleared under the premarket notifications listed in 1.6. No additional sterilization testing is required or was performed for these devices.

1.10.7 Packaging

The packaging materials and process of the subject and predicate Indigo System are identical. There are no changes to the previously provided packaging material listing or the packaging process for these devices, which were reviewed and cleared under the premarket notifications listed in 1.6. No additional packaging testing is required or was performed.

1.11 Summarv of Substantial Equivalence

Compared to the predicate device, the expanded indication of the Indigo Aspiration System does not change the intended use. Based on the leveraged results of pre-clinical testing and

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the EXTRACT-PE Clinical Study, the data supports that the Indigo Aspiration System is substantially equivalent to the predicate device.

Regulation Number and Section

§ 870.5150 Embolectomy catheter.

(a)
Identification. An embolectomy catheter is a balloon-tipped catheter that is used to remove thromboemboli, i.e., blood clots which have migrated in blood vessels from one site in the vascular tree to another.(b)
Classification. Class II (performance standards).