← Product Code MAE · P120009

# NIT-OCCLUD PDA (P120009)

_Pfm Medical, Inc. · MAE · Aug 16, 2013 · Cardiovascular · APPR_

**Canonical URL:** https://fda.innolitics.com/device/P120009

## Device Facts

- **Applicant:** Pfm Medical, Inc.
- **Product Code:** MAE
- **Decision Date:** Aug 16, 2013
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic, Pediatric

## Indications for Use

The Nit-Occlud® PDA is a permanently implanted prosthesis indicated for percutaneous, transcatheter closure of small to moderate size patent ductus arteriosus with a minimum angiographic diameter less than 4 mm.

## Device Story

Nit-Occlud® PDA is a nitinol spiral coil prosthesis for transcatheter closure of patent ductus arteriosus (PDA). The device features a cone-in-cone configuration with reverse-wound proximal windings to facilitate secure placement. It is delivered via a catheter-based system with a disposable handle and a patented detachment mechanism. Available in flexible (no core wire) and medium (tapered core wire) types. Used in a clinical/cath lab setting by interventional cardiologists. The physician navigates the delivery system through the vasculature to the PDA site under fluoroscopic guidance. Once deployed, the coil mechanically occludes the ductus; tissue ingrowth occurs over 6-12 weeks, permanently immobilizing the device. This procedure provides a minimally invasive alternative to surgical ligation, reducing risks associated with open-heart surgery and promoting rapid closure of the shunt.

## Clinical Evidence

Prospective, multi-center, single-arm Sentinel study (n=357). Primary endpoints at 12 months: clinical closure rate 98.1% (95% CI lower bound 96.7% > 95% OPC); echocardiographic closure rate 96.8% (95% CI lower bound 95% > 85% OPC); serious adverse event rate 0% (95% CI upper bound 0.95% < 1% OPC). Study met all primary safety and effectiveness criteria.

## Technological Characteristics

Nitinol spiral coil prosthesis; cone-in-cone configuration. Available in flexible (no core wire) and medium (tapered core wire) types. Delivery system includes transportation sheath, implantation catheter, and y-connector. Sterilized via ethylene oxide (SAL 10^-6). MR-conditional (3T or less). Biocompatibility per ISO 10993. Corrosion resistance per ASTM F2129-08.

## Reference Devices

- Amplatzer Duct Occluder
- Nit-Occlud® VSD occlusion device

## Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Transcatheter Patent Ductus Arteriosus (PDA) Occlusion Device

Device Trade Name: Nit-Occlud® PDA

Device Procode: MAE

Applicant’s Name and Address: pfm medical ag
Wankelstrasse 60
Cologne, 50996
Germany
ERN: 9617465

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P120009

Date of FDA Notice of Approval: August 16, 2013

Expedited: Not applicable

II. INDICATIONS FOR USE

The Nit-Occlud® PDA is a permanently implanted prosthesis indicated for percutaneous, transcatheter closure of small to moderate size patent ductus arteriosus with a minimum angiographic diameter less than 4 mm.

III. CONTRAINDICATIONS

- Endocarditis, endarteritis or active infection at the time of the implantation
- Patients with a body weight &lt; 5 kg
- Pulmonary hypertension (calculated PVR greater than 5 Wood Units)
- Thrombus in a blood vessel through which access to the PDA must be obtained
- Thrombus in the vicinity of the implantation site.

IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Nit-Occlud® PDA labeling.

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# V. DEVICE DESCRIPTION

Nit-Occlud® PDA is a system for transcatheter occlusion of Patent Ductus Arteriosus (PDA) with spiral coils. The system consists of the following parts:

- Nit-Occlud® Spiral Coil with disposable handle

![img-0.jpeg](img-0.jpeg)
Figure 1. Nit-Occlud® Spiral Coil

The spiral coil is mounted in a straightened fashion on a delivery system including a disposable handle to which it is connected by means of a patented detachment mechanism.

The Nit-Occlud® PDA is available as Flexible and Medium Type. The flexible coils do not have a core wire, while the medium coils have core wires that are  $0.1\mathrm{mm}$  in diameter tapered to  $0.25\mathrm{mm}$  flat.

The flexible and medium types are pre-loaded into the transportation sheath. For insertion the transportation sheath must be connected to the implantation catheter.

![img-1.jpeg](img-1.jpeg)
Figure 2. Delivery System

The Nit-Occlud® PDA has a cone in cone configuration which results from the fact that the proximal windings of the coil are wound the reverse direction (see Fig.3).

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![img-2.jpeg](img-2.jpeg)
Figure 3. Coil Configuration
Fig.: Nit-Occlud® Coil

(D=Distal diameter, P=Proximal diameter, Lc=Length configured).

The following types and sizes are available:

Table 1: Nit-Occlud® PDA Sizes

|  Description | Catalog #  |
| --- | --- |
|  Nit-Occlud® PDA, 4 x 4 mm, Flexible, Sheath 4F x 85 cm | 145044  |
|  Nit-Occlud® PDA, 5 x 4 mm, Flexible, Sheath 4F x 85 cm | 145054  |
|  Nit-Occlud® PDA, 6 x 5 mm, Flexible, Sheath 4F x 85 cm | 145065  |
|  Nit-Occlud® PDA, 7 x 6 mm, Medium, Sheath 5F x 85 cm | 145076  |
|  Nit-Occlud® PDA, 9 x 6 mm, Medium, Sheath 5F x 85 cm | 145096  |
|  Nit-Occlud® PDA, 11 x 6 mm, Medium, Sheath 5F x 85 cm | 145116  |

Table 2: Nit-Occlud® Device by D1 and D2

|  PDA Dimensions |   | Recommended Device  |   |
| --- | --- | --- | --- |
|  D1 | D2 | Size (DxP) | Type  |
|  1 mm | Up to 3 mm | 4x4 | Flex  |
|  1 mm | 4 mm | 5x4 | Flex  |
|  1 mm | 5 mm or greater | 6x5 | Flex  |
|  2 mm | Up to 5 mm | 6x5 | Flex  |
|  2 mm | 6-7 mm | 7x6 | Medium  |
|  2 mm | 8 mm or greater | 9x6 | Medium  |
|  3 mm | Up to 7 mm | 7x6 | Medium  |
|  3 mm | 8-9 mm | 9x6 | Medium  |
|  3 mm | 9 mm or greater | 9x6 / 11x6 | Medium  |
|  4 or 5 mm | 9 mm or greater | 11x6 | Medium  |
|  D1 = Narrowest diameter; D2 = Aortic Ampulla diameter  |   |   |   |

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VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternatives for the correction of a PDA:

- Surgical ligation/division
- Medication to help close the PDA or treat symptoms of the PDA
- Interventional use of the Amplatzer Duct Occluder (St. Jude Medical -formerly AGA Medical Corp.- Golden Valley MN)

Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.

VII. MARKETING HISTORY

The Nit-Occlud® PDA has had CE Mark Approval since 2001 and has been in commercial distribution primarily in Europe and Latin American countries as well as Asia, Eastern Europe and the Middle East.

|  Argentina | Germany | Poland  |
| --- | --- | --- |
|  Australia | Great Britain | Portugal  |
|  Austria | Greece | Romania  |
|  Belarus | Hungary | Russia  |
|  Bolivia | India | Saudi Arabia  |
|  Brazil | Iran | Serbia  |
|  Bulgaria | Israel | South Africa  |
|  Canada | Italy | Spain  |
|  China | Jordan | Sweden  |
|  Columbia | Kazakhstan | Switzerland  |
|  Czech Republic | Korea | Turkey  |
|  Denmark | Latvia | Ukraine  |
|  Ecuador | Malaysia | Venezuela  |
|  Egypt | Netherlands |   |
|  France | Oman |   |

Between 2001 and 2011 a total of 14,490 devices were sold. The device has never been withdrawn from Market for any safety or effectiveness issues.

VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device.

- Air embolism

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- Allergic reaction to drug/contrast
- Apnea
- Arrhythmia requiring medical treatment or pacing
- Arteriovenous Fistula
- Bacterial Endocarditis
- Blood loss requiring transfusion
- Chest Pain
- Damage to the tricuspid or pulmonary valves
- Death
- Embolization of the occluder, requiring percutaneous or surgical intervention
- Endarteritis
- False aneurysm of the femoral artery
- Fever
- Headache/migraine
- Heart failure
- Hemolysis after implantation of the occluder
- Hypertension
- Hypotension or shock
- Infection
- Myocardial infarction
- Occluder fracture or damage
- Perforation of the heart or blood vessels
- Stenosis of the left pulmonary artery or descending thoracic aorta
- Stroke/TIA
- Thromboembolism (cerebral or pulmonary)
- Valvular Regurgitation
- Vessel damage at the site of groin puncture (loss of pulse, hematoma etc.).

For the specific adverse events that occurred in the clinical studies, please see Section X below.

## IX. SUMMARY OF PRECLINICAL STUDIES

### A. Laboratory Studies

A1. In vitro bench testing

Table 3 lists the bench testing conducted on the Nit-Occlud® PDA.

Table 3. Engineering Tests

|  TEST | PURPOSE/DESCRIPTION | ACCEPTANCE CRITERIA | RESULTS AVE ± SD (RANGE) | CONCLUSION  |
| --- | --- | --- | --- | --- |
|  Tensile Strength Pin / Pusher Core Wire | The tensile strength of the pin / pusher core wire connection is measured. | F>40 N | 125.32N ± 12.05 (102.4 – 147.0N) | PASS  |
|  Tensile Strength Pusher | The tensile strength of the pusher core | F>100N | 125.10N ± 3.78 | PASS  |

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|  Core Wire | wire is measured. |  | (115.34–130.61N) |   |
| --- | --- | --- | --- | --- |
|  System Release Force | The force on the delivery system when releasing the implant is measured. | 20N<F<30N | Flex.:26.82N ± 1.05
(24.5 – 28.8N)
Med.: 26.04N ± 1.25
(23.6 – 28.5N) | PASS  |
|  Repeated System Release Force (10X) | The reproducibility of the release force after repeated re-mounting of the implant is determined. | No deterioration of the release force.
20N<F_{aver}<30N | 1: 26.37N ± 3.46
(20.50-33.34N)
2: 25.59N ± 2.60
(22.63-29.58N)
3: 23.84N ± 3.81
(18.08-32.75N) | PASS  |
|  Coil Fixation (holding force) | The proximal coil fixation force is a proof test with the tensile testing machine applying 20N for 10 seconds on the delivery system to show that the implant is connected correctly to the delivery system. | 20 N; t=10s without detaching the implant from the delivery system | Flex.:20.36N ± 0.51
(20.0-23.3N)
Med.: 20.45N ± 0.45
(20.0-23.3N) | PASS  |
|  Distal Coil Fixation Force | The force necessary to pull the implant off the delivery system is determined in a tensile test. Meeting the specification prevents loss of the coil during intervention (e.g. during retraction of the implant into the catheter or pulling the device through the defect). | >9 N | 12.69N ± 1.23
(9.75 – 16.85N) | PASS  |
|  Pull through PDA model | The purpose of this test was to prove in a simulated use environment, that if the coil is inadvertently pulled through the defect in its configured/expanded state, it will not disconnect from the delivery system, it will still be possible to pull the implant back into the implantation catheter, and it will correctly (re-)configure when again released. | <6N | 5.11N ± 0.69
(3.2 N – 5.9 N) | PASS  |
|  Retraction Force into Sheath | The catheter retraction force is determined in a simulated use environment in order to ensure that during retraction the spiral may not detach from the delivery system. | <6 N | 4.39N ± 1.65
(3.27 – 5.87N) | PASS  |
|  System Friction Test – Pushability | This test determined the force needed to advance the implant through the implantation catheter. It should be possible to push the implant easily through the implantation catheter in order to avoid possible damage to the device and to facilitate the application of the device for the user. | <6 N | 1.26N ± 0.06
(1.0 – 1.5N) | PASS  |
|  Introducer/ Connector Bond Strength | This test was performed to determine if the overmolded connection between luer and catheter meets the specification thus avoiding breakage of the sheath at the hub or leakage of liquids at this junction of luer hub and tube. | F>10N | 4F: 18.24N ± 3.54
(14.19 N – 25.92N)
5F: 25.85N ± 6.58
(17.70 N – 41.75N) | PASS  |
|  Y-Connector / T. Sheath Bond Strength | The purpose of this test was to verify, that the tensile strength of the connection y-connector – transportation sheath meets the specification in order to ensure that the connection does not break during clinical use. | F>10N | 189.64N ± 67.7
(46.14 – 255.72N) | PASS  |
|  Catheter / Y-Connector Bond Strength | The purpose of this test was to verify, that the tensile strength of the luer connection between y-connector and implantation catheter meets the | F>10N | 4F: 64.1N ± 10.76
(42.86 – 78.37N)
5F: 63.1N ± 11.58
(49.13 – 81.76N) | PASS  |

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|   | specification in order to ensure that the connection does not break during clinical use. |  |  |   |
| --- | --- | --- | --- | --- |
|  Radiopacity | This test was performed according to American Society for Testing and Materials (ASTM) F640 to verify that the radiopacity of the device results in an adequate fluoroscopic contrast/visibility during clinical use. | contrast >>0.1 | contrast 42.6 ± 5.5 | PASS  |
|  3 year Functional Shelf Life Testing | Bench-testing above was repeated on devices that were accelerated aged for an equivalent of 3 years shelf life to ensure device functionality and integrity at the end of the labeled shelf life. All tests used the same test methods and acceptance criteria as for the unaged samples. |   | PASS | PASS  |
|  F = Force N = Newtons T = time S = seconds Ave = Average SD = Standard Deviation  |   |   |   |   |

# Physio-Chemical Tests

- Corrosion Test - The electrochemical characterization of Nit-Occlud® PDA was performed using potentiodynamic methods according to ASTM F2129-08. The rest potential  $\mathrm{E_r}$  of the implant as well as the breakdown potential  $\mathrm{E_b}$  were determined. The test parameters were set appropriate to the standard. A total of 22 of the 30 implants tested showed no breakdown up to  $1100\mathrm{mV}$ , 6 had a breakdown potential of more than  $600\mathrm{mV}$ , 2 implants had breakdown potentials between  $600\mathrm{mV}$  and  $300\mathrm{mV}$ . With an average breakdown potential of at least  $990\mathrm{mV}$  and no breakdown potentials observed below  $300\mathrm{mV}$  the device shows adequate corrosion resistance and fulfilled all preset acceptance criteria.
- Fatigue Testing - Evaluation of 84 angiogram sequences of 42 representative PDA patients from the US clinical trial showed that the coil implant can move as a whole with the tissue and vasculature, but that there is minimal structural deformation of the implant over the heart cycle, i.e. the elongation/compression forces and bending/torsional moments on the coil are essentially zero. Ingrowth of a Nit-Occlud® PDA within 6 – 12 weeks following implantation further immobilizes the device and the surrounding tissue. Fatigue resistance of the pfm medical Nit-Occlud® VSD occlusion device, which also consists of a nitinol coil with a very similar design as the Nit-Occlud® PDA, has been tested and is leveraged to support the fatigue resistance of the Nit-Occlud® PDA. The Nit-Occlud® VSD occlusion device was subjected to a fatigue test which mimics the oscillating deflection due to the heart's contractions in the septum, i.e. a cyclic deformation of about  $1\mathrm{mm}$  amplitude between the distal and proximal part of the device. After 400 million cycles, there were no fractures and the comparison of SEM pictures of the fatigued and non-fatigued VSD implants showed no change of the surface, e.g. cracks or beginning cracks. Long-term coil structural integrity of the Nit-Occlud® PDA is also supported by the evaluation of 45 follow-up

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angiograms (time interval from implantation ranging from 0-75 months, mean 27m, median 20m) where no deformation or fracture was observed.

## Abrasion Resistance/Particulate Test

Particulate testing was performed to determine the amount of particles generated and/or released from the device under anatomically relevant simulated use conditions. Baseline testing and a simulated use with a tortuous path model (developed in conjunction with the intended use of the Nit-Occlud® PDA) were performed. The investigation was performed with the device (implant and delivery system) and the accessories as manufactured. Particulate detection and analysis was performed according to USP 788 (Particulate Matter in Injections) and for all tests, the limits set forth by USP 788 for small-volume injections were not exceeded.

## Magnetic Resonance (MR) Imaging Safety

The Nit-Occlud® PDA coil was determined to be MR-conditional according to the terminology specified in the ASTM International, Designation: F2503-05.

Non-clinical testing demonstrated that the Nit-Occlud® PDA coil is MR conditional. A patient with this device can be scanned safely immediately after placement under the following conditions:

- Static magnetic field of 3 Tesla or less;
- Maximum spatial gradient magnetic field of 720 Gauss/cm or less; and
- The maximum whole-body averaged specific absorption rate (SAR) shall be limited to 2.0 W/kg (normal operating mode only) for 15 minutes of scanning.

## MRI-Related Heating

- In non-clinical testing, the Nit-Occlud® PDA coil produced the following temperature rise during MRI performed for 15-min in the 3-Tesla (3-Tesla/128-MHz, Excite, HDx, Software 14X.M5, General Electric Healthcare, Milwaukee, WI) MR system: Highest temperature change +1.6°C.

Therefore, the MRI-related heating experiments for the Nit-Occlud® PDA coil at 3-Tesla using a transmit/receive RF body coil in an MR system reported whole body averaged SAR of 2.9 -W/kg (i.e., associated with a calorimetry measured whole body averaged value of 2.7-W/kg) indicated that the greatest amount of heating that occurred in association with these specific conditions was equal to or less than +1.6°C.

## Artifact Information

- MR image quality may be compromised if the area of interest is in the exact same area or relatively close to the position of the Nit-Occlud® PDA coil. Therefore, optimization of MR imaging parameters to compensate for the presence of this device may be necessary.

## A2. Biocompatibility

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Based on extensive chemical investigations according to United States Pharmacopeia (USP 661) Physiochemical Tests – Plastics and ISO 10993-18 (Chemical Characterization of Materials) a biological safety evaluation was established focusing on the requirements of ISO 10993-1 as well as FDA General Program Memorandum #G95-1. According to the nature and duration of patient contact, for biological/toxicological testing performed, the Nit-Occlud® PDA system was divided into its two main components: The implant and the accessories, i.e. the implantation catheter, transportation sheath, delivery system, y-connector and the handle.

- Based on the tests in the Table 4, the Nit-Occlud® PDA is considered safe for its intended use:

Table 4. Implant Biocompatibility Testing

|  Test | Results, Justification  |
| --- | --- |
|  Cytotoxicity Study according to ISO 10993-5 with Extract | Non-cytotoxic  |
|  Maximization Sensitization Study according to ISO 10993-10 | Saline and sesame oil extracts were not a sensitizer  |
|  Genotoxicity Study according to ISO 10993-3, Mouse Bone Marrow Micronucleus Study | Saline and sesame oil extracts are not mutagenic  |
|  Genotoxicity Study according to ISO 10993-3, In Vitro Chromosomal Aberration Study in Mammalian Cells | Saline and dimethyl sulfoxide extracts are not genotoxic  |
|  Genotoxicity Study according to ISO 10993-3, Bacterial Reverse Mutation | Saline and dimethyl sulfoxide extracts are not mutagenic  |
|  Hemocompatibility according to ISO 10993-4, ISO 10993 and ASTM Hemolysis | Non-hemolytic  |
|  Hemocompatibility according to ISO 10993-4, ISO C3a Complement Activation Test | Not an activator  |
|  Hemocompatibility according to ISO 10993-4, ISO SC5b-9 Complement Activation Test | Not an activator  |

- Based on the tests in Table 5, the implantation catheter, transportation sheath, delivery system, y-connector and the handle (termed "accessories") are considered safe for the intended use of the device:

Table 5. Delivery System and Accessories Biocompatibility Testing

|  Test | Results, Justification  |
| --- | --- |
|  Cytotoxicity Study according to ISO 10993-5 with Extract on the handle | Non-cytotoxic  |
|  Cytotoxicity Study according to ISO 10993-5 with | Non-cytotoxic  |

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|  Extract on the accessories (beside handle) |   |
| --- | --- |
|  Maximization Sensitization Study according to ISO 10993-10 | Saline and sesame oil extracts were not a sensitizer  |
|  Intracutaneous Irritation Test by Intradermal Injection in the Rabbit according to ISO 10993-10 | Saline and sesame oil extracts met study requirements  |
|  Acute Systemic Toxicity Study in the Mouse according to ISO 10993-11 | Saline and sesame oil extracts met study requirements  |
|  Rabbit Pyrogen Study according to USP 34-NF 29 | Non-pyrogenic  |
|  Hemocompatibility according to ISO 10993-4, ISO 10993 and ASTM Hemolysis | Non-hemolytic  |
|  Hemocompatibility according to ISO 10993-4, ISO C3a Complement Activation Test | Not an activator  |
|  Hemocompatibility according to ISO 10993-4, ISO SC5b-9 Complement Activation Test | Not an activator  |
|  Hemocompatibility according to ISO 10993-4, In vivo Thromboresistance Following Acute Implantation in the Jugular Vein of the Domestic Pig | Test articles showed sufficient thromboresistance In addition to this neither the clinical study nor post market surveillance identified any thromboembolic risk associated with the accessory  |

A pyrogen test on the accessories was performed in order to detect any substances causing a rise in body temperature in a rabbit model after intravenous injection of the accessories extract. The procedures corresponded to the requirements of USP 34 - NF29, Rabbit Pyrogen Study. The Nit-Occlud® PDA Accessories met the requirements of the USP 34 - NF 29 and are rated as non-pyrogenic as well as the Nit-Occlud® PDA Implant as worst case article which met the requirements of the USP 24 for the absence of pyrogens.

## A3. Shelf Life

Samples of the Nit-Occlud® PDA system were subjected to accelerated aging and evaluated through functional testing to ensure adherence to the product specifications. The data collected to date supports a product shelf life of three (3) years for the Nit-Occlud® PDA.

## A4. Sterilization

The Nit-Occlud® PDA is sterilized with ethylene oxide to achieve a sterility assurance level (SAL) of $10^{-6}$. The sterilization plant is validated and operated in accordance to EN ISO 11135-1:2007 Sterilization of healthcare products – Ethylene Oxide – Part 1: Requirements for development, validation and routine control of sterilization process for medical devices. The Sterilization is validated and controlled per ISO 11135-2:2007 Medical Devices – Validation and Routine Control of Ethylene Oxide Sterilization. Sterilization residual limits meet the

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requirements of ANSI/AAMI/ISO 10993-7:2008 (Biological evaluation of medical devices – Part 7: Ethylene Oxide sterilization residuals).

## B. Animal Studies

The two animal studies conducted on the Nit-Occlud® PDA are described in Tables 6 and 7 below:

Table 6. PDA Occlusion in a chronic ovine model

|  Objective | To evaluate practicability and effectiveness of the device in occluding large PDAs (>6mm) in a lamb model of a chronic PDA.  |
| --- | --- |
|  Endpoint assessment | The Nit-Occlud® PDA was placed into nine neonatal lambs. At follow-up (Day 1, Day 4, and prior to euthanasia) all nine lambs had no audible murmur and seven of the nine lambs showed complete occlusion just prior to euthanasia. Average survival was 107 days (range 7-278 days).  |
|  Histology | Macroscopic examination of the ductal orifices post-mortem showed little if any protrusion of the outer rings of the coils into the lumen of the aorta or the pulmonary artery. Depending on the duration of implantation the coils were partially or completely covered by a thin, shiny tissue.
Scanning electron microscopy (SEM) and Histology. Most of the coils were covered by a monolayer of cells resembling neointimal coverage, starting as early as 7 days after implantation. Comparing different intervals after implantation, the cellular coverage was more pronounced with longer intervals of implantation.  |
|  Adverse Events | No adverse events reported  |
|  GLP conformity | Study was performed in accordance with the GLP and the German Animal Protection Law and approved by the supervising state agency for animal experiments.  |

Table 7. Closure of Patent Foramen Ovale in an ovine model

|  Objectives | To assess the biocompatibility of the device for closure of patent foramen ovale in the ovine model (8 lambs at the age of 6 to 12 weeks)  |   |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  Endpoints | • Ingrowth of the coil into surrounding tissue
• Calcification
• Inflammatory infiltrates as shown by infiltration of lympho-plasmatocytes
• Lympho-histiocytic reaction as a sign of foreign body reaction  |   |   |   |   |   |   |
|  Endpoint assessment | After a period of implantation of at least 47 days, devices were completely ingrown without any signs of thrombus formation or local inflammation. Few signs of calcification and moderate foreign body reaction were observed in single animals. The results suggest good biocompatibility of the Nitinol devices tested.  |   |   |   |   |   |   |
|  Histology | Ani-mal | Time of implantation | Ingrowth | Calcifi-cations | Amorphous particles | Inflammatory infiltrates | Histiocytic reaction  |
|   |  1 | 4 days | no | no | no | No | no  |
|   |  2 | 47 days | complete | no | no | No | moderate  |
|   |  3 | 47 days | complete | no | moderate | No | moderate  |
|   |  4 | 47 days | complete | no | no | no | moderate  |
|   |  5 | 72 days | complete | few | no | No | moderate  |
|   |  6 | 72 days | complete | no | few | No | no  |
|   |  7 | 113 days | complete | few | few | No | moderate  |

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|   | 8 | 113 days | complete | no | no | No | no  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  Adverse events | No adverse events reported  |   |   |   |   |   |   |
|  GLP conformity | Study was not conducted in accordance with GLP, but with the guidelines of the German Animal Protection Law and approved by the supervising state agency for animal experiments  |   |   |   |   |   |   |

# X. SUMMARY OF PRIMARY CLINICAL STUDY(IES)

Patients were treated between November 2002 and October 2007. The database for this PMA reflected data collected through October 2008 and included 357 patients. There were 15 investigational sites.

The Sentinel Study was conducted in the US under IDE # G010278 to establish a reasonable assurance of safety and effectiveness of the Nit-Occlud® PDA for the treatment of patent ductus arteriosus of diameter  $&lt; 4 \, \text{mm}$ . Data from this clinical study (including continued access patients) were the basis for the PMA approval decision. A summary of the clinical study is presented below.

# A. Study Design

The Sentinel Study is a prospective, multi-center, single-arm study. The primary effectiveness endpoints were echocardiographic and clinical closure rates at 12 months. The primary safety endpoint was the serious adverse event rate at 12 months.

The endpoint rates were compared to an Objective Performance Criteria. The study paradigm (primary effectiveness and safety endpoints) was recommended by a 1997 Circulatory System Devices Advisory Panel to FDA for the assessment of PDA closure. The OPC was specified in the Panel's report [2].

An independent Core Echocardiography Laboratory reviewed and validated a subset of echo videotapes or CD's for the 12 month follow-up echocardiograms. A Data Safety Monitoring Board (DSMB) reviewed and adjudicated all adverse events.

# A1. Clinical Inclusion and Exclusion Criteria

Enrollment in the Sentinel study was limited to patients who met the following inclusion criteria:

Primary Inclusion Criteria:

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1. PDA with  $4\mathrm{mm}$  or smaller minimum diameter by color Doppler
2. Patent weight  $\geq 5\mathrm{Kg}$ , Age 6 months to 21 years (Patients older than 21 years may have device implanted and be included in a study registry.)
3. Previous treatment by surgery or Nit-Occlud® device with residual PDA noted at least 6 months after the procedure

Secondary Inclusion Criterion:

Angiographic minimum PDA diameter (D1) less than  $4\mathrm{mm}$ . (Patients with angiographic diameters larger than  $4\mathrm{mm}$  and smaller or equal to  $5\mathrm{mm}$  were eligible for Nit-Occlud® device implantation but were included in a separate study registry.)

Patients were not permitted to enroll in the Sentinel study if they met any of the following exclusion criteria:

1. Associated cardiac anomalies requiring surgery
2. Known bleeding or blood clotting disorders
3. Ongoing febrile illness
4. Pregnancy
5. Pulmonary hypertension/increased pulmonary vascular resistance (&gt;5 Wood Units)
6. Known hypersensitivity to contrast medium

# A2. Follow-up Schedule

Clinical follow-up, including medical history, physical examination, and complete echocardiogram, were required after device implant at hospital discharge, 6 months, and 12 months.

Table 8. Patient Follow-up Plan

|  Visits | Pre-Diagnostics | Intervention | Post Procedural Care / Discharge | FU 1 | FU 2  |
| --- | --- | --- | --- | --- | --- |
|  Period |  | 0 | >+1 day | 6 months | 12 months  |
|  In/Exclusion criteria | X |  |  |  |   |
|  Informed consent | X |  |  |  |   |
|  Admission | X |  |  |  |   |
|  Medical history | X |  |  | X | X  |
|  Physical examination including auscultation of murmur | X |  | X | X | X  |
|  Echocardiographic examination of the heart and the great vessels including color Doppler | X |  | X | X | X  |

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|  with imaging of the PDA shunt, measuring the width of the color flow stream |  |  |  |  |   |
| --- | --- | --- | --- | --- | --- |
|  Routine post catheterization care and observation |  |  | X |  |   |
|  Coil implantation |  | X |  |  |   |
|  Intrainterventional data |  | X |  |  |   |
|  Follow Up Visits |  |  | X | X | X  |
|  Final visit | X | X | X | X | X  |
|  Adverse Events |  | X | X | X | X  |

Adverse events and complications were recorded at all visits.

The key timepoints are shown below in the tables summarizing safety and effectiveness.

## A3. Clinical Endpoints

The primary effectiveness endpoints were echocardiographic and clinical closure rates at 12 months. Echocardiographic closure was defined as absence of detectable residual PDA flow by color Doppler echocardiographic examination. Clinical closure was defined as absence of a heart murmur and/or complete echocardiographic closure. Failures of clinical closure had a residual PDA by echocardiogram as well as a heart murmur audible by stethoscope examination.

The primary safety endpoint was the serious adverse event rate at 12 months. Serious adverse events were defined as events that were life-threatening, required surgery to correct, resulted in hospitalization or prolonged hospital stay, caused long-term disability, or resulted in genetic damage or birth defect. These included but were not limited to death, cerebral or pulmonary embolism, bacterial endocarditis, device embolization requiring surgery, and persistent cardiac arrhythmia requiring a pacemaker.

## B. Accountability of PMA Cohort

At the time of database lock, of 378 patients enrolled in the PMA study, 94.4% (357) patients are available for analysis. At 12 month- study completion, 83.1% (314) subjects were available.

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![img-3.jpeg](img-3.jpeg)
Figure 4. Patient Study Flow Diagram

# C. Study Population Demographics and Baseline Parameters

The mean age of the study patients was 4.26 years, mean weight was  $18.1\mathrm{Kg}$ . A total of  $68.1\%$  (243) of enrolled patients were female and  $31.9\%$  (114) were male. Tables 9-12 describe the characteristics and baseline parameters of patients in the study:

Table 9. Patient Age

|  Age (Years) | N (%)  |
| --- | --- |
|  < 2 | 126 (36.3%)  |
|  2 - 6 | 138 (39.8%)  |
|  6 - 12 | 62 (17.9%)  |

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Table 10. Patient Weight

|  Weight (Kg) | N (%) Tech Success  |
| --- | --- |
|  < 10 Kg | 76 (21.9%)  |
|  10 - 25 | 213 (61.4%)  |
|  25 - 50 | 41 (11.8%)  |
|  > 50 Kg | 17 (4.9%)  |

Table 11. Patient Body-Mass Index

|  BMI (kg/m2) | N (%) Tech Success  |
| --- | --- |
|  < 15.2 | 88 (25.4%)  |
|  15.2-16.5 | 89 (25.7%)  |
|  16.5-18.0 | 82 (23.6%)  |
|  > 18.0 | 87 (25.1%)  |

Table 12. Baseline Congenital Heart Disease

|  Other CHD | Occurrences  |
| --- | --- |
|  Atrial Septal Defect | 10  |
|  Ventricular Septal Defect | 15  |
|  Stenosis | 10  |
|  Patent Foramen Ovale | 5  |
|  Other | 8  |

Note: Some patients had more than one Other Congenital Heart Disease

Previous Cardiac Procedures:  $n = 6$  (1.7%)

- Atrioventricular Septal Defect repair

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- PDA ligation &amp; PA Band, PA Band tightening
- Balloon pulmonary valvuloplasty (n=2)
- PDA ligation (n=2)

Baseline physical examinations were performed on all patients. A systolic murmur was reported in 336 patients (96.8%). Eleven patients had no audible murmurs.

Baseline echocardiograms and color Doppler examinations were performed on all patients. A PDA with minimum diameter of the color flow stream less than 4.0 mm was noted in all patients.

## Angiographic Classification

In addition to hemodynamic and these dimensional characteristics, PDA were classified according to their configuration on the lateral angiogram using the Krichenko nomenclature illustrated below [1]:

![img-4.jpeg](img-4.jpeg)
Figure 5. Angiographic Classification of PDA on Lateral Aortogram

## D. Safety and Effectiveness Results

## D1. Safety and Effectiveness Results

The principal safety and effectiveness results are shown in Table 13.

- The 12 month clinical closure rate was 98.1% and the lower bound of the exact one-sided 95% confidence interval was 96.7%. Since this lower bound is greater than the established objective performance criteria of 95%, the objective performance criterion is considered to have been met.
- The 12-month echocardiographic closure rate was 96.8% and the lower bound of the exact one-sided 95% confidence interval was 95%. Since this lower bound is greater than the established objective performance criteria of 85%, the objective performance criterion is considered to have been met.
- The 12-month serious adverse event rate was 0% and the upper bound of the exact one-sided 95% confidence interval was 0.95%. Since this upper bound is less than the established objective performance criteria of 1%, the objective performance criterion is considered to have been met.

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Table 13. Principal Safety and Effectiveness Results

|   | OPC Rates | Nit-Occlud® Patients | Percent | 95% Lower Bound | 95% Upper Bound  |
| --- | --- | --- | --- | --- | --- |
|  Technical Success at Implantation | 95%² | 347/357 | 97.2% | 95.6% |   |
|  Clinical Closure at 12 Month Follow-up | 95%¹ | 308/314 | 98.1% | 96.7% |   |
|  Echocardiographic Closure at 12 Month Follow-Up | 85%¹ | 299/309 | 96.8% | 95.0% |   |
|  Mortality at 12 Months | 0%¹ | 0 | 0.0% |  | 0.95%  |
|  Serious Adverse Events at 12 Months | 1%¹ | 0 | 0% |  | 0.95%  |
|  Total Device and Procedure Related Adverse Events at 12 Months | 6% | 15/316* | 4.7% |  | 7.21%  |
|   |   |  14/316** | 4.4% |  | 6.84%  |
|  Composite Success at 12 Months | 80%³ | 294/309 | 95.1% | 93.0% |   |
|  ¹ Objective Performance Criteria (OPC) specified by the 1997 Circulatory System Devices Advisory Panel report [2] ² Inferred from technical success rate of Gianturco coil technical success cited in the 1997 Circulatory System Devices Advisory Panel report [2] ³ Defined in IDE protocol but not defined by the 1997 Circulatory System Devices Advisory Panel report * Numerator is number of events; denominator is number with 12 months follow-up + 2 with AE before 12 months ** Numerator is number of person; denominator is number with 12 months follow-up + 2 with AE before 12 months  |   |   |   |   |   |

Table 14 shows procedural and fluoroscopy times listed by device size and type.
Table 14. Procedure and Fluoroscopy Times by Nit-Occlud® Device

|  Catalog # | Device Size Distal x Proximal Diameter | Device Type | Number of Implants | Mean Procedure Duration [min.] | Median Procedure Duration [min.] | Mean Fluoroscopy Time [min.] | Median Fluoroscopy Time [min.]  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  145044 | 4 x 4 mm | Flex | 38 | 68.6 | 66.0 | 17.2 | 14.0  |
|  145054 | 5 x 4 mm | Flex | 27 | 77.8 | 72.0 | 19.6 | 17.0  |
|  145065 | 6 x 5 mm | Flex | 57 | 91.5 | 82.0 | 19.8 | 18.5  |
|  145076 | 7 x 6 mm | Medium | 110 | 83.3 | 73.5 | 17.0 | 15.0  |
|  145096 | 9 x 6 mm | Medium | 97 | 92.0 | 79.0 | 18.8 | 16.0  |
|  145116 | 11 x 6 mm | Medium | 26 | 93.0 | 85.0 | 25.5 | 23.5  |

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Differing Technical Failure Rates were observed based on Angiographic Classification of the PDA on the lateral aortogram and are summarized in the Table 15 below.

Table 15: Technical Failure rate by Angiographic Classification (See Figure 5)
|  Classification | N(% of Total) | Technical Failure Rate | n/N (%)  |
| --- | --- | --- | --- |
|  Conical (A) | 267 (74.8%) | 4/267 | (1.5%)  |
|  Short (B) | 17 (4.8%) | 3/17 | (17.6%)  |
|  Tubular (C) | 5 (1.4%) | 1/5 | (20%)  |
|  Complex (D) | 18 (5.0%) | 1/18 | (11.1%)  |
|  Elongated (E) | 50 (14.0%) | 1/50 | (2%)  |
|  TOTAL | 357 (100%) | 10/357 | (2.8%)  |

## Adverse effects that occurred in the PMA clinical study:

Study Adverse events were defined as follows:

Serious Adverse Events - Procedural or device related events which were life-threatening, required surgery to correct, resulted in hospitalization or prolonged hospital stay, caused long-term disability, or resulted in genetic damage or birth defect.

Major Adverse Events - Procedural or device related events which were not life-threatening, required interventional (catheter based) and /or medical treatment to correct up to one year follow-up evaluation but were resolved without surgical intervention.

Minor Adverse Events - Procedural or device related events which were not life-threatening, and were resolved without intervention or with a brief specific non-surgical intervention up to one year follow-up evaluation.

Observed adverse event experience with the Nit-Occlud® PDA is derived from the Sentinel study. Clinical events for this study are shown in Table 16 below.

Table 16. Adverse Events
|  DSMB Adjudication | Category | No of Events  |
| --- | --- | --- |
|  Major Device Related | Device embolization | 2  |
|   |  Device Retrieval/Removal | 2  |
|   |  Obstruction of descending aorta | 1  |
|  Minor Device Related | Possible Thrombus | 1  |
|  Major Procedure Related | Decreased Pulse in Right Foot | 1  |
|   |  Reaction to anesthesia | 2  |
|  Minor Procedure Related | Reaction to anesthesia | 1  |
|   |  Vascular access site complication | 1  |
|   |  Other Adverse Event | 2  |
|   |  Nausea | 1  |

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|  DSMB Adjudication | Category | No of Events  |
| --- | --- | --- |
|   | Fever | 1  |

# D2. Subgroup Analyses

# Gender Analysis

A post hoc evaluation of the Sentinel Study was conducted to identify possible sex-based differences in baseline characteristics and clinical outcomes. The Sentinel study was not designed nor powered to study safety and effectiveness differences between sexes, so this analysis is considered exploratory without definitive conclusions.

In the Sentinel study, 243/357 (68.1%) subjects were female and 114/357 (31.9%) were male. This is reflective of the imbalance of prevalence of persistent PDA in the patient population in the United States (i.e., the PDA population is greater in females compared to males).

With the inclusion of  $68.1\%$  female, the Sentinel study of the Nit-Occlud® PDA is representative of contemporary studies.

Table 17 shows baseline demographics and characteristics.
Table 17. Baseline demographics and characteristics by gender.

|   | Sex | n | min | median | mean | max | sd | sem | p value  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Stats for age in years | F | 212 | 0.52 | 3.30 | 4.37 | 19.59 | 3.90 | 0.27 | 0.27  |
|   |  M | 102 | 0.13 | 2.50 | 4.16 | 21.99 | 4.21 | 0.42 |   |
|  Stats for weight in kg | F | 212 | 5.2 | 14.45 | 18.26 | 65.5 | 12.44 | 0.85 | 0.54  |
|   |  M | 102 | 4.7 | 13.20 | 18.51 | 109.0 | 15.45 | 1.52 |   |
|  Stats for bmi in kg/m2 | F | 211 | 10.63 | 16.33 | 17.34 | 114.78 | 7.42 | 0.51 | 0.21  |
|   |  M | 102 | 7.34 | 16.92 | 17.29 | 32.20 | 3.70 | 0.37 |   |
|  Stats for D1 in mm | F | 212 | 0.5 | 1.9 | 1.95 | 3.9 | 0.74 | 0.05 | 0.09  |
|   |  M | 102 | 0.5 | 1.7 | 1.76 | 3.6 | 0.68 | 0.07 |   |
|  Stats for Qp/Qs | F | 211 | 0.81 | 1.3 | 1.42 | 3.4 | 0.42 | 0.029 | 0.20  |
|   |  M | 102 | 0.00 | 1.3 | 1.36 | 3.5 | 0.41 | 0.04 |   |
|  F = Female |   |   |   |   | SD = Standard Deviation  |   |   |   |   |
|  M = Male |   |   |   |   | Sem = Standard Error  |   |   |   |   |
|  N = Study Population |   |   |   |   | p-value =  |   |   |   |   |
|  Min = Minimum value |   |   |   |   | kg = Kilograms  |   |   |   |   |
|  Median = Middle value |   |   |   |   | bmi = Body mass index  |   |   |   |   |
|  Mean = Average value |   |   |   |   | D1 = PDA at Narrowest Diameter  |   |   |   |   |
|  Max = Maximum value |   |   |   |   | Qp/Qs = Ratio of pulmonary flow (Qp) to Systemic flow (Qs)  |   |   |   |   |

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In the post-hoc analysis conducted, no statistically significant differences by gender were found in the outcomes or the five covariates (age, weight, body mass index, PDA diameter and pulmonary-systemic flow ratio [Qp/Qs]).

Table 18 below shows safety and effectiveness results by gender.

Table 18. Safety and Effectiveness Results by Gender.

| Frequency
Row Percent | Sex | No | Yes | Total | Fisher p value |
| --- | --- | --- | --- | --- | --- |
| Technical Success by Gender | Female | 8
3.29 | 235
96.71 | 243 |  |
| Male | 2
1.75 | 112
98.25 | 114 |  |
| Total | 10 | 347 | 357 | 0.5121 |
| Clinical Closure at 12 months by Gender | Female | 5
2.36 | 207
97.64 | 212 |  |
| Male | 1
0.98 | 101
99.02 | 102 |  |
| Total | 6 | 308 | 314 | 0.6679 |
| Echo Closure (no leak) at 12 months by Gender^{1} | Female | 8
3.83 | 201
96.17 | 209 |  |
| Male | 2
2.00 | 98
98.00 | 100 |  |
| Total | 10 | 299 | 309 | 0.5089 |
| Composite Success at 12 months by Gender^{1} | Female | 12
5.74 | 197
94.26 | 209 |  |
| Male | 3
3.00 | 97
97.00 | 100 |  |
| Total | 15 | 294 | 309 | 0.4012 |
| Number of Device & Procedure Adverse Events by Gender | Frequency
Row Pct | 0 | 1 | 2 | Total |
| Female | 232
95.47 | 11
4.53 | 0
0.00 | 243 |
| Male | 111
97.37 | 2
1.75 | 1
0.88 | 114 |
| Total | 343 | 13 | 1 | 357 | 0.1497 |
| ^{1} Frequency Missing = 5 |

## E. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included 14 investigators of which none were full-time or part-time employees of the sponsor and two had disclosable financial interests/arrangements as defined in 21 CFR 54.2(a), (b), (c) and (f) and described below:

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- Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: none
- Significant payment of other sorts: two investigators
- Proprietary interest in the product tested held by the investigator: none
- Significant equity interest held by investigator in sponsor of covered study: none

The applicant has adequately disclosed the financial interest/arrangements with clinical investigators. Statistical analyses were conducted by FDA to determine whether the financial interests/arrangements had any impact on the clinical study outcome. The information provided does not raise any questions about the reliability of the data.

## XI. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION

In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Circulatory System Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.

## XII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES

The safety and effectiveness of the Nit-Occlud® PDA are based on the results obtained from: evaluation of biocompatibility; in vitro engineering testing; in vivo animal testing; sterilization information; shelf life testing; and clinical studies. These studies revealed the following:

### A. Effectiveness Conclusions

The results of the Sentinel study demonstrated that the primary endpoint of clinical closure at 12 months was 98.1% and the lower bound of the exact one-sided 95% confidence interval was 96.7%. Since this lower bound is greater than the established objective performance criteria of 95%, the objective performance criterion is considered to have been met. In addition, the primary endpoint of echocardiographic closure at 12 months was 96.8% and the lower bound of the exact one-sided 95% confidence interval was 95%. Since this lower bound is greater than the established objective performance criteria of 85%, the objective performance criterion is considered to have been met.

### B. Safety Conclusions

The biocompatibility testing and in vivo animal testing conducted on the Nit-Occlud® PDA demonstrate that the performance characteristics of the product provide reasonable assurance of safety and acceptability for clinical use.

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The in vitro engineering testing conducted on the occluder and delivery system demonstrated that the performance characteristics met the product specifications. The test results obtained from the sterilization testing demonstrated that the product can be adequately sterilized and is acceptable for clinical use. The functional shelf life and package integrity testing demonstrated that the product can be labeled with a shelf life of 3 years.

The results of the Sentinel study demonstrated the safety of the Nit-Occlud® PDA through evaluation of the safety endpoint of serious adverse events (including but were not limited to death, cerebral or pulmonary embolism, bacterial endocarditis, device embolization requiring surgery, and persistent cardiac arrhythmia requiring a pacemaker) within 12 months of the treatment.

## C. Benefit-Risk Conclusions

The probable benefits of the device are based on data collected in a clinical study conducted to support PMA approval as described above. The benefits of the Nit-Occlud® PDA include clinical and echocardiographic closure of PDA, curative closure for PDA and avoidance of an open surgical procedure.

The probable risks of the Nit-Occlud® PDA include procedure related risks such as device embolization, malposition, risk of anesthesia, access site complications, and thrombus, for which the total incidence is less than 5%.

In conclusion, given the available information above, the data support that for percutaneous, transcatheter closure of small to moderate size patent ductus arteriosus with a minimum angiographic diameter less than 4 mm, the probable benefits outweigh the probable risks.

## D. Overall Conclusions

The clinical and preclinical testing conducted demonstrated that the Nit-Occlud® PDA provides a reasonable assurance of safety and effectiveness when used as indicated in accordance with the instructions for use.

## XIII. CDRH DECISION

CDRH issued an approval order on August 16, 2013. The final conditions of approval cited in the approval order are described below.

The Nit-Occlud PDA Post-Approval Study: The study must be conducted as per agreed protocol received on July 25, 2013. The study will consist of a newly enrolled, prospective, single-arm, multi-center trial of patients treated with Nit-Occlud PDA, and followed for 5-years post-procedure.

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The primary safety objective is to demonstrate that the 5-year serious adverse event rate for the device is no worse than the Objective Performance Criterion (OPC) of 1%.

The primary effectiveness objective is to demonstrate that the 5-year complete closure rate for the device is no worse than the OPC of 85%. The closure of the ductus arteriosus will be assessed by absence of residual flow at 5 years by transthoracic echocardiograph.

The secondary safety objective is to demonstrate that the rate of adverse events reported through 5 years post procedure is no worse than 6% (OPC rate of 3% plus an added 3% margin).

The secondary effectiveness is to demonstrate that echocardiographic closure at 12 and 36 months is no worse than an OPC of 85%.

A total of 215 patients will be enrolled to ensure 150 patients treated with the Nit-Occlud PDA per device labeling will be available at 5 years post-procedure. Clinical exams will be conducted at 2, 12, 24, 36, 48, and 60 months and an echocardiography will be conducted at 2, 12, 36, and 60 months.

The applicant's manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).

## XIV. APPROVAL SPECIFICATIONS

Directions for use: See device labeling.

Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling.

Post-approval Requirements and Restrictions: See approval order.

## XV. REFERENCES

1. Krichenko A et al. Angiographic Classification of the Isolated, Persistently Patent Ductus Arteriosus and Implications for Percutaneous Catheter Occlusion. Am J Cardiol 1989; 63:877-880.)
2. Multiorganization Advisory Panel to FDA for Pediatric Cardiovascular Devices, Proposed Standards for Clinical Evaluation of Patent Ductus Arteriosus Occlusion Devices. Cath Cardiovasc Interv 2000;51:293-296.

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