← Product Code MRA · P150030

# R3 DELTA CERAMIC HIP SYSTEM (P150030)

_Smith & Nephew, Inc. · MRA · Oct 17, 2016 · Orthopedic · APWD_

**Canonical URL:** https://fda.innolitics.com/device/P150030

## Device Facts

- **Applicant:** Smith & Nephew, Inc.
- **Product Code:** MRA
- **Decision Date:** Oct 17, 2016
- **Decision:** APWD
- **Device Class:** Class 3
- **Review Panel:** Orthopedic
- **Attributes:** Therapeutic

## Intended Use

The R3 delta Ceramic Acetabular System is indicated for use in skeletally mature patients requiring primary total hip arthroplasty due to non-inflammatory arthritis (degenerative joint disease) such as osteoarthritis, avascular necrosis, or traumatic arthritis.

## Device Story

The R3 delta Ceramic Acetabular System is a total hip prosthesis consisting of a ceramic-on-ceramic bearing couple (zirconia toughened alumina) and a metal acetabular shell, used with compatible femoral stems. The device is implanted by orthopedic surgeons in a clinical/hospital setting. It replaces the natural hip joint to address non-inflammatory arthritis. The system utilizes a mechanical taper-lock mechanism to secure the ceramic liner into the metal shell. The device provides a stable, low-wear bearing surface intended to improve patient hip function, reduce pain, and restore range of motion. Clinical outcomes are assessed by surgeons using standardized scores (mHHS, WOMAC, UCLA) and radiographic evaluation to monitor for loosening, subsidence, or component failure. The system benefits patients by providing a durable alternative to traditional bearing surfaces, potentially reducing the need for revision surgery.

## Clinical Evidence

Prospective, consecutive, concurrently controlled, non-randomized, multi-center study (European Post-Market Study) of 268 subjects (137 DOD, 131 OxZr/XLPE control). Primary endpoint: 3-year clinical composite success (implant survivorship, mHHS >= 80, radiographic success). Results: 86.4% DOD vs 80.2% OxZr/XLPE success rate (non-inferiority p=0.0004). Survivorship: 99.3% DOD vs 94.7% OxZr/XLPE at 3 years. Radiographic failure: 4 DOD vs 9 OxZr/XLPE subjects. Mean mHHS improved significantly in both groups; WOMAC and UCLA scores were comparable.

## Technological Characteristics

Bearing surfaces: Zirconia toughened alumina (BIOLOX delta). Acetabular shell: Ti-6Al-4V (ASTM F1472/ISO 5832-3) with sintered CP-titanium porous coating (ASTM F67/ISO 5832-2). Femoral stems: Ti-6Al-4V or Ti-6Al-7Nb (ASTM F1472/F1295). Locking mechanism: Titanium band (ASTM F1472). Sterilization: Gamma radiation (min 25 kGy, SAL 10^-6). Packaging: PETG trays with Tyvek lids.

## Reference Devices

- REFLECTION ceramic couples
- BIOLOX forte ceramic-on-ceramic
- Oxidized zirconium-on-XLPE (OxZr/XLPE)
- metal-on-XLPE (MoXLPE)
- metal-on-metal (MoM)

## Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Prosthesis, Total Hip System, Semi-constrained, Metal/Ceramic/Ceramic/Metal, Cemented or Uncemented

Device Trade Name: R3™ delta Ceramic Acetabular System

Device Procode: MRA

Applicant’s Name and Address: Smith & Nephew, Inc.
Advanced Surgical Devices Division
7135 Goodlett Farms Parkway
Cordova, TN 38016 U.S.A.

Date of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P150030

Date of FDA Notice of Approval: 10/17/2016

II. INDICATIONS FOR USE

The R3 delta Ceramic Acetabular System is indicated for use in skeletally mature patients requiring primary total hip arthroplasty due to non-inflammatory arthritis (degenerative joint disease) such as osteoarthritis, avascular necrosis, or traumatic arthritis.

III. CONTRAINDICATIONS

The R3 delta Ceramic Acetabular System is contraindicated in individuals exhibiting any of the following:

- Insufficient quantity or quality of bone support; metabolic bone disease; osteoporosis
- Neurological or muscular conditions that would place an extreme load upon the hip joint or cause joint instability
- Active joint infections or chronic systemic infection
- Obese patients where obesity is defined as a BMI > 40
- Skeletal immaturity
- Known allergy to any of the implant materials

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## IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the R3 delta Ceramic Acetabular System labeling.

## V. DEVICE DESCRIPTION

The R3 delta Ceramic Acetabular System consists of a ceramic on ceramic acetabular bearing couple combined with a compatible metal shell and one of four commercially available Smith & Nephew femoral stems. All implantable devices are supplied sterile and are for single use.

The bearing surfaces consist of zirconia toughened alumina ceramic acetabular liners and zirconia toughened alumina ceramic femoral heads; both are manufactured from BIOLOX® delta Zirconia Toughened Aluminum Oxide.

### R3 delta Acetabular Liner

The ceramic acetabular liners feature a pre-assembled titanium band (ASTM F1472 and ISO 5832-3) and the male taper of the titanium band is designed for mechanical assembly to the internal female taper of the mating acetabular shell. The ceramic liners are available in ten sizes with two internal diameters, i.e., 32mm and 36mm. The 32mm liners are offered with two outer diameters of 48mm and 50mm, and the 36mm liners are offered with eight outer diameters of 48-66mm in 2mm increments.

### Femoral Head

The ceramic ball heads are available in two diameter sizes: 32mm and 36mm. Each diameter head size has three different neck lengths, short (+0), medium (+4), and long (+8) for proper anatomic and musculature fit. All ball heads have an internal bore with an angle designed for conformity with the 12/14 cone taper of the femoral stems.

### R3 Acetabular Shell and Ancillary Components

The R3 delta Ceramic Liners are intended to be used in conjunction with Smith & Nephew's R3 Acetabular Shells for cementless use. The R3 acetabular shells are manufactured from Ti-6Al-4V (ASTM F1472 and ISO5832-3). The outer shell geometry is hemispherical and has a sintered asymmetric porous coating from commercially pure titanium (ASTM F67 and ISO5832-2). The interior of the R3 Acetabular Shell features a female taper which is designed for mechanical assembly to the male taper of the outer titanium band of the mating R3 delta Ceramic Liner. There are eleven sizes of acetabular shells available, ranging from 48mm through 68mm outer diameter in 2mm increments. Each shell features an apex hole to accept the cup positioner / impactor instruments. Shells have either no screw holes or three screw holes arranged about the apex hole. These holes are for optional, adjunctive screw fixation to the superior acetabulum with Spherical Head Screws, which have a diameter of 6.35mm and lengths of 15-70mm. Hole covers are available to cover the shell holes if desired. Screws and hole covers are manufactured from Ti-6Al-4V ELI (ASTM F136).

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# Femoral Stems

The ceramic femoral heads of the R3 delta Ceramic Acetabular System are intended to be used in conjunction with one of the following four, legally marketed femoral stems from Smith & Nephew (all featuring a 12/14 Taper):

- Titanium alloy (Ti-6Al-4V per ASTM F1472), cementless SYNERGY™ femoral stems (Standard and High Offset versions),
- Titanium alloy (Ti-6Al-4V per ASTM F1472), cementless POLARSTEM™ femoral stems (Standard and Lateral versions) *,
- Titanium alloy (Ti-6Al-7Nb per ASTM F1295), cementless SL-PLUS™ femoral stems (Standard and Lateral versions),
- Titanium alloy (Ti-6Al-4V per ASTM F1472), cementless ANTHOLOGY™ femoral stems (Standard and High Offset versions),

The SYNERGY and ANTHOLOGY stems have a sintered, beaded porous coating made from commercially pure titanium (ASTM F67) on the proximal surface. The POLARSTEM femoral stems have a plasma sprayed titanium and hydroxyapatite (Ti/HA) dual coating on the surface*.

* Note that the POLARSTEM stems legally marketed in the US have identical materials, design, dimensions, and sizes, as well as a similar coating thickness as the POLARSTEM stems used in the clinical trial (not available in the US) except that they were coated by Smith & Nephew while the POLARSTEM stems used in the clinical trial were coated by a supplier; see Section IX Summary of Nonclinical Studies for safety and effectiveness justification.

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

There are several other alternative treatments of non-inflammatory arthritis of the hip including:

- The use of other commercially available total hip replacement implants which may include alternative bearing surfaces;
- Non-surgical treatment such as reduced activity, weight loss, physical therapy, and/or pain medication; and
- Other surgical treatments that do not involve the use of an implant, such as hip joint fusion.

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 the patient's expectations and lifestyle.

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# VII. MARKETING HISTORY

The R3 delta Ceramic Acetabular System has been commercially available outside the United States (OUS) since 2008 with use in Australia, Austria, Belgium, Canada, China, Finland, Germany, Hong Kong, Italy, Japan, the Middle East, Netherlands, New Zealand, Norway, Poland, Portugal, South Africa, South Korea, Spain, Switzerland, and the United Kingdom. The product has not been withdrawn from any market due to safety and effectiveness reasons.

# 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.

## Potential Complications Associated with Any Total Hip Arthroplasty surgery

- Excessive wear of the implant components secondary to impingement of components or damage of articular surfaces
- Fracture, migration, loosening, subluxation, or dislocation of the prosthesis or any of its components; any of which may require a second surgical intervention or revision;
- Increased hip pain and/or reduced hip function
- Bone fractures
- Osteolysis and/or other peri-prosthetic bone loss
- Metal sensitivity reactions or other allergic/histological reactions to implant material
- Vascular damage resulting in significant blood loss, or
- Neurologic injury resulting in transient or permanent functional and/or sensory deficits
- Leg length change/discrepancy
- Deep venous thrombosis
- Pulmonary or vascular embolism
- Superficial or deep infection, delayed wound healing
- Periarticular calcification
- Myocardial infarction
- Gastrointestinal complications
- Genitourinary complications
- Decreased range of motion
- Aggravation of other joint or back conditions (due to positioning during surgery, postoperative leg length discrepancy, muscular deficiencies, etc.)
- Death

## Potential Complications Associated with Ceramic on Ceramic Hip Systems

Due to the materials of the device, these may include, but are not limited to, femoral head breakage, acetabular insert (liner) fracture, and device related noise such as

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squeaking. Other adverse events, common to other hip systems may also occur but at different frequencies.

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

## IX. SUMMARY OF NONCLINICAL STUDIES

### A. Laboratory Studies

A battery of preclinical laboratory tests were conducted on the alumina composite matrix ceramic material used to manufacture the ceramic components. The metal components that comprise the rest of this system are made from materials that have been used for many years in total hip replacement (THR) surgery.

Non-clinical laboratory testing was provided in support of the R3 delta Ceramic Acetabular System including:

- Acetabular Shell-Liner Locking Mechanism Testing (push-out, lever-out, and torque to failure)
- Pre-fatigue Burst Testing of Acetabular Liner
- Pre- and Post-fatigue Burst Testing of Femoral Head and Acetabular Liner after Hydrothermal Aging
- Pre- and Post-Fatigue Burst Testing of Femoral Head
- Hip Simulator Wear Testing (pristine conditions, third-body (abrasive) conditions, and subluxation conditions)
- Stress Induced Zirconia Phase Transformation Testing
- Impact Load Testing
- Porous Coating Testing
- Ti/HA Dual Coating Testing
- Range of Motion (ROM) Analysis

|  Test | Purpose and Methods | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|  Acetabular Shell-Liner Locking Mechanism Testing (push-out, lever-out, and torque to failure) | The purpose of this test was to evaluate the locking mechanism of the BIOLOX® delta liners in the R3 shells.
Push-out, lever-out, and torque to failure testing was performed using 32mm ID BIOLOX® delta liners in 48mm OD R3 shells which represents the worst-case (the | Push-out: The push-out loads were greater or comparable to previously tested metal/UHMWPE constructs of legally marketed devices.
Lever-out: The lever-out moments | Push-out: The average (± std. dev.) push-out load of six R3 delta liners from R3 shells was 1006±384 N.
Push-out loads of the R3 delta liners did not display a statistically significant difference compared to previously tested metal/UHMWPE  |

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|  Test | Purpose and Methods | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|   | smallest and thinnest liner and the least liner-shell contact area). Shell and liner constructs were assembled using the drop weight assembly method in ASTM F2009-00 (2011) using 3 impacts. Testing was performed per ASTM F1820-13 and a total of six shell-liner constructs were tested for each test. | were greater or comparable to previously tested metal/ Ultra-high-molecular-weight polyethylene (UHMWPE) constructs of legally marketed devices.

**Torque to Failure:** The acceptance criterion required the torque-to-failure moment to exceed the reported 2.4 N-m torque due to friction at the ball-liner interface [1] by a safety factor of five (e.g., 12 N-m). | constructs used for comparison.

**Lever-out:** The average (± std. dev.) lever-out moment of six R3 delta liners from R3 shells was 14.4±6.2 N-m. Lever-out moments of R3 delta ceramic liners did not display a statistically significant difference compared to the lever-out moments of previously tested metal/UHMWPE constructs used for comparison.

**Torque to Failure:** The average (± std. dev.) torque-to-failure moment of six R3 delta liners from R3 shells was 12.6±3.8 N-m. Torque-to-failure moments of R3 delta ceramic liners met the acceptance criterion.  |
|  Pre-fatigue Burst Testing of Acetabular Liner | The purpose of this test was to determine the axial compressive burst strength of the R3 delta ceramic acetabular liners through mechanical testing.

The testing was conducted using the method specified in the FDA “Guidance Document for the Preparation of Premarket Notifications for Ceramic Ball Head System” [*]. Seven 32/39G | The acceptance criteria were an average burst strength exceeding an average failure load of 46 kN, with no component failing at less than 20 kN. | The average (± std. dev.) burst load of the seven R3 delta ceramic acetabular liners was 101 kN±12 kN and the minimum burst load was 87.0 kN.

Burst strengths of R3 delta ceramic acetabular liners met the acceptance criteria.  |

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|  Test | Purpose and Methods | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|   | BIOLOX® delta liners in combination with R3 shells were tested, which represents the worst case. |  |   |
|  Pre- and Post-fatigue Burst Testing of Femoral Head and Acetabular Liner after Hydrothermal Aging | The purpose of this study was to determine the pre- and post-fatigue static burst strength of R3 delta 32mm ceramic liners and heads after autoclaving.
Twelve couples of R3 delta heads and liners were autoclaved for 10 cycles with a cumulative exposure time of 20 hours to simulate hydrothermal aging and resultant phase transformation of yttria-stabilized zirconia in the matrix of delta liners and heads. Six couples were burst tested using the method specified in the FDA “Guidance Document for the Preparation of Premarket Notifications for Ceramic Ball Head System” [*]. The other six couples were fatigue tested using a compressive load of 1.4/14 kN at 15 Hz and subsequently burst tested. | Pre-fatigue Burst Strength: The acceptance criteria were an average burst strength exceeding an average failure load of 46 kN, with no component failing at less than 20 kN.
Post-fatigue Burst Strength: The acceptance criteria required the couples to pass 10 million cycles at 14kN with no macroscopically visible component failure and have no post-fatigue burst strength below 20 kN. | Pre-fatigue Burst Strength: The couples had an average (± std. dev.) pre-fatigue burst strength of 94.2±17.9 kN with a minimum pre-fatigue burst strength of 69.6 kN.
Post-fatigue Burst Strength: All six couples completed 10 million cycles of fatigue without failure. The couple had an average (± std. dev.) post-fatigue burst strength of 111.6±10.2 kN with a minimum post-fatigue burst strength of 100.4 kN.
All test results met the acceptance criteria.  |
|  Pre- and Post-Fatigue Burst Testing of Femoral Head | The purpose of this test was to determine the axial compressive burst strength of the delta ceramic femoral heads before and after fatigue testing.
Axial compressive burst strength testing was conducted on five 28mm | Pre-fatigue Burst Strength: The acceptance criteria were an average burst strength exceeding an average failure load of 46 kN, with no component failing at less than 20 kN. | Pre-fatigue Burst Strength: The average burst load of the five BIOLOX® delta Ceramic femoral heads was 57.5 kN (minimum burst load of 41.4 kN).
Post-fatigue Burst Strength: All three  |

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|  Test | Purpose and Methods | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|   | long (+8) BIOLOX® delta ceramic on 12/14 taper cobalt chrome (CoCr) trunnions using the method specified in the FDA “Guidance Document for the Preparation of Premarket Notifications for Ceramic Ball Head System” [*] . The test construct of a 28mm long (+8) femoral head on a CoCr trunnion was chosen because it represents worst case; the tapers were manufactured from CoCrMo which has the highest elastic modulus of any Smith & Nephew hip stem material and therefore transfers the greatest stress to the femoral head. A total of three 28 mm +8 mm offset (Long) femoral heads were fatigue tested and subsequently burst-tested. | Post-fatigue Burst Strength: The acceptance criteria required the ceramic head to pass 10 million cycles at 14kN with no macroscopically visible component failure and have no post-fatigue burst strength below 20 kN. | constructs completed 10 million cycles of fatigue at a maximum load of 14 kN without failure, and had an average post-fatigue burst load of 66.6 kN (minimum post-fatigue burst load of 64 kN). All testing results met the acceptance criteria.  |
|  Femoral Head Pull-off testing | The purpose of this study was to determine the static pull-off strength of BIOLOX® delta ceramic femoral heads on trunnions with 12/14 tapers. Six 32mm +8mm femoral heads were impacted onto Ti-6Al-4V and Ti-6Al-7Nb trunnions, respectively using the drop weight method described in ASTM F2009-00(2011), which utilizes a 2.0 lbf (907 g) weight dropped from 10 in. (25.4 cm) height. Each head was impacted 3 times per trunnion. Pull-off | The pull-off loads were greater or comparable to CoCrMo heads on CoCrMo tapers used on legally marketed devices. | The average pull-off load for six (6) BIOLOX® delta femoral heads was 3,602±366 N and 3,275±428 N for the Ti-6Al-4V trunnions and Ti-6Al-7Nb trunnions, respectively. Pull-off loads for delta heads on Ti-6Al-4V and Ti-6Al-7Nb trunnions were 49% and 35% higher when compared to 32 mm +8 mm offset 12/14 taper CoCrMo heads on CoCrMo tapers used  |
|   | on Ti-6Al-4V and Ti-6Al-7Nb trunnions, respectively. |  |   |

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|  Test | Purpose and Methods | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|   | testing was performed, and the maximum pull-off load was recorded. |  | for comparison.  |
|  Hip Simulator Wear testing – Benign (Pristine) Conditions | The purpose of this testing was to determine the wear and durability characteristics of the R3 delta device under standard ‘pristine’ conditions.Three (3) R3 delta liners (32/48mm) and 32mm delta heads were subjected to 5.0 million cycles (Mc) of hip joint simulation as per ISO 14242-1 using an AMTI machine. Tests were performed in bovine serum (20 g/L) at 1 Hz, with a peak load of 3.0 kN, and a cup inclination of 35°. Wear was measured gravimetrically.The wear results were compared to alumina (BIOLOX® forte) couples tested previously under similar conditions.Wear particles were collected and analysis as per ASTM F1877-05. | Test was performed for characterization only. | The average wear rate for the R3 delta specimens to 5.0 Mc was 0.08 ± 0.05 mm3/Mc. The weighted average wear particle size under pristine testing was 0.2 micron. The wear behavior and surface features were comparable to that of alumina (BIOLOX® forte) couples tested previously.These results demonstrated that the ceramic-on-ceramic articulation surfaces used for the R3 delta system produced no significant wear after 5.0 Mc of pristine wear testing.  |
|  Hip Simulator Wear Testing with titanium transfer on Biolox delta heads– Third-Body (Abrasive) Conditions | The purpose of this testing was to determine the wear and durability characteristics of the R3 delta device under abrasive conditions simulating titanium contamination.Six R3 delta couples (32mm) were subjected to 3.0 Mc of hip simulation. The delta | Lower volumetric wear rates compared to the control MoM bearing couples. | Under third-body abrasive conditions, the average wear rate for the R3 delta couples remained low at 0.02 ± 0.01 mm3/Mc. In contrast, the control MoM couples produced a wear rate of ~45 mm3/Mc. All ceramic surfaces  |

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|  Test | Purpose and Methods | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|   | heads were purposely (heavily) smeared with titanium, covering the entire articular surfaces. All other experimental methods were identical as described above (as per ISO 14242-1).These results were compared to metal-on-metal (MoM) couples (n=2) tested under similar conditions.Wear particles were collected and analyzed as per ASTM F1877-05. |  | appeared visually unaltered after testing, although there were areas of grain-pullout observed. This grain-pullout was less extensive than that observed under subluxation conditions. The weighted average wear particle size under third-body abrasive testing was 0.09 micron.These results demonstrated that the R3 delta system produced no significant wear after 3.0 Mc of third-body wear testing.  |
|  Hip Simulator Wear Testing – Bone cement Third-Body (Abrasive) Conditions | To determine the wear and durability characteristics of the R3 delta device under abrasive conditions simulating bone cement contamination.Three R3 delta specimens (32mm) were subjected to 2.0 Mc of hip simulation (AMTI) using a bovine serum lubricant that was contaminated with 10 g/L of Versabond™ bone cement powder (PMMA).All other experimental methods were identical as described above (as per ISO 14242-1). This test was carried out after the pristine (benign) wear testing using the same couples. | Test was performed for characterization only. | The average wear rate for the R3 delta specimens under bone cement contamination was -0.01±0.02 mm3/Mc. Overall, this adverse wear test using PMMA powder was unable to cause increases in wear rates or cause notable damage for ceramic-on-ceramic couples.These results demonstrated that the R3 delta system produced no significant wear after 2.0 Mc of bone cement third-body wear testing.  |

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|  Test | Purpose and Methods | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|   | No control couples were tested. No wear particle analysis was performed. |  |   |
|  Hip Simulator Wear Testing – Subluxation (Micro-separation) Conditions | To determine the wear and durability characteristics of the R3 delta device under repeated subluxation events, commonly known as micro-separation (MSX) testing.

Three R3 delta specimens (32mm) were subjected to 3.0 Mc of MSX hip simulations that introduced 1.0 mm of joint separation (subluxation) during the swing phase of loading. This subluxation method was developed to produce stripe wear and grain-pullout on alumina implants. All other experimental methods were identical as described above (as per ISO 14242-1). The bovine serum lubricant did not contain PMMA or titanium particles. This test was carried out after the bone cement abrasive phase described above using the same couples.

The wear results were compared to alumina (BIOLOX® forte) couples tested previously under similar methods.

Wear particles were collected and analysis as per ASTM F1877-05. | The volumetric wear rates were lower or comparable to the control BIOLOX® forte couples. | Under subluxation conditions (MSX), the average wear rate for the R3 ZTA-Delta couples remained low at 0.28 ± 0.06 mm3/Mc. Subluxation created stripe features, characterized by inter-granular fracture and grain-pullout, on heads and liners. The wear behavior and surface features were comparable to that of alumina (BIOLOX® forte) couples tested previously. The weighted average wear particle size under subluxation testing was 0.16 micron.

These results demonstrated that the R3 delta system produced no significant wear after 3.0 Mc of subluxation wear testing.  |

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|  Test | Purpose and Methods | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|  Stress Induced Zirconia Phase Transformation Testing | The purpose of this analysis was to measure the monoclinic zirconia phase content after micro separation hip simulator wear testing.Samples analyzed were tested on the hip simulator for 10 million cycles, 3 million of which were under subluxation conditions.Monoclinic phase content was measured on the area of severe contact and a polished reference area utilizing X-ray diffraction. | Acceptance criterion is based on comparable investigation report that monoclinic content after very severe conditions can be increased to values up to ~50% without loss of residual strength. | The monoclinic content on the femoral head increased from 6% of the total zirconia phase content on the reference area to 12% on the severe wear area. The monoclinic content on the acetabular liner increased from 6% on the reference area to 7% on the severe wear area.The small amount of phase transformation from tetragonal to monoclinic in the delta ceramic should not deteriorate the long-term safety of these devices.  |
|  Impact Load Testing | The purpose of this test was to evaluate the impact strength of R3 delta ceramic liner and head couples.Acetabular shells were assembled by cementing them into wood blocks, and ceramic liners (32 mm ID, 48 mm OD R3 delta Ceramic Acetabular Liners, BIOLOX® delta) were assembled into the shells using the drop weight method in ASTM F2009-00(2011) which specifies a 2.0 lbf (907 g) drop weight and a drop height of 10.0 inches (25.4 cm). Ceramic femoral heads (32 mm +8, 12/14 taper BIOLOX® delta femoral | The acceptance load of 900 lbf (4 kN) was specified based on in vivo loading [2]. The impact loads were greater or comparable to REFLECTION™ ceramic couples. | Six delta ceramic couples completed one million cycles of impact loading at 8,000 lbf (35.6 kN).This impact load represents approximately 8.9 times the acceptance loads. This load is also greater than the run-out load of REFLECTION ceramic couples.  |

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|  Test | Purpose and Methods | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|   | heads) were assembled onto the stem taper using the drop weight method. Components were placed in a computer-controlled test frame and impact tested for 1 million cycles using 0.5 mm of separation and an impact force of 8,000 lbf (35.6 kN) (impact ramp time is 0.25 s).The approved REFLECTION ceramic couples were tested under identical conditions as control. |  |   |
|  Porous Coating Testing | The purpose of this testing was to characterize the STIKTITE™ porous coating of the R3 Acetabular Shells.Metallurgical, microstructural and mechanical characterization testing of the porous coating was provided in accordance with the FDA's “Guidance Document for Testing Orthopedic Implants with Modified Metallic Surfaces Apposing Bone or Bone Cement”, dated 4/28/94 [**]. | In accordance with Guidance document [**] and standards. | Smith & Nephew presented all testing in accordance with the Guidance document.The STIKTITE porous coating is sintered from asymmetric CP-titanium particles (ASTM F67) and has an average coating thickness of 941.3 μm, an average mean void intercept length of 148.8 μm or 144.5 μm (at two different thickness levels), an average volume percent of voids of 56.8%, an average static tensile strength of 48.2 MPa, and an average static shear strength of 38.4 MPa.The testing results met the requirements in Guidance document and standards.  |

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|  Test | Purpose and Methods | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|  |   |   |   |
|  Ti/HA Dual Coating Testing | The purpose of this testing was to characterize the plasma sprayed titanium and hydroxyapatite (Ti/HA) dual coating on the POLARSTEM stems with regard to chemical / crystallographic, physical and mechanical requirements in accordance with the FDA's “Guidance Document for Testing Orthopedic Implants with Modified Metallic Surfaces Apposing Bone or Bone Cement”, dated 4/28/94 [**], and “510(K) Information Needed for Hydroxyapatite Coated Orthopedic Implants” dated March 10, 1995 (revised 2/20/97) [**].Testing to characterize both the Ti/HA coating applied by the supplier on the POLARSTEM stems used in the clinical study and the Ti/HA coating applied by Smith & Nephew on the POLARSTEM stems cleared by the FDA was presented in order to demonstrate that the difference in coating supplier does not impact the safety and performance of the POLARSTEM stems. | The acceptance criteria are in accordance with the Guidance documents [**], and the voluntary consensus standards. | The testing results met the requirements in Guidance documents and standards.It can be concluded from the coating testing data as well as the stem testing referenced or provided in this PMA (i.e., fatigue testing, pull-off testing, and range of motion analysis) that the minor difference in characteristics of the Ti-HA coatings on the POLARSTEM stems will not impact the safety and performance of the POLARSTEM stems and the R3 delta Ceramic Acetabular System.  |
|  Range of Motion (ROM) Analysis | The purpose of this analysis was to evaluate the range of motion of the R3 delta Ceramic Acetabular System. A computer aided design | The acceptance criteria were specified per ISO 21535:2007(E) and the minimum values for each | The minimum values for each motion obtained across all combinations analyzed are (per each of the four stems):  |

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|  Test | Purpose and Methods | Acceptance Criteria | Results  |
| --- | --- | --- | --- |
|   | (CAD) analysis was performed in accordance with ISO 21535:2007(E) to evaluate the range of motion of the worst case constructs including R3 acetabular shell, R3 delta liner, delta head, and each of the four femoral stems intended for use with the R3 delta Ceramic Acetabular System. | motion are: 100° in flexion/extension (Delta); 60° in abduction/adduction (Epsilon); and 90° in internal/external rotation (Gamma). | SYNERGY: 148° (Delta)/ 134° (Epsilon)/222° (Gamma)
POLARSTEM: 140° (Delta)/ 130° (Epsilon)/220° (Gamma)
SL-PLUS: 142° (Delta)/ 112° (Epsilon)/170° (Gamma)
ANTHOLOGY: 148° (Delta)/ 132° (Epsilon)/220° (Gamma)
All ROM results exceeded the minimum criteria.  |

*Guidance Document for the Preparation of Premarket Notifications for Ceramic Ball Hip Systems, available at: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080786.pdf

** Guidance Document for Testing Orthopedic Implants With Modified Metallic Surfaces Apposing Bone Or Bone Cement (April 28, 1994), available at: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm081247.pdf

*** 510(K) Information Needed for Hydroxyapatite Coated Orthopedic Implants March 10, 1995 (revised 2/20/97), available at: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080225.pdf

## B. Animal Studies

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No animal studies have been performed. Animal studies were not deemed necessary to determine the safety and effectiveness of the R3 delta Ceramic Acetabular System.

## C. Additional Studies

### Biocompatibility

The materials for use in the R3 delta Ceramic Acetabular System are standard materials used in permanently implanted orthopedic implants, including titanium alloy (ASTM F1472, ASTM F1295, and ASTM F136) and zirconia toughened alumina (ZTA) ceramic material (BIOLOX® delta).

### Sterilization

The Smith & Nephew R3 delta Ceramic femoral heads and acetabular liners are sterilized by gamma radiation sterilization (Cobalt 60 Source) at a minimum dose of 25 kGy (2.5 Mrad). The process is validated using Method VDmax per the requirements of ISO 11137 to yield a minimum Sterility Assurance Level (SAL) of 10⁻⁶. The products are not labeled "pyrogen free." The components are packaged in PETG trays sealed with Tyvek lids to maintain sterility.

### Shelf Life

Shelf life testing was performed to verify sterile packaging integrity equivalent to 10 years for the R3 delta Ceramic Acetabular System.

## X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study outside of the United States ("European Post-Market Study") to establish a reasonable assurance of safety and effectiveness of hip arthroplasty with the R3 delta Ceramic Acetabular System for use in skeletally mature patients requiring primary total hip arthroplasty due to non-inflammatory arthritis (degenerative joint disease) such as osteoarthritis, avascular necrosis, or traumatic arthritis in the United States. Data from this clinical study was the basis for the PMA approval decision. A summary of the clinical study is presented below.

### A. Study Design

Patients were treated between June 1, 2009 and September 1, 2014. The database for the European Post-Market Study, from which the PMA data were abstracted, reflected data collected through October 31, 2014 and included 505 patients. There were 8 investigational sites, which included the countries of Germany, Finland, Denmark, the Netherlands, the United Kingdom, Belgium, and Spain.

The European Post-market Study was a prospective, consecutive, concurrently controlled, non-randomized, multi-center, clinical outcome study designed to collect safety and effectiveness data of the R3 acetabular cup with all bearing options

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marketed in Europe. The subject selection process was predefined in the study protocol. The treatment option for patients requiring total hip arthroplasty was chosen by the surgeon during a preoperative visit. All available bearing options for the R3 acetabular cup were used in subjects enrolled in the study: BIOLOX® forte ceramic-on-ceramic, BIOLOX® delta ceramic-on ceramic (DOD), ceramic-on-crosslinked polyethylene (XLPE) (CoXLPE), Oxidized zirconium-on-XLPE (OxZr/XLPE), metal-on-XLPE (MoXLPE), and metal-on-metal (MoM).

In order to demonstrate the safety and effectiveness of the R3 delta Ceramic Acetabular System, a control group from the European Post-market Study was defined whose data had been collected concurrently according to the same study protocol. Per the applicant, "To serve as an effective control for the DOD, the control group must have been implanted with a head and liner articulation couple that is cleared or approved in the US, has a good performance record, and represents state of the art technology. The oxidized zirconium-on-XLPE (OxZr/XLPE) articulation coupling met the requirements for a suitable control group and had enrolled a comparable number of subjects to the DOD group; therefore, it was selected as the control device." The control treatment was a legally marketed alternative with similar indications for use.

Data were abstracted for all subjects implanted with either a DOD or OxZr/XLPE articulation. The two treatment groups contained a combined total of 268 subjects from 7 sites and included all countries identified above except Germany. 131 subjects were implanted with the R3 acetabular cup combined with an OxZr/XLPE articulation couple and one of five femoral stems (SYNERGY, ANTHOLOGY, POLARSTEM, SL-PLUS, and SPECTRON stems) while 137 subjects were implanted with the R3 acetabular cup combined with a DOD articulation couple and one of four femoral stems (all above stems except SPECTRON).

The primary endpoint for the analysis was an overall success outcome determination at a minimum of 3 years post-surgery, which included implant survivorship, a modified Harris Hip Score (mHHS), and radiographic evaluation. In order to meet overall success, a subject must have demonstrated all of the following at the 3-year time point:

- No component revision; and
- mHHS of at least 80 points; and
- Radiographic success, defined as:
- No radiolucencies greater than 2 mm in 50% or more in any of the cup or stem zones; and
- No femoral or acetabular subsidence greater than or equal to 5mm from baseline; and
- No acetabular cup inclination changes greater than 4 degrees (4°)

Secondary safety and effectiveness measures included the individual subcomponents of overall success as well as the Western Ontario and McMaster Universities Arthritis

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Index (WOMAC), as part of the Hip disability and Osteoarthritis Outcomes Score (HOOS), and the UCLA Activity Level Rating (UCLA).

In addition, safety evaluations included adverse events monitored over the course of the study. Adverse events were captured from the time of surgery until subjects completed the study or their data were abstracted from the study database, whichever came sooner. Adverse event adjudication was performed by an independent Clinical Events Committee (CEC) composed of three board-certified orthopedic surgeons.

Study success was defined as establishing non-inferiority of the DOD cohort compared to the OxZr/XLPE cohort based upon the 3-year clinical composite success (CCS) rates with a non-inferiority delta of 10%. The following hypothesis was tested to establish clinical non-inferiority of DOD relative to OxZr/XLPE:

$$
\mathrm{H}_0: \pi_{\mathrm{DOD}} - \pi_{\mathrm{OxZr/XLPE}} \leq \delta
$$

$$
\mathrm{H}_a: \pi_{\mathrm{DOD}} - \pi_{\mathrm{OxZr/XLPE}} > \delta
$$

where $\pi_{\mathrm{DOD}}$ and $\pi_{\mathrm{OxZr/XLPE}}$ are the 3-year clinical composite success (CCS) rates of the investigational and control device, respectively.

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the European Post-market was limited to patients who met the following inclusion criteria:

- Patient is 18-75 years old and he/she is skeletally mature
- Patient requires primary total hip arthroplasty due to non-inflammatory degenerative joint disease (e.g. osteoarthritis, post-traumatic arthritis, avascular necrosis, dysplasia/developmental dysplasia of the hip) or inflammatory joint disease (e.g. rheumatoid arthritis)
- Patient has met an acceptable preoperative medical clearance and is free from or treated for cardiac, pulmonary, hematological, etc., conditions that would pose excessive operative risk
- The patient is willing to comply to the follow-up schedule

Patients were not permitted to enroll in the European Post-market Study if they met any of the following exclusion criteria:

- Patient has active infection or sepsis (treated or untreated)
- Patient is a prisoner or has an emotional or neurological condition that would pre-empt their ability or unwillingness to participate in the study including mental illness, mental retardation, linguistic insufficiencies (i.e. immigrants), or drug/alcohol abuse
- Patients with acute hip trauma (femoral neck fracture)

Further, enrollment in the R3 delta Ceramic Acetabular System study was limited to patients who met the following inclusion criteria:

- Subject of the European Post-market Study
- Must have a signed informed consent

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- Must have been implanted with a DOD or OxZr/XLPE articulation couple
- Must have all device labels available to allow confirmation of devices implanted

and

Patients were not permitted to enroll in the R3 delta Ceramic Acetabular System study if they met any of the following exclusion criteria:

- Any subject in the OxZr/XLPE arm who was implanted with any hip system component that is not 510(k) cleared for use in the US with the OxZr femoral head and XLPE acetabular liner*
- Any subject in the DOD arm who was implanted with any hip system component (other than the ceramic acetabular liner) that is not 510(k) cleared for use with the ceramic head

* Note that the POLARSTEM stems legally marketed in the US have identical materials, design, dimensions, and sizes, as well as a similar coating thickness as the POLARSTEM stems used in the clinical trial (not available in the US) except that they were coated by Smith & Nephew while the POLARSTEM stems used in the clinical trial were coated by a supplier; see Section IX Summary of Nonclinical Studies for safety and effectiveness justification.

## 2. Follow-up Schedule

All subjects were scheduled to return for post-operative follow-up examinations at 3 months (±2 weeks), 1 year (±2 months), and 3 years (±2 months) in the R3 delta Ceramic Hip System study. The European Post-market Study also included post-operative follow-up examinations at 5, 7, and 10 years postoperatively (Table 1).

Table 1: Visit Schedule with Date Ranges

|  Window | Description | In-window Relative Day |   | Continuous Visit Window Relative Date  |   |
| --- | --- | --- | --- | --- | --- |
|   |   |  Min | Max | Min | Max  |
|  Pre-op | Pre-operative | -28 | -1/0 | N/A | -1/0  |
|  Day 0 | Operative | 0 | 0 | 0 | 0  |
|  Discharge | Discharge | N/A | N/A | N/A | N/A  |
|  Day 90 | 3 Month Visit | 76 | 104 | 1 | 227  |
|  Day 365 | 1 Year Visit | 305 | 425 | 228 | 730  |
|  Day 1095 | 3 Year Visit | 1005 | 1185 | 731 | 1460  |
|  Day 1825 | 5 Year Visit (1) | 1645 | 2005 | 1461 | 2190  |
|  Day 2555 | 7 Year Visit (1) | 2375 | 2735 | 2191 | 3102  |
|  Day 3650 | 10 Year Visit (1) | 3470 | 3830 | 3103 | N/A  |
|  (1) Not included in PMA analyses. Note: Table includes “In-Window” follow-up time frames to allow for classification of in-window and out-of-window visits as well as SAP defined “Continuous Visit Windows” to “maximize the  |   |   |   |   |   |

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data included and to pre-specify how the data collected outside of the "In-Window" follow-up ranges would be included in the analyses".

Evaluations were performed according to the visit schedule below. Adverse events and complications were recorded at all visits (Table 2).

Table 2: Assessments by Visit
|  Visit  |   |   |   |   |   |
| --- | --- | --- | --- | --- | --- |
|  Data | Pre-op | Discharge | 3 Months | 1 Year | 3 Years  |
|  Informed Consent | X |  |  |  |   |
|  Demographics/Medical History | X |  |  |  |   |
|  mHHS | X |  | X | X | X  |
|  UCLA | X |  | X | X | X  |
|  HOOS | X |  | X | X | X  |
|  Radiographic Evaluation |  | X |  | X | X  |
|  Adverse Events |  | On occurrence  |   |   |   |

3. Clinical Endpoints

With regards to safety, the following data were collected: adverse events, device survivorship (revisions), and radiographic success/failure.

With regards to effectiveness, the following data were collected: mHHS, WOMAC scores, and UCLA scores.

With regard to success/failure criteria, the primary composite endpoint used to determine individual success was:

- No component revision; and
- mHHS of at least 80 points; and
- Radiographic success, defined as:
- No radiolucencies greater than 2 mm in 50% or more in any of the cup or stem zones; and
- No femoral or acetabular subsidence greater than or equal to 5mm from baseline; and
- No acetabular cup inclination changes greater than 4 degrees (4°)

Study success was defined as establishing non-inferiority of the DOD cohort compared to the OxZr/XLPE cohort based upon the 3-year clinical composite success (CCS) rates with a non-inferiority delta of 10%. The following hypothesis was tested to establish clinical non-inferiority of DOD relative to OxZr/XLPE:

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$$
\mathrm{H}_0: \pi_{\mathrm{DOD}} - \pi_{\mathrm{OxZr/XLPE}} \leq \delta
$$

$$
\mathrm{H}_a: \pi_{\mathrm{DOD}} - \pi_{\mathrm{OxZr/XLPE}} > \delta
$$

where $\pi_{\mathrm{DOD}}$ and $\pi_{\mathrm{OxZr/XLPE}}$ are the 3-year clinical composite success (CCS) rates of the investigational and control device, respectively.

Revision was defined as reoperation where any component (acetabular cup, acetabular liner, femoral head, or femoral stem) was replaced.

## Modified Harris Hip Score (mHHS)

The mHHS is a clinician-based outcome measure used to assess patient pain, function, deformity, and range of motion. Scoring assessment ranges from 0 (worst) to 100 (best). The mHHS is a modified version of the HHS, which has been found to be reliable and valid in measuring outcomes following total hip arthroplasty, and was collected pre-operatively as well as at each post-operative follow-up visit.

## Western Ontario and McMaster Universities Arthritis Index (WOMAC)

The WOMAC is a self-administered health status measure for osteoarthritis of the hip and is used to evaluate a patient's pain, stiffness, and physical function. It has been validated for evaluating outcomes following total hip arthroplasty. The WOMAC was collected using the Hip disability and Osteoarthritis Outcome Score (HOOS), which includes the WOMAC in its complete and original format. Only the WOMAC portion of the HOOS was collected in the European Postmarket Study. The WOMAC scoring assessment ranges from 0 (worst) to 96 (best). The WOMAC score was collected at the preoperative, 3-month, 1-year, and 3-year follow-up visits.

## UCLA Activity Level Rating (UCLA)

The UCLA Activity Level Rating scale is a self-assessment of a person's activity level that ranges from wholly inactive (level 1) to regular participation in impact sports (level 10). The UCLA Activity Level Rating is a valid instrument for routine activity assessment in subjects undergoing total joint arthroplasty. The UCLA score was collected at the preoperative, 3-month, 1-year, and 3-year follow-up visits.

## B. Accountability of PMA Cohort

Data for the subjects of the PMA study were abstracted from the European Postmarket study. The population of subjects ultimately analyzed was determined according to the following flowchart (Figure 1):

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Figure 1: Flowchart of PMA Cohort Accountability
![img-0.jpeg](img-0.jpeg)
*Includes 1 Death (DOD) and 8 Other Termination (7 DOD and 1 OxZr/XLPE)

A total of 268 subjects (137 DOD and 131 OxZr/XLPE) were enrolled in the study at 7 sites. At the time of database lock, 121/135 expected DOD subjects  $(89.6\%)$  and 121/124 expected OxZr/XLPE  $(97.6\%)$  subjects had any 3 year primary endpoint data available for analysis. Complete 3 year overall success (primary endpoint) data were available for 109/135 expected DOD subjects  $(80.7\%)$  and 119/124  $(96.0\%)$  expected OxZr/XLPE subjects (Table 3). A success/failure determination based upon the primary endpoint, which included revisions, was able to be made for 110/137  $(80.3\%)$  of the DOD cohort and 126/131  $(96.1\%)$  of the OxZr/XLPE cohort.

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Table 3: Subject Accounting, mITT Population

|   | Pre-Op |   | 3 Months |   | 1 Year |   | 3 Years  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Summary | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE  |
|  Theoretical [1] | 137 | 131 | 137 | 131 | 137 | 131 | 137 | 131  |
|  Deaths [2] | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0  |
|  Failures [3] | 0 | 0 | 1 | 4 | 1 | 5 | 1 | 7  |
|  Expected [4] | 137 | 131 | 136 | 127 | 135 | 126 | 135 | 124  |
|  ActualA | NA | NA | NA | NA | 123 | 122 | 109 | 119  |
|  % Follow-up [5] | NA | NA | NA | NA | 91.1% | 96.8% | 80.7% | 96.0%  |
|  ActualB | 137 | 131 | 133 | 125 | 127 | 122 | 121 | 121  |
|  % Follow-up [6] | 100.0% | 100.0% | 97.8% | 98.4% | 94.1% | 96.8% | 89.6% | 97.6%  |
|  NA: Not applicable ActualA: Subjects with complete data for the primary endpoint (modified Harris Hip Score, radiographic evaluation and safety assessments), evaluated per protocol, in the window time frame ActualB: Subjects with any follow-up data reviewed or evaluated by investigator (“all evaluated” accounting). [1] Number of subjects that would have reached the beginning of the study window associated with each visit if all subjects returned. [2] Cumulative number of subjects that died during or prior to the study visit. [3] Cumulative number of subjects that failed (revision) during or prior to the study visit. [4] Theoretical subjects minus the number of deaths and revisions. [5] ActualA/Expected*100 [6] ActualB/Expected*100  |   |   |   |   |   |   |   |   |

The modified intention to treat (mITT) population is defined as all subjects who consented to study participation and received the R3 Acetabular Cup System with the BIOLOX® delta ceramic on BIOLOX® delta ceramic or the OxZr/XLPE articulation couple. The per-protocol (PP) population is defined as all mITT subjects with complete 3 year primary endpoint data and no deviations to the inclusion and exclusion criteria. In the analyses completed, aside from the sensitivity analyses and tipping point analysis, no data were imputed for the missing data, and therefore the mITT population and PP populations were identical as there were no deviations to the inclusion and exclusion criteria.

# C. Study Population Demographics and Baseline Parameters

The available population demographics and baseline parameters of the study population and individual study cohorts are provided in Table 4 and Table 5. The available demographics and baseline characteristics are typical of the patient

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population in the US undergoing total hip arthroplasty. The study cohorts had no statistically significant difference in demographics or baseline parameters.

Table 4: Demographics, mITT Population

|  Outcomes | Treatment |   | P-value [1]  |
| --- | --- | --- | --- |
|   |  DOD | OxZr/XLPE  |   |
|   |  N = 137 | N = 131  |   |
|  Age (years) |  |  |   |
|  Mean (SD) | 61.8 (9.12) | 62.9 (9.01) | 0.3495  |
|  Median | 63.2 | 64.8 |   |
|  Min, Max | 27, 75 | 32, 76 [2] |   |
|  Gender |  |  |   |
|  Female | 90 (65.7%) | 73 (55.7%) | 0.1046  |
|  Male | 47 (34.3%) | 58 (44.3%) |   |
|  BMI (kg/m2) |  |  |   |
|  Mean (SD) | 27.7 (4.74) | 28.2 (5.38) | 0.3803  |
|  Median | 27.4 | 27.5 |   |
|  Min, Max | 19.1, 44.4 | 17.9, 43.0 |   |
|  [1] P-value from Fisher's exact test for categorical variables and two-sample t-test for continuous variables. [2] Subject 6041 was aged 75.7 years at surgery and subject 3028 75.8 years, rounding leads to maximum age 76 years  |   |   |   |

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Table 5: Baseline Characteristics, mITT Population

|  Outcomes | Treatment |   | P-value [1]  |
| --- | --- | --- | --- |
|   |  DOD | OxZr/XLPE  |   |
|   |  137 | 131 |   |
|  Diagnosis |  |  |   |
|  Primary Osteoarthritis | 116 (84.7%) | 123 (93.9%) | 0.1122  |
|  Dysplasia | 4 (2.9%) | 3 (2.3%) |   |
|  Posttraumatic Osteoarthritis | 1 (0.7%) | 0 |   |
|  Osteonecrosis (AVN) | 13 (9.5%) | 4 (3.1%) |   |
|  Rheumatoid Arthritis | 2 (1.5%) | 1 (0.8%) |   |
|  Ankylosing Spondyloarthritis | 1 (0.7%) | 0 |   |
|  Surgical History on the Study Hip |  |  |   |
|  None | 135 (98.5%) | 126 (96.2%) | 0.2365  |
|  Internal Fixation | 1 (0.7%) | 3 (2.3%) |   |
|  Proximal Femoral Osteotomy | 0 | 1 (0.8%) |   |
|  Acetabular Osteotomy | 0 | 1 (0.8%) |   |
|  Other | 1 (0.7%) | 0 |   |
|  Charnley Classification |  |  |   |
|  Only Ipsilateral Hip Involved | 79 (57.7%) | 71 (54.2%) | 0.8584  |
|  Both Hips Involved | 51 (37.2%) | 53 (40.5%) |   |
|  Other Factors Affecting Locomotion | 7 (5.1%) | 7 (5.3%) |   |
|  [1] P-value from Fisher's exact test for categorical variables and two-sample t-test for continuous variables.  |   |   |   |

No data on racial demographics of those enrolled were collected to allow for assessment of the potential for differing outcomes or success rates amongst subjects of differing races. It is not expected racial differences would result in different

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outcomes or success rates based upon use of the delta ceramic on delta ceramic bearing surface, which was the focus of this PMA. Racial demographic information will be collected as part of the new enrollment US PAS to further assess any impact of race on patient outcomes.

## D. Safety and Effectiveness Results

### 1. Safety Results

The analysis of safety was based on the mITT cohort of patients (268 total subjects) defined as all subjects who consented to study participation and received the R3 Acetabular Cup System with the BIOLOX® delta ceramic on BIOLOX® delta ceramic or the OxZr/XLPE articulation couple. The key safety outcomes for this study, adverse events, device survivorship (revisions), and radiographic failure, are presented below in Table 6 to Table 15.

### Adverse Events:

A summary of the total number of adverse events (AE), events adjudicated as serious, events adjudicated as related (device-related, procedure-related: operative site, procedure-related: systemic, and systemic), deaths, and removals or revisions are shown in Table 6 and Table 7. The AE seriousness and relatedness to the device and/or procedure were adjudicated by a CEC which consisted of three independent board-certified orthopedic surgeons. The AE data, including a narrative for each AE, were also reviewed by the FDA and the adjudication was modified for multiple AEs with agreement by the applicant.

A total of 487 events were reported in both treatment groups. There was no statistically significant difference in the number of hips reported as experiencing an AE between the DOD and OxZr/XLPE treatment groups, but there was a statistically significant difference in the total number of AEs reported between the groups. This difference in overall AEs was accounted for by a greater number of non-serious and non-device or procedure related AEs. Overall, the higher number of non-serious and non-device or procedure related AEs does not appear clinically meaningful based upon the lack of relationship to the device or procedure.

In the DOD group, 296 AEs were reported in 105 hips (76.6%). Of those, 168 events in 71 hips (51.8%) were assessed as non-serious and 128 events in 73 hips (53.3%) were assessed as serious (SAEs). In the OxZr/XLPE group, 191 events were reported in 89 hips (67.9%). Of those, 68 events in 46 hips (35.1%) were assessed as non-serious and 123 events in 66 hips (50.4%) were assessed as serious. The treatment group difference in non-serious AEs was statistically significant by the number of hips and the number of events (p=0.0068 and p<0.0001 respectively) while the difference in SAEs was not statistically significant by the number of hips or the number of events (p=0.7138 and p=0.9123 respectively) (Table 6).

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In the DOD group, 33 events in 31 (22.6%) hips were assessed as device-related, 50 events in 41 (29.9%) hips were assessed as procedure-related: operative site, 13 events in 10 (7.3%) hips were assessed as procedure-related: systemic, and 232 events in 89 (65.0%) hips were assessed as systemic (not related to the device or procedure). In the OxZr/XLPE group, 38 events in 26 (19.8%) hips were assessed as device-related, 46 events in 32 (24.4%) hips were assessed as procedure-related: operative site, 3 events in 3 (2.3%) hips were assessed as procedure-related: systemic, and 142 events in 71 (54.2%) hips were assessed as systemic. NOTE: some adverse events were assessed as both device and procedure-related (operative site or systemic); thus, the total of device-related, procedure-related: operative site, procedure-related: systemic, and systemic adverse events exceeds the total number of AEs. There were no statistically significant differences in AEs between the treatment groups by the number of hips or the number of events in terms of device or procedure relationship (Table 6). Further, there were no statistically significant differences in AEs between the treatment groups by the number of hips or the number of events in terms of device or procedure relationship when additionally classified by seriousness (Note: statistical significance could not be calculated for the number of serious procedure-related: systemic AEs) (Table 7).

In the DOD group, 1 (0.7%) subject died from a head injury, which was believed to be unrelated to the device or procedure. In the OxZr/XLPE group, no subjects died.

Table 6: Adverse Events, mITT Population

|  Type of AE or Outcome | Treatment Group |   | Fisher's Exact Test P-value | Negative Binomial P-value [2]  |
| --- | --- | --- | --- | --- |
|   |  DOD N = 137 No. of Hips (%) | OxZr/XLPE N = 131 No. of Hips (%)  |   |   |
|  Event Classification  |   |   |   |   |
|  All AE/SAE | 105 (76.6%) | 89 (67.9%) | 0.1329 |   |
|  All AE/SAE Events | 296 | 191 |  | 0.0016  |
|  Outcomes, Death and Revision  |   |   |   |   |
|  Death | 1 (0.7%) | 0 | 1.0000 |   |
|  Removal or Revision | 1 (0.7%) | 7 (5.3%) | 0.0329 |   |
|  Seriousness per CEC [1]  |   |   |   |   |
|  Non-serious AE | 71 (51.8%) | 46 (35.1%) | 0.0068 |   |
|  Non-serious AE Events | 168 | 68 |  | <0.0001  |
|  SAE | 73 (53.3%) | 66 (50.4%) | 0.7138 |   |
|  SAE Events | 128 | 123 |  | 0.9123  |
|  Relationship per CEC [1]  |   |   |   |   |
|  Device related | 31 (22.6%) | 26 (19.8%) | 0.6547 |   |
|  Number of Device related | 33 | 38 |  | 0.5555  |
|  Procedure-related Operative Site | 41 (29.9%) | 32 (24.4%) | 0.3386 |   |

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Table 7: Adverse Events by Relationship and Seriousness, mITT Population

|  Relationship per CEC [1] | Treatment Group |   | Fisher's Exact Test P-value | Negative Binomial P-value [2]  |
| --- | --- | --- | --- | --- |
|   |  DOD N = 137 No. of Hips (%) | OxZr/XLPE N = 131 No. of Hips (%)  |   |   |
|  Device related  |   |   |   |   |
|  Serious Number of Serious | 9 (6.6%) 9 | 13 (9.9%) 19 | 0.3765 | 0.1107  |
|  Non-Serious Number of Non-Serious | 22 (16.1%) 24 | 16 (12.2%) 19 | 0.3868 | 0.4939  |
|  Procedure-related: Operative Site  |   |   |   |   |
|  Serious Number of Serious | 13 (9.5%) 14 | 17 (13.0%) 24 | 0.4395 | 0.1440  |
|  Non-Serious Number of Non-Serious | 32 (23.4%) 36 | 18 (13.7%) 22 | 0.0591 | 0.0894  |
|  Procedure-related: Systemic  |   |   |   |   |
|  Serious Number of Serious | 4 (2.9%) 6 | 1 (0.8%) 1 | 0.3709 | NE  |
|  Non-Serious Number of Non-Serious | 6 (4.4%) 7 | 2 (1.5%) 2 | 0.2826 | 0.1344  |

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The severity of AEs was adjudicated by the investigators as mild, moderate, or severe as AE severity was unable to be determined by the CEC based on review of study records (Table 8)

There were greater numbers of hips and events in all three severity categories (mild, moderate, and severe) in the DOD cohort as expected by the overall greater number of AEs in the DOD cohort, but when assessed by device or procedure relatedness again almost all the greater numbers were accounted for by systemic (non-device or procedure related) AEs. The only statistically significant difference in AEs by severity was for severe systemic AEs (p=0.0010 for hips and p=0.0002 for events) (Table 8).

Table 8: Adverse Events by Severity per Investigator and Relationship per CEC

|  Severity Per Investigator | Treatment Group |   | Fisher's Exact Test P-value | Negative Binomial P-value [2]  |
| --- | --- | --- | --- | --- |
|   |  DOD N = 137 No. of Hips (%) | OxZr/XLPE N = 131 No. of Hips (%)  |   |   |
|  Mild  |   |   |   |   |
|  Mild | 74 (54.0%) | 66 (50.4%) | 0.6248 |   |
|  Number of Mild | 144 | 104 |  | 0.0509  |
|  Relationship per CEC [1]: |  |  |  |   |
|  Device related | 23 (16.8%) | 18 (13.7%) | 0.5028 |   |
|  Number of Device related | 25 | 27 |  | 0.7821  |
|  Procedure-related Operative Site | 29 (21.2%) | 22 (16.8%) | 0.4368 |   |
|  Number of Procedure-related Operative Site | 34 | 31 |  | 0.7898  |
|  Procedure-related Systemic | 7 (5.1%) | 1 (0.8%) | 0.0668 |   |
|  Number of Procedure-related Systemic | 9 | 1 |  | NE  |
|  Systemic (Not related to device or procedure) | 59 (43.1%) | 51 (38.9%) | 0.5353 |   |
|  Number of Systemic (Not related to device or procedure) | 100 | 72 |  | 0.0953  |
|  Moderate  |   |   |   |   |
|  Moderate | 48 (35.0%) | 44 (33.6%) | 0.8977 |   |
|  Number of Moderate | 89 | 62 |  | 0.0994  |

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|  Severity Per Investigator | Treatment Group |   | Fisher's Exact Test P-value | Negative Binomial P-value [2]  |
| --- | --- | --- | --- | --- |
|   |  DOD N = 137 No. of Hips (%) | OxZr/XLPE N = 131 No. of Hips (%)  |   |   |
|  Relationship per CEC [1]: |  |  |  |   |
|  Device related | 6 (4.4%) | 6 (4.6%) | 1.0000 |   |
|  Number of Device related | 6 | 7 |  | NE  |
|  Procedure-related Operative Site | 9 (6.6%) | 9 (6.9%) | 1.0000 |   |
|  Number of Procedure-related Operative Site | 11 | 10 |  | NE  |
|  Procedure-related Systemic | 2 (1.5%) | 1 (0.8%) | 1.0000 |   |
|  Number of Procedure-related Systemic | 2 | 1 |  | NE  |
|  Systemic (Not related to device or procedure) | 42 (30.7%) | 37 (28.2%) | 0.6894 |   |
|  Number of Systemic (Not related to device or procedure) | 76 | 51 |  | 0.0912  |
|  Severe  |   |   |   |   |
|  Severe | 44 (32.1%) | 22 (16.8%) | 0.0044 |   |
|  Number of Severe | 63 | 25 |  | 0.0007  |
|  Relationship per CEC [1]: |  |  |  |   |
|  Device related | 2 (1.5%) | 4 (3.1%) | 0.4386 |   |
|  Number of Device related | 2 | 4 |  | NE  |
|  Procedure-related Operative Site | 4 (2.9%) | 5 (3.8%) | 0.7449 |   |
|  Number of Procedure-related Operative Site | 5 | 5 |  | NE  |
|  Procedure-related Systemic | 2 (1.5%) | 1 (0.8%) | 1.0000 |   |
|  Number of Procedure-related Systemic | 2 | 1 |  | NE  |
|  Systemic (Not related to device or procedure) | 41 (29.9%) | 17 (13.0%) | 0.0010 |   |
|  Number of Systemic (Not related to device or procedure) | 56 | 19 |  | 0.0002  |
|  [1] Includes definitely and possibly related.[2] Analysis is based on a negative binomial model with number of events as the dependent variable, treatment as the factor, and log of time of study as the offset.Note: NE: Not Estimable due to lack of model convergence.  |   |   |   |   |

Table 9 provides the AEs identified as device-related in both treatment cohorts by onset interval. The most common device related AEs were bone fracture femur/fissure/fracture subtrochanteric (DOD, 5; OxZr/XLPE, 5), dislocation (DOD, 0; OxZr/XLPE, 5), study sided groin pain (DOD, 3; OxZr/XLPE, 4), study sided hip pain (DOD, 5; OxZr/XLPE, 11), and trochanteritis (DOD, 4; OxZr/XLPE, 1).

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Table 9: Device-related Adverse Events by Onset Interval

|   | Intraoperative (0 Days) |   | 3 Months (1-227 Days) |   | 1 Year (228-730 Days) |   | 3 Years (731-1460 Days) |   | >3 Years (>1460 Days) |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | DOD | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE  |
|  Number of Hips | 137 | 131 | 137 | 131 | 133 | 129 | 126 | 127 | 4 | 6 | 137 | 131  |
|  Bone Fracture-Femur | 0 | 1 | 2 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 4  |
|  Bursitis | 0 | 0 | 0 | 2 | 2 | 0 | 0 | 0 | 0 | 0 | 2 | 2  |
|  Dislocation | 0 | 0 | 0 | 3 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 5  |
|  Elevated Metal Ions | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 3 | 0  |
|  Femoral Component | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3  |
|  Fissure | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1  |
|  Fracture-Subtrochanteric | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Groin pain, study hip side | 0 | 0 | 2 | 0 | 1 | 1 | 0 | 3 | 0 | 0 | 3 | 4  |
|  Inflammation | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Leg Length Change | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 2 | 0  |
|  Leg Pain | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Limp, study hip side | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 2 | 0  |
|  Muscular/Connective Tissue | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1  |
|  Nervous | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0  |
|  Operative side pain from other than study hip | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Pain at Op site | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2  |
|  Pain in study hip | 0 | 0 | 2 | 4 | 2 | 2 | 1 | 4 | 0 | 1 | 5 | 11  |
|  Pain, unknown etiology | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1  |
|  Skeletal | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2  |
|  Subluxation, no component specified | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0  |
|  Trendelenberg gait | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1  |
|  Trochanteritis | 0 | 0 | 2 | 0 | 2 | 0 | 0 | 1 | 0 | 0 | 4 | 1  |
|  Uncoded - Hip weakness | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Total | 2 | 2 | 14 | 16 | 11 | 7 | 6 | 12 | 0 | 1 | 33 | 38  |

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Table 10 provides the AEs identified as procedure-related: operative site in both treatment cohorts by onset interval. The most common procedure-related: operative site related AEs were bone fracture femur/fissure/fracture subtrochanteric (DOD, 7; OxZr/XLPE, 5), dislocation (DOD, 0; OxZr/XLPE, 5), study sided groin pain (DOD, 3; OxZr/XLPE, 4), study sided hip pain (DOD, 6; OxZr/XLPE, 11), trochanteritis (DOD, 4; OxZr/XLPE, 1), and superficial infection only (DOD, 1; OxZr/XLPE, 3).

Table 10: Procedure-related: Operative Adverse Events by Onset Interval

|   | Intraoperative (0 Days) |   | 3 Months (1-227 Days) |   | 1 Year (228-730 Days) |   | 3 Years (731-1460 Days) |   | >3 Years (>1460 Days) |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE  |
|  Number of Hips | 137 | 131 | 137 | 131 | 133 | 129 | 126 | 127 | 4 | 6 | 137 | 131  |
|  Bone Fracture-Femur | 1 | 1 | 2 | 3 | 0 | 0 | 1 | 0 | 0 | 0 | 4 | 4  |
|  Bursitis | 0 | 0 | 0 | 2 | 2 | 0 | 0 | 0 | 0 | 0 | 2 | 2  |
|  Deep Infection > 6 weeks | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1  |
|  Deep Vein Thrombosis | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1  |
|  Delayed Wound Healing | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0  |
|  Dislocation | 0 | 0 | 0 | 3 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 5  |
|  Elevated Metal Ions | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 3 | 0  |
|  Femoral Component | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3  |
|  Fissure | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1  |
|  Fracture-Subtrochanteric | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Groin pain, study hip side | 0 | 0 | 2 | 0 | 1 | 1 | 0 | 3 | 0 | 0 | 3 | 4  |
|  Hematoma, Hemarthrosis | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1  |
|  Heterotopic Ossification-Generic Reporting | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |

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|   | Intraoperative (0 Days) |   | 3 Months (1-227 Days) |   | 1 Year (228-730 Days) |   | 3 Years (731-1460 Days) |   | >3 Years (>1460 Days) |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE  |
|  Heterotopic Ossification: Grade I | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Infection | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1  |
|  Inflammation | 0 | 0 | 2 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 3 | 0  |
|  Leg Length Change | 1 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 3 | 0  |
|  Leg Pain | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Limp, study hip side | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 2 | 0  |
|  Lymphatic | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Muscular/ Connective Tissue | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 1  |
|  Nervous | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 2 | 0  |
|  Operative side pain from other than study hip | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Pain at Op site | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2  |
|  Pain in study hip | 0 | 0 | 3 | 4 | 2 | 2 | 1 | 4 | 0 | 1 | 6 | 11  |
|  Pain, unknown etiology | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1  |
|  Post-op swelling of study leg | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1  |
|  Skeletal | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2  |
|  Subluxation, no component specified | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0  |
|  Superficial Infection Only | 0 | 0 | 1 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3  |
|  Trendelenberg gait | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1  |
|  Trochanteritis | 0 | 0 | 2 | 0 | 2 | 0 | 0 | 1 | 0 | 0 | 4 | 1  |
|  Uncoded - Hip weakness | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Total | 4 | 2 | 26 | 24 | 13 | 7 | 7 | 12 | 0 | 1 | 50 | 46  |
|  Note: Number of Hips = Number of hips evaluated at that time period and overall. Note: Includes the number of occurrences for each type of event. Note: Three hips (#7019, 7073, and 7098) have a missing AE start date; therefore, date of readmission was used for determining the AE onset interval. Note: Hips with missing AE start date that could not be determined are excluded since AE onset is unknown.  |   |   |   |   |   |   |   |   |   |   |   |   |

Table 11 provides the AEs identified as procedure-related: systemic in both treatment cohorts by onset interval. The most common procedure-related: systemic related AEs were circulatory (DOD, 2; OxZr/XLPE, 0), digestive/GI (DOD, 2; OxZr/XLPE, 0), fever (DOD, 2; OxZr/XLPE, 0), nervous (DOD, 4; OxZr/XLPE, 0), and urinary (DOD, 1; OxZr/XLPE, 1), and superficial infection

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only (DOD, 1; OxZr/XLPE, 3).

Table 11: Procedure-related: Systemic Adverse Events by Onset Interval

|   | Intraoperative (0 Days) |   | 3 Months (1-227 Days) |   | 1 Year (228-730 Days) |   | 3 Years (731-1460 Days) |   | >3 Years (>1460 Days) |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE  |
|  Number of Hips | 137 | 131 | 137 | 131 | 133 | 129 | 126 | 127 | 4 | 6 | 137 | 131  |
|  Circulatory | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0  |
|  Digestive/Gastrointestinal | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0  |
|  Fever | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0  |
|  Hematologic/Immune System | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1  |
|  Mental/behavioral | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1  |
|  Nervous | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0  |
|  Perioperative Pulmonary Embolism | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Post-op swelling of study leg | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Respiratory | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Urinary | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1  |
|  Total | 1 | 0 | 12 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 13 | 3  |
|  Note: Number of Hips = Number of hips evaluated at that time period and overall.Note: Includes the number of occurrences for each type of event.Note: Three hips (#7019, 7073, and 7098) have a missing AE start date; therefore, date of readmission was used for determining the AE onset interval.Note: Hips with missing AE start date that could not be determined are excluded since AE onset is unknown.  |   |   |   |   |   |   |   |   |   |   |   |   |

Table 12 provides the AEs identified as systemic (not related to the device or procedure) in both treatment cohorts. The most common systemic AEs were skeletal (DOD, 92; OxZr/XLPE, 67), digestive/GI (DOD, 26; OxZr/XLPE, 8), endocrine/nutritional/ metabolic (DOD, 8; OxZr/XLPE, 4), nervous (DOD, 17; OxZr/XLPE, 9), eye/adnexa (DOD, 10; OxZr/XLPE, 6), respiratory (DOD, 14; OxZr/XLPE, 4), and urinary (DOD, 14; OxZr/XLPE, 3).

Table 12: Systemic (Not Related to Device or Procedure) Adverse Events by Onset Interval

|   | Intraoperative (0 Days) |   | 3 Months (1-227 Days) |   | 1 Year (228-730 Days) |   | 3 Years (731-1460 Days) |   | >3 Years (>1460 Days) |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE  |
|  Number of Hips | 137 | 131 | 137 | 131 | 133 | 129 | 126 | 127 | 4 | 6 | 137 | 131  |
|  Cancer, known origin | 0 | 0 | 1 | 0 | 2 | 0 | 3 | 2 | 0 | 2 | 6 | 4  |
|  Circulatory | 0 | 0 | 1 | 0 | 4 | 10 | 5 | 8 | 0 | 0 | 10 | 18  |

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|   | Intraoperative (0 Days) |   | 3 Months (1-227 Days) |   | 1 Year (228-730 Days) |   | 3 Years (731-1460 Days) |   | >3 Years (>1460 Days) |   | Total  |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE | DOD | OxZr/XLPE  |
|  Death from unknown cause | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Digestive/Gastrointestinal (GI) | 0 | 0 | 3 | 2 | 9 | 3 | 14 | 1 | 0 | 2 | 26 | 8  |
|  Ear/Mastoid Process | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 2 | 0  |
|  Elevated Metal Ions | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Endocrine/Nutritional/Metabolic | 0 | 0 | 1 | 3 | 5 | 1 | 2 | 0 | 0 | 0 | 8 | 4  |
|  Eye/Adnexa | 0 | 0 | 0 | 0 | 2 | 1 | 7 | 5 | 1 | 0 | 10 | 6  |
|  Hematologic/Immune System | 0 | 0 | 0 | 1 | 1 | 0 | 5 | 0 | 0 | 0 | 6 | 1  |
|  Infection | 0 | 0 | 0 | 1 | 2 | 1 | 1 | 0 | 0 | 0 | 3 | 2  |
|  Lymphatic | 0 | 0 | 1 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 2 | 2  |
|  Mental/behavioral | 0 | 0 | 0 | 0 | 1 | 3 | 1 | 2 | 1 | 0 | 3 | 5  |
|  Muscular/Connective Tissue | 0 | 0 | 0 | 0 | 1 | 3 | 4 | 0 | 0 | 0 | 5 | 3  |
|  Nervous | 0 | 0 | 1 | 3 | 11 | 5 | 5 | 1 | 0 | 0 | 17 | 9  |
|  Pain, unknown etiology | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0  |
|  Reproductive System | 0 | 0 | 3 | 0 | 0 | 1 | 3 | 0 | 0 | 0 | 6 | 1  |
|  Respiratory | 0 | 0 | 2 | 0 | 2 | 2 | 10 | 2 | 0 | 0 | 14 | 4  |
|  Skeletal | 0 | 0 | 13 | 12 | 40 | 31 | 39 | 23 | 0 | 1 | 92 | 67  |
|  Skin/Subcutaneous Tissue | 0 | 0 | 2 | 0 | 1 | 1 | 0 | 2 | 0 | 0 | 3 | 3  |
|  Urinary | 0 | 0 | 3 | 2 | 5 | 1 | 6 | 0 | 0 | 0 | 14 | 3  |
|  Total | 0 | 0 | 32 | 24 | 89 | 65 | 107 | 46 | 2 | 5 | 230 | 140  |
|  Note: Number of Hips = Number of hips evaluated at that time period and overall.Note: Includes the number of occurrences for each type of event.Note: Three hips (#7019, 7073, and 7098) have a missing AE start date; therefore, date of readmission was used for determining the AE onset interval.Note: Hips with missing AE start date that could not be determined are excluded since AE onset is unknown.  |   |   |   |   |   |   |   |   |   |   |   |   |

## Survivorship (Revision):

Revision was defined as reoperation where any component (acetabular cup, acetabular liner, femoral head, or femoral stem) was replaced. In the DOD group, 1 (0.7%) subject had a device revision. In the OxZr/XLPE group, 7 (5.3%) subjects had a device revision. The treatment group difference in the revision rate was nominally significant (p=0.0329). Despite a p-value less than 0.05, statistical significance is not ensured due to the potential for bias introduced by performing multiple analyses.

A Kaplan-Meier survival analysis was performed to determine the expected rate of revision for any reason for both treatment groups. The survival time was calculated using time from surgery to revision, regardless of the reason. Subjects

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without revision had time calculated one of two ways: (1) time from surgery to last clinical or radiographic evaluation, or (2) time from surgery to death. Subjects without a revision had their time variable censored.

The Kaplan-Meier estimates for implant survivorship are presented over time in Table 13. When revision was defined as the endpoint for survivorship, the results at 3 years showed a  $99.3\%$  survivorship (95% CI:  $97.4\% - 100.0\%$ ) for the DOD group and a  $94.7\%$  survivorship (95% CI:  $89.5\% - 99.8\%$ ) for the OxZr/XLPE group. There was a nominally significant difference between the two treatment groups (log rank p-value = 0.0284).

Table 13: Kaplan-Meier Estimates for Implant Survivorship, mITT Population

|  Time (in Months) | Treatment Group |   |   |   |   |   |   |   | P-value [2]  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  DOD |   |   |   | OxZr/XLPE  |   |   |   |   |
|   |  n. risk [1] | Cumulative Events | KM Estimate | 95% CI | n. risk [1] | Cumulative Events | KM Estimate | 95% CI  |   |
|  3 | 137 | 1 | 0.993 | (0.978, 1.000) | 131 | 4 | 0.969 | (0.940, 0.999) |   |
|  12 | 135 | 1 | 0.993 | (0.978, 1.000) | 127 | 6 | 0.954 | (0.918, 0.990)  |   |
|  24 | 133 | 1 | 0.993 | (0.978, 1.000) | 124 | 7 | 0.947 | (0.908, 0.985)  |   |
|  36 | 126 | 1 | 0.993 | (0.974, 1.000) | 123 | 7 | 0.947 | (0.895, 0.998) | 0.0284  |
|  [1] n. risk is the number of hips at risk at the beginning of the time interval. [2] Log-Rank test of equality over treatment groups.  |   |   |   |   |   |   |   |   |   |

Details regarding the device revisions including the treatment group involved, device/procedural relatedness, survival time of the implant, and reasons for the revision are provided in Table 14.

Table 14: Device Revisions, mITT Population

|  Study Group | Subject ID | Device(s) Revised | Device-Related | Procedure-Related | Survival Time [months] | Reason for Revision  |
| --- | --- | --- | --- | --- | --- | --- |
|  DOD | 6013 | S | Possibly | Definitely, Operative Site | 1.6 | Heavy fall resulting in femoral fracture  |
|  OxZr/XLPE | 4004 | S, H | Possibly | Definitely, Operative Site | 0.1 | Subject tripped and fell resulting in a peri-prosthetic fracture femur  |
|   |  3022 | S, H | Possibly | Definitely, Operative Site | 1.0 | Femur fracture  |
|   |  4007 | S, H | Possibly | Definitely, Operative Site | 11.2 | Loosening of stem, femoral pain and shortening of leg  |

PMA P150030: FDA Summary of Safety and Effectiveness Data

{36}

|  Study Group | Subject ID | Device(s) Revised | Device-Related | Procedure-Related | Survival Time [months] | Reason for Revision  |
| --- | --- | --- | --- | --- | --- | --- |
|   | 4023 | S, H, T | Possibly | Definitely, Operative Site | 12.9 | More pain, loosening stem  |
|   |  3049 | S, H, C, T, L | Possibly | Definitely, Operative Site | 0.7 | Subsidence of the femur component  |
|   |  7079 | S, H, C, T, L | No | Definitely, Operative Site | 1.9 | Hip infection  |
|   |  4024 | C | Possibly | Definitely, Operative Site | 6.2 | More pain (acute)  |
|  Note: Revision Procedure (s): S=femoral stem; H= femoral head; C=acetabular cup; T=taper sleeve; L=acetabular liner  |   |   |   |   |   |   |

## Radiographic Failure

The radiographic analysis was performed by an independent board-certified radiologist reviewer according to a pre-defined Radiographic Analysis Protocol. Radiographic failure was defined as evidence of radiolucencies greater than 2 mm in 50% or more of the cup or stem zones, a position change of the cup or stem (subsidence of the femoral or acetabular components of greater than or equal to 5 mm), or acetabular cup inclination changes greater than 4 degrees.

At the 3-year follow-up visit, no hips in either group met the definition of failure due to radiolucencies, 4 (3.4%) hips in the DOD group and 8 (6.7%) hips in the OxZr/XLPE group had evidence of cup or stem subsidence greater than or equal to 5 mm, and one hip in the OxZr/XLPE group had evidence of an inclination change in the acetabular cup greater than 4 degrees. There were no statistically significant differences in overall radiographic outcomes between the two treatment groups (Table 15).

Table 15: Radiographic Failure at 3 years, mITT Population

|  Independent Radiographic Evaluation | Treatment Group  |   |
| --- | --- | --- |
|   |  DOD | OxZr/XLPE  |
|…

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**Source:** [https://fda.innolitics.com/device/P150030](https://fda.innolitics.com/device/P150030)

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