BIRMINGHAM HIP RESURFACING (BHR) SYSTEM

P040033 · Smith & Nephew, Inc. · NXT · May 9, 2006 · Orthopedic

Device Facts

• Record ID: P040033
• Device Name: BIRMINGHAM HIP RESURFACING (BHR) SYSTEM
• Applicant: Smith & Nephew, Inc.
• Product Code: NXT · Orthopedic
• Decision Date: May 9, 2006
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic, Expedited Review

Intended Use

The Birmingham Hip Resurfacing (BHR) System is a single use device intended for hybrid fixation: cemented femoral head component and cementless acetabular component. The BHR system is intended for use in patients requiring primary hip resurfacing arthroplasty due to: - Non-inflammatory arthritis (degenerative joint disease) such as osteoarthritis, traumatic arthritis, avascular necrosis, or dysplasia/developmental dislocation of the hip (DDH), or - Inflammatory arthritis such as rheumatoid arthritis. The BHR System is intended for patients who, due to their relatively younger age or increased activity level, may not be suitable for traditional total hip arthroplasty due to an increased possibility of requiring future ipsilateral hip joint revision.

Device Story

The BHR System is a metal-on-metal hip resurfacing prosthesis used in orthopedic surgery to treat hip arthritis. It consists of a stemmed femoral head component (cemented) and a hemispherical acetabular cup (cementless, press-fit). The device is implanted by orthopedic surgeons in a clinical setting. By resurfacing only the femoral head rather than replacing the entire femoral neck and shaft, the device preserves femoral bone stock. The metal-on-metal bearing surface is designed for durability in younger, active patients. Surgeons use the device to reduce pain and restore hip function. Clinical outcomes are monitored via patient-reported scores (OSHIP) and radiographic assessment. The device benefits patients by potentially delaying the need for more invasive total hip arthroplasty and facilitating a return to active lifestyles.

Clinical Evidence

Clinical evidence includes a primary cohort of 2,385 hips (Overall McMinn Cohort) followed from 1997-2004, supplemented by 3,374 worldwide cases and literature reviews. Primary endpoints included survivorship, adverse events, and OSHIP pain/function scores. 5-year revision-free survivorship was 98.5% (95% CI, 97.4-99.6%). Mean OSHIP scores improved from 60.1 (baseline) to 94.8 (5 years). Adverse events included femoral neck fracture (0.4%), femoral head collapse (0.25%), and infection (0.3%). Metal ion studies indicated postoperative increases in Co/Cr levels but remained within safe reference ranges (EKA/BEI).

Technological Characteristics

Metal-on-metal hip resurfacing prosthesis. Components: Stemmed femoral head and hemispherical acetabular cup. Material: High carbon, as-cast cobalt chrome (CoCr) alloy (ASTM F75, ISO 5832-4). Acetabular cup features: Integrally-cast CoCr beads on outer surface coated with hydroxyapatite (ASTM F1185). Fixation: Hybrid (cemented femoral, cementless acetabular). Sterilization: Gamma irradiation (Cobalt 60, 25-35kGy).

Indications for Use

Indicated for patients requiring primary hip resurfacing arthroplasty due to non-inflammatory arthritis (osteoarthritis, traumatic arthritis, avascular necrosis, dysplasia/DDH) or inflammatory arthritis (rheumatoid arthritis), particularly younger or active patients at risk for future revision with traditional total hip arthroplasty. Contraindicated in patients with infection/sepsis, skeletal immaturity, severe vascular/muscular/neuromuscular disease, inadequate bone stock (severe osteopenia/osteoporosis), osteonecrosis/AVN >50% of femoral head, femoral head cysts >1cm, child-bearing age females, moderate/severe renal insufficiency, immunosuppression, severe obesity, or metal sensitivity.

Regulatory Classification

Identification

Prosthesis, hip, semi-constrained, metal/metal, resurfacing device relieves hip pain and improves hip function by replacing the parts of the hip that have been severely damaged by degenerative joint diseases. This device is indicated for patients with degenerative joint diseases including osteoarthritis, rheumatoid arthritis, traumatic arthritis, dysplasia, or avascular necrosis and for patients who, due to their relatively younger age or increased activity level, may not be suitable for traditional total hip replacement due to an increased possibility of requiring future hip joint revision.

Reference Devices

• Howmedica Osteonics ABC System (P000013)
• Trident System (P000013)
• Wright Medical Ceramic Transcend Articulation System (P030027)

Submission Summary (Full Text)

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Summary of Safety and Effectiveness Data

# I. GENERAL INFORMATION

Device Generic Name: Prosthesis, Hip, Semi-constrained, Resurfacing, metal/metal, hybrid fixation

Device Trade Name: Birmingham Hip Resurfacing (BHR) System

Applicant Name and Address: Smith & Nephew, Inc. Orthopaedics Division
1450 Brooks Road
Memphis, Tennessee 38116

PMA Number: P040033

Date of Panel Recommendation: September 8, 2005

Date of Notice of Approval to Applicant: May 9, 2006

# II. INDICATION FOR USE

The Birmingham Hip Resurfacing (BHR) System is a single use device intended for hybrid fixation: cemented femoral head component and cementless acetabular component. The BHR system is intended for use in patients requiring primary hip resurfacing arthroplasty due to:

- Non-inflammatory arthritis (degenerative joint disease) such as osteoarthritis, traumatic arthritis, avascular necrosis, or dysplasia/developmental dislocation of the hip (DDH), or
- Inflammatory arthritis such as rheumatoid arthritis.

The BHR System is intended for patients who, due to their relatively younger age or increased activity level, may not be suitable for traditional total hip arthroplasty due to an increased possibility of requiring future ipsilateral hip joint revision.

# III. CONTRAINDICATIONS

- Patients with infection or sepsis
- Patients who are skeletally immature
- Patients with any vascular insufficiency, muscular atrophy, or neuromuscular disease severe enough to compromise implant stability or postoperative recovery
- Patients with bone stock inadequate to support the device including:
- Patients with severe osteopenia should not receive a BHR procedure. Patients with a family history of severe osteoporosis or severe osteopenia.

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- Patients with osteonecrosis or avascular necrosis (AVN) with >50% involvement of the femoral head (regardless of FICAT Grade) should not receive a BHR.
- Patients with multiple cysts of the femoral head (>1cm) should not receive a BHR.
- Note: In cases of questionable bone stock, a dual-energy x-ray absorptiometry (DEXA) scan may be necessary to assess inadequate bone stock.

- Females of child-bearing age due to unknown effect on the fetus of metal ion release
- Patients with known moderate to severe renal insufficiency
- Patients who are immunosuppressed with diseases such as AIDS or persons receiving high doses of corticosteroids
- Patients who are severely overweight
- Patients with known or suspected metal sensitivity (e.g., jewelry)

## IV. WARNINGS AND PRECAUTIONS

- Patients on medications (such as high-dose or chronic aminoglycoside treatment) or with comorbidities (such as diabetes) that increase the risk of future, significant renal impairment should be advised of the possibility of increase in systemic metal ion concentration. Preoperative and postoperative monitoring of renal function (such as creatinine, glomerular filtration rate (GFR), blood urea nitrogen (BUN)) will be necessary.
- Only physicians who have received appropriate training and are familiar with the implant components, instruments, procedure, clinical applications, adverse events, and risks associated with the BHR System should use this device. Contact Smith & Nephew, Inc. for the surgical technique manual and procedural training protocol.
- Currently, Smith & Nephew, Inc. does not have a commercially available modular metal femoral head for use with a BHR resurfacing shell. Therefore, if the BHR resurfacing head must be revised to a total hip arthroplasty, the acetabular shell should also be revised, even if well fixed.

See complete list of Warnings and Precautions in the Instructions for Use for the BHR System.

## V. DEVICE DESCRIPTION

The Birmingham Hip Resurfacing (BHR) prosthesis is a metal-on-metal hip resurfacing prosthesis. The device consists of a stemmed femoral head resurfacing component designed for cemented fixation, and a hemispherical acetabular cup designed for cementless, press-fit, fixation. Both components are manufactured from high carbon, as-cast, cobalt chrome (CoCr) alloy (ASTM F75, Specification for Cobalt-Chromium-Molybdenum Alloy for Surgical Implant Applications, and ISO 5832-4, Implants for Surgery – Metallic Materials – Part 4). The BHR is a “resurfacing” prosthesis because only the surface of the femoral head is removed to implant the femoral head resurfacing component. The acetabular cups are configured in standard, dysplasia, and bridging designs. All acetabular cups have a single layer of integrally-cast CoCr-alloy (ASTM F75 and ISO 5832-4) beads on the outer surface that are coated with hydroxyapatite (HA) (ASTM F1185, Standard Specification for Composition of Hydroxylapatite for Surgical Implants). Instrumentation sets are provided as standard; several additional instruments are available as options.

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# Resurfacing Femoral Head

The resurfacing femoral head is supplied in a range of six sizes. The femoral head central stem is parametric and varies proportionally with the external diameter. There are 6 equally spaced internal recesses intended to provide antirotational locking for the cement mantle.

## Acetabular Cups

The standard acetabular component is supplied in a range of twelve sizes (two for each femoral head size to address the condition of occasional head cup mismatch). For those patients with a deficiency in the superolateral aspect of the acetabulum, the dysplasia cup is available. The dysplasia cup is designed with two superolateral screw holes that accommodate CoCr-alloy dysplasia cup screws. There is a range of six sizes for the dysplasia cup. A bridging cup is designed with a thicker wall section than the dysplasia cup to allow for mismatch between femoral head size and surgically prepared acetabulum. The bridging cup is also designed with two superolateral screw holes that accommodate the CoCr-alloy dysplasia cup screws. The bridging cup is available in five sizes.

## Dysplasia Cup Screws

The dysplasia cup screws are threaded through a threaded lug on the superolateral aspect of either the dysplasia or bridging cup and lock in situ. The screws also lock into the posterior cortical bone of the ilium. Screws are available in sizes ranging from 24mm to 88mm, in 2mm increments.

## Sizing and System Compatibility

Each femoral head resurfacing component is compatible with two standard acetabular cup sizes and one dysplasia or bridging cup size as shown in Table 1 below.

| Table 1: BHR Head and Cup Sizing and System Compatibility | | | |
| --- | --- | --- | --- |
| BHR Femoral Head Resurfacing Component (identified by head outer diameter) | Mating BHR Standard Cup Sizes (2 cups available per head component size) | Mating BHR Dysplasia Cup Sizes | Mating BHR Bridging Cup Sizes |
| 38mm | 44mm or 46mm | 46mm | 50mm |
| 42mm | 48mm or 50mm | 50mm | 54mm |
| 46mm | 52mm or 54mm | 54mm | 58mm |
| 50mm | 56mm or 58mm | 58mm | 62mm |
| 54mm | 60mm or 62mm | 62mm | 66mm |
| 58mm | 64mm or 66mm | 66mm | |

## VI. ALTERNATIVE PRACTICES OR PROCEDURES

Depending on individual circumstances, alternative procedures may include non-surgical treatment such as reduced activity and/or pain management; other surgical treatments that do not involve use of an implant such as a Girdlestone procedure; or use of other commercially available total hip replacement systems. Commonly used implant bearing materials for total hip arthroplasty include metal on ultra-high molecular weight polyethylene (UHMWPE), ceramic on

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UHMWPE, metal on metal, and ceramic on ceramic. Total hip prostheses are implanted by either cemented or uncemented techniques.

## VII. MARKETING HISTORY

The BHR is marketed in Australia, Austria, Belgium, Bermuda, Canada, Denmark, Egypt, Germany, Hong Kong, India, Ireland, Israel, Italy, Japan, Korea, Netherlands, Portugal, Romania, South Africa, Spain, Sweden, and Switzerland. The BHR has not been withdrawn from any country due to safety and effectiveness reasons.

## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

### Reported Device Related Adverse Effects

The most commonly reported BHR device related adverse events are:

- femoral neck fracture
- femoral head collapse
- infection
- avascular necrosis
- dislocation
- component migration/loosening, and
- impingement

A complete list of the frequency and rate of complications and adverse events identified in the case series review is provided below in Section X: Summary of Clinical Studies, Tables 17 and 18.

### Potential Adverse Effects

The following adverse effects may occur in association with hip replacement surgery including the BHR System:

- Cardiovascular complications including venous thrombosis, pulmonary embolism, or myocardial infarction
- Sudden, pronounced, intraoperative blood pressure decrease due to the use of bone cement,
- Hematoma or damage to blood vessels resulting in large blood loss
- Delayed wound healing
- Superficial or deep infection. Infections may occur months to years after surgery and these infections are difficult to treat and may require reoperation with removal surgery and later replacement at another time
- Temporary or permanent nerve damage resulting in functional and/or sensory deficits in the affected limb
- Metal sensitivity reactions or allergic reactions or metallosis
- Dislocation or subluxation leading to post-operative joint instability (which may be caused by malpositioning of the implants, or muscle or fibrous tissue laxity)

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- Component loosening or migration due to trauma, loss of fixation, malalignment, or bone resorption
- Limb length discrepancy
- Increased hip pain and/or reduced hip function
- Fatigue fracture of the implants as a result of excessive loading, malalignment, or trauma,
- Osteolysis and/or other peri-prosthetic bone loss
- Unintended bone perforation or fracture occurring either intra-operatively or post-operatively as a result of trauma, excessive loading, osteolysis, or osteoporosis
- Periarticular calcification or ossification
- Wear or deformation of the articular surface as a result of excessive loading or implant malalignment

Any of these adverse effects may require medical or surgical intervention. Rarely, these adverse effects may lead to death.

## IX. SUMMARY OF PRECLINICAL STUDIES

Non-clinical laboratory information was provided in support of the BHR System, including information on biocompatibility, wear, friction, surface topography, kinematics, component stress analysis, beaded surface and HA coating characterization, explant analysis, sterilization and shelf-life.

### Biocompatibility Studies

The chemical composition of the BHR device is defined in ISO 5832-4, *Implants for Surgery – Metallic Materials – Part 4*, and ASTM F75, *Specification for Cobalt-Chromium-Molybdenum Alloy for Surgical Implant Applications*, and is outlined in Table 2 below.

| Table 2: BHR Component Chemical Composition | | | |
| --- | --- | --- | --- |
| Chromium 27-30% | Molybdenum 5-7% | Nickel 0.5% max. | Iron 0.75% max. |
| Carbon 0.35% max. | Manganese 1% max. | Silicon 1% max. | Cobalt balance |

Technical specifications for hydroxyapatite coating of the BHR acetabular cup meet the requirements for ISO 13779-1, ISO 13779-2, and ISO 13779-4 (draft), *Implants for Surgery - Hydroxyapatite - Parts 1, 2 and 4*. Because the device is comprised of well-accepted materials for a permanent implant, and meets the ISO standard, additional biocompatibility testing is not required.

### Articulating Wear, Friction, and Surface Topography Analyses

A tribological study of the BHR was conducted to analyze volumetric wear rates for 5 million cycles. The study used a hip joint simulator to compare the volumetric wear rates of five devices subjected to dynamic loads and motions and one control specimen that was dynamically loaded but experienced no tangential motions. Also, with a hip friction simulator, friction was measured before, during and after the wear test. In addition, surface topography of the bearing surfaces before and throughout the wear simulator study was evaluated.

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All femoral head prostheses were 50mm outer diameter size components. Taking into account competing factors such as sliding distance, fluid-film lubrication thickness, fluid entraining velocity, and clearance between the head and acetabular cup, the 50mm components were selected as representative of a “worst-case” wear couple. The joints were tested in the anatomical position (the femoral component being below the acetabular component) with the acetabular component oriented at 33° to the horizontal. The force vector applied provided a minimum load of 100 N and the maximum load was 2975 N.

Over the 5 million cycles, the average wear rate was 1.33 mm³/million cycles. Initially the wear rate was high compared with later cycles (0.5 to 1 million cycles, 3.00 mm³/million cycles), but by 3-5 million cycles the wear rate had reduced to 0.4 mm³/million cycles. The results were compared to other total metal on metal hip systems. The wear testing, in conjunction with the clinical data and metal ion evaluations summarized in the “Summary of Clinical Data” section below, provided an acceptable characterization of the wear performance of the device.

On one of the head/cup couples, friction tests were carried out before, during and after wear testing. A modified Paul curve was used to provide a dynamic loading cycle with a maximum load of 2000N and a minimum load of 100N. The femoral head was in an inverted position but with a relative position between the head and cup the same as the wear simulator. As flexion-extension motion took place, the friction generated within the prosthesis was measured throughout the cycle. Tests were performed using several lubricants with varying degrees of viscosity. Decreasing friction over the course of the test was reported. Frictional torque ranged from 4.48-4.81Nm pre-test, to 0.75-1.88Nm after 3 million cycles, to 0.89-1.32Nm after 5 million cycles. Frictional torque appeared to be a bit higher for lower lubricant viscosities but this was not consistent for all components tested.

Surface topography was measured by profilometry before and throughout the wear simulator study. As supplied, the heads exhibited surface topography with irregular shaped peaks often seen as rectilinear arrays that looked like carbides within the CoCrMo. The peak-to-valley heights (PV) averaged 0.320 (SD 0.081) μm with a positive skewness, indicating that the majority of the height ranges were above the mean line and thus were peaks. It was indicated that these surfaces are typical for this alloy system where the surface has “relief polishing” due to the differences in hardness between the carbide and matrix phases. At the end of the test the PV values had generally increased for the heads. In the case of the cups, some increased and some decreased. The positively skewed distribution for the heads had generally worn to a negative one by the end of the test, indicating that most variations from the mean plane were in the form of scratches while the peaks had been smoothed. The skew had decreased for all the cups also but still remained slightly positive.

In summary, the wear rates, frictional results and surface topography of the BHR hip resurfacing device are within the range of other metal-on-metal total hip replacement (THR) bearings cleared through premarket notification and results reported in published literature.

## Kinematics

The range of motion (ROM) test procedure was performed according to that described in Annex A of ISO 21535: 2002 (EN 12563: 1998), Non-Active Surgical Implants - Joint Replacement Implants - Specific Requirements for Hip-Joint Replacement Implants. ISO 21535 was written for diaphyseal anchored types of hip implants; therefore, the test procedure was modified because the femoral implant component is attached to the proximal femoral head directly and not to an intramedullary stem. Since the ROM of the resurfacing head is restricted by impingement

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between the femoral neck and the rim of the acetabular cup, to simulate the femoral neck, a cylindrical plastic component with the inner diameter of the femoral head was placed on the stem of the femoral head. The ROM is limited by the contact between the cylindrical “femoral neck” and the rim of the acetabular cup. A rationale for components and methods as representative of “worst case” scenario determined the 58mm femoral head size paired with the 64 or 66mm acetabular cup to have the smallest angular displacement. For the purpose of this test the 66mm cup was utilized.

The test result for flexion-extension was an average of 106.4 deg., for abduction-adduction was 73.6 deg., and for internal/external rotation was 106.6 deg. These values were reported to be higher than the ISO minimum values of 80 deg. for flexion-extension, 60 deg. for abduction-adduction, and 90 deg. for internal/external rotation per ISO 21535-2002.

## Stress Analysis

While the BHR has been designed to minimize necessary bone resection of both the acetabulum and femoral head, the component design and materials utilized maintain sufficient material volume to withstand potential forces. Both instrumentation and surgical techniques are developed to allow checking of all cuts, etc., and to make appropriate corrections as necessary. The potential for surgical error, resulting in increase implant stress, is minimized by the policies on product labeling, operative technique and training of user surgeons on use of the device.

Static strength testing showed the average maximum load for dysplasia/bridging fixation screws was 88.4lbf (393 N) and 1099.6 lbf (4890 N) for the dysplasia/bridging cup flange; concluding the loads measured during testing under worst-case conditions indicate both components should be able to withstand predicted in vivo loads. The femoral head demonstrated an average yield point of 5620 N (1263 lbf). Fatigue testing of five femoral stems at a load of 143lbf for 5 million cycles showed no deformation or cracking. The results of these static tests demonstrate that the BHR components should withstand predicted in vivo loads.

## Evaluation of equatorial roundness after simulated implantation

The equatorial roundness of the cup was evaluated after finishing, after insertion of cables and impaction into a balsa wood model. The equatorial roundness was 4.9 micrometers after finishing, 3.4 micrometers after insertion of cables, and 4.3 micrometers after impaction. The impaction of the cup into balsa wood model appeared to have no detrimental effect on the equatorial roundness.

## Acetabular Shell Beaded Surface and HA Coating Characterization

All acetabular cups have a single layer of integrally-cast CoCr-alloy (ASTM F75 and ISO 5832-4) beads on the outer surface that are coated with hydroxyapatite (HA) (ASTM F1185).

Microstructural analyses and bench testing were performed to characterize the beaded surface and the HA coating. The average total thickness of the beaded surface with HA coating was 931 micrometers. The average pore size (mean void intercept length) was 712 micrometers and the average % porosity (volume percent of void) was 34% for the beaded surface with HA coating.

Chemical and crystallographic analyses including XRD and IR spectra were provided to characterize the HA powder and coating materials. In addition, environmental stability of the HA coating on the fixation surface of the BHR acetabular cup was provided which characterized the

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average solubility product (Ksp) of the plasma sprayed HA coating and the dissolution rate of the plasma sprayed HA powder.

The static shear strength of the beaded surface was 46MPa (6658psi). The static tensile strength of the beaded surface was 43MPa (6182psi). The results of the static shear and tensile strength tests surpassed the recommended value of 20 MPa (2900 psi) in the FDA Guidance Document for Testing Orthopedic Implants with Modified Metallic Surfaces Apposing Bone or Bone Cement. The shear fatigue strength of the beaded surface was 11MPa (1595psi). For all of these tests, ASTM methods were used, all failures were due to debonding epoxy, and no beads failed during testing. Because the beaded surface is cast with the substrate and not sintered, it is integral with the substrate. Therefore, the abrasion resistance should be equivalent to currently available CoCr porous beaded coatings.

The average shear strength for the HA coating was 30.5MPa. The average tensile strength for the HA coating was 12.8MPa. All failures were a result of debonding HA from the surface of the test specimen.

This characterization demonstrates that the beaded surface and HA coating has adequate strength and physical properties to perform as it is intended.

## Explant Analysis

Two explant analysis reports for the BHR titled “Wear Retrieval Analysis of Birmingham Resurfacing,” and “Finsbury Test Report “FI98001” were provided.

In the first report, the wear characteristics of the BHR device were investigated using 3 pairs of BHR bearings that were explanted from patients at 6-18mo post-implant. The 3 BHR devices were retrieved for the following reasons: (1) patient died of unrelated causes; (2) avascular necrosis of the femoral head; and (3) infection. These patients were known to be active for at least 6 months after receiving the device. An instrument with a resolution of 0.01 micrometers was used and no measurable wear was detected as compared to their manufactured form.

In the “Finsbury Test Report, FI98001” an explant analysis of one BHR device was performed to evaluate roundness and surface finish. The device was retrieved following femoral neck fracture. The device was in place for 4 months. Results showed that the BHR head diameter was unchanged. Roundness was changed slightly equatorial from 0.3μm to 4μm and polar from 3.9μm to 6.5μm. Cup roundness increased on the equatorial from 0.6μm to 3.4μm. The report stated that the head showed approximately 80% as slightly dulled or “worn;” but, the authors reported that there was no undue damage or abnormalities. Surface finish changes were not significant.

The analysis of these 4 retrieved BHR devices demonstrated that they had undergone little change up to 18-months post-implantation.

## Sterilization

Sterilization of the BHR components is in conformance with the following standards:

- BS EN 552:1994, Sterilization of Medical Devices - Validation and Routine Control of Sterilization by Irradiation;
- EN 46002:1997, Quality Systems - Medical Devices - Particular Requirements for the Application of BS EN ISO 9002;

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- ISO 11137:1995, Sterilization of health care products - Requirements for validation & routine control - Radiation & Sterilization

The principal sterilization process is the Gamma Irradiation utilizing Cobalt 60, dose of 25-35kGy. The sterility assurance level (SAL) is 10⁻⁶. The product is not labeled "pyrogen free".

## Shelf Life Testing

The BHR components are packaged in a Tyvek™ vacuum peel pouch to maintain sterility. Shelf life testing was performed to verify sterile packaging integrity equivalent to five years.

## X. SUMMARY OF CLINICAL STUDIES

### INTRODUCTION:

A clinical data series was used to support the safety and effectiveness of the Birmingham Hip Resurfacing (BHR) system. The BHR was implanted in 2,385 hips by a single investigator, Mr. Derek J.W. McMinn, FRCS. Mr McMinn performed his surgeries at the Birmingham Nuffield and Little Aston Hospitals, Birmingham, United Kingdom from July 1997 through May 2004. Additionally, unpublished data on 3,374 hips implanted by 140 surgeons and published reports from the experience of multiple surgeons implanting over 3,800 hips supported the safety and effectiveness of the BHR System.

### STUDY OBJECTIVES AND ASSESSMENTS:

The objective of the clinical data series was to demonstrate the safety and effectiveness of the Birmingham Hip Resurfacing (BHR) System. The safety assessments included data on revisions, adverse events, deaths and a metal ion literature review. The effectiveness assessments included survivorship and radiographic data, pain and function data as evaluated by the Oswestry-modified Harris Hip (OSHIP) Score, and patient satisfaction data.

### PATIENT SELECTION METHODS AND INDICATIONS FOR USE:

In the case series, patients were not enrolled by the single investigator for pre-defined conditions; instead, a list of diagnoses for the BHR patients was provided. It was noted that during the same time period the investigator implanted the BHR devices, he also had patients who either had no surgery or a total hip replacement (THR). Therefore, to retrospectively develop the indications for use and physician labeling from the experience gained from the 2,385 implantations, a list of the factors that contributed to the investigator's decision to perform a THR in certain patients rather than the BHR hip resurfacing procedure was provided. These factors included:

- Advanced age: Patients of advanced age, especially those with low activity levels, were typically candidates for THR rather than BHR. Only 8.1% of the 2,385 cases included in the Overall McMinn cohort were >65 years of age. In these cases, BHR was selected despite advanced age if the patients had high activity levels, and had good bone stock of the femoral head.

- Low activity level: Patients with a low activity level were considered at lowered risk for future revision, and therefore good candidates for THR. Low activity level was characterized by no participation in sports activities, no heavy work required by job, a sedentary/retired lifestyle, or comorbidities that precluded a high activity level, such as severe arthritis in other joints or severe heart disease.

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- Poor bone stock: Patient with poor bone stock were selected for THR rather than BHR because they were considered at risk for femoral neck fracture or femoral head collapse with a hip resurfacing procedure. Poor bone stock was characterized as severe osteopenia of the femoral head or femoral neck (determined by risk factors, medical history and/or diagnostic imaging), extensive AVN (>50% of femoral head, regardless of FICAT Grade), or the presence of multiple cysts.

The investigator's collection of a patient's pre-operative history, physical, and diagnostic work-up was commonly sufficient to screen candidates for BHR versus THR, and that only in rare instances would the planned surgical procedure be revised intraoperative. Although the investigator rarely changed his preoperative plan based on intraoperative findings, all patients were consented for a hip arthroplasty, and informed about the probable type of prosthesis they would receive. As with any surgical procedure, patients were also informed that based on the intraoperative findings, there could be changes to the planned procedure. The patients were thus consented for both a BHR and THR procedure. Based upon the 2,385 procedures studied, the factors outline above, and an analysis of the BHR revisions in the Overall McMinn Cohort (i.e., femoral neck fracture, femoral head collapse, dislocation, AVN, and infection), the indications for use and physician labeling were developed.

In addition to the factors described above, the literature findings were also considered. For example, the review of 50 BHR femoral neck fractures reported by Shimmin and Back¹ aided in the development of the labeling. In this publication, the authors reported on a review of 3,497 BHR cases performed in Australia by 89 surgeons. There were 50 femoral neck fractures in the series (or 1.46%) which the authors attributed to osteoporosis, and difficulties in implantation of the head and cup leading to notching of the superior femoral neck, varus placement of the device by more than 5°, difficulty in intra-operative alignment, impaction of the femoral component, and poor exposure. Based on these findings, warnings and precautions in the labeling that address these device related failures were included.

## DESCRIPTION OF COHORTS AND DATA COLLECTED

The 2,385 procedures implanted with the Birmingham Hip Resurfacing (BHR) device by a single investigator from July 1997 through May 2004 were divided into the following three main cohorts for the purposes of data analysis:

- X-ray cohort: First 124 BHR cases performed from July 1997 through December 1997.
- Oswestry cohort: Next 1502 BHR cases performed from January 1998 through March 2002.
- McMinn cohort: Next 759 BHR cases performed from April 2002 through May 2004.

Table 3 outlines the dates of implantation, number of procedures, and types of safety and effectiveness data collected for these 3 cohorts:

| Table 3: Cohorts and Data Collected | Types of Safety and Effectiveness Data Collected | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Safety Data Collected | | | Effectiveness Data Collected | | | |
| Cohort | Dates of Implantation | Number of Procedures | Adverse Events | Revisions | Deaths | Survivorship | Radiographic | Pain and Function (OSHIP) | Patient Satisfaction |
| X-ray | 7/97-12/97 | 124 | X | X | X | X | X | X** | X |
| Oswestry | 1/98-3/02 | 1502 | X | X | X | X | | X** | X |
| McMinn | 4/02-5/04* | 759* | X | X | X | X | | *** | |

¹ Shimmin AJ, Back D. Femoral neck fractures following Birmingham hip resurfacing: A national review of 50 cases. J Bone Joint Surg [Br] 87-B:463-4, 2005.

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Note: An X in the table indicates that this data was collected for the respective cohort
* There were 5 cases in the McMinn cohort whose implantations were performed prior to 4/02. These cases should have been part of the Oswestry cohort, but for unknown reasons were not. Therefore, unlike the majority of the McMinn cohort, some of these 5 cases have longer term follow-up.
** See note in Table 4 below regarding the number of procedures contributing to the pain and function (OSHIP) effectiveness data.
*** The pain and function data for the procedures in the McMinn cohort were collected using the Oxford Hip Score evaluation method (and not the OSHIP Score assessment method). Because the 759 procedures in the McMinn Cohort were not tracked by the Oswestry Outcome Center but by the National Health Services (NHS) Center, the FDA and Smith & Nephew, Inc. did not have access to the Oxford hip score data.

As noted in the Table above (with the large bolded “X”), 124 procedures in the X-ray cohort contributed to the assessment of radiographic effectiveness in the PMA. Radiographic evaluations were not provided for the 1502 procedures in the Oswestry cohort or the 759 procedures in the McMinn cohort.

Where there were common data elements collected in the 3 cohorts outlined above, this information was pooled into the following two combined cohorts:

- X-ray/Oswestry/McMinn combined cohort or Overall McMinn cohort: Note that for the rest of this document, this cohort will be referred to as the Overall McMinn cohort.
- X-ray/Oswestry combined cohort

Table 4 outlines the dates of implantation, number of procedures, and types of safety and effectiveness data collected for these 2 combined cohorts:

| Table 4: Combined Cohorts and Data Collected | Types of Safety and Effectiveness Data Collected | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | Safety Data Collected | | | Effectiveness Data Collected | | | |
| Cohort | Dates of Implantation | Number of Procedures | Adverse Events | Revisions | Deaths | Survivorship | Radiographic | Pain and Function (OSHIP) | Patient Satisfaction |
| Overall McMinn Cohort | 7/97-5/04 | 2,385 | X | X | X | X | * | * | * |
| X-ray/ Oswestry Combined | 7/97-3/02 | 1,626 | X | X | X | X | * | X** | X |

Note: An X in the table indicates that this data was collected for the respective cohort
* Although data (e.g., x-ray or pain and function) was collected for one of the cohorts identified in this row, it was not collected for all procedures in the combined cohort; therefore, an X is not included in this part of the table.
** 1,111 unilateral procedures in the X-ray/Oswestry combined cohort contributed to the assessment of pain and function effectiveness data, as evaluated by the Oswestry-modified Harris Hip (OSHIP) Score assessment method.

As noted in the Table above (with large bolded “X”s), the 2,385 procedures in the Overall McMinn cohort contributed to the assessment of safety including adverse events, revisions, and deaths. The 1,626 procedures in the X-ray/Oswestry combined cohort contributed to the assessment of survivorship. Also, as noted in the Table above, 1,111 unilateral procedures in the X-ray/Oswestry combined cohort contributed to the assessment of pain and function effectiveness data, as evaluated by the Oswestry-modified Harris Hip (OSHIP) Score. Unilateral procedures

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were evaluated separately as it is difficult to distinguish pain and function status of each hip separately in patients with bilateral hip involvement. Finally, 1,626 procedures in the X-ray/Oswestry Combined cohort contributed to the patient satisfaction effectiveness.

## Additional Data Sources:

In addition to the clinical data series cohorts, less complete data was provided on 3,374 BHR cases performed by 140 surgeons worldwide (other than the single investigator). The follow-up for these cases was also contracted to the Oswestry Outcomes Centre and includes primarily the same parameters as the follow up for the X-ray/Oswestry combined cohort (adverse events, revisions, deaths, pain and function (OSHIP) scores, and patient satisfaction). The Oswestry Outcomes Centre, therefore, collected data on a total of 5,000 BHR cases. These 5,000 cases are referred to as the Oswestry Worldwide Cohort. The Oswestry Worldwide Cohort consists of 1) the 1,626 cases of the X-ray/Oswestry cohort (the single investigator), and 2) an additional 3,374 non-McMinn (“all other”) cases. The Oswestry Outcomes Centre has provided access to all available data for the BHR cases from its database. Although the data from the 3,374 “all other” cohort was of some value, the applicant and FDA have no ability to independently verify any of the data provided to the Oswestry Outcomes Centre by sites other than the McMinn Center, and have no ability to request additional follow-up or clarifications of any kind from non-McMinn patients or physicians. For these reasons, the analysis on the Oswestry Outcomes Centre worldwide database has some limitations, and is not considered the primary data source.

Several literature references were also included which described the use of over 3,800 BHR devices implanted by multiple surgeons in several countries around the world. One example is the literature reference by Shimmin and Back, discussed above, which was used in the development of the labeling.

## DATA COLLECTION METHODS

### Safety Data Collection Methods

The safety data including adverse events, revisions, and deaths were collected by:

- The Oswestry Outcomes Center using an annual, patient-completed, mail-in questionnaire (deaths were identified while attempting to perform scheduled follow-up);
- The McMinn Center by recording the findings of post-operative patient visits to the McMinn Center in patient records; and
- Recording information provided to the single investigator by primary care physicians.

A summary was provided of the investigator's patient follow-up procedures which included regular evaluations in the preoperative and postoperative time periods according to standard practice and the investigator performed all revision surgeries (except in one known case). Therefore, the revision status was directly known to the investigator.

In addition, a summary was provided of the Oswestry Outcome Center’s (OOC) follow-up procedures which included a collection of data on revisions and adverse events using an annual, patient-completed, mail-in questionnaire. Of the 180 cases missing their last theoretical expected mail-in questionnaire follow-up, 84 are missing at least 2 yearly evaluations, while 96 are only missing their last evaluation. These cases represent only 11.1% (180/1626) of the cases in the Oswestry/X-Ray Combined Cohort. With the exception of 8 cases classified by OOC as “no consent” (subjects who withdrew or did not agree to participate in the study), all other cases are not considered lost-to-follow-up by OOC since they continue to make attempts to contact patients.

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Also, a 100% audit of all 2,385 procedures in the Overall McMinn Cohort was performed.

In addition to the safety data collection methods outlined above, a metal ion literature analysis was provided. Included in the analysis was an unpublished report by Daniel J, Ziaee H, and McMinn D, entitled, “Metal ion studies in patients treated with the Birmingham Hip Resurfacing, a comparable marketed device and historic metal-metal total hip replacements.” The authors conducted 4 metal ion studies in patients who received BHR, Metasul metal-metal total hip replacements, and other marketed (historic) metal-metal total hip replacements.

In addition, summary of several literature references pertaining to the medium and long-term safety of cobalt and chromium ion exposure in the subject device (BHR), metal-on-metal total hip replacements, and metal-on-polyethylene total hip replacements was provided. These literature references are summarized below in the Summary of Safety Data.

## Effectiveness Data Collection Methods

### Survivorship Data Collection Method:

The primary effectiveness measurement was the X-Ray/Oswestry combined cohort survivorship study that included 1626 procedures performed from July 1997 through March 2002 at the Birmingham Nuffield Hospital. These procedures were a minimum of 2 years post-op. Of the 1626 procedures, data are available for 546 of the 601 BHR procedures eligible for 5-year follow up (90.8%). The data for the survivorship study was collected using the same methods presented above for the safety data collection methods.

### Radiographic Data Collection Method:

The clinical data used to support this series contained the results of an independent radiographic review of the X-Ray Cohort, the first 124 procedures performed in the series from July 1997 through December 1997. Radiographic evaluations were not provided for the 1502 procedures in the Oswestry Cohort or the 759 procedures in the McMinn Cohort.

Baseline films for the purposes of comparisons were made in each of the 108 cases in the postoperative time period (usually within 3 months, but 8 of the 108 procedures had baseline evaluations performed at time points ranging from 110-860 days).

The radiographs were interpreted by an independent radiologist. A prospective protocol was developed and used to assess the radiographs. The 5-year anterior/posterior (AP) and lateral view radiographs were compared with the baseline radiographs for the medial-lateral migration, acetabular orientation (tilt angle), femoral and acetabular radiolucencies, heterotopic ossification (HO), bone resorption, acetabular protrusion, cysts, buttressing, and other abnormalities. Radiolucency was defined as a lucent area parallel to and in close proximity to the prosthesis/bone interface encompassing at least 50% of the zone and at least 1mm in width.

A radiographic success was defined as having all of the following:

- Absence of radiolucencies or a radiolucency in any one or two zones (a score of 0-6);
- Component migration ≤2mm; and
- Change in acetabular angle <5°

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A radiographic failure was defined as the following:

- Presence of incomplete or complete radiolucencies or a radiolucency in all zones (a score of 7 or 8);
- A migration of the component >2mm; or
- A change in acetabular orientation of ≥5°

The individual success criterion was the absence of radiographic findings that suggest revision is necessary.

## Oswestry-Modified Harris Hip (OSHIP) Score Data Collection Method

The clinical data used to support this series were collected by the Oswestry Outcomes Center (OOC) using an annual, patient-completed, mail-in questionnaire. The responses to the pain, function, and movement questions in the questionnaire were used to generate the Oswestry-modified Harris Hip (OSHIP) Score.

The OSHIP questionnaire allows patient assessments without direct physician or examiner evaluation. To address how the OSHIP data was collected, the OOC’s standard operating procedures for data input and clarification were summarized for the patient-administered OSHIP questionnaires:

- Any questionnaires with missing, unclear, or conflicting information were returned to the patients with specific instructions on completing the form. The preferred method of follow-up was by mail; however, e-mail and telephone were also used.
- If the data were not collected, the score for any missing item was assumed to be the lowest possible (typically zero).

To address how the OSHIP scoring system was developed, an unpublished paper titled, “A Self-completed Tool for Evaluation of Hip Function: The Oswestry Hip Score,” D. Barnes and co-workers reported that the OSHIP was developed by Professor James Richardson FRCS (Orth), Professor of Orthopaedics at the Institute of Orthopaedics, Robert Jones and Agnes Hunt Orthopaedics and District Hospital—NHS Trust in Oswestry, Shropshire, England. According to Barnes’ paper, creation of the OSHIP began with the following premises:

- Long-term evaluation following hip replacement is essential, follow-up must be regular, and large-samples are necessary.
- Long-term and large-sample follow-up is difficult to obtain when using a score that requires surgeon- or radiologist-assessment.
- Physician-administered surveys are susceptible to bias (which may inflate the final scores) and may not truly represent the patients’ own feelings; and
- Questionnaires needed to be simple and relatively short to make long-term and large-scale collection of data more efficient.

Building on these premises, Professor Richardson developed the OSHIP by combining elements of both the Harris and Merle d’Aubigne scores. The OSHIP produces an overall index score similar to that of the Harris score between 0 (worst) and 100 (best). Both the OSHIP and Harris Hip Score (HHS) are made up of the three domains of pain, function, and hip movement, with function being further divided into gait (walking, limp, and distance), and activity (stairs, sitting and transport).

The main difference between the OSHIP questionnaire and the HHS is that the OSHIP allows patient assessments without direct physician or examiner evaluation. In addition, the OSHIP questionnaire does not include the three HHS questions regarding physician assessment of Range

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of Motion (5 pts.), Absence of Deformity (4 pts.), and the patient’s ability to put on socks/tie shoes (4 pts.) but substitutes a “movement” question (13 pts.) that is intended for the patient to estimate their ability to flex their hip.

To justify the use of the OSHIP scoring system and the validity of patient self-administered questionnaires, several literature references were summarized.

Several researchers have reported a close correlation between patient self-assessment and physician assessment. Research by Mahomed et al.² demonstrated that patients are able to accurately respond to Harris Hip Score questions regarding pain and function with little difficulty, and that there is excellent correlation between the overall HHS pain/function scores reported by patients and the overall HHS pain/function scores reported by physicians (with a correlation of r=0.99, p<0.0001). Note that the Mahomed study did not include patient or physician evaluations of range of motion or deformity, these questions were eliminated from both the patient and physician assessments. Furthermore, McGrory et al.³ found that a brief follow-up phone call (similar to the OOC follow-up procedure discussed above) was effective in capturing missing data and clarifying multiple or contradictory responses from mailed patient self-assessment questionnaires.

In addition, Barnes et al. evaluated the reliability and validity of the Oswestry Hip Score as documented in the research paper, “A Self-completed Tool for Evaluation of Hip Function: The Oswestry Hip Score.” When evaluating the reproducibility of responses to two OSHIP questionnaires completed two weeks apart by 61 patients, the total intra-class correlation coefficient was 0.93 with intra-class correlation coefficients for the individual items and domains ranging from 0.67 to 0.92.

The correlation between the patients’ overall self-administered OSHIP scores and physiotherapist-administered overall HHS scores in 28 consecutive patients was 0.91 (p<0.0001). Correlation between the individual corresponding domains of the Oswestry Hip Score and Harris Hip Score ranged from 0.60 and 0.89. The strongest correlation was between the domains of ‘stairs’ and ‘walking/support’ (0.89) and the lowest for the domains of ‘limp’ (0.60). Additional correlations not included in Mr. Barnes’ study were provided. Correlation between the OSHIP “movement” domain and the HHS “shoes & socks,” “deformity,” and “range of motion” domains were performed. The correlation between OSHIP “movement” and HHS “shoes and socks,” and HHS “range of motion,” was 0.40 and 0.21, respectively. The correlation between OSHIP “movement” and HHS “deformity” was not included and not useful because all 28 subjects scored the maximum of 4 points on the HHS scale (score is either 0 or 4). Additional correlations were performed between OSHIP “movement” domain and the sum of the scores for the HHS “range of motion,” “shoes and socks,” and “deformity.” The correlation between these items was calculated because the OSHIP “movement” domain is the substitute for the HHS “range of motion,” “shoes and socks,” and “deformity” domains. The correlation was calculated to be 0.40. In addition, a linear regression analysis was performed to predict HHS total score from OSHIP total score for the 28 subjects. The linear regression analysis calculated R² is approximately 0.83, which measures the proportion of total variation about the mean explained by the linear regression model. Due to an unclear randomization scheme and questionable masking procedure used to select these 28 sample patients, it is not

² Mahomed NN, Arndt DC, McGrory BJ, Harris WH. *The Harris Hip Score: Comparison of patient self-report with surgeon assessment*. J Arthroplasty 16(5):575-80, 2001.

³ McGrory BJ, Shinar AA, Freiberg AA, Harris WH. *Enhancement of the value of hip questionnaires by telephone follow-up evaluation*. J Arthroplasty 12(3), 1997.

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easy to generalize the above correlations to the general target patient population and clinical judgment was sought from the Orthopaedic and Rehabilitation Devices Advisory Panel.

A review of the raw data from the 28 patient Barnes’ study revealed the following:

- The average OSHIP score was lower than the HHS score, 62 and 67, respectively.
- Fewer subjects had an OSHIP score greater than 80 and more subjects had an OSHIP score less than 70 as compared to their HHS score.
- There were 14 pairs of data where the OSHIP and HHS scores differed by more than 5 points. Of the 14 pairs, the HHS score was higher in 12 cases while the OSHIP was higher in only 2 cases.

Therefore, Barnes emphasized the tendency of the OSHIP scores to be somewhat lower relative to the HHS scores, suggests that the OSHIP is a very close, although conservative, estimate of the HHS.

A paper by Ragab⁴ and co-workers reported a lack of correlation between patient self-assessment of pain and function and physician assessment of pain and function (with a correlation of r=0.467, p<0.01). Like the Barnes study, Ragab⁵ also reported a relative lack of correlation between patient assessment of limp and physician assessment of limp which he believed was due to the physician’s tendency not to report limps that occurred only after long walks or during weather change, while patients were likely to report such limps. However, unlike the Barnes study in which the OSHIP and HHS item regarding “pain” had a correlation of 0.83, Ragab found that when the patients reported significant pain, they were often attributing the pain to their hips when the pain, in most cases, was not truly hip related. The author reported that the physician was better able to distinguish “true” hip pain from pain coming from other sources (for examples, secondary to trochanteric bursitis, lumbar spondylosis, and arthrosis of the contralateral hip). Although Ragab concluded that there is a lack of correlation between patient and physician assessments, Ragab’s research does confirm Barnes’ findings that patient self-assessments tend to be lower than physician assessments.

An additional finding by McGrory and co-workers⁶ was that questions about whether patients could cut their toenails and put on socks/shoes correlated significantly with the HHS range of motion calculation with correlations of r=0.57 and r=0.53, respectively. The authors concluded that responses to these two questions could therefore be used to estimate the weighted HHS range of motion. In addition, Johnston and Smidt⁷ reported that there is a distinct relationship between hip flexion and shoe tying. These articles suggest that an evaluation of a patient’s movements during specific activities of daily living correlate well and may substitute for a physician evaluation of ROM as outlined in the HHS.

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Patient Satisfaction Data Collection Method

Patient satisfaction data were also collected using the annual, patient-completed, mail-in questionnaire. For the purpose of the BHR study, an additional question about patient satisfaction was appended to the end of the OSHIP assessment questionnaire.

## LITERATURE REFERENCES:

A literature search was performed to find published studies of ceramic-on-ceramic total hip replacements to provide a comparison for the BHR clinical study data. PaperChase internet service was used to conduct the literature search and found 400 citations. The abstracts were reviewed and excluded if the article was not in English; was conducted prior to 1990; was a review article; was a small case series with <25 patients; had a highly select patient population; had no specific device identification available; did not use the Harris Hip Score; and did not have a 2-year minimum follow-up. Only two literature articles met these criteria:

D’Antonio J., et al.: New experience with alumina-on-alumina ceramic bearings for total hip arthroplasty. J. Arthroplasty, 17(4): 2002.

This clinical dataset is the same group of 514 procedures that are included in the Howmedica Osteonics ABC System and Trident System PMA (P000013) that used a CoCr alloy femoral stem and a porous-coated Ti alloy acetabular shell with Alumina Bearing Couple (ABC) and the hydroxyapatite-coated titanium shell.

Garino JP: Modern ceramic-on-ceramic total hip systems in the United States: Early results. Clin. Orthop., 379: 2000.

This clinical dataset is the same group of 333 procedures presented in Wright Medical’s Ceramic Transcend Articulation System PMA (P030027).

The data in these references have some differences as compared to the data provided for the BHR device in this clinical data series, including

- Different evaluations, (OSHIP for BHR and HHS for literature)
- Length of follow-up, (18-36mo and 2-4 years for the controls and 2-5 years for the BHR study)
- Mean baseline pain and function scores (e.g., 60 for OSHIP in BHR Oswestry cohort, 44 for HHS Garino study, and not reported for D’Antonio study), and
- Indications for use, (including differences in the rate of dysplasia and AVN diagnostic indications)

However, the literature information provided valuable information on approved ceramic-on-ceramic THR systems for comparison purposes including patient demographics, diagnostic indications, patient accounting, adverse events, revision rates, pain, function, and radiographic results. This information is summarized in several sections below for reference purposes.

## PATIENT DEMOGRAPHICS

### Demographics for X-Ray, Oswestry, McMinn, and Overall McMinn cohorts

Patients in the Overall McMinn cohort were 70.6% men and 29.4% women, ages 13-86 years (average 53.1 years). The primary diagnosis was osteoarthritis in 75.0%, dysplasia in 15.8%, avascular necrosis in 4.1%, inflammatory arthritis in 2.4%, and “other” in 2.7% (Table 5).

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| Table 5: Procedure Demographics | | | | |
| --- | --- | --- | --- | --- |
| | X-Ray Cohort | Oswestry Cohort | McMinn Cohort | Overall McMinn |
| Hips | 124 | 1502 | 759 | 2385 |
| Men | 81 (65.3%) | 1082 (72.0%) | 520 (68.5%) | 1683 (70.6%) |
| Women | 43 (34.7%) | 420 (28.0%) | 239 (31.5%) | 702 (29.4%) |
| Age (range) | 52.8 (27.8-75.3) | 53.0 (13.4-86.5) | 53.3 (21.6-79.5) | 53.1 (13.4-86.5) |
| Age ≤65 years | 111 (89.5%) | 1388 (92.4%) | 692 (91.2%) | 2191 (91.9%) |
| | | | | |
| Dx: OA | 92 (74.2%) | 1171 (78.0%) | 526 (69.3%) | 1789 (75.0%) |
| Dx: DDH | 22 (17.7%) | 197 (13.1%) | 158 (20.8%) | 377 (15.8%) |
| Dx: AVN | 7 (5.6%) | 59 (3.9%) | 31 (4.1%) | 97 (4.1%) |
| Dx: Inflammatory | 2 (1.6%) | 39 (2.6%) | 16 (2.1%) | 57 (2.4%) |
| Dx. Other | 1 (0.8%) | 36 (2.4%) | 28 (3.7%) | 65 (2.7%) |

## Demographics for X-Ray/Oswestry combined cohort

Patients in the survivorship study (X-ray/Oswestry combined cohort) ranged in age from 13.4 to 86.5 years (mean 53 years); 72% of the patients are male, and 28% are female. Of the 1,626 BHR procedures in this cohort, 1,499 (92%) were performed in patients ≤ 65 years old, and 127 (8%) were performed in patients > 65 years old.

## Diagnostic Indications for Unilateral and Bilateral procedures in X-Ray/Oswestry combined cohort

One thousand one hundred and eleven (1,111) of the X-ray/Oswestry combined cohort cases (68%) were unilateral procedures and 515 (32%) were bilateral procedures. The indication for the majority of cases was osteoarthritis. Table 6 provides the breakdown of unilateral and bilateral cases by indication.

| Table 6: Diagnostic Indication for BHR | | | |
| --- | --- | --- | --- |
| Diagnosis | Unilateral | Bilateral | TOTAL |
| Osteoarthritis | 849 (76.4%) | 414 (80.4%) | 1263 (77.7%) |
| Dysplasia | 160 (14.4%) | 59 (11.5%) | 219 (13.5%) |
| Avascular necrosis | 52 (4.7%) | 14 (2.7%) | 66 (4.1%) |
| Inflammatory arthritis | 18 (1.6%) | 23 (4.5%) | 41 (2.4%) |
| Other | 32 (2.9%) | 5 (1.0%) | 37 (2.3%) |
| TOTAL | 1111 (68%) | 515 (32%) | 1626 |

Some of the patients with bilateral hip replacements were included in different groups depending on when the second hip procedure was performed (Table 7).

| Table 7: Hip Procedures | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Cohort | Patients** | Hips*** | Unilateral | Bilateral | Contralateral Single Hip Cohort* | | | Singles |
| | | | | | X-Ray | Oswestry | McMinn | |
| X-Ray | 113 | 124 | 83 | 11 | - | 11 | 8 | 19 |
| Oswestry | 1301 | 1502 | 1028 | 201 | 11 | - | 61 | 72 |
| McMinn | 685 | 759 | 542 | 74 | 8 | 61 | - | 69 |

* Patients with bilateral hip replacements with the contralateral hip not included in the first hip replacement's evaluation cohort.

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** Number of patients equals unilateral + bilateral + singles
*** Number of hips equals unilateral + (2 x bilateral) + singles

## Demographics: Literature References

The study published by D'Antonio et al. reported findings from a multicenter study conducted at 22 investigational sites; the study published by Garino was conducted at 11 investigational sites (Table 8).

| Table 8: Demographics for Literature References | | | | |
| --- | --- | --- | --- | --- |
| Author | Patients | Procedures | Age (Average) | Bilateral Procedures |
| D'Antonio J et al | 458 | 514:
• 349 ceramic
• 165 control | 53 | 19 |
| Garino JP | 333
(f=132, m=201) | 333 | 52 | 0 |

D'Antonio et al. reported the indication for THR as osteoarthritis in 399/514 procedures (77.6%) and avascular necrosis in 82/514 procedures (16%) (Table 9).

### Indication for Arthroplasty

| Table 9: Indications for Use for Literature References | |
| --- | --- |
| Diagnosis | D’Antonio |
| OSTEOARTHRITIS | 399 |
| TRAUMATIC OSTEOARTHRITIS / DJD | 21 |
| AVASCULAR NECROSIS | 82 |
| OTHER / NOT REPORTED | 12 |
| TOTAL | 514 |

## DESCRIPTION OF DEVICE IMPLANTATIONS

The following information on the femoral head sizes and acetabular cup styles and sizes implanted in the 2385 procedures in the Overall McMinn cohort was provided (Table 10).

| Table 10: Surgical Data: Implant Sizes
All Patients | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Acetabular Cup | Femoral Resurfacing Component/Head | | | | | |
| | 38mm | 42mm | 46mm | 50mm | 54mm | 58mm |
| 44mm | 2 (0.1%) | | | | | |
| 46mm | 5 (0.2%)
4^{D} (0.2) | | | | | |
| 48mm | | 119 (5.0%) | | | | |
| 50mm | | 67 (2.8%)
39^{D} (1.6) | | | | |
| 52mm | | | 342 (14.3%) | | | |
| 54mm | | | 154 (6.5%)
1^{F} (0.0)
50^{D} (2.1) | | | |
| 56mm | | | | 683 (28.6%) | | |
| 58mm | | | 3^{B} (0.1%) | 167 (7.0%)
28^{D} (1.2) | | |

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| Table 10: Surgical Data: Implant Sizes
All Patients | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Acetabular Cup | Femoral Resurfacing Component/Head | | | | | |
| | 38mm | 42mm | 46mm | 50mm | 54mm | 58mm |
| 60mm | | | | | 460 (19.3%) | |
| 62mm | | | | 1^{B} (0.0) | 137 (5.7%)
38^{D} (1.6) | |
| 64mm | | | | | | 51 (2.1%) |
| 66mm | | | | | 1^{B} (0.0) | 22 (0.9%)
10^{D} (0.4) |

B Bridging cups
C Custom cups
D Dysplastic cups

## Stratification of Results by Hybrid/Cement/Uncemented:

There was only one case (of the 1,626 cases in the X-ray/Oswestry combined cohort) in which the femoral component was not cemented (a customized implant to accommodate broken metal that remained in the femoral head from a previous event). Therefore, the number of non-hybrid implants (cemented femoral resurfacing component/uncemented acetabular cup) was negligible.

## PATIENT ACCOUNTING

The follow-up rates for the Combined X-Ray / Oswestry Cohort, upon which the effectiveness analyses were performed, at the 1-year, 2-year, 3-year, 4-year, and 5-year postoperative evaluation time points were 76.6%, 77.3%, 88.1%, 88.6%, and 90.8%, respectively. There were 546 procedures (hips) evaluated at 5 years in this cohort (Table 11).

| Table 11: Patient Accounting
Based on the number procedures | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Baseline | 1 year | 2 years | 3 years | 4 years | 5 years |
| Accounting for Survivorship (% Revision Free) | | | | | | |
| Cohort | | # Patients observed at beginning of each study year (# revisions, # censored)^{1} | | | | |
| X-Ray | - | 124 (1,0) | 123 (0,0) | 123 (1,0) | 122 (0,0) | 122 (0,20)^{2} |
| Oswestry | - | 1502 (9,63) | 1430 (5,49) | 1376 (4,256) | 1116 (1,321) | 794 (1,392) |
| McMinn | - | 759 (3,290) | 466 (0,379) | 87 (0,84) | 3 (0,0)^{3} | 3 (0,0)^{3} |
| X-Ray Cohort | | | | | | |
| Expected^{1,8} | 124 | 123 | 123 | 122 | 122 | 118^{3} |
| Evaluated^{2} | 82 | 101 | 51 | 122 | 119 | 112 |
| F/U %^{3} | 66.1% | 82.1% | 41.4% | 100.0% | 97.5% | 94.9%^{3} |
| Evaluated^{4} | 124 | - | - | - | - | 108 |
| F/U%^{4} | 100% | - | - | - | - | 91.5% |
| Oswestry Cohort | | | | | | |
| Expected^{1,8} | 1502 | 1493 | 1484 | 1227 | 885 | 482 |
| Evaluated^{2} | 1229 | 1137 | 1192 | 1067 | 773 | 434 |
| F/U %^{2} | 81.8% | 76.2% | 80.3% | 87.0% | 87.3% | 90.0% |
| X-ray / Oswestry Combined Cohort | | | | | | |
| Theoretical^{1} | 1626 | 1626 | 1626 | 1385 | 1045 | 647 |
| Deaths (procedures) | 0 | 2 | 7 | 16 | 18 | 26 |
| Revisions (cumulative) | 0 | 10 | 15 | 20 | 21 | 23 |
| Expected^{1,8} | 1626 | 1616 | 1607 | 1349 | 1007 | 601 |
| Evaluated^{2} | 1311 | 1238 | 1243 | 1189 | 892 | 546 |
| F/U %^{2} | 80.6% | 76.6% | 77.3% | 88.1% | 88.6% | 90.8% |

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| Table 11 Continued: Patient Accounting
Based on the number procedures | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Baseline | 1 year | 2 years | 3 years | 4 years | 5 years |
| | | | | | | |
| F/U +base^{5} | 1311 | 1067/1304 | 1050/1294 | 944/1046 | 660/726 | 368/397 |
| +base % | | 82% | 81% | 90% | 91% | 93% |
| F/U -base^{5} | 315 | 171/312 | 193/313 | 245/303 | 232/281 | 178/204 |
| -base % | | 55% | 62% | 81% | 83% | 87% |

1 Note that for the Survivorship data the “year 1” data is starting from day 1 and the “year 2” data is starting from day 366, etc. but for the OSHIP scores, the “year 1” data was collected between day 366-730, the “year 2” data was collected between day 731-1095, etc.
2 Evaluated by OSHIP score
3 OSHIP score was available for one hip that was revised shortly after the 5-year follow-up interval, OSHIP data available on 112/119 (94.1%) of hips surviving to 5 years
4 Evaluated by X-Ray
5 The follow-up of those who had baseline OSHIP scores (+base) and those without baseline OSHIP scores (-base).
6 Note that there were 2 revisions in the x-ray cohort at >5 years
7 There were 5 cases in the McMinn cohort whose implantations were performed prior to 4/02. These cases should have been part of the Oswestry cohort, but for unknown reasons were not. Therefore, unlike the majority of the McMinn cohort, some of these 5 cases have longer term follow-up.
8 The expected and evaluated values in each interval include hips with a recorded OSHIP even if the subject died or was revised during the interval.

For the unilateral patients in the X-Ray / Oswestry combined cohort, the follow-up rates at the 1-year, 2-year, 3-year, 4-year, and 5-year postoperative evaluation time points were 75.7%, 76.6%, 88.2%, 88.4%, and 91.1%, respectively (Table 12).

| Table 12: Patient Accounting
Summary of the Oswestry and X-Ray Cohorts - Unilateral
Based on Available OSHIP Data | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | Baseline | 1 year | 2 years | 3 years | 4 years | 5+ years |
| | | | | | | |
| Theoretical | 1111 | 1103 | 1100 | 927 | 687 | 395 |
| OSHIP data | 892 | 835 | 842 | 818 | 607 | 360 |
| % | 80.3 | 75.7 | 76.5 | 88.2 | 88.4 | 91.1 |

Accounting identified in the literature references were as provided in Table 13.

| Table 13: Patient Accounting: Literature References | | |
| --- | --- | --- |
| Author | Mean follow-up (range) | Number of hips (patients) included |
| D’Antonio | 35.2 mos (24 to 48 mos) for ceramic on ceramic.
33.6 mo (24 to 48 mo) for control (metal on polyethylene) | 349 ceramic-on-ceramic THR procedures (318 patients)
• 335 hips (307 pts) at 24 mos
• 243 hips (227 pts) at 36 mos
• 72 hips (71 pts) at 48 mos
165 control THR procedures (161 patients),
• 149 hips (147 pts) at 24 mos
• 111 hips (111 pts) at 36 mos
• 26 hips (26 pts) at 48 mos |
| Garino | Range 18-36 months | “100% follow up for all 333 procedures” |

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# SAFETY DATA

## Safety: Revisions

There were 27 procedures that required revision. Two of the 27 revisions occurred beyond the 5-year follow-up time point in the X-Ray cohort (Table 14).

| Table 14: Revisions Stratified by Cohort | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| | X-Ray Cohort
N=124 | | | | | |
| | Preop | 1 year | 2 years | 3 years | 4 years | 5+ years |
| Number of procedures* | 124 | 124 | 123 | 123 | 122 | 122 |
| Revisions | - | 1 | 0 | 1 | 0 | 2 |
| | Oswestry Cohort
N=1502 | | | | | |
| Number of procedures* | 1502 | 1502 | 1430 | 1376 | 1116 | 794 |
| Revisions | - | 9 | 5 | 4 | 1 | 1 |
| | McMinn Cohort
N=759 | | | | | |
| Number of procedures* | 759 | 759 | 466 | 87 | 3 | 3 |
| Revisions | - | 3 | 0 | 0 | 0 | 0 |
| | X-Ray + Oswestry Combined Cohort
N=1626 | | | | | |
| Number of procedures* | 1626 | 1626 | 1553 | 1499 | 1238 | 916 |
| Revisions | - | 10 | 5 | 5 | 1 | 3 |
| | Overall McMinn Cohort
N=2385 | | | | | |
| Number of procedures* | 2385 | 2385 | 2019 | 1586 | 1241 | 919 |
| Revisions | - | 13 | 5 | 5 | 1 | 3 |

* The number of procedures is the number of hips that were surviving at the end of the previous year based on the survival analysis. Note that for the Survivorship data the “year 1” data is starting from day 1 and the “year 2” data is starting from day 366, etc.

There were 10 revisions due to a femoral neck fracture, 6 for femoral head collapse, 1 for dislocation, 2 for AVN (1 led to femoral head collapse and 1 led to a femoral neck fracture), and 8 for infections (2 led to head collapse, 1 led to a femoral neck fracture) (Table 15). Altogether, there were 12 femoral neck fractures that required revisions. Factors that may have contributed to the femoral neck fractures include age-related osteopenia (2 patients), poor preoperative bone quality as evidenced by cysts in the femoral head and acetabulum (1 case), systemic lupus erythematosus (SLE) (1 case), severe rheumatoid arthritis (RA) (1 case), infection that led to bone death (1 case), femoral head cysts (1 case), and malpositioned component (1 case). The 9 cases with femoral head collapse (6 primary femoral head collapses, 2 collapses due to infection and 1 due to AVN). Factors that may have contributed to the femoral head collapse include infection (2 cases), AVN (2 cases), femoral head cysts and soft bone (3 cases), osteopenia (1 case), and 1 unknown.

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| Table 15: Number and reason for revisions stratified by study cohort (all hips) | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Cohort | Infection | Femoral neck fracture | Collapse femoral head | Avascular Necrosis (AVN) | Dislocation | Mean in days (SD) |
| X-Ray | 3/124* (2.4%) | 1/124 (0.8%) | 0/124 | 0/124 | 0/124 | 1252 days (848) |
| Oswestry | 5/1502 (0.3%) | 7/1502 (0.47%) | 6/1502 (0.4%) | 2/1502 (0.13%) | 0/1502 | 495 days (466) |
| McMinn | 0/759 | 2/759 (0.26%) | 0/759 | 0/759 | 1/759 (0.13%) | 58.3 days (72.6) |
| Total | 8/2385 (0.3%) | 10/2385 (0.4%) | 6/2385 (0.25%) | 2/2385 (0.08%) | 1/2385 (0.04%) | |
| Mean in years | 3.12 yrs | 0.2 yrs | 2.2 yrs | 0.66 yrs | (1 day) | |

* Two of the 3 revisions due to infections beyond 5-year follow-up

## Safety: Revisions Comparison with Literature References

A comparison of the revision rates between the BHR study cohorts and the two literature reference groups was provided. The revision rate for the primary efficacy cohort was 1.47% at 5 years compared to 1.2%, 5.2%, and 1.2%, respectively, for the D'Antonio ceramic-ceramic, D'Antonio metal-poly, and Garino literature reference groups (Table 16).

| Table 16: Revision Rate Comparisons | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | Cohort | | | | | Literature Reference Data | | |
| | X-Ray | Oswestry | X-Ray/Oswestry Combined | McMinn | Overall McMinn | D'Antonio C/C* | D'Antonio M/P* | Garino |
| N | 124 | 1502 | 1626 | 759 | 2385 | 338 | 151 | 333 |
| Revised | 4 | 20 | 24 | 3 | 27 | 4 | 8 | 4 |
| Rate % | 3.2% | 1.3% | 1.47% | 0.3% | 1.13% | 1.2% | 5.2% | 1.2% |
| f/u years | 5 | 4 | 4-5 | 1 | 3 | 3 | 3 | 1-3 |

* Revision rates are based on a minimum of 2-year follow-up

## Safety: Adverse Events

A time course distributions of adverse events was provided (Table 17). The Overall McMinn Cohort contains the X-Ray, Oswestry, and McMinn cohorts, and can be considered the safety cohort for this study. Also, presented below, is a table with the total number of adverse events in the Overall McMinn Cohort stratified by adverse event type and compared with Literature Reference Groups (Table 18).

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| Table 17: Adverse Events*
Overall McMinn Cohort | | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Adverse Event* | Overall McMinn Cohort
N=2385 | | | | | |
| | Postop | 1 year | 2 years | 3 years | 4 years | 5+ years |
| Number of procedures | 2385 | 2157 | 1667 | 1378 | 1018 | 620 |
| Procedures with AE (%) | 1126
(46.2%) | 847
(39.3%) | 155
(9.3%) | 64 (4.6%) | 34 (3.3%) | 53 (8.5%) |
| | | | | | | |
| AVN femoral head/neck | 31 (1.3%) | 2 (<0.1%) | 1 (<0.1%) | 0 | 0 | 1 (0.2%) |
| Femoral head collapse | 7 (0.3%) | 3 (0.1%) | 3 (0.2%) | 1 (<0.1%) | 0 | 1 (0.2%) |
| Component migration/loosening | 1 (<0.1%) | 7 (0.3%) | 8 (0.5%) | 2 (0.1%) | 0 | 1 (0.2%) |
| Femoral neck fracture | 0 | 10 (0.5%) | 0 | 2 (0.1%) | 0 | 1 (0.2%) |
| Impingement | 2 (<0.1%) | 1 (<0.1%) | 0 | 0 | 0 | 0 |
| Infection (device related) | 0 | 7 (0.3%) | 3 (0.2%) | 1 (<0.1%) | 1 (<0.1%) | 2 (0.3%) |
| Dislocation | 0 | 5 (0.2%) | 0 | 2 (0.1%) | 0 | 2 (0.3%) |
| | | | | | | |
| Cardiac event | 15 (0.6%) | 1 (<0.1%) | 0 | 1 (<0.1%) | 0 | 0 |
| Hg drop | 179 (7.5%) | 2 (<0.1%) | 0 | 0 | 0 | 0 |
| Heterotopic Ossification | 0 | 33 (1.5%) | 19 (1.1%) | 3 (0.2%) | 1 (<0.1%) | 3 (0.5%) |
| Hypotension | 33 (1.4%) | 4 (0.2%) | 0 | 0 | 0 | 0 |
| Limp | 0 | 203
(9.4%) | 4 (0.2%) | 2 (0.1%) | 0 | 1 (0.2%) |
| Event at implant site (clicking, etc.) | 0 | 51 (2.4%) | 14 (0.8%) | 9 (0.7%) | 1 (<0.1%) | 3 (0.5%) |
| Reaction at incision site | 8 (0.3%) | 62 (2.9%) | 1 (<0.1%) | 1 (<0.1%) | 0 | 2 (0.3%) |
| Other (see description below) | 171 (7.2%) | 121
(5.6%) | 19 (1.1%) | 7 (0.5%) | 7 (0.7%) | 5 (0.8%) |
| Thromboembolic event | 3 (0.1%) | 3 (0.1%) | 0 | 0 | 0 | 0 |
| Pain | 26 (1.1%) | 223
(10.3%) | 76 (4.6%) | 22 (1.6%) | 20 (2.0%) | 29 (4.7%) |
| Deep Vein Thrombosis | 5 (0.2%) | 1 (<0.1%) | 2 (0.1%) | 0 | 0 | 0 |
| Infection (hip/procedure related) | 28 (1.2%) | 13 (0.6%) | 0 | 0 | 0 | 0 |
| Pneumonia | 2 (<0.1%) | 0 | 0 | 0 | 0 | 0 |
| Fever | 171 (7.2%) | 1 (<0.1%) | 1 (<0.1%) | 0 | 0 | 0 |
| X-ray report comment | 0 | 23 (1.1%) | 12 (0.7%) | 7 (0.5%) | 3 (0.3%) | 7 (1.1%) |
| Stiffness, weakness, flexion deformity, restricted ROM | 0 | 184
(8.5%) | 11 (0.7%) | 9 (0.7%) | 3 (0.3%) | 3 (0.5%) |
| Urinary | 234 (9.8%) | 1 (<0.1%) | 0 | 0 | 0 | 0 |
| Wound exudate | 588 (24.7%) | 1 (<0.1%) | 0 | 0 | 0 | 0 |

* Time course of events shows the number and % of subjects with at least 1 complication of the specified type in the specified time period. Subjects may appear in more than one time period. Events without time information were not included in the table.

## Safety: Adverse Events Overall McMinn Cohort and Comparison with Literature Reference Groups

The rate of wound exudates differs significantly between the two literature reference groups and the Overall McMinn Cohort, 3.4% and 1.4% versus 25%. It was reported that this is probably due to a difference in the definition or reporting requirements. There does not appear to be a correlation between wound exudates and superficial or deep infections. AVN of the femoral head

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(1%), femoral head collapse (&lt;1%), and femoral neck fracture (&lt;1%), which are not possible in conventional total hip replacements, occurred at low rates. The “other” adverse events in the Overall McMinn Cohort included non-device and non-procedure related adverse events, such as dizzy spells, rashes, illnesses, ankle fracture, prostate cancer, or other pre-existing medical conditions.

| Table 18: Comparison of Adverse Events
Overall McMinn Cohort vs. Literature Reference Groups | | | | | |
| --- | --- | --- | --- | --- | --- |
| Adverse Event | Overall McMinn Cohort Totals* | Garino Reference | D'Antonio Reference
N=349 | | |
| | | | ABC with porous | ABC with HA | Control M/P |
| Number of procedures | 2385 | 333 | 172 | 177 | 165 |
| Procedures with AE (%) | 1669 (70%) | | | | |
| Total AEs | 2912 | | | | |
| | | | | | |
| AVN femoral head/neck | 35 (1%) | | | | |
| Femoral head collapse | 15 (<1%) | | | | |
| Component migration/loosening | 21 (<1%) | | | | |
| Femoral neck fracture | 13 (<1%) | | | | |
| Impingement | 3 (<1%) | | | | |
| Infection (device related) | 15 (<1%) | 1 (<1%) | | | |
| Dislocation | 8 (<1%) | 3 (1%) | 2.3% | 3.4% | 4.2% |
| Radiological AE | - | | | | |
| Femoral calcar fracture | | 3 (1%) | | | |
| Acet liner misplaced | | 2 (1%) | | | |
| Liner chipped insertion | | 3 (1%) | 2.9% | 2.3% | - |
| Acetabular migration | | 1 (<1%) | | | |
| Shell malposition | | 1 (<1%) | | | |
| | | | | | |
| Bursitis | | 1 (<1%) | | | |
| Cardiac event | 21 (<1%) | | | | |
| Femoral fracture | | | 2.4% | 1.2% | 1.2% |
| Hg drop | 182 (8%) | | | | |
| Heterotopic Ossification | 56 (2%) | | 2.9% | 3.4% | 6.1% |
| Hypotension | 37 (2%) | | | | |
| Limp | 211 (9%) | | 2% | 4% | 3% |
| Event at implant site (clicking, etc.) | 75 (3%) | | | | |
| Reaction at incision site | 74 (3%) | | | | |
| Other (see above description) | 328 (14%) | | | | |
| Thromboembolic event | 7 (<1%) | 1 (<1%) | | | |
| Pain | 367 (15%) | 2 (<1%) | 9% | 8% | 7% |
| Deep Vein Thrombosis | 8 (<1%) | | | | |
| Infection (hip/procedure related) | 41 (2%) | 1 (<1%) | | | |
| Pneumonia | 2 (<1%) | | | | |
| Fever | 177 (7%) | | | | |
| X-ray report comment | 53 (2%) | | | | |
| Stiffness | 206 (9%) | | | | |
| Urinary | 235 (10%) | | | | |
| Wound exudate | 589 (25%) | | 3.4% | 1.4% | |

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| Table 18 Continued: Comparison of Adverse Events
Overall McMinn Cohort vs. Literature Reference Groups | | | | | |
| --- | --- | --- | --- | --- | --- |
| Adverse Event | Overall McMinn Cohort Totals* | Garino Reference | D'Antonio Reference
N=349 | | |
| | | | ABC with porous | ABC with HA | Control M/P |
| Not applicable (pre-existing condition) | 3 (<1%) | | | | |
| Foot-drop | | 1 (<1%) | | | |
| Vertebral fracture | | 1 (<1%) | | | |
| Other local complication | | 8 (2.5%) | | | |

* Overall event count shows the number and % of subjects that had an event at any time. Subjects were counted only once for an event regardless of the number of times the event was recorded. Events without time information are included in this table.

## Safety: Adverse Events - Discussion of Infections

The infections identified in the clinical data series were categorized, based on data collection procedures, as hip/procedure-related or device-related based on the time of occurrence. There were 41 infections associated with the index hip resurfacing procedure within 30 days of surgery and were thus categorized as hip/procedure-related. All of these events were wound exudates or wound infections that resolved with antibiotics. There were 15 infections that occurred more than 30 days after surgery and were thus categorized as device-related. Of these 15 infections, 6 required revisions and 9 “resolved with antibiotics.” There were two patients who were revised for other indications (component migration and femoral neck fracture) who were found to be infected.

Infections that involve the prosthesis will not typically be successively treated with antibiotics alone. Therefore, it is unlikely the 41 “hip/procedure-related” infections and 9 “device-related” infections that were resolved with antibiotics were actually device-related infections. Therefore, these should be categorized in the hip/procedure-related category, probably as wound problems or superficial infections.

## Safety: Adverse Events - Deaths

There were 20 patient deaths (26 procedures) in the Overall McMinn Cohort. It was stated that in no case was a death related to the BHR procedure. The causes were reported to be: 2 stroke, 4 cancer, 1 motor neuron disease, 1 esophageal cancer and pneumonia, 1 myocardial infarction, 1 suicide, 1 ruptured aorta, 1 carcinoma prostate with metastases, 1 unconfirmed – either diving accident or myocardial infarction, 7 unreported.

## Safety: Metal Ion Literature Analysis

The literature references were provided to address concerns for metal ion release.

- An unpublished report by Daniel J, Ziaee H, and McMinn D, entitled, “Metal ion studies in patients treated with the Birmingham Hip Resurfacing, a comparable FDA-approved device and historic metal-metal total hip replacements” was provided.

The authors conducted 4 metal ion studies in patients who received BHR, Metasul metal-metal total hip replacements, and other marketed (historic) metal-metal total hip replacements:

1. A short-term longitudinal study of urinary Co and Cr levels in patients with the BHR and the Metasul metal-metal total hip replacement.

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12-hour urine collections were obtained preoperatively and postoperatively at 5 days, 2 months, 6 months, 1 year and 2 years for 26 consecutive patients who underwent BHR. The inclusion criteria were unilateral end-stage arthritis; 50mm and 54mm femoral heads; no other implanted metallic devices; and no renal failure. A comparison group of 28 Metasul metal-metal total hip replacement patients operated on 1-3 years previously were studied. The metal ion analyses were performed using a High Resolution Inductively Coupled Plasma Mass Spectrometer (HRICPMS). The mean urinary Co output was 0.4μg/day, 4.0μg/day, 9.0μg/day, 19.2μg/day, 13.4μg/day, and 12.3μg/day for the preoperative, 5-day, 2-month, 6-month, 1-year and 2-year postoperative time points, respectively. A comparison was made between these values with the mean of 11.6μg/day in the 28 Metasul metal-metal total hip replacement patients at 1-3 years. The mean urinary Cr output was 1.6μg/day, 2.1μg/day, 4.0μg/day, 7.3μg/day, 5.3μg/day, and 5.3μg/day for the preoperative, 5-day, 2-month, 6-month, 1-year and 2-year postoperative time points, respectively. In addition, a comparison was made between these values with the mean of 3.7μg/day in the 28 Metasul metal-metal total hip replacement patients at 1-3 years.

2. A long-term cross-sectional study of urinary Co and Cr levels in patients with the BHR and the Metasul metal-metal total hip replacement.

12-hour urine collections were obtained from 58 patients who 5 years previously underwent BHR and 23 patients who received a Metasul metal-metal total hip replacement. At 5 years, the mean urinary Co output was 13.3μg/day for the BHR patients and 14.2μg/day for the Metasul patients. At the same time period, the mean urinary Cr output was 6.4μg/day for the BHR patients and 4.1μg/day for the Metasul patients.

3. A longitudinal study of whole blood Co and Cr levels in patients with the BHR.

Whole blood samples were obtained preoperatively and 1 year postoperatively for 26 consecutive patients who underwent BHR (the same patients as the longitudinal study described above). In addition, the 58 patients who underwent BHR 5 years previously were also studied. The whole blood Co levels were 0.2μg/l, 1.3μg/l, and 1.8μg/l at the preoperative and 1-year time points and the 5-year study patients, respectively. The whole blood Cr levels were 0.3μg/l, 2.4μg/l, and 1.6μg/l at the preoperative and 1-year t…