OPRA Implant System

P190009 · Integrum AB · PJY · Dec 18, 2020 · Orthopedic

Device Facts

• Record ID: P190009
• Device Name: OPRA Implant System
• Applicant: Integrum AB
• Product Code: PJY · Orthopedic
• Decision Date: Dec 18, 2020
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic

Indications for Use

The OPRA™ Implant System is indicated for patients who have transfemoral amputation due to trauma or cancer and who have or are anticipated to have rehabilitation problems with, or cannot use, a conventional socket prosthesis. The OPRA™ Implant System is intended for skeletally mature patients. The patient failed to receive benefit from socket prostheses or is expected to not tolerate socket use due to problems such as: - Recurrent skin infections and ulcerations in the socket contact area - Pain - A short stump preventing the use of socket prosthesis - Volume fluctuation in the stump - Soft tissue scarring - Extensive area of skin grafting - Socket retention problems due to excessive perspiration - Restricted mobility

Device Story

OPRA™ Implant System is a bone-anchored prosthesis for transfemoral amputees. System consists of a titanium fixture (implanted in femoral medullary canal) and a skin-penetrating abutment. Two-stage surgical procedure: Stage 1 implants fixture; Stage 2 connects abutment. External Axor™ II safety coupling connects abutment to standard prosthetic knee/foot components. Axor™ II provides mechanical overload protection by twisting during excessive force (e.g., falls) to prevent fixture/bone damage. Used in clinical settings by orthopedic surgeons; patients manage daily attachment/detachment. Device eliminates socket-related issues (skin irritation, retention problems, volume fluctuations); improves hip range of motion, proprioception, and mobility. Benefits include increased prosthetic use time and improved quality of life. Risks include superficial/deep infection, mechanical complications, and loosening.

Clinical Evidence

PMA approval based on prospective clinical study of 65 subjects (51 original cohort + 14 additional). Primary endpoints: overall success (composite of safety and effectiveness). Effectiveness: Q-TFA score improvement (MCID 20.25) and radiographic success. Safety: no secondary surgical interventions and limited superficial infections. Results: 70.8% effectiveness success at 2 and 5 years; 47.7% overall success at 2 years. Significant improvements in Q-TFA and SF-36 scores (p<0.0001). Adverse events included superficial infection (55%), deep infection (6%), and mechanical complications (8%).

Technological Characteristics

Materials: Grade 5 titanium (Biohelix fixture, central screw, abutment, washer, graft screw). Design: Two-stage osseointegrated system. Connectivity: Standard European 4-hole interface for prosthetic components. Sterilization: Validated to SAL 10^-6. MR Conditional (1.5T/3.0T). Mechanical: Axor™ II safety coupling for overload protection (torsion/bending).

Indications for Use

Indicated for skeletally mature patients with transfemoral amputation due to trauma or cancer who have or are anticipated to have rehabilitation problems with or cannot use conventional socket prostheses. Contraindicated in patients with incomplete skeletal growth, atypical skeletal anatomy, osteoporosis, age <22 or >65, weight >220 lbs, severe peripheral vascular disease, diabetes with complications, skin disorders, neuropathy, active infection, metabolic bone disease, pregnancy, or inability to comply with follow-up.

Regulatory Classification

Identification

The device is a percutaneous prosthetic device for the direct skeletal attachment of a prosthetic limb.

Submission Summary (Full Text)

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SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

I. GENERAL INFORMATION

Device Generic Name: Osseoanchored Prostheses for the Rehabilitation of Amputees (OPRA™)

Device Trade Name: OPRA™ Implant System

Device Procode: PJY

Applicant’s Name and Address: Integrum AB
Krokslätts Fabriker 50,
SE-431 37 Mölndal, Sweden

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P190009

Date of FDA Notice of Approval: December 18, 2020

II. INDICATIONS FOR USE

The OPRA™ Implant System is indicated for patients who have transfemoral amputation due to trauma or cancer and who have or are anticipated to have rehabilitation problems with, or cannot use, a conventional socket prosthesis. The OPRA™ Implant System is intended for skeletally mature patients.

The patient failed to receive benefit from socket prostheses or is expected to not tolerate socket use due to problems such as:

- Recurrent skin infections and ulcerations in the socket contact area
- Pain
- A short stump preventing the use of socket prosthesis
- Volume fluctuation in the stump
- Soft tissue scarring
- Extensive area of skin grafting
- Socket retention problems due to excessive perspiration
- Restricted mobility

III. CONTRAINDICATIONS

The OPRA™ Implant System is not recommended for patients if any of the following is applicable:

- The patient’s skeletal growth is not complete. Completed skeletal growth is defined through the finding of generally closed epiphyseal zones on X-ray.

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- The patient has atypical skeletal anatomy which may affect treatment with OPRA™ Implant System. Examples of atypical skeletal anatomy:
- Skeletal dimensions outside defined interval.
- Development anomalies.
- Conditions which are not amenable to device insertion such as deformities, fracture, infection.
- The patient would have less than 2 mm of remaining cortex bone available around the implant, if implanted.
- The patient has osteoporosis (weak bones).
- The patient is older than 65 years or younger than 22 years.
- The patient's body weight is higher than 220 lbs including the prosthesis.
- Do not treat patients with the following concurrent diseases:
- Severe peripheral vascular disease.
- Diabetic mellitus with complications.
- Skin disorders involving the residual extremity.
- Neuropathy or neuropathic disease and severe phantom pain.
- Active infection or dormant bacteria.
- Metabolic bone disease and/or metastatic lesions in the residual femur.
- The patient is pregnant.
- The patient is not expected to comply with treatment and follow up requirements.

## IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the OPRA™ Implant System labeling.

## V. DEVICE DESCRIPTION

The OPRA™ Implant System consists of an anchorage element (Fixture) and a skin-penetrating device (Abutment). The Fixture is surgically inserted in the medullary canal of the remaining femoral skeleton and, after a healing time of approximately six months, the Abutment is connected to the Fixture. The amputation prosthesis is then attached directly to the external part of the Abutment, via the OPRA™ Axor™ II. A list of component parts in the table below.

| Component | Description |
| --- | --- |
| Fixture
(Biohelix, Grade 5) | A titanium screw that will anchor the artificial leg prosthesis to the femur. |
| Central Screw
(Ridge) | A screw made of titanium that allows access to the bone without removing the Fixture. |

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| Component | Description |
| --- | --- |
| | A part made of titanium that prevents bone from growing into the Fixture opening where the Abutment will be placed during the second surgery. The Healing Cylinder is implanted during the first surgery and removed during the second surgery. |
| Washer | A washer made of titanium that together with the Graft screw holds the bone graft in place. It is implanted during the first surgery and removed during the second surgery. |
| Graft Screw | A titanium screw inserted into the Healing Cylinder that holds the bone graft in place. It is implanted during the first surgery and removed during the second surgery. |
| Abutment | A titanium part that attaches to the Fixture and extends outside the skin to allow the attachment of the prosthesis. It is implanted during the second surgery. |
| Abutment Screw | A screw made of titanium alloy that locks the Abutment to the Fixture. It is implanted during the second surgery. |
| Axor™ II | An external prosthetic connection device that provides a standard connection to other |

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| Component | Description |
| --- | --- |
| | prosthetic components that would include the prosthetic knee and foot. |

The OPRA™ Implant System is implanted in two surgical stages: Stage 1 (S1) and Stage 2 (S2). Figures 1 and 2 show the components as implanted after the surgical stages.

Figure 1. OPRA™ Implant System Parts Implanted in Stage 1 (S1).

Figure 2. Abutment and Abutment Screw inserted in the Fixture during Stage 2 (S2) (superior cortex removed for visualization of the device).

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The OPRA™ Axor™ II attaches to the Abutment end that is outside of the skin and acts as a safety connection between the Abutment and the prosthesis. It is designed to prevent damage to the bone-anchored Fixture if it is overloaded. If an overload occurs, the Axor™ II twists the prosthesis to protect the Fixture from damage.

The Axor™ II provides a standard connection to other prosthetic components that would include the prosthetic knee and foot. A standard European 4-hole male/female mounting system is utilized according to Figure 3 below. This allows the OPRA™ Implant System to be connected to all prosthetic systems that utilize this standardized connection method.

The OPRA™ Implant System is intended for use with commercially available non-microprocessor controlled prosthetic knees and microprocessor controlled prosthetic knees that do not include powered activation of flexion and extension of the prosthetic knee.

Figure 3. Pictures showing the standard European 4-hole interface prosthetic connection.

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Figure 4 shows the OPRA™ Implant System and the Axor™ II with an amputation prosthesis attached on a person.
Figure 4. The OPRA™ Implant System, Axor™ II and Artificial Leg and Foot.

# VI. ALTERNATIVE PRACTICES AND PROCEDURES

The rehabilitation of transfemoral amputees has traditionally been performed using socket prostheses; however, the indication for use for the OPRA™ Implant System is for patients who have or are anticipated to have rehabilitation problems with, or cannot use, a conventional socket prosthesis. For example, in some patients, the use of socket prostheses may lead to complications related to prosthesis retention and function, including inadequate retention, problems due to excessive perspiration, restricted mobility, soft tissue pain or scarring, skin ulcerations, and recurrent infections. In addition, socket prostheses are not an option for some amputees who have a short femur stump or volume fluctuations in the stump. If patients are unable to use socket prostheses, they may use crutches and/or wheelchairs, although these greatly restrict mobility.

# VII. MARKETING HISTORY

The OPRA™ Implant System has been marketed outside of the United States as a custom made device since 1990 and CE marked since 2000. The OPRA™ Implant System has been, and/or currently is, distributed in the following countries: Austria, Australia, Belgium, Chile, Denmark, France, Italy, Jordan, Netherlands, Norway, Portugal, Spain, Sweden, and the United Kingdom. The OPRA™ Implant System has been marketed under a Humanitarian Device Exemption (HDE) marketing application in the U.S. since 2015. The OPRA™ Implant System has not been withdrawn from distribution/ marketing in any country for any safety or effectiveness reasons.

# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

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

Superficial infection
- Mechanical complication of abutment or abutment screw
Pain
- Loosening of the fixture
- Deep infection
- Osteomyelitis (bone infection)
- Injury due to gait instability and/or falls
- Bone fracture
Skin necrosis
- Pyrexia
- Soft tissue necrosis
Chills
- Impaired healing
- Wound necrosis
- Joint injury
Post procedural hematoma
- Myositis
- Blister
- Antibiotic toxicity from repeated administration
Sepsis

For the specific adverse events that occurred in the primary clinical study, other clinical experience, and other literature studies, please see Section X below.

## IX. SUMMARY OF NONCLINICAL STUDIES

## A. Laboratory Studies

Table 1. Laboratory Studies Overview

| Test | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Laboratory Studies of OPRA™ Implant System Fixture and Abutment Components | | | | |
| Bending Fatigue Testing | Validate sufficient mechanical strength for intended use life | Bending test where axial load translates into bending moment | Survive 10M cycles at 85 Nm 6 samples | Passed test with no crack initiation in any component. |
| Bending Fatigue Testing | Validate sufficient mechanical strength for intended use life | Rotation bending | Equal or better fatigue life at 60 Nm than OPRA™ 1.0 6 samples | Passed the test. OPRA™ 1.2 outperformed the fatigue life of OPRA™ 1.0 systems. |

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| Test | Purpose | Method | Acceptance Criteria | Results |
| --- | --- | --- | --- | --- |
| Torsion and Wear Fatigue Testing | Validate sufficient mechanical strength for intended use life in saline | Torsion test | Equal or better fatigue life at 5M cycles of ±15 Nm than OPRA™ 1.0 3 samples | Passed the test. OPRA™ 1.2 showed less wear than OPRA™ 1.0. Both systems fulfilled the requirement. |
| Torsion and Wear Fatigue Testing | Validate sufficient wear and corrosion resistance for intended use life in saline | Torsion test | Equal or better fatigue life at 10M cycles of ±15 Nm than OPRA™ 1.0 3 samples | Passed the test. OPRA™ 1.2 showed less wear than OPRA™ 1.0 after 10M cycles. |
| Laboratory and Simulated Use Studies to Support Changes since Original HDE Approval for the OPRA™ Implant System | | | | |
| FEM Modeling for Material Change | Comparative analysis of stress gradients between possible new designs | Finite element analysis | Lower stress gradients than OPRA™ 1.0 | Passed. Comparative stress gradients for OPRA™ 1.0 vs OPRA™1.2 confirmed the possible fatigue life improvement.
Comparative analysis of OPRA™ 1.0 system with and without bone support confirmed the reduction in stress level in the presence of bone support. |
| Leakage Rate Testing | Validate sufficient leakage rate performance to meet performance requirement | Leakage test | Leakage rate less than 6 μl/min | Passed the test. The updated central screw with ridge design showed an average leakage rate 0.29 μL/min. |
| Healing Component Simulated Use Testing | Functional test of new healing components | Surgical procedure according to instructions for use/surgical technique | Positive clinical outcome at implantation and removal | Passed. The surgical team could verify functionality and performance during implantation and removal. |
| Laboratory Studies of Axor™ II OPRA™ Implant System Component | | | | |
| Maximum Axial Testing | Structural integrity during rare events such as a fall | An axial load of 2700 N was applied via the Abutment. | No mechanical failure 6 samples | No failure was seen in the system. |
| Maximum Bend Testing | Structural integrity during rare events such as a fall | The Abutment was placed in the Axor™ II and 250 Nm moment was applied | No mechanical failure 6 samples | No failure was seen in the system. |

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## B. Additional Studies

Table 2. Additional Testing Overview

| Test | Purpose | Test Method (*see all abbreviations below) | Results |
| --- | --- | --- | --- |
| Biocompatibility | Demonstrate that the OPRA™ Implant System is biocompatible. | ISO 10993-1 | All patient contacting materials are biocompatible. |
| Stability | Shelf life determination | ASTM F1980-02
ISO 11607-1 | Shelf life period of 2 years substantiated. |

## T.2. Clinical Trial

### 1.1. Clinical Trial

The study was conducted in a 12-month-old male with a 18-year-old female who had been treated with a 1000 mg/kg diet for 12 months. The 18-year-old male had been treated with a 1000 mg/kg diet for 12 months. The 18-year-old female had been treated with a 1000 mg/kg diet for 12 months. The 18-year-old male had been treated with a 1000 mg/kg diet for 12 months.

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| Test | Purpose | Test Method (*see all abbreviations below) | Results |
| --- | --- | --- | --- |
| Sterilization | Sterilization validation ensures the sterilization process is adequate | ISO 11137-1 and -2 | SAL 10^{-6} was achieved. |
| Cleaning/Sterility of Reusable Components | Steam sterilization validation and cleaning validation | ANSI/AAMI ST79, AAMI TIR12, ANSI/AAMI/ISO 17665, USP<1211> AAMI TIR30:2011 | SAL 10^{-6} was achieved. Cleaning methods sufficiently reduced soil on the instruments. |
| Magnetic Resonance Imaging (MRI) Testing | Demonstrate device safety in Magnetic Resonance (MR) environment | Displacement force and torque effects according to ASTM F2052-15 and ASTM F2213-17
RF Heating test according to ASTM F2182-19
Image artifacts at 3T according to ASTM F2119-07 | The OPRA^{TM} Implant System is MR Conditional. The MR system used to scan a patient should meet the following conditions:
•Static Magnetic field of 1.5 and 3.0 T
•Maximum spatial field gradient of 4500 gauss/cm (45 T/m)
•Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 2 W/kg (normal operation mode) when the implant is at least 20 cm out of isocenter.

RF heating tests of the OPRA^{TM} Implant System showed high expected temperature increase for a wbSAR of 2W/kg after 15 minutes of continuous scanning when at the isocenter. Moving the device 20 cm out of iso center, as listed in the conditions above, reduced heating to 3.9°C.

The image artifact caused by the device extends approximately up to 45 mm from the OPRA^{TM} Implant System when imaged with a gradient echo pulse sequence and a 3.0 T MRI system. It is likely that clinical MR protocols may show smaller artifacts. |
| * AAMI: Association for the Advancement of Medical Instrumentation
ANSI: American National Standards Institute
ASTM: ASTM, International
ISO: International Standardization Organization
USP: United States Pharmacopeia | | | |

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# X. SUMMARY OF PRIMARY CLINICAL STUDY

The OPRA™ Implant System was evaluated for safety and effectiveness from clinical study data of 65 participants.

## Summary of the OPRA™ Implant System Clinical Investigation

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of the OPRA™ Implant System for patients who have transfemoral amputation due to trauma or cancer and who have, or are anticipated to have rehabilitation problems with, or cannot use, a conventional socket prosthesis. Data from this clinical study and literature studies supported HDE approval in 2015 and were the basis for the PMA approval decision. For the PMA approval, a total of 65 subjects were analyzed, including 51 subjects from the primary clinical study with 14 additional subjects who were implanted at Sahlgrenska University Hospital, Gothenburg, Sweden between March 2007 and November 2011 with an OPRA™ implant very similar to the study implant, in principle only excluding the tantalum beads which does not affect clinical outcomes and met the same eligibility criteria as the OPRA™ study. Two and five-year outcomes are presented for the N=65 cohort.

The data with the 65 subjects presented below was obtained with an older version of the OPRA™ Implant System device. Since that time, the device has undergone incremental improvements for safety. Specifically, the Fixture, the Abutment, and the connection between the Fixture and Abutment have been redesigned with improved mechanical characteristics, both in fatigue and ultimate strength, leading to a stronger and more durable device. The safety device connection (the Axor™ II) between the Abutment and external prosthetic components has been further improved and adds control not only in torsion but also in bending.

## A. Study Design

A prospective investigation was performed at Sahlgrenska University Hospital on transfemoral bone-anchored amputation prostheses. The study began in 1999. Each of the 51 subjects served as his/her own historical control, as the study was not randomized. Six of the 51 patients were bilateral subjects. The remaining forty-five patients were unilateral subjects. Due to the small sample size of the bilateral patients, this group was unable to be separated and studied alone. The length of the study was 2 years.

### 1. Clinical Inclusion and Exclusion Criteria

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

- Transfemoral amputee patients with problems using a conventional socket prosthesis OR patients anticipated to experience significant problems with socket use
- Undergone pre-operative Radiographic assessment including CT of the femur stump
- Skeletal maturity
- Normal retained femur anatomy
- Body weight less than 100 kg (220 lb)
- Suitable for surgery based on upon medical history and physical examination
- Ability to comply with the rehabilitative and follow up regimen
- Ability to give written Informed Consent

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

- Over 70 years of age
- Severe peripheral vascular disease, diabetes mellitus with complications, skin diseases involving the amputated limb or other diseases that could affect the suggested treatment negatively
- Systemically administrated corticosteroids, chemotherapy drugs or other drugs in a way that could affect the suggested treatment negatively
- Pregnant

2. Follow-up Schedule

Surgery was performed in two stages. The first to implant the OPRA™ Implant System fixture and the second to mount an abutment on which a safety coupling for the actual prosthesis could be attached. Visits were done at 3, 6, 12 and 24 months.

The Clinical Investigation consisted of 7 assessment visits. The multiple procedures performed at each visit (marked with X at each time point) are outlined in Table 3.

1. Pre-Operative Assessments.
2. Surgery Stage I Assessments.
3. Surgery Stage II Assessments.
4. Assessments 3 Months Post Surgery Stage II.
5. Assessments 6 Months Post Surgery Stage II.
6. Assessments 12 Months Post Surgery Stage II.
7. Assessments 24 Months Post Surgery Stage II.

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Table 3. Study Assessments

| ASSESSMENTS | PRE | S I | S II | 3 M | 6 M | 12 M | 24 M |
| --- | --- | --- | --- | --- | --- | --- | --- |
| PRE-OPERATIVE:
· ELIGIBILITY CHECKLIST
· SUBJECT DETAILS
· RADIOGRAPHY
· COMPUTED TOMOGRAPHY
· MEDICATION
· PRE-OP HIP JOINT MOTION
· PRE-OP QUESTIONNAIRES
· PCI
· STRENGTH
· REGISTRATION OF EXTERNAL COMPONENTS
· VIBRAMETRY | X | | | | | | |
| SURGERY STAGE I:
· SURGERY DETAILS
· POST-OP CLINICAL DETAILS
· POST-OP RADIOGRAPHY
· POST-OP RSA
· MEDICATION | | X | | | | | |
| SURGERY STAGE II:
· PRE-OP RADIOGRAPHY
· SURGERY DETAILS
· POST-OP CLINICAL DETAILS
· POST-OP RADIOGRAPHY
· POST-OP RSA
· 3 WEEKS POST-OP CLINICAL ASSESSMENT
· MEDICATION | | | X | | | | |
| POST-OP STAGE II – 3 AND 6 MONTHS:
· CLINICAL ASSESSMENT
· RADIOGRAPHY
· RSA
· MEDICATION
· REHABILITATION DETAILS | | | | X | X | | |

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| ASSESSMENTS | PRE | S I | S II | 3 M | 6 M | 12 M | 24 M |
| --- | --- | --- | --- | --- | --- | --- | --- |
| POST-OP STAGE II–12 AND 24 MONTHS:
· CLINICAL ASSESSMENT
· RADIOGRAPHY
· RSA
· MEDICATION
· REHABILITATION DETAILS
· POST-OP HIP JOINT MOTION
· POST-OP QUESTIONNAIRES
· PCI
· STRENGTH
· REGISTRATION OF EXTERNAL COMPONENTS
· VIBRAMETRY | | | | | | X | X |
| ADVERSE EVENTS | When applicable | When applicable | When applicable | When applicable | When applicable | When applicable | When applicable |
| REOPERATION | | When applicable | When applicable | When applicable | When applicable | When applicable | When applicable |
| COMPLETION / WITHDRAWAL | When applicable | When applicable | When applicable | When applicable | When applicable | When applicable | X |

S: surgery; M: month.

Following the original 2-year study, patients were followed for an extended period of time after Surgery Stage II. Five-year outcomes for a subset of patients are summarized further below.

## 3. Clinical Endpoints

The primary effectiveness endpoint of the original clinical investigation was to evaluate the improvement of Prosthetic Use Score captured by the Questionnaire for Persons with a Transfemoral Amputation (Q-TFA), a patient reported outcome measure, comparing the OPRA™ Implant System to baseline (i.e., to socket prosthesis).

The primary safety endpoint was time to revision defined as removal of fixture and removal of abutment. Infection, reoperation, and other safety data were also collected.

The secondary effectiveness endpoints included the Q-TFA problem, mobility, and global sub-scales and individual questions regarding time usage of the prosthesis per week. The SF-36 (i.e., Short Form (36) Health Survey, which is a 36-item, patient-reported survey of patient health) was also included.

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## B. Accountability of OPRA™ Clinical Study Cohort

The accounting of the subjects over the duration of the study in the Intent-to-Treat (ITT) population is presented below in Table 4.

Table 4. Subject Accountability, ITT Population

| | Baseline | 12 months | 24 months |
| --- | --- | --- | --- |
| Theoretical [1] | 51 | 51 | 51 |
| Deaths [2] | 0 | 1 | 1 |
| Failures [3] | 0 | 1 | 4 |
| Expected [4] | 51 | 49 | 46 |
| Actual^{A} | 47 | 42 | 36 |
| % Follow-up [5] | 92.2 | 85.7 | 78.3 |
| Actual^{B} | 51 | 47 | 45 |
| % Follow-up [6] | 100.0 | 95.9 | 97.8 |
| NA: Not applicable
Actual^{A}: Subjects with complete data for each endpoint, evaluated per protocol, in the window of time.
Actual^{B}: Subjects with any follow-up data reviewed or evaluated by the 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 (Fixture revision) during or prior to the study visit.
[4] Theoretical subjects minus the number of deaths and revisions.
[5] Actual^{A}/Expected*100
[6] Actual^{B}/Expected*100 | | | |

Missing is defined as lack of data for any reason, e.g. visit not done, data not captured during a visit or subject lost to follow-up.

## C. Study Population Demographics and Baseline Parameters

The subjects' demographics and baseline characteristics for the ITT population are presented in Table 5 below. The study enrolled 28 males (55%) and 23 females (45%) with a mean age of 44.2 years and mean Body Mass Index (BMI) of 28.1 kg/m².

The major reason for amputation was trauma in 33 (65%) followed by tumor in 12 (24%) of the subjects. Six (12%) of the subjects had vascular disease or other reason for the amputation.

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Forty-two (82%) of the subjects were using socket prosthesis at enrollment, and 8 (16%) had been using a socket prosthesis at some point prior to enrollment. In addition, one patient (2%) was a bilateral amputee who never used a socket prosthesis because of very short stumps. Data from baseline may therefore be considered a comparison to socket prosthesis. The mean time between amputation and surgery stage I in the study was 12.1 years. Eleven (22%) of the subjects were smokers at inclusion.

About half of the subjects were using concomitant medication at study start.

Table 5. Subject Demographics and Baseline Characteristics (ITT Population)

| Variable | ITT Population (n=51) |
| --- | --- |
| Gender | |
| Male | 28 (54.9%) |
| Female | 23 (45.1%) |
| Age at inclusion (years) | 44.2 (12.2)
46.4 (19.9; 64.7)
n=51 |
| Unilateral/bilateral amputated | |
| Unilateral | 45 (88.2%) |
| Bilateral | 6 (11.8%) |
| Reason for amputation | |
| Trauma | 33 (64.7%) |
| Peripheral Vascular Disease | 2 (3.9%) |
| Tumor | 12 (23.5%) |
| Other | 4 (7.8%) |
| Time between amputation and surgery SI (years) | 12.1 (11.1)
8.0 (0.9; 41.8)
n=51 |
| Age at amputation (years) | 32.4 (13.6)
31.6 (13.0; 63.8)
n=50 |
| Estimated weight at inclusion (kg)^{1} | 83.5 (18.6)
83.4 (50.4; 128.8)
n=50 |
| Height at inclusion (cm) | 172.4 (10.2)
173.5 (154.0; 194.0)
n=48 |

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| Variable | ITT Population (n=51) |
| --- | --- |
| Estimated BMI at inclusion (kg/m²)² | 28.1 (4.9)
26.9 (17.4; 42.1)
n=48 |
| Smoker at inclusion | 11 (21.6%) |
| Prosthetic user at inclusion | 42 (82.4%) |
| Ever used prosthesis if not Prosthetic user at inclusion | 8 (88.9%)³ |
| Level of education | |
| Primary school | 11 (23.9%) |
| Secondary school | 23 (50.0%) |
| Exam from University | 12 (26.1%) |
| Data missing | 5 |
| Civil status | |
| Single | 19 (37.3%) |
| Married/cohabiting | 32 (62.7%) |
| Nationality | |
| England | 1 (2.0%) |
| Norway | 14 (27.5%) |
| Spain | 11 (21.6%) |
| Sweden | 25 (49.0%) |
| Employment at inclusion (%) | 35.1 (41.7)
10.0 (0.0; 100.0)
n=51 |
| Medication at inclusion | |
| Yes | 26 (51.0%) |
| No | 25 (49.0%) |
| For categorical variables n (%) is presented.
For continuous variables Mean (SD) / Median (Min; Max) / n= is presented.
¹ Weight has been measured without prosthesis. For unilateral patients, 12% have been added to calculate the estimated weight, and for bilateral, approximately 27.3% have been added.
² The estimated BMI is based on estimated weight and height. Height is measured with prosthesis.
³ One observation is missing. The patient was a bilateral amputee who never used a socket prosthesis because of very short stumps. However, one of the limbs was long enough to be treated with the OPRA™ Implant System and the patient was using a bone-anchored prosthesis. The treatment was performed only 10 months after amputation. | |

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D. Safety and Effectiveness Results

1. Safety Results

**Adverse effects that occurred in the primary clinical study:**

Adverse Events (AEs) were captured from the enrollment of the subject and until the subject had the 24-month visit. Five-year safety data for a subset of patients are presented further below.

An AE was defined as any undesirable clinical occurrence in a subject whether it was considered to be related to the OPRA™ Implant System or not. All AEs during the study were to be recorded. An AE could be both objective and subjective. The primary Safety variable was time to revision. Adverse events were captured as the following:

- Onset of Adverse Event
- Expected AEs
- Superficial Infection
- Deep Infection
- Pain
- Mechanical complication of OPRA™
- Skeletal fracture
- Loosening of OPRA™
- Unexpected AEs
- Severity of Adverse Event

The AEs were classified as mild, moderate or severe with respect to their intensity. The following definitions were used:

- Mild: AE which was easily tolerated
- Moderate: AE which causes sufficient discomfort to interfere with daily activities
- Severe: AE which caused marked limitation in activity, some assistance may have been needed, medical intervention/therapy required, hospitalization was possible

The AEs were evaluated for seriousness. A Serious Adverse Event (SAE) was defined as any untoward medical occurrence that:

- Resulted in death
- Was life-threatening
- Required inpatient hospitalization or prolongation of existing hospitalization
- Resulted in persistent or significant disability/incapacity

The relationship to the OPRA™ Implant System was classified as:

- Not related: The Adverse Event was definitely not related to the OPRA™ Implant System

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- Probably Unrelated: Cause and effect relationship between the AE and OPRA™ Implant System was not demonstrated, was improbable, but not impossible
- Possibly Related: A direct cause and effect relationship between the AE and the OPRA™ Implant System was not demonstrated, but is possible or likely
- Related: There is a direct cause and effect relationship between the AE and the OPRA™ Implant System.

Early loosening was the most common adverse event requiring surgical removal of the OPRA™ Implant System and removal was normally performed within the first two years after the Stage 2 surgery. No implant fracture was reported with the OPRA™ Implant System. In no subject, regardless of adverse event, was it necessary to revise the femoral bone by resecting further proximally thereby shortening the femur.

There was a total of 101 treatment emergent AEs. Table 6 summarizes all adverse events that were either related or possibly related to use of the OPRA™ device. The most frequent AEs related to the treatment during the 2-year study were:

- Infection: 31 (61%) subjects with 44 events
- Superficial infection: 28 (55%) subjects with 40 events
- Deep infection: 3 (6%) subjects with 4 events
- Mechanical complication of the implant: 4 (8%) subjects with 9 events
- Pain: 6 (12%) subjects with 6 events
- Injury: 4 (8%) subjects with 4 events
- Loosening of the Fixture: 4 (8%) subjects with 4 events

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Table 6. Treatment Emergent Related and Possible Related Adverse Events (Safety Population)

| System Organ Class PT | Safety Population (n=51) | |
| --- | --- | --- |
| | AEs | Total Subjects with AEs n (%) |
| Any AE | 84 | 44 (86.3%) |
| General disorders and administration site conditions | 20 | 12 (23.5%) |
| Chills | 1 | 1 (2.0%) |
| Impaired healing | 1 | 1 (2.0%) |
| Mechanical complication of implant | 9 | 4 (7.8%) |
| Pain | 6 | 6 (11.8%) |
| Pyrexia | 2 | 2 (3.9%) |
| Wound necrosis | 1 | 1 (2.0%) |
| Infections | 44 | 31 (60.8%) |
| Superficial | 40 | 28 (54.9%) |
| Deep | 4 | 3 (5.9%) |
| Injury, poisoning and procedural complications | 13 | 13 (25.5%) |
| Loosening of the fixture resulting in device removal/failure | 4 | 4 (7.8%) |
| Skeletal fracture | 3 | 3 (5.9%) |
| Injury* | 4 | 4 (7.8%) |
| Joint injury | 1 | 1 (2.0%) |
| Post procedural hematoma | 1 | 1 (2.0%) |
| Musculoskeletal and connective tissue disorders | 3 | 3 (5.9%) |
| Myositis | 1 | 1 (2.0%) |
| Soft tissue necrosis | 2 | 2 (3.9%) |
| Skin and subcutaneous tissue disorders | 4 | 4 (7.8%) |
| Blister | 1 | 1 (2.0%) |
| Skin necrosis | 3 | 3 (5.9%) |

* 4 events of trauma resulting from falls

As noted above, 28 subjects experienced a superficial infection. Three subjects experienced a deep infection. In the study, none of the superficial infections developed into a deep infection; no patient who developed a deep infection had a previous superficial infection.

Among the 84 treatment emergent related and possibly related AEs, the most frequent SAEs were:

- Superficial infection, 4 (7.8%) subjects with 4 (4.8%) events,
- Deep infection, reported by 3 (5.9%) subjects with 4 (4.8%) events, and

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- Secondary surgical intervention (including reoperation, component replacement/revision, removal): 13 $(15.5\%)$ events reported by 13 $(25.5\%)$ subjects; of the 13 events, 4 $(4.8\%)$ events reported by 4 $(7.8\%)$ subjects were specific to implant (fixture) removal (3 implants removed during the study and 1 shortly after the study, giving 4 events in 4 patients).

Table 7 shows the distribution of subjects with treatment emergent adverse events for the different time periods throughout the study. This table shows the number of subjects with treatment emergent adverse events whether or not they were deemed to be related, possibly related, or not related to the $\mathrm{OPRA^{TM}}$ Implant System. Please note, Table 7 shows 'subjects with events' at each time point; therefore, one subject may be represented multiple times in the table if they experienced an adverse event at more than one time point. However, as Table 7 counts 'subjects with events', not 'total events', if a subject had multiple events occur within one time period, it would only be captured once. Please also note, all adverse events listed in Table 6 are captured in Table 7; however, they are categorized differently, such that major adverse events, such as infection, pain and loosening are called out; while, minor events, such as chills or bruising, are captured as other.

Table 7. Subjects with Treatment Emergent Adverse Events over Time

| | Immed. Post-op Surgery 1 (n=51) | After Immed. Post-op Surgery 1 – Surgery 2 (n=51) | Immed. Post-op Surgery 2 (n=51) | After Immed. Post-op Surgery 2 – 3 months (n=51) | 3 months – 6 months (n=51) | 6 months – 12 months (n=48) | 12 months – End of Study (n=48) |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | Subjects with Events n (%) | Subjects with Events n (%) *None | Subjects with Events n (%) | Subjects with Events n (%) | Subjects with Events n (%) | Subjects with Events n (%) | Subjects with Events n (%) |
| Operative Site Events | | | | | | | |
| Superficial Infection | | | 6 (11.8%) | 3 (5.9%) | 4 (7.8%) | 13 (27.1%) | 12 (25.0%) |
| Deep Infection | 2 (3.9%) | | 3 (5.9%) | | | | |
| Pain | | | | | 1 (2.0%) | 3 (6.3%) | 3 (6.3%) |
| Onset of loosening of OPRA™ Implant System | | | 1 (2.0%) | | | 3* (5.5%) | |
| Skeletal fracture | | | | 1 (2.0%) | | 2 (3.9%) | 1 (2.1%) |
| Trauma | | | | | 2 (3.9%) | 2 (3.9%) | 3 (6.3%) |
| Mechanical complication of OPRA™ Implant System | | | | | | 1 (2.1%) | 4 (8.3%) |
| Systemic Events | | | | | | | |

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| | Immed. Post-op Surgery 1 (n=51) | After Immed. Post-op Surgery 1 – Surgery 2 (n=51) | Immed. Post-op Surgery 2 (n=51) | After Immed. Post-op Surgery 2 – 3 months (n=51) | 3 months – 6 months (n=51) | 6 months – 12 months (n=48) | 12 months – End of Study (n=48) |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | Subjects with Events n (%) | Subjects with Events n (%) *None | Subjects with Events n (%) | Subjects with Events n (%) | Subjects with Events n (%) | Subjects with Events n (%) | Subjects with Events n (%) |
| Myocardial infarction *None | | | | | | | |
| Pulmonary emboli *None | | | | | | | |
| Urinary tract infection | | | | | | 1 (2.1%) | |
| Other | 3 (5.9%) | | 6 (11.8%) | 1 (2.0%) | 2 (3.9%) | 4 (8.3%) | 4 (8.3%) |
| Immediately Post-op Surgery is defined within 42 days.
* 1 patient showed signs of loosening of OPRA™ within the study, but the fixture was removed 4 months after the 24 month follow-up
*None: The grey cells denote that no events were reported in these categories. | | | | | | | |

## 2. Effectiveness Results

For the primary endpoint, the mean prosthetic use score at baseline was 46.7 (standard deviation or SD: 36.7) out of 100. The score increased significantly, from baseline to 12 months, mean score 79.7 (22.7) and was sustained at 24 months, mean score 79.9 (27.1) (p&lt;0.0001) (Table 8). The OPRA™ Implant System was also able to provide subjects with benefits such as longer walking distances, easier attachment and de-attachment of the prosthesis and increased sitting comfort.

Cumulative survival rate of the Fixture (defined as lack of Fixture removal or revision) after two years of follow up was 92% in terms of patient survival and 93% in terms of implant survival. This calculation was based on standard Kaplan-Meier curves and the fact that four patients were treated bilaterally who have two implants/fixtures (i.e., for a total of 51 patients, 55 implants were used, and four patients had a fixture removal) with an assumption that non-observed data is non-informative.

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Table 8. Primary Effectiveness Analysis: Q-TFA derived Prosthetic Use Score (ITT Population)

| | | | | Change from Baseline to 12 months | | Change from Baseline to 24 months | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Variable | Baseline (n=51) | 12 months (n=48) | 24 months (n=45) | | p-value | | p-value |
| Prosthetic Use score | 46.7 (36.7) | 79.7 (22.7) | 79.9 (27.1) | 34.4 (29.0) | | 32.0 (41.0) | |
| | 52.0 | 90.0 | 90.0 | 29.0 | | 29.0 | |
| | (0.0; 100.0) | (6.0; 100.0) | (0.0; 100.0) | (-23.0; 100.0) | | (-100.0; 100.0) | |
| | n=51 | n=44 | n=45 | n=44 | <0.0001 | n=45 | <0.0001 |
| For continuous variables Mean (Standard Deviation) / Median (Min; Max) / n= is presented.
For comparison over time Wilcoxon Signed Rank test was used for continuous variables.
Note: In terms of effectiveness, higher score is expected for the Prosthetic Use score. | | | | | | | |

The average of the Q-TFA prosthetic use score stratified by baseline score and the changes in scores at 12 and 24 months are shown in Figure 5. As shown, low prosthetic users (baseline score &lt;25) saw a large increase in prosthetic use at 1 and 2 years. The moderate prosthetic users (baseline scores 25-75) saw a slight increase and the high functional prosthetic users (baseline score &gt;75) saw a slight decrease.

Figure 5. Mean Q-TFA Prosthetic Use Score by Visit.

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Figure 6 shows the daily and weekly usage of the prosthetic device at baseline, 12 months and 24 months. As shown, the number of subjects using their prostheses increased during the study, both on an hourly and daily basis.

Figure 6. Prosthesis Use by Visit.

The following scores changed statistically significantly (p&lt;0.0001) from baseline to the follow-up visits:

- The problem score decreased from baseline to 12 and to 24 months.
- The prosthetic mobility score, the walking habits sub-score, the capability sub-score and the global score increased from baseline to 12 and to 24 months.

There was no statistically significant change from baseline to 12 and 24 months in the walking aids subscore, though numerical improvements were observed. The Q-TFA secondary effectiveness variables are presented below in Table 9.

Table 9. Q-TFA Subscales

| | | | | Change from Baseline to 12 months | | Change from Baseline to 24 months | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Variable | Baseline (n=51) | 12 months (n=48) | 24 months (n=45) | | p-value | | p-value |
| Problem Score | 43.9 (18.7) 47.5 (5.0; 77.0) n=42 | 15.2 (10.0) 13.0 (2.0; 48.0) n=42 | 16.8 (12.3) 13.5 (1.0; 54.0) n=44 | -28.4 (16.2) -33.0 (-57.0; 2.0) n=36 | <0.0001 | -26.6 (16.3) -30.0 (-59.0; 7.0) n=37 | <0.0001 |
| Prosthetic Mobility Score | 52.5 (20.4) 56.0 (0.0; 82.0) n=42 | 60.0 (23.3) 64.5 (0.0; 91.0) n=44 | 64.1 (21.7) 71.0 (4.0; 91.0) n=44 | 14.0 (16.8) 15.0 (-29.0; 46.0) n=36 | <0.0001 | 17.6 (15.6) 17.0 (-29.0; 48.0) n=37 | <0.0001 |
| Walking Habits (Subscore) | 34.5 (19.2) 32.5 (0.0; 75.0) n=42 | 47.3 (22.6) 50.0 (0.0; 80.0) n=43 | 47.8 (23.9) 55.0 (0.0; 85.0) n=44 | 16.5 (16.9) 20.0 (-20.0; 50.0) n=36 | <0.0001 | 18.8 (20.3) 15.0 (-20.0; 70.0) n=37 | <0.0001 |

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| | | | | Change from Baseline to 12 months | | Change from Baseline to 24 months | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Variable | Baseline (n=51) | 12 months (n=48) | 24 months (n=45) | | p-value | | p-value |
| Walking Aids (Subscore) | 73.4 (25.9)
83.0 (33.0; 100.0)
n=39 | 66.5 (24.4)
75.0 (17.0; 100.0)
n=40 | 71.6 (24.5)
83.0 (17.0; 100.0)
n=40 | -2.13 (26.70)
0.00 (-67.00; 50.00)
n=32 | 0.5223 | 2.06 (21.18)
0.00 (-67.00; 50.00)
n=33 | 0.4506 |
| Capability (Subscore) | 53.4 (23.5)
58.0 (0.0; 92.0)
n=42 | 70.4 (29.2)
83.0 (0.0; 100.0)
n=45 | 76.7 (23.6)
83.0 (8.0; 100.0)
n=44 | 23.6 (24.9)
25.0 (-75.0; 75.0)
n=37 | <0.0001 | 27.9 (17.4)
25.0 (-25.0; 59.0)
n=37 | <0.0001 |
| Global Score | 37.7 (19.3)
33.0 (0.0; 92.0)
n=42 | 73.6 (18.9)
75.0 (8.0; 100.0)
n=42 | 75.0 (19.3)
75.0 (25.0; 100.0)
n=44 | 37.3 (25.5)
34.0 (-17.0; 84.0)
n=36 | <0.0001 | 38.8 (24.3)
34.0 (0.0; 92.0)
n=37 | <0.0001 |
| For continuous variables Mean (SD) / Median (Min; Max) / n= is presented.
For comparison over time Wilcoxon Signed Rank test was used for continuous variables.
Note: In terms of effectiveness, lower scores are expected for the Problem Sub-score, while higher scores are expected for the Prosthetic Mobility, Walking Habits, Capability, and Global Sub-scores. | | | | | | | |

With respect to the SF-36 questionnaire, statistically significant increases from baseline to 12 months and to 24 months were found for

- Physical Function (p&lt;0.0001 for both 12 and 24 months)
- Role-Physical (p=0.0004 for 12 months and p&lt;0.0001 for 24 months)
- Physical Component Summary (p&lt;0.0001 for both 12 and 24 months)

Bodily pain, general health, vitality, social functioning, role-emotional, mental health, mental component summary and SF-36 first question "health in general" did not change significantly from baseline to either 12 or 24 months in the ITT population.

Furthermore, range of movement around the hip joint improved, physiological cost decreased, and abduction/adduction increased between baseline and 24 months.

3. Pediatric Extrapolation

In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

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# E. Financial Disclosure

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

- Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study;
- Significant payment of other sorts;
- Proprietary interest in the product tested by the investigator; or
- Significant equity interest held by investigator in sponsor of covered study.

FDA also previously reviewed the OPRA™ Implant System and associated financial disclosures as part of the HDE submission and determined that the information provided did not raise questions about the reliability of the data.

# F. Additional Analyses of OPRA™ Study with Additional Patients

As noted above, for PMA approval, 51 subjects from the primary clinical study used for HDE approval were analyzed with 14 additional subjects who had stage 1 surgery with the OPRA™ implant at Sahlgrenska University Hospital between March 2007 and November 2011 and met the same eligibility criteria as the primary clinical study. A summary of these analyses is below.

1. Baseline and Demographics Characteristics for Additional 14 Subjects

Table 10 presents baseline and demographic characteristics for the 14 additional subjects. The 14 subjects had similar characteristics to the original 51 OPRA™ study patients with the exception that 100% of the additional 14 subjects were male as compared to the 55%/45% male/female ratio in the original 51 subjects.

Table 10: Baseline and Demographic Characteristics for Additional 14 Subjects

| Variable | 14 Additional Patients |
| --- | --- |
| Gender | |
| Male | 14 (100.0%) |
| Age at amputation (years) | 36.1 (13.0)
33.5 (20; 58)
n=14 |
| Reason for amputation | |
| Trauma | 11 (78.6%) |
| Peripheral Vascular Disease | 0 (0.0%) |

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| Variable | 14 Additional Patients |
| --- | --- |
| Tumor | 1 (7.1%) |
| Other | 2 (14.3%) |
| Age at inclusion (years) | 45.8 (11.7) |
| | 47.5 (27; 63) |
| | n=14 |
| Estimated weight at inclusion (kg) | 76.8 (12.5) |
| | 77 (55; 100) |
| | n=14 |
| Height at inclusion (cm) | 178.0 (5.8) |
| | 177 (170; 190) |
| | n=14 |
| Smoker at inclusion | 3 (21.4%) |
| Prosthetic user at inclusion | 12 (92.3%) |
| Level of education | |
| Primary school | 1 (20.0%) |
| Secondary school | 3 (60.0%) |
| Exam from University | 1 (20.0%) |
| Missing | 9 |
| Civil status | |
| Single | 1 (12.5%) |
| Married/cohabiting | 7 (87.5%) |
| Missing | 6 |
| Nationality | |
| Sweden | 8 (57.1%) |
| Norway | 4 (28.7%) |
| Spain | 1 (7.1%) |
| Italy | 1 (7.1%) |
| Medication at inclusion | |
| No | 3 (25.0%) |
| Yes | 9 (75.0%) |
| Missing | 2 |
| For categorical variables n (%) is presented.
For continuous variables Mean (SD) / Median (Min; Max) / n= is presented. | |

2. Endpoints

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For the analysis with 65 subjects, new co-primary safety and effectiveness endpoints combined into a composite overall success endpoint, thus the composite primary endpoint is rate of overall success (i.e., success in both the primary effectiveness and safety endpoints).

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

- Primary safety endpoints:
- At 2 years: No subsequent secondary surgical interventions and at most 2 superficial infections.
- At 5 years: No subsequent secondary surgical interventions and at most 3 superficial infections.

- Primary effectiveness endpoints: Patients achieved the minimally clinically important difference (MCID) for the total Q-TFA score (mean of all subscores, i.e., prosthetic use score, prosthetic mobility score, problem score, and global score) of 20.25 points* and radiographic success. Radiographic success was defined as “no radiographic loosening of the implant with a radiolucent zone wider than the thread depth surrounding the entire implant”. These endpoints were measured 2 and 5 years after the stage 2 surgery.

Rates of overall success and overall no success (not achieving success in both primary safety and effectiveness) at 2 and 5 years were provided. Proportion of patients who achieved either primary safety endpoints or primary effectiveness endpoints at 2 and 5 years was also assessed, respectively. These analyses included imputations for patients with missing data.

Secondary endpoint: Proportion of patients who achieved the MCID for the Q-TFA Prosthetic Use subscore (19 points*), Prosthetic Mobility subscore (11 points*), Problem subscore (-23 points*) and Global subscore (33 points*), individually.

*The MCIDs for change from baseline for the Q-TFA subscales were derived individually and totally by the applicant using the validated SF-36 physical function subscore in a relevant population as an anchor (Escobar et al. (2007) and Keurentjes et al. (2012)).

## 3. Results

Table 11 presents the results of the primary effectiveness endpoints with 65 subjects. The data below demonstrates a high proportion of patients with effectiveness success at both time points (70.8% at 2 and 5 years), supporting the device's benefits to patients.

Table 11: Primary Effectiveness Results (Total Q-TFA and Radiographic Success)

| Variable | Total (n=65) |
| --- | --- |
| Primary effectiveness endpoint: Total Q-TFA ≥ MCID and radiographic success (2 years) | |
| Success | 46 (70.8%) |
| Not Success | 19 (29.2%) |

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| Variable | Total (n=65) |
| --- | --- |
| Primary effectiveness endpoint: Total Q-TFA ≥ MCID and radiographic success (5 years) | |
| Success | 46 (70.8%) |
| Not Success | 19 (29.2%) |
| For categorical variables n (%) is presented. | |

The additional 14 subjects had a total of 30 treatment related adverse events including 23 surgical interventions, 20 mechanical complications, 2 deep infections, and 6 superficial infections. The surgical interventions addressed the mechanical complications and/or deep infections.

Table 12 presents the results of the primary safety endpoint with 65 subjects. At 2 years, 67.7% of patients met the safety endpoint and at 5 years, 43.1% of patients met the safety endpoint. The applicant used the safety criteria outlined above for the analysis with 65 subjects, but the rate of patients without success should be interpreted cautiously as patients who are technically not successful still derive clinical benefit from the device. For example, an uncontrolled fall not related to the device causes a high bending moment on the device and the bone. The device protects the bone from fracture by plastic deformation of the abutment and thereby absorbs energy from the fall and avoids a bone fracture. A femoral bone fracture, which can happen also in socket users, is typically treated with a major surgical intervention and up to 6 months of restricted loading. A bent abutment, however, is replaced under local anesthesia in less than 30 minutes and directly postoperatively, the patient can ambulate without restrictions. However, from a strict safety analysis perspective, this patient would be considered not to be successful under this safety endpoint. Thus, these values should be interpreted with caution as they do not take into account the design intent of the device into account.

Table 12: Primary Safety Results

| Variable | Total (n=65) |
| --- | --- |
| Primary safety endpoint (2 years) | |
| Success | 44 (67.7%) |
| Not Success | 21 (32.3%) |
| Primary safety endpoint (5 years) | |
| Success | 28 (43.1%) |
| Not Success | 37 (56.9%) |
| For categorical variables n (%) is presented. | |

Table 13 presents rates for overall success at 2 and 5 years. As shown, 47.7% and 35.4% were overall successes at 2 and 5 years, respectively. Notably, only 9.2% and 21.5% did not achieve both effectiveness and safety success at 2 and 5 years, respectively. Thus, at 2 years, 90.8% of patients had some level of success, whether effectiveness, safety, or both. The same is true for 78.5% of patients at 5 years.

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Table 13: Overall Success

| Variable | Total (n=65) |
| --- | --- |
| 2 years | |
| Overall success | 31 (47.7%) |
| Overall not success | 6 (9.2%) |
| Primary safety success and no primary effectiveness success | 13 (20.0%) |
| Effectiveness success and no primary safety success | 15 (23.1%) |
| 5 years | |
| Overall success | 23 (35.4%) |
| Overall not success | 14 (21.5%) |
| Primary safety success and no primary effectiveness success | 5 (7.7%) |
| Effectiveness success and no primary safety success | 23 (35.4%) |
| For categorical variables n (%) is presented. | |

The applicant also provided additional data with SF-36 and Q-TFA for the 65 subjects, as presented below.

Table 14 presents changes in the SF-36 variables from before treatment to two and five years after treatment for the 65 subjects. As shown, there are statistically significant improvements across most SF-36 subscores two- and five-years post surgery.

Table 14: Change in SF-36 Variables from before Treatment to 2 Years and 5 Years

| | Change from before treatment to 2 years (n=65) | | Change from before treatment to 5 years (n=65) | |
| --- | --- | --- | --- | --- |
| Variable | | p-value within group | | p-value within group |
| Physical Function | 23.6 (20.2) | <0.0001 | 26.2 (23.1) | <0.0001 |
| | 25 (-30; 75) | | 25 (-38.1; 85) | |
| | (18.4; 28.8) | | (20.3; 32.1) | |
| | n=62 | | n=61 | |
| | SRM=1.17 | | SRM=1.13 | |
| | ES=1.11 | | ES=1.22 | |
| Role Physical | 23.0 (41.8) | 0.0002 | 17.8 (54.2) | 0.014 |
| | 18.9 (-100; 100) | | 0 (-100; 100) | |
| | (12.4; 33.5) | | (4.0; 31.8) | |
| | n=62 | | n=61 | |

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| | Change from before treatment to 2 years (n=65) | | Change from before treatment to 5 years (n=65) | |
| --- | --- | --- | --- | --- |
| | SRM=0.55 ES=0.56 | | SRM=0.33 ES=0.43 | |
| Bodily Pain | 12.4 (36.4) 10 (-74; 100) (3.1; 21.6) n=62 SRM=0.34 ES=0.46 | 0.0090 | 8.17 (32.14) 10 (-69; 90) (-0.11; 16.45) n=61 SRM=0.25 ES=0.30 | 0.054 |
| General Health | 1.40 (18.09) 0 (-42; 52.99) (-3.20; 5.97) n=62 SRM=0.08 ES=0.08 | 0.55 | 5.18 (21.57) 5 (-55; 61.65) (-0.39; 10.68) n=61 SRM=0.24 ES=0.30 | 0.068 |
| Vitality | 6.44 (25.62) 5 (-70; 70) (-0.14; 12.95) n=62 SRM=0.25 ES=0.30 | 0.055 | 6.81 (23.56) 5 (-55; 70) (0.85; 12.79) n=61 SRM=0.29 ES=0.32 | 0.023 |
| Social Function | 6.66 (30.92) 0 (-100; 87.5) (-1.16; 14.42) n=62 SRM=0.22 ES=0.26 | 0.096 | 7.47 (32.62) 0 (-62.5; 87.5) (-0.76; 15.79) n=61 SRM=0.23 ES=0.29 | 0.074 |
| Role Emotional | 4.77 (50.44) 0 (-100; 100) (-8.18; 17.50) n=62 SRM=0.09 ES=0.11 | 0.48 | 5.25 (46.17) 0 (-100; 100) (-6.63; 17.02) n=61 SRM=0.11 ES=0.12 | 0.39 |
| Mental Health | 4.99 (24.40) 8 (-76; 48) (-1.20; 11.10) n=62 SRM=0.20 ES=0.25 | 0.11 | 4.23 (22.54) 4 (-56; 52) (-1.57; 9.96) n=61 SRM=0.19 ES=0.21 | 0.15 |

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| | Change from before treatment to 2 years (n=65) | | Change from before treatment to 5 years (n=65) | |
| --- | --- | --- | --- | --- |
| Physical Composite | 8.80 (10.03)
9.87 (-14.22; 29.83)
(6.23; 11.36)
n=62
SRM=0.88
ES=1.05 | <0.0001 | 8.76 (10.76)
8.27 (-12.6; 37.04)
(6.03; 11.49)
n=61
SRM=0.81
ES=1.05 | <0.0001 |
| Mental Composite | -0.698 (16.081)
0.426 (-44.799; 33.067)
(-4.834; 3.390)
n=62
SRM=-0.04
ES=-0.05 | 0.74 | -0.652 (14.725)
0.349 (-35.648; 26.479)
(-4.427; 3.087)
n=61
SRM=-0.04
ES=-0.05 | 0.73 |
| For continuous variables Mean (SD) / Median (Min; Max) / (95% CI) / n= / SRM / ES is presented.
For comparison within groups 95% CI based on the Fisher's Non-Parametric Permutation test for matched pairs was used.
SRM = Standardized Response Mean= mean difference / SD for difference
ES = Effect Size = mean difference / SD for Baseline values
Out of 65 patients, four patients lost their prosthesis and should not be imputed at the 2- and 5-year time points. Of those four patients, one patient had SF-36 data (but no Q-TFA data) at 2 years. Thus, the 2-year timepoint includes n=62 at 2 years and n=61 at 5 years. | | | | |

Responder analyses for the SF-36 data are presented in Table 15 using the MCIDs from Keurentjes et al. (2012). These data demonstrate that majority of patients had clinically meaningful improvements on the SF-36, especially with regard to physical function, general health, and vitality. It should be noted that the SF-36 records patients' general health and experiences and is not specific to the implant. Thus, some of the variables below, such as social function and emotional role, should not be considered specific to patients' experience with the $\mathrm{OPRA^{TM}}$ Implant System.

Table 15: SF-36 Responder Analyses

| Variable | Change from before treatment to 2 years (n=65) | Change from before treatment to 5 years (n=65) |
| --- | --- | --- |
| Physical Function improvements | | |
| Success | 44 (71.0%) | 45 (73.8%) |
| Not success | 18 (29.0%) | 16 (26.2%) |

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| Variable | Change from before treatment to 2 years (n=65) | Change from before treatment to 5 years (n=65) |
| --- | --- | --- |
| Role Physical improvements | | |
| Success | 32 (51.6%) | 28 (45.9%) |
| Not success | 30 (48.4%) | 33 (54.1%) |
| Bodily Pain improvements | | |
| Success | 34 (54.8%) | 32 (52.5%) |
| Not success | 28 (45.2%) | 29 (47.5%) |
| General Health improvements | | |
| Success | 44 (71.0%) | 47 (77.0%) |
| Not success | 18 (29.0%) | 14 (23.0%) |
| Vitality improvements | | |
| Success | 38 (61.3%) | 34 (55.7%) |
| Not success | 24 (38.7%) | 27 (44.3%) |
| Social Function improvements | | |
| Success | 26 (41.9%) | 28 (45.9%) |
| Not success | 36 (58.1%) | 33 (54.1%) |
| Role Emotional improvements | | |
| Success | 15 (24.2%) | 19 (31.1%) |
| Not success | 47 (75.8%) | 42 (68.9%) |
| Mental Health improvements | | |
| Success | 32 (51.6%) | 29 (47.5%) |
| Not success | 30 (48.4%) | 32 (52.5%) |
| For categorical variables n (%) is presented.Out of 65 patients, four patients lost their prosthesis and should not be imputed at the 2- and 5-year time points. Of those four patients, one patient had SF-36 data (but no Q-TFA data) at 2 years. Thus, the 2-year timepoint includes n=62 at 2 years and n=61 at 5 years. | | |

Table 16 presents change in the Q-TFA variables from before treatment to 2 and 5 years for the 65 subjects. As shown, there were statistically significant improvements across all Q-TFA variables (total and individual subscores).

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Table 16: Change in Q-TFA Variables from Before Treatment to 2 Years and 5 Years

| | Change from before treatment to 2 years (n=65) | | Change from before treatment to 5 years (n=65) | |
| --- | --- | --- | --- | --- |
| Variable | | p-value within group | | p-value within group |
| Total Q-TFA score | 30.1 (16.0)
29.8 (-7.5; 60.8)
(26.0; 34.3)
n=61
SRM=1.88
ES=1.55 | <0.0001 | 31.8 (16.4)
30.8 (-6.1; 76.8)
(27.6; 36.0)
n=61
SRM=1.94
ES=1.64 | <0.0001 |
| Prosthetic Use score | 35.1 (33.4)
29 (-81; 100)
(26.6; 43.7)
n=61
SRM=1.05
ES=0.98 | <0.0001 | 39.6 (32.7)
29 (-10; 100)
(31.2; 48.1)
n=61
SRM=1.21
ES=1.11 | <0.0001 |
| Prosthetic Mobility score | 16.5 (15.6)
17 (-29; 50)
(12.6; 20.5)
n=61
SRM=1.06
ES=0.80 | <0.0001 | 20.0 (17.4)
20 (-24; 78)
(15.5; 24.5)
n=61
SRM=1.15
ES=0.97 | <0.0001 |
| Problem score | -29.1 (16.1)
-31 (-74.3; 7)
(-33.3; -25.0)
n=61
SRM=-1.80
ES=-1.53 | <0.0001 | -28.9 (18.2)
-32 (-75.3; 17.5)
(-33.6; -24.2)
n=61
SRM=-1.59
ES=-1.51 | <.0001 |
| Global score | 39.6 (21.5)
34 (0; 92)
(34.1; 45.2)
n=61
SRM=1.84
ES=2.04 | <0.0001 | 38.5 (22.7)
33 (-18; 100)
(32.7; 44.3)
n=61
SRM=1.70
ES=1.98 | <0.0001 |

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| | Change from before treatment to 2 years (n=65) | | Change from before treatment to 5 years (n=65) | |
| --- | --- | --- | --- | --- |
| Variable | | p-value within group | | p-value within group |
| For continuous variables Mean (SD) / Median (Min; Max) / (95% CI) / n= / SRM / ES is presented. For comparison within groups 95% CI based on the Fisher's Non-Parametric Permutation test for matched pairs was used. SRM = Standardized Response Mean= mean difference / SD for difference ES = Effect Size = mean difference / SD for Baseline values Out of 65 patients, four patients lost their prosthesis and should not be imputed at the 2- and 5-year time points. Thus, n=61 for the Q-TFA time points at 2 and 5 years. In the overall success analysis, these four patients are treated as not successes. | | | | |

Table 17 presents the responder analyses using the anchor-based MCIDs for the Q-TFA. As shown, majority of patients met the MCID for all Q-TFA variables at 2 and 5 years.
Table 17: Q-TFA Responder Analysis Using Anchor-Based MCID

| Variable | Change from before treatment to 2 years (n=65) | Change from before treatment to 5 years (n=65) |
| --- | --- | --- |
| Total Q-TFA score MCID improvements | | |
| Success | 46 (75.4%) | 46 (75.4%) |
| Not success | 15 (24.6%) | 15 (24.6%) |
| Prosthetic Use score MCID improvements | | |
| Success | 45 (73.8%) | 45 (73.8%) |
| Not success | 16 (26.2%) | 16 (26.2%) |
| Prosthetic Mobility score MCID improvements | | |
| Success | 43 (70.5%) | 41 (67.2%) |
| Not success | 18 (29.5%) | 20 (32.8%) |
| Problem score MCID improvements | | |
| Success | 39 (63.9%) | 39 (63.9%) |
| Not success | 22 (36.1%) | 22 (36.1%) |
| Global score MCID improvements | | |
| Success | 37 (60.7%) | 37 (60.7%) |
| Not success | 24 (39.3%) | 24 (39.3%) |

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| Variable | Change from before treatment to 2 years (n=65) | Change from before treatment to 5 years (n=65) |
| --- | --- | --- |
| For categorical variables n (%) is presented. | | |
| Out of 65 patients, four patients lost their prosthesis and should not be imputed at the 2- and 5-year time points. Thus, n=61 for the Q-TFA time points at 2 and 5 years. In the overall success measure, these patients are treated as not successes. | | |

## XI. SUMMARY OF SUPPLEMENTAL CLINICAL INFORMATION

### A. Transfemoral Amputation Osseointegration Study (TFAOS)

As part of PMA approval, the applicant also provided to FDA preliminary data from the ongoing TFAOS study at Walter Reed National Military Medical Center. The current OPRA™ Implant System that is the subject of this PMA is used in this study. There have been no cases of fixture loosening, deep infection, or bent, worn, or fractured abutments in the TFAOS study to date. So far, the changes described above have improved the implant performance.

### B. Literature Studies

Several articles have been published based on the same patient population as the OPRA™ study or portions thereof. Key articles are summarized below. Please note that the term osseointegration is used in the literature but is a claim that the applicant will not use for the subject device at this time.

#### 1. Hagberg and Brånemark (2009)

Hagberg and Brånemark presented 100 patients treated with 106 implants (6 bilaterally; 61% males, 39% females; mean age 43 years; mean time since amputation 11.5 years) between May 1990 and June 2008. Of the 100 patients, 51 are included in the OPRA™ study. The majority had amputations due to trauma (67%) or tumor (21%) (other = 12%). At the time of article publication, 68 patients were using their prostheses (follow-up: 3 months - 17.5 years) and 32 were not (4 are deceased, 7 are before second surgery, 6 are in initial training, 4 are not using prosthesis, and 11 had the implant removed). The majority of treatment failures occurred in patients using pre-OPRA™ systems, before the OPRA™ protocol was established. The implementation of graded rehabilitation is considered to be of utmost importance for improved results.

#### 2. Tranberg et al. (2011)

Tranberg et al. presented data on the changes in hip and pelvic kinematics in 19 transfemoral amputees, who were treated with an osseointegrated trans-femoral prosthesis. The post-operative gait analysis was carried out at the 2 year follow-up visit. Fifty-seven; age-, side- and gender-matched healthy subjects served as controls. Post-operative data showed that patients who had an osseointegrated transfemoral prosthesis increased their hip

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extension by 7.3° (p=0.007), changing from -2.6° (range -13.4° to 10.7°) to -9.9° (range -29.4° to 5°). Moreover, the pre-operative anterior pelvic tilt was reduced by 4.0° (p=0.016), changing from 21.7° (range 11.9-34.8°) to 17.7° (range 5.5-25.7°). Values for hip extension and pelvic tilt changed toward those of controls. These results confirm that patients treated with osseointegrated trans-femoral prosthesis encounter significant changes of their kinematic pattern in terms of hip extension and anterior pelvic tilt. Even though the changes were moderate they may, in the long-term have a positive influence on low-back biomechanics and could contribute to reducing the risk of further problems with low back pain.

## 3. Nebergall et al. (2012)

The study performed by Nebergall et al. addresses radiostereometric analysis (RSA) and periprosthetic bone remodeling, to assess long-term fixation of the implant system (OPRA™). The following number of implants were analyzed with RSA at each follow-up interval: 47 implants at 6 months, 42 implants at 1 year, 40 implants at 2 years, 15 implants at 5 years, 12 implants at 7 years, and 3 implants at 10 years. The RSA analysis for the OPRA™ system indicated stable fixation of the implant (no substantial motion) up to 7 years after the second surgical procedure. At 5 years, the median (Standard Error) migration of the implant was very small (-0.02 (0.06) mm). The rotational movement was 0.42 (0.32) degrees around the longitudinal axis. There was no statistically significant difference in median rotation or migration at any follow-up time. Although some implants showed slight initial motion, the implants had stabilized at the 5-year follow-up. Of the 3 implants that loosened, the motion detected using RSA was only slightly greater than the median degree of motion in the rest of the cohort. Unfortunately, films for the latest follow-up were only available for the failed implants and films were not taken just prior to implant removal. Kinematics at the latest follow-up did not necessarily indicate loosening or substantial migration. Cancellation of the cortex appeared in at least 1 zone in over half of the patients at 2 years, but the prevalence had decreased by the 5-year follow-up, indicating a stabilization of bone remodeling. The majority of radiographs showed only minimal amounts of bone remodeling around the implant, and ultimately this remodeling did not compromise implant fixation of performance. Even the cases that experienced more moderate bone loss did not show any indication of loosening or implant failure.

Nebergall et al. concluded that there are several distinct advantages in using the OPRA™ system over the use of a conventional socket prosthesis. The transcutaneous nature of the OPRA™ system permits easy attachment and removal of the artificial limb through a quick-release mechanism. Ease of proper attachment also eliminates discomfort from wearing a limb that is improperly fitted. Similarly, since the skin-to-prosthesis interface is minimized and since the dermatological problems often associated with prosthesis attachment occur less frequently; there was only 1 superficial infection per patient every 2 years. Nebergall concluded that he OPRA™ system provides a solution for patients who are unsuitable candidates for a conventional socket prosthesis, due either to amputation that has been at too high a level or due to damage to the stump that has been too severe to allow fitting of a socket prosthesis. The rehabilitation problems identified by Nebergall et al. are consistent with the adverse events summarized above.

## 4. Brånemark et al. (2014)

The results of the 51-patient OPRA study described in Section X. A-D were published in Brånemark et al. This article is included for completeness. The authors of this peer-reviewed publication concluded that the high cumulative survival rate at two years (92%) combined with enhanced prosthetic use and mobility, fewer

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problems and improved quality of life, supported the 'revolutionary change' that patients with transfemoral amputation had reported after treatment with osseointegrated percutaneous prostheses.

5. Tillander et al. (2017)

Tillander, et al. studied the risk of osteomyelitis to characterize the clinical effect of osteomyelitis (including risk of implant extraction and impairments to function), and determine whether common patient factors (age, sex, body weight, diabetes, and implant component replacements) are associated with osteomyelitis in patients using the OPRA™ System.

The study retrospectively analyzed 96 patients that included study subjects within the primary OPRA™ System Study described above. These patients used custom design and commercial OPRA™ System and received femoral implants (102 implants including bilateral treatments; mean implant time, 95 months) treatment between 1990 and 2010 for osteomyelitis. Six patients were lost to follow-up. The reason for amputation was tumor, trauma, or ischemia in 97 limbs and infection in five. All patients were referred from other orthopedic centers owing to difficulty with use or to be fitted with socket prostheses.

Osteomyelitis was diagnosed by medical chart review of clinical signs, tissue culture results, and plain radiographic findings. Proportion of daily prosthetic use when osteomyelitis was diagnosed was semi-quantitatively graded as 1 to 3. Survivorship free from implant associated osteomyelitis and extraction attributable to osteomyelitis respectively was calculated using the Kaplan-Meier estimator. Indication for extraction was infection not responsive to conservative treatment with or without minor debridement or loosening of implant.

Implant-associated osteomyelitis was diagnosed in 16 patients corresponding to a 10-year cumulative risk of 20% (95% CI 0.12–0.33). Ten implants were extracted owing to osteomyelitis, with a 10-year cumulative risk of 9% (95% CI 0.04–0.20). Prosthetic use was temporarily impaired in four of the six patients with infection who did not undergo implant extraction. With the numbers available, an association between age, BMI, or diabetes with osteomyelitis was not identified; however, this study was underpowered on this endpoint.

The authors concluded that although the overall risk of implant osteomyelitis in patients who receive percutaneous osseointegrated implants after transfemoral amputation increases with time, the improved daily living outweighs the risks and inconvenience of treatment for most patients in this respect.

6. Brånemark et al. (2019)

Brånemark, et al. presented 5-year outcomes for a subset of patients in the OPRA™ System Study. Out of 51 patients from the OPRA™ System Study, 40 patients had five-year follow-up data. The five-year fixture cumulative survival rate was 92% and revision-free rate was 45%. The most common AE was superficial infection, occurring 70 times in 34 patients from baseline to the five-year follow-up. Superficial skin infections were normally treated with oral antibiotics for 10 days, but 16 of them required longer treatment. A total of 85 SAEs were reported in 26 patients:

- Removal of the fixture (4 patients)
- Stump revisions (3 patients)

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- Deep infections (11 patients)
- Exchange of abutment and/or abutment screw (15 patients)

Fourteen (14) deep infections were diagnosed in 11 patients during the five-year period. One of these infections caused early loosening/failure of the fixture. Nine patients with deep infections were successfully treated with oral antibiotics, with a mean time of five months. One deep infection had not resolved at the five-year follow-up.

Forty-three (43) mechanical complications occurred in 15 patients, resulting in replacement of the damaged abutment and/or the abutment screw. Accidental overload (falling, stumbling causing the abutment to bend) was the cause in sixteen bent abutments in 9 patients. One patient had the abutment temporarily removed (fixture in situ) four months before the five-year follow-up appointment, due to mechanical problems with the abutment and abutment screw.

Analyses of differences between baseline and the five-year follow-up revealed statistically significant improvements in all four Q-TFA scores (p&lt;0.0001) and in the physical function (PF) (p&lt;0.0001), role physical (RP) (p=0.020) and physical component score (PCS) (p&lt;0.0001) on the SF-36. All other differences were non-significant. Details of prosthetic use at baseline showed that 29/42 (69%) used their prostheses on a daily basis for at least 13 hours/day. At 5-year follow-up, this was reported by 28/40 (70%) of the patients.

To address a possible relation between higher prosthetic activity and mechanical complications, the group of 40 patients at the five-year follow-up was divided into those that had experienced any mechanical complication to the abutment and/or abutment screw and those without any such complication and compared with regard to their Q-TFA mobility score at the five-year follow-up. The results showed a statistically significant higher mean mobility score in the group of patients that had had a mechanical complication (p=0.035). The group with any mechanical complication (n=15) had a mobility score of 74 (SD 20.5, 8-92) as compared to the group without any complication (n=25) which had a mobility score of 64 (SD 20.2, 4-97).

In sum, this study demonstrated that 5-year outcomes were similar to those at 2-year follow-up, and that the benefits were clinically relevant. No additional patients lost the anchorage (fixture) of the implant system. Mechanical complications increased and were more frequent in patients with higher activity. Superficial infections per patient and year remained constant. Though the number of deep infections increased, only one implant had to be removed because of infection. This case was an early deep infection before successful osseointegration had been established.

7. Hagberg et al. (2020)

Hagberg et al. presented long term data with the OPRA™ device, at 2, 5, 7, 10 and 15 years post-S2 surgery. This study includes patients treated in Sweden between January 1999 and December 2017. Thus, original OPRA™ study patients are included, as well as others from the same hospital outside the original OPRA™ study. Integrum is not the sponsor of this study. In addition, several versions of the OPRA™ device are included in this study, and it should be noted that some patients were treated off-label in Sweden. Despite these limitations, the Q-TFA scores generally demonstrated significantly more prosthetic use, better mobility, fewer problems, and an improved global score at 2, 5, 7, and 10 years compared with baseline. At 15 years, there is

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limited patient data but what data are available (see Figure 4 in Hagberg, et al. (2020); n=11 for prosthetic use subscore and n=9 for other subcores) show maintenance in the prosthetic use and mobility subscores and improvement in the problem and global Q-TFA subscores from 2-year data.

## XII. PANEL MEETING RECOMMENDATION

In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Orthopedics and Rehabilitation Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.

## XIII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES

### A. Effectiveness Conclusions

Clinical experience with the OPRA™ Implant System indicates that patients implanted with the OPRA™ Implant System experienced statistically significant and clinically meaningful improvements in prosthetic use, mobility, level of function, and quality of life after two and five years. The number of subjects using their prosthetic device increased during the study, both on an hourly and daily basis, demonstrating patient satisfaction with using the prostheses.

Outcomes from the 2-year OPRA™ study are supported by an additional analysis and endpoints that measure device safety and effectiveness with 65 subjects (51 subjects from the original OPRA™ study and 14 additional subjects) at 2 and 5 years. Majority of patients (70.8% of 65) met the new primary effectiveness endpoints (i.e., total Q-TFA score achieved MCID and met radiographic success) and second effectiveness endpoints (each Q-TFA subscore achieved MCID) defined for the 65-patient cohort at 2 and 5 years. Changes over time in the SF-36 and Q-TFA scores further support device effectiveness.

The provided clinical data supports the effectiveness of the OPRA™ Implant System for patients who have transfemoral amputation due to trauma or cancer and who have or are anticipated to have rehabilitation problems with, or cannot use, conventional socket prosthesis.

### B. Safety Conclusions

Infection, mechanical complications, and pain were the most frequent reported AEs in the OPRA™ study, as expected for an osseointegrated device. As noted, in the original 51-patient OPRA™ study, after 2 years, there were 28 subjects with 40 superficial infections, 3 subjects with 4 deep infections and 4 subjects with 9 events of mechanical complications. After 5 years, 34 subjects had 70 superficial infections, 11 subjects had deep infections, and 15 subjects had 43 mechanical complications. In the 65-patient cohort, using the new safety endpoint in the 65-patient cohort, 67.7% of patients met this endpoint at 2 years and 43.1% at 5 years. Cumulative survival rate of the Fixture was 93.6% and 94% in terms of patient survival and implant survival, respectively, at both 2 and 5 years, with an assumption that non-observed data is non-informative at 5 years.

Superficial skin infections were normally treated with oral antibiotics, most deep infections (i.e., defined as extending below fascia) were successfully treated with oral antibiotics, and mechanical complications resulted in

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replacement of the damaged abutment and/or the abutment screw. As noted, preliminary data from the ongoing TFAOS study so far support that the company's incremental improvements to the device address the infection and mechanical complications previously observed with the OPRA™ Implant System.

The risks associated with this device should be compared to the amputated population as a whole. For instance, up to 72% socket-related problems including pain, skin sores and discomfort from socket suspended prosthesis were reported during a four-week period by a group of 97 transfemoral non-vascular amputees who were mailed the Q-TFA [Hagberg and Brånemark (2001)]. In the original 51-patient OPRA™ study, the incidence of pain and discomfort is less than 15% over a period of 2 years, and superficial in…