+-----------------------------------+-----------------------------------+
| **DEPARTMENT OF HEALTH AND HUMAN  | **PMA MEMORANDUM**                |
| SERVICES**                        |                                   |
+-----------------------------------+-----------------------------------+
| **Division of General,            | **Food and Drug Administration**  |
| Restorative and Neurological      |                                   |
| Devices**                         | **Office of Device Evaluation**   |
|                                   |                                   |
| **Orthopedic Devices Branch,      | **Center for Devices and          |
| HFZ-410**                         | Radiological Health**             |
|                                   |                                   |
| **(301) 594-2036**                | **9200 Corporate Boulevard**      |
|                                   |                                   |
|                                   | **Rockville, MD 20850**           |
+-----------------------------------+-----------------------------------+
| **Charité™ Artificial Disc**      |                                   |
|                                   |                                   |
| **DePuy Spine**                   |                                   |
|                                   |                                   |
| **325 Paramount Drive**           |                                   |
|                                   |                                   |
| **Raynham, MA 02767-0350**        |                                   |
|                                   |                                   |
| **(508) 880-8100**                |                                   |
+-----------------------------------+-----------------------------------+

**[CLINICAL REVIEW]{.underline}**

**[SUMMARY]{.underline}**

The subject device is the Charité™ Artificial Disc, consisting of two
CoCrMo alloy endplates and an UHMWPE core, indicated for spinal
arthroplasty in patients with single-level lumbar degenerative disc
disease (DDD) from L~4~ to S~1~. The sponsor conducted a non-inferiority
randomized, prospective clinical trial comparing the clinical results of
treatment with the subject device and anterior interbody fusion using
the BAK fusion cage. The study demonstrated that the Charité™ Artificial
Disc is safe and effective in the treatment of lumbar DDD compared to
anterior interbody fusion with the BAK cage.

# REVIEW

The subject of this review is P040006, the clinical module for
M020026/M003, dated 2/13/04 and received 2/13/04.

[Regulatory History]{.underline}

The Modular Shell was approved 3/4/03. The first module, M001, was filed
on 3/12/03. The second module, M002, was filed 4/17/03.

# CLINICAL INFORMATION

The subject device (as well as previous design versions) has been
commercially available in other countries since 1987. The sponsor
estimates that over 7,000 patients worldwide have received a Charité
Artificial Disc replacement. The Waldemar Link Company in Hamburg,
Germany is manufacturer of the device.

# CLINICAL TRIALS

# 

# INVESTIGATIONAL PLAN

The sponsor states that five versions of the protocol were utilized in
this study. The sponsor provided a summary of the changes in Volume 14,
pp.1-8. The investigational plan is summarized below with the protocol
changes noted in the applicable section.

## **Purpose**

The stated purpose of the investigation is to evaluate the safety and
effectiveness of the SB Charité™ III (SB III) compared to the BAK
Interbody Fusion Device (BAK Cage) for the treatment of single-level
degenerative disc disease, as per 21 CFR 812.25(a). The sponsor makes no
unsubstantiated statements about expected outcomes and makes no
concluding statements about the safety or effectiveness of the device.

## **Study Design**

The sponsor proposed a randomized, prospective, multicenter clinical
trial consisting of 341 patients with single-level DDD of the lumbar
spine (L~4~L~5~ or L~5~S~1~) in patients who have not previously
received surgical treatment, except for a prior discectomy, laminotomy,
or nucleolysis at the same level, and have failed to improve with
conservative treatment for at least 6 months prior to enrollment. After
enrollment, the patients will be randomized in a 2:1 ratio to two
treatment groups: SB III or BAK control. Each investigational site has
an independent block randomization schedule. There will be a maximum of
15 investigational sites. The first 5 patients at each investigational
site will not be randomized but will all receive the SB III device.

**[Controls]{.underline}** (Volume 14, Section 8.13.1.1, p.12) The
patients randomized to the control treatment will undergo lumbar
interbody fusion with a BAK cage.

**[Intended Use]{.underline}**

"The Charité Artificial Disc is indicated for spinal arthroplasty in
skeletally mature patients with degenerative disc disease (DDD) at one
level from L~4~ to S~1~. DDD is defined as discogenic back pain with
degeneration of the disc confirmed by patient history and radiographic
studies. These DDD patients may also have up to 3mm of spondylolisthesis
at the involved level. Patients receiving the Charité Artificial Disc
should have had at least 6 months of conservative treatment prior to
implantation of the Charité Artificial Disc; these treatments may
include discectomy, laminotomy/ectomy (without accompanying facetotomy),
or nucleolysis at the same level to be treated."

**[Device Description]{.underline}**

The subject device is the Charité™ Artificial Disc. The device consists
of two endplates manufactured from CoCrMo alloy (ASTM F75) and an UHMWPE
sliding core (ASTM F648). The bi-convex core articulates between the two
concave endplates. The endplates are available in 5 sizes, and each size
is available in 4 angles: plane-parallel (0ْ) and oblique (5ْ, 7.5ْ, and
10ْ). The undersurface of the endplates is slightly convex and has 6
tooth-like projections that anchor the plates to the bone. The UHMWPE
core is available in 5 diameters, and each is available in 5 heights for
sizes 1-3, and 4 heights for sizes 4-5. The core also has a radio-opaque
CoCr alloy wire for x-ray visualization.

  ----------------- ----------------- ----------------- -----------------
  **Charite                                             
  Endplates**                                           

  **Size**          **AP width (mm)** **Lateral width   **Angles
                                      (mm)**            (degrees)**

  1                 23                28.5              0, 5, 7.5, 10

  2                 25                31.5              0, 5, 7.5, 10

  3                 27                35.5              0, 5, 7.5, 10

  4                 29                38.5              0, 5, 7.5, 10

  5                 31                42.0              0, 5, 7.5, 10
  ----------------- ----------------- ----------------- -----------------

  ------------------ ----------------------------- -----------------------
  **Charite Cores**                                

  **Size**           **Diameter (mm)**             **Heights (mm)**

  1                  23                            7.5, 8.5, 9.5, 10.5,
                                                   11.5

  2                  25                            7.5, 8.5, 9.5, 10.5,
                                                   11.5

  3                  27                            7.5, 8.5, 9.5, 10.5,
                                                   11.5

  4                  29                            8.5, 9.5, 10.5, 11.5

  5                  31                            8.5, 9.5, 10.5, 11.5
  ------------------ ----------------------------- -----------------------

There were three generations of the subject device: Charité I, Charité
II, and Charité III. The Charité I and II devices had 1mm thick
stainless steel endplates. The Charité I device was implanted in 13
patients beginning in 1984, but had a problem with endplate subsidence,
attributed to the small surface area of the implant. The Charité II had
a new oval-shaped endplate design with a large surface area, and these
were implanted in 58 patients beginning in 1985. However, the endplates
of these devices fractured, and this problem was attributed to the
non-forged stainless steel material. The Charité III design was
introduced in 1987. The device design incorporated changes in endplate
material (CoCrMo alloy); number, shape and position of the endplate
teeth; addition of additional endplate sizes and angles; and changes in
the core shape and size. The device has been named the SBIII, SBC, Link
SBC, and others. In June 2003, DePuy Spine acquired the device.

**[Statistical Plan]{.underline}**

The study has been designed as a non-inferiority trial.

**Success definition:**

The protocol (Volume 2, p.38) states that the individual patient will be
determined to be a success if all of the following are found:

1.  Improvement in the Oswestry Disability Index ≥25% at 24 months
    compared to the score at baseline.

2.  No device failures requiring revision, re-operation, or removal.

3.  Absence of major complications, defined as major blood vessel
    injury, neurological damage, or nerve root injury.

4.  Maintenance or improvement in neurological status at 24 months, with
    no new permanent neurological deficits compared to baseline.

The study was designed as a non-inferiority trial with a δ = 0.15.

H~0~: μ~s~ ≥ μ~t~ + δ H~1~: μ~c~ \< μ~t~ + δ

μ~s~: Clinical success rate in the BAK Cage Control group

μ~e~: Clinical success rate in the SB Charité™ III group

δ: Clinically significant difference between the treatment groups. δ =
0.15

Because the δ includes confidence intervals, the observed success rate
for the SB Charité™ III group could be no more that 4.9% lower than the
success rate for the BAK Cage Control group to conclude that the two
groups are equivalent.

**Sample Size Justification:**

The sponsor assumed a 70% success rate for both treatment groups.

δ = 0.15

α = 0.05

β = 0.80

The estimated sample size was 174 patients for the treatment group and
87 patients for the control group, or 261 patients total. With a 10%
dropout rate, the treatment group sample size is 194 patients and the
control group is 97 patients, for a total of 291 patients. Assuming 5
training cases per site at 15 sites, the total is 366 patients (269
investigational and 97 control).

**Analysis Populations:**

The sponsor also defined the following populations for analysis:

-   Intent-to-Treat (ITT) population: all patients who were randomized
    in the study and had either a 24-month follow-up evaluation or had
    been declared an "early discontinuation" (i.e., lost to follow-up).
    Patients who were not yet due for follow-up or those who were
    overdue for the 24-month evaluation were not included in the ITT
    group.

-   All Randomized Subjects population: all patients enrolled.

-   Completers population: patients who were evaluated at 24 months
    regardless of whether the visit was within the defined evaluation
    time window (22 months to 26 months)

-   Completers In-Window population: patients who had the 24-month
    evaluation within the defined evaluation time window (22 months to
    26 months)

-   Safety population: all patients who were randomized and received
    treatment.

**Missing Data:**

Patients with incomplete or missing data were classified as failures for
the efficacy analysis. Missing values were ignored for the analysis of
secondary endpoints, summaries of baseline characteristics, and other
summaries.

**Endpoints**

Primary Endpoints:

-   Oswestry Score (μ) at 24-months or later.

Secondary Endpoints:

-   Pain VAS improvement of ≥20mm

-   SF-36 improvement ≥15%

-   Disc height (lateral x-ray)

-   Displacement or migration of the device

-   Radiolucency around the implant for Charité patients at 24 months

**Interim Analyses**

None.

**[Inclusion/Exclusion Criteria]{.underline}** (Volume 14, pp.17-14)

+-----------------------------------+-----------------------------------+
| **Inclusion**                     | **Exclusion**                     |
+-----------------------------------+-----------------------------------+
| -   Male or female                | -   Previous or other spinal      |
|                                   |     surgery at any level, except  |
| -   Age 18-60 years               |     prior discectomy, laminotomy, |
|                                   |     laminectomy, or nucleolysis   |
| -   Symptomatic degenerative disc |     at the same level             |
|     disease with objective        |                                   |
|     evidence of lumbar DDD by CT  | -   Multiple level degeneration   |
|     or MR scan, followed by       |                                   |
|     discogram                     | -   Previous trauma to the L~4~,  |
|                                   |     L~5~, or S~1~ levels in       |
| -   Single level disease at       |     compression or burst          |
|     L~4~L~5~ or L~5~S~1~          |                                   |
|                                   | -   Non-contained or extruded     |
| -   Minimum of 6 months of        |     herniated nucleus pulposus    |
|     unsuccessful conservative     |                                   |
|     treatment                     | -   Mid-sagittal stenosis of      |
|                                   |     \<8mm (by CT or MR)           |
| -   Oswestry Low Back Pain        |                                   |
|     Disability Questionnaire ≥30  | -   Spondylolisthesis \>3mm       |
|     points                        |                                   |
|                                   | -   Lumbar scoliosis (\>11ْ        |
| -   Patient a surgical candidate  |     sagittal plane deformity)     |
|     for an anterior approach to   |                                   |
|     the lumbar spine (\<3         | -   Spinal tumor                  |
|     abdominal surgeries)          |                                   |
|                                   | -   Active systemic or surgical   |
| -   Back pain at the operative    |     site infection                |
|     level only (by discogram)     |                                   |
|                                   | -   Facet joint arthrosis         |
| -   Leg pain and/or back pain in  |                                   |
|     the absence of nerve root     | -   Arachnoiditis                 |
|     compression, per MRI or CT    |                                   |
|     scan, without prolapse or     | -   Isthmic spondylolisthesis     |
|     narrowing of the lateral      |                                   |
|     recess.                       | -   Chronic steroid use           |
|                                   |                                   |
| -   VAS ≥40mm                     | -   Metal allergy                 |
|                                   |                                   |
| -   Able to comply with protocol  | -   Pregnancy                     |
|                                   |                                   |
| -   Informed consent              | -   Autoimmune disorders          |
|                                   |                                   |
| DDD is defined as discogenic back | -   Psychsocial disorders         |
| pain with degeneration of the     |                                   |
| disc as confirmed by history and  | -   Morbid obesity (BMI \>40)     |
| radiographic studies with one or  |                                   |
| more of the following factors:    | -   Bone growth stimulator use in |
|                                   |     spine                         |
| -   Contained herniated nucleus   |                                   |
|     pulposus                      | -   Investigational drug or       |
|                                   |     device use within 30 days     |
| -   Facet joint                   |                                   |
|     degeneration/changes          | -   Osteoporosis or osteopenia or |
|                                   |     metabolic bone disease        |
| -   Decreased disc height by      |                                   |
|     ≥2mm, and/or                  | -   Positive single or bilateral  |
|                                   |     straight leg raising test     |
| -   Scarring/thickening of        |                                   |
|     ligamentum flavum, annulus    |                                   |
|     fibrosus, or facet joint      |                                   |
|     capsule                       |                                   |
+-----------------------------------+-----------------------------------+

**[Study Treatments]{.underline}** (Volume 14, Section 8.13.1.1, p.22)

[SB Charité™ III Treatment Group]{.underline}

All investigational group patients will undergo a discectomy and
implantation of the SB Charité™ III device through an anterior
retroperitoneal approach

[BAK Interbody Fusion Device Control Treatment Group]{.underline}

Patients randomized to the control group will have an anterior lumbar
interbody fusion at one or two contiguous levels (L~2~-S~1~) with
autogenous bone grafting and stabilization with the BAK Cage using the
anterior retroperitoneal approach.

**Postoperative Protocol**

The investigational and control groups will have the same postoperative
protocol. Lumbar strengthening ("stabilization therapy") begins at 2-4
weeks postop. No lifting or bending for 6 months.

**[Evaluations]{.underline}** (Volume 14, Section 8.31.1.1, pp.23) The
protocol specifies that patient assessments will be performed
preoperatively, and postoperatively prior to discharge, 6 weeks (±2
weeks), 3 months (±2 weeks), 6 months (±1 month), 12 months (±1 month),
24 months (±2 months) (schedule of evaluations, Section 8.4.1, Table 9).

**Clinical Evaluation**

The following clinical assessments will be performed:

-   Work status: Baseline, 6 wks, 3 mo, 6 mo, 12 mo, 24 mo

-   Visual Analog Scale (VAS) for Pain: Baseline, 6 wks, 3 mo, 6 mo, 12
    mo, 24 mo

-   Oswestry Disability Index (ODI): Baseline, 6 wks, 3 mo, 6 mo, 12 mo,
    24 mo

> Each question is scored on a 6-point scale. The responses are added,
> then doubled, and expressed as a percentage. ODI are rated as follows:
> 0-20 minimal disability; 20-40 moderate disability; 40-60 severe
> disability; and \>60 severely disabled/bed-bound.

-   SF-36 Health Related Quality of Life Survey: Baseline, 6 mo, 12 mo,
    24 mo

Neurological status: Baseline, 6 wks, 3 mo, 6 mo, 12 mo, 24 mo

-   Range of Motion: Baseline, 6 mo, 12 mo, 24 mo

-   History and physical examination: Baseline, 24 mo

-   Adverse events: Postop, 6 wks, 3 mo, 6 mo, 12 mo, 24 mo

**Radiographic Evaluation**

-   X-rays---AP, lateral, flexion/extension laterals: Within 6 mo of
    enrollment, postoperatively at 6 wks, 3 mo, 6 mo, 12 mo, 24 mo

All radiographs will be evaluated by the investigator and another
evaluator at that investigational site. If there disagreements, a third
evaluator will review the films. In the 4/5/00 protocol version, the
protocol was modified to require all radiographic evaluations to be
performed by a core laboratory. The radiographic evaluation protocol was
provided in Volume 14, Section 8.13.1.2. The recommended radiographic
technique was provided. The radiographs are scanned into the computer,
and all calculations are made with the BioQuant Image Analysis System
software program.

The radiographic criteria for fusion were defined as follows:

-   Absence of radiolucent lines around ≥50% of the assembly

-   Translation motion \<3mm (on flexion/extension), and

-   Angulation motion \<5 degrees (on flexion/extension)

Device migration or displacement was defined as movement \>3mm (the
measurement error for plain radiographs).

**[U.S. CLINICAL TRIAL RESULTS]{.underline}**

Two related U.S. studies of the subject device are described below. The
Pivotal Study was the prospective, randomized, controlled, multicenter
IDE clinical trial. The Continued Access Study was the prospective,
uncontrolled, multicenter registry of patients implanted with the device
under continued access. For the Pivotal Trial, the database closure date
was 1/16/04.

+-------------+---------------------------+---------------------------+
| **Summary   |                           |                           |
| of U.S.     |                           |                           |
| Clinical    |                           |                           |
| Trials**    |                           |                           |
+-------------+---------------------------+---------------------------+
|             | **Pivotal Study**         | **Continued Access        |
|             |                           | Study**                   |
+-------------+---------------------------+---------------------------+
| Design      | Multicenter               | Multicenter               |
|             |                           |                           |
|             | Training arm (5 pts/site) | Registry                  |
|             |                           |                           |
|             | Randomized arm            | 24-month follow-up        |
|             |                           |                           |
|             | -   2:1                   |                           |
|             |                           |                           |
|             |   investigational:control |                           |
|             |                           |                           |
|             | 24-month follow-up        |                           |
+-------------+---------------------------+---------------------------+
| Sites       | 15                        | 15                        |
+-------------+---------------------------+---------------------------+
| Subjects    | Approved: 194:97 + 75     | 615 approved              |
|             | training cases            |                           |
|             |                           | 350 enrolled              |
|             | 375 enrolled              | (approximately)           |
|             |                           |                           |
|             | -   71 training arm       | 71 (with \>12 months      |
|             |     (Charité)             | follow-up)                |
|             |                           |                           |
|             | -   205 randomized        |                           |
|             |     (Charité)             |                           |
|             |                           |                           |
|             | -   99 randomized (BAK    |                           |
|             |     control)              |                           |
+-------------+---------------------------+---------------------------+
| Enrollment  | Training: 3/21/00 --      | 5/17/02 to present        |
| period      | 5/22/01                   |                           |
|             |                           |                           |
|             | Randomized: 5/16/00 --    |                           |
|             | 4/24/02                   |                           |
+-------------+---------------------------+---------------------------+
| Inve        | Charité Artificial Disc   | Charité Artificial Disc   |
| stigational |                           |                           |
| Rx          |                           |                           |
+-------------+---------------------------+---------------------------+
| Control Rx  | BAK Cage                  | None                      |
+-------------+---------------------------+---------------------------+

**[Study Population]{.underline}**

There were 71 training patients implanted with the Charité Artificial
Disc. There were 304 randomized patients, 205 implanted with the Charité
Artificial Disc and 99 fused with the BAK Cage. In addition, there were
71 patients implanted with the Charité Artificial Disc in the continued
access study. The training cases will be analyzed separately from the
randomized patients.

The sponsor divided the patients into two analysis groups: the
Intent-To-Treat (ITT) group and the All Randomized Subjects group. The
ITT group consists of all treated patients who were treated with only
the patients who died or were discontinued. The All Randomized Subjects
group consists of all patients enrolled into the study. The All
Randomized Subjects analysis group consists of 304 patients (205 Charité
patients and 99 BAK patients). The ITT group consists of 267 patients
(182 Charité patients and 85 BAK patients).

The mean age of the study group was 39.5 years (19-60 years) in the
Charité group, and 40.1 years (20-60 years) in the BAK group. There were
83 (46%) men and 99 (54%) women in the Charité group and 47 (55%) men
and 38 women (45%) in the BAK group. The demographic data are reproduced
in the following table.

+-----------------------+-----------------------+-----------------------+
| **ITT Population      |                       |                       |
| Characteristics**     |                       |                       |
+-----------------------+-----------------------+-----------------------+
|                       | **Charité Artificial  | **BAK Cage**          |
|                       | Disc**                |                       |
+-----------------------+-----------------------+-----------------------+
| N                     | 182                   | 85                    |
+-----------------------+-----------------------+-----------------------+
| Sex, Men (%)          | 83 (46%)              | 47 (55%)              |
|                       |                       |                       |
| Women (%)             | 99 (54%)              | 38 (45%)              |
+-----------------------+-----------------------+-----------------------+
| Age, mean             | 39.5                  | 40.1                  |
|                       |                       |                       |
| Range                 | 19-60                 | 20-60                 |
+-----------------------+-----------------------+-----------------------+
| Age Category \>45     | 41 (23%)              | 28 (33%)              |
| years                 |                       |                       |
|                       | 141 (77%)             | 57 (67%)              |
| Age Category ≤45      |                       |                       |
| years                 |                       |                       |
+-----------------------+-----------------------+-----------------------+
| Level L~4~L~5~        | 53 (29%)              | 28 (33%)              |
+-----------------------+-----------------------+-----------------------+
| Level L~5~S~1~        | 129 (71%)             | 57 (67%)              |
+-----------------------+-----------------------+-----------------------+

There was no significant difference in the duration of prior
conservative treatment for DDD: 33.7 months for the Charité group and
27.0 months for the BAK group. There were 62 patients (34%) in the
Charité group and 27 patients (32%) in the BAK group who had undergone
previous surgical treatment (Appendix 1, Table 13.1). There was one
patient in each group (2% and 4%, respectively) who had osteoporosis
based on DXA.

## **Surgical variables**

  ----------------------- ----------------------- -----------------------
  **ITT Surgical                                  
  Procedures**                                    

                          **Charité Artificial    **BAK Cage**
                          Disc**                  

  N                       182                     85

  Level L~4~L~5~          53 (29%)                28 (33%)

  Level L~5~S~1~          129 (71%)               57 (67%)
  ----------------------- ----------------------- -----------------------

The operative times were 111 minutes and 115.3 minutes, respectively for
the Charité and the BAK groups (p=0.5462). The estimated blood loss was
207cc and 224cc, respectively (p=0.6012).

For the Charité group, the implant configurations (craniad/caudad
endplates) were as follows: 109 oblique/oblique; 12 oblique/parallel; 54
parallel/oblique; and 30 parallel/parallel. The implant component sizes
were as follows:

+-----+------------+------------+------------+------------+------------+
| **C |            |            |            |            |            |
| har |            |            |            |            |            |
| ite |            |            |            |            |            |
| A   |            |            |            |            |            |
| rti |            |            |            |            |            |
| fic |            |            |            |            |            |
| ial |            |            |            |            |            |
| D   |            |            |            |            |            |
| isc |            |            |            |            |            |
| Im  |            |            |            |            |            |
| pla |            |            |            |            |            |
| nte |            |            |            |            |            |
| d** |            |            |            |            |            |
|     |            |            |            |            |            |
| **  |            |            |            |            |            |
| (Ta |            |            |            |            |            |
| ble |            |            |            |            |            |
| 1   |            |            |            |            |            |
| 7.2 |            |            |            |            |            |
| )** |            |            |            |            |            |
+-----+------------+------------+------------+------------+------------+
| **  | **Cephalad |            | **Caudad   |            | **Core**   |
| Siz | E          |            | E          |            |            |
| e** | ndplates** |            | ndplates** |            |            |
+-----+------------+------------+------------+------------+------------+
|     | Parallel   | Oblique    | Parallel   | Oblique    |            |
+-----+------------+------------+------------+------------+------------+
| 1   | 0          | 0          | 0          | 0          | 0          |
+-----+------------+------------+------------+------------+------------+
| 2   | 6          | 11         | 6          | 11         | 17         |
+-----+------------+------------+------------+------------+------------+
| 3   | 54         | 77         | 24         | 107        | 131        |
+-----+------------+------------+------------+------------+------------+
| 4   | 24         | 33         | 12         | 45         | 57         |
+-----+------------+------------+------------+------------+------------+
| 5   | 0          | 0          | 0          | 0          | 0          |
+-----+------------+------------+------------+------------+------------+

For the 99 randomized control group patients, the cage sizes were as
follows:

+-----------------------------------+-----------------------------------+
| **Lengths:** 61 20mm              | **Diameters:** 1 11mm             |
|                                   |                                   |
| 24 24mm                           | 17 13mm                           |
|                                   |                                   |
|                                   | 50 15mm                           |
|                                   |                                   |
|                                   | 17 17mm                           |
+-----------------------------------+-----------------------------------+

## **Patient Accounting**

There were 177 Charité patients (86%) and 78 BAK patients (79%) who were
evaluated at 24 months. There were 5 (3%) and 7 (8%) patients,
respectively, who discontinued early from the study for the following
reasons: patient non-compliance (6), voluntary withdrawal (3), lost to
follow-up (left the U.S.) (1), patient refusal (1), death (1). There
were 18 patients (10 Charité and 8 BAK) who were overdue for their
24-month evaluation, and 19 patients (13 Charité and 6 BAK) who were not
yet due for the 24-month follow-up. Of the 205 Charité patients, 3
patients had not reached the 24-month evaluation time point at the time
of database closure, 1/16/04. Therefore, the theoretical number of
patients due at the 24-month time point for the Charité group was 202
patients.

  --------------------- -------------- -------------- ------------ -------------
  **Patient                                                        
  Populations**                                                    

                        **Randomized                               **Continued
                        Study**                                    Access**

                        Training Arm   Charité        BAK Cage     
                                       Artificial                  
                                       Disc                        

  Enrolled              71             205            99           71

  All Randomized                       205            99           

  Not overdue for                      13 (6%)        6 (6%)       
  24-month                                                         

  **Completers**                       **177 (86%)**  **78 (79%)** 

  **Early                              **5 (2%)**     **7 (7%)**   
  Discontinuation**                                                

  **ITT**                              **182 (89%)**  **85 (86%)** 

  Overdue for 24-month                 10 (5%)        8 (8%)       
  --------------------- -------------- -------------- ------------ -------------

The sponsor also defined the following populations for analysis:

-   All Randomized Subjects population: all patients enrolled.

-   Intent-to-Treat (ITT) population: all patients who were randomized
    in the study and had either a 24-month follow-up evaluation or had
    been declared an "early discontinuation" (i.e., lost to follow-up).
    Patients who were not yet due for follow-up or those who were
    overdue for the 24-month evaluation were not included in the ITT
    group.

-   Completers population: patients who were evaluated at 24 months
    regardless of whether the visit was within the defined evaluation
    time window (22 months to 26 months)

-   Completers In-Window population: patients who had the 24-month
    evaluation within the defined evaluation time window (22 months to
    26 months)

-   Safety population: all patients who were randomized and received
    treatment.

The patients were categorized as "early discontinuations" if they were
non-compliant with the investigational protocol, voluntarily withdrew
from the study, refused to return for follow-up, or died. In the Charité
group, there were 5 patients who were early discontinuations: 2 patients
who were non-compliant, 1 voluntary withdrawal, 1 refusal to return for
follow-up, and 1 death. For the BAK group, there were 7 patients who
were early discontinuations: 4 patients who were non-compliant, 2
voluntary withdrawals, and 1 lost to follow-up (left the U.S. and unable
to return). These early discontinuations were infrequent and were more
frequent in the BAK control group (7% v. 2%).

Because the sponsor closed the database before the end of the 24-month
evaluation time window, there are some patients who have reached the
24-month time point but are not outside the 24 month ± 2 month time
window. There are 10 (5%) Charité and 8 (8%) BAK patients in this "Not
Yet Overdue" category. These have been eliminated from the ITT
population.

Thus, the ITT group (182 Charité patients and 85 BAK patients) consisted
of All Randomized Subjects who either returned for follow-up within the
24-month evaluation time window (158 Charité patients and 72 BAK
patients), or outside the 24-month time window (19 Charité patients and
6 BAK patients), as well as those categorized as "early
discontinuations" (5 Charité patients and 7 BAK patients).

There were 19 patients (13 patients, or 6%, in the Charité group and 8
patients, or 6%, in the BAK group) who were "not yet overdue" for the
24-month follow-up evaluation, i.e., they had reached the 24-month
evaluation time point but were still within the 24-month evaluation time
window (±2 months).

<table>
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<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
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</colgroup>
<tbody>
<tr class="odd">
<td colspan="15"><p><strong>Patient &amp;</strong> <strong>Data
Accountability</strong></p>
<p><strong>Appendix 1, Tables 4-6</strong></p></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"><strong>Post-op</strong></td>
<td colspan="2"><strong>6 wks</strong></td>
<td colspan="2"><strong>3 mo</strong></td>
<td colspan="2"><strong>6 mo</strong></td>
<td colspan="2"><strong>12 mo</strong></td>
<td colspan="2"><strong>24 mo</strong></td>
<td colspan="2"><strong>24+ mo</strong></td>
</tr>
<tr class="odd">
<td><strong>PATIENTS</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
</tr>
<tr class="even">
<td><h3 id="theoretically-due">Theoretically due</h3></td>
<td>205</td>
<td>99</td>
<td>205</td>
<td>99</td>
<td>205</td>
<td>99</td>
<td>205</td>
<td>99</td>
<td>205</td>
<td>99</td>
<td>202*</td>
<td>96</td>
<td>205</td>
<td>96</td>
</tr>
<tr class="odd">
<td><strong>Deaths</strong></td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
</tr>
<tr class="even">
<td><strong>Failures</strong></td>
<td>3</td>
<td>1</td>
<td>3</td>
<td>1</td>
<td>3</td>
<td>1</td>
<td>3</td>
<td>1</td>
<td>7</td>
<td>4</td>
<td>7</td>
<td>7</td>
<td>11</td>
<td>8</td>
</tr>
<tr class="odd">
<td><strong>Withdrawn</strong></td>
<td>4</td>
<td>7</td>
<td>4</td>
<td>7</td>
<td>4</td>
<td>7</td>
<td>4</td>
<td>7</td>
<td>4</td>
<td>7</td>
<td>4</td>
<td>7</td>
<td>4</td>
<td>7</td>
</tr>
<tr class="even">
<td><strong>Not yet overdue</strong></td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>9</td>
<td>3</td>
<td>9</td>
<td>63</td>
</tr>
<tr class="odd">
<td><strong>Expected</strong></td>
<td>198</td>
<td>91</td>
<td>198</td>
<td>91</td>
<td>198</td>
<td>91</td>
<td>198</td>
<td>91</td>
<td>194</td>
<td>88</td>
<td>182</td>
<td>79</td>
<td>178</td>
<td>78</td>
</tr>
<tr class="even">
<td><strong>Missed</strong></td>
<td>2</td>
<td>1</td>
<td>4</td>
<td>1</td>
<td>11</td>
<td>3</td>
<td>12</td>
<td>6</td>
<td>12</td>
<td>9</td>
<td>26</td>
<td>14</td>
<td>6</td>
<td>6</td>
</tr>
<tr class="odd">
<td><strong>Actual</strong></td>
<td>196</td>
<td>90</td>
<td>194</td>
<td>90</td>
<td>187</td>
<td>88</td>
<td>186</td>
<td>85</td>
<td>182</td>
<td>79</td>
<td>156</td>
<td>65</td>
<td>172</td>
<td>72</td>
</tr>
<tr class="even">
<td><strong>% follow-up</strong></td>
<td>98.9</td>
<td>98.9</td>
<td>98.0</td>
<td>98.9</td>
<td>94.4</td>
<td>96.7</td>
<td>93.9</td>
<td>93.4</td>
<td>93.8</td>
<td>89.8</td>
<td>85.7</td>
<td>81.0</td>
<td>96.6</td>
<td>92.3</td>
</tr>
<tr class="odd">
<td colspan="15"></td>
</tr>
<tr class="even">
<td><strong>DATA</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
<td><strong>Charite</strong></td>
<td><strong>BAK/C</strong></td>
</tr>
<tr class="odd">
<td><h3 id="theoretically-due-1">Theoretically due</h3></td>
<td>205</td>
<td>99</td>
<td>205</td>
<td>99</td>
<td>205</td>
<td>99</td>
<td>205</td>
<td>99</td>
<td>205</td>
<td>99</td>
<td>202*</td>
<td>96</td>
<td>205</td>
<td>96</td>
</tr>
<tr class="even">
<td><strong>Expected (denominator)</strong></td>
<td><strong>198</strong></td>
<td><strong>91</strong></td>
<td><strong>198</strong></td>
<td><strong>91</strong></td>
<td><strong>198</strong></td>
<td><strong>91</strong></td>
<td><strong>198</strong></td>
<td><strong>91</strong></td>
<td><strong>194</strong></td>
<td><strong>88</strong></td>
<td><strong>182</strong></td>
<td><strong>79</strong></td>
<td><strong>178</strong></td>
<td><strong>78</strong></td>
</tr>
<tr class="odd">
<td><strong>Oswestry</strong></td>
<td>205</td>
<td>99</td>
<td>197</td>
<td>91</td>
<td>189</td>
<td><strong>93</strong></td>
<td>189</td>
<td>88</td>
<td>186</td>
<td>80</td>
<td>178</td>
<td>78</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>%</strong></td>
<td>100.0</td>
<td>100.0</td>
<td>99.5</td>
<td>100.0</td>
<td>95.5</td>
<td>100.0</td>
<td>95.5</td>
<td>96.7</td>
<td>95.9</td>
<td>90.9</td>
<td>97.8</td>
<td>98.7</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Neuro</strong></td>
<td>205</td>
<td>99</td>
<td>197</td>
<td><strong>97</strong></td>
<td>192</td>
<td><strong>94</strong></td>
<td>190</td>
<td>88</td>
<td>187</td>
<td>81</td>
<td>178</td>
<td>79</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>%</strong></td>
<td>100.0</td>
<td>100.0</td>
<td>99.5</td>
<td>100.0</td>
<td>97.0</td>
<td>100.0</td>
<td>96.0</td>
<td>96.7</td>
<td>96.4</td>
<td>92.0</td>
<td>97.8</td>
<td>100.0</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Pain VAS</strong></td>
<td>205</td>
<td>99</td>
<td>196</td>
<td><strong>92</strong></td>
<td>188</td>
<td><strong>93</strong></td>
<td>188</td>
<td>87</td>
<td>185</td>
<td>79</td>
<td>179</td>
<td>78</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>%</strong></td>
<td>100.0</td>
<td>100.0</td>
<td>99.0</td>
<td>100.0</td>
<td>94.9</td>
<td>100.0</td>
<td>94.9</td>
<td>95.6</td>
<td>95.4</td>
<td>89.8</td>
<td>98.4</td>
<td>98.7</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>SF-36</strong></td>
<td>185</td>
<td>92</td>
<td>178</td>
<td>79</td>
<td>168</td>
<td>85</td>
<td>166</td>
<td>76</td>
<td>160</td>
<td>68</td>
<td>144</td>
<td>62</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>%</strong></td>
<td>90.2</td>
<td>92.3</td>
<td>89.9</td>
<td>86.8</td>
<td>94.4</td>
<td>93.4</td>
<td>83.8</td>
<td>83.5</td>
<td>82.5</td>
<td>77.3</td>
<td>79.1</td>
<td>78.5</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>X-rays</strong></td>
<td>199</td>
<td>95</td>
<td>195</td>
<td><strong>95</strong></td>
<td>187</td>
<td><strong>93</strong></td>
<td>186</td>
<td>86</td>
<td>184</td>
<td>82</td>
<td>179</td>
<td>78</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>%</strong></td>
<td>97.1</td>
<td>95.9</td>
<td>98.5</td>
<td>100.0</td>
<td>94.4</td>
<td>100.0</td>
<td>93.9</td>
<td>94.5</td>
<td>94.8</td>
<td>93.2</td>
<td>98.4</td>
<td>98.7</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Complete</strong></td>
<td>181</td>
<td>89</td>
<td>170</td>
<td>78</td>
<td>162</td>
<td>83</td>
<td>162</td>
<td>74</td>
<td>156</td>
<td>66</td>
<td>139</td>
<td>60</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>%</strong></td>
<td>88.3</td>
<td>89.9</td>
<td>85.9</td>
<td>85.7</td>
<td>81.8</td>
<td>91.2</td>
<td>81.8</td>
<td>81.3</td>
<td>80.4</td>
<td>75.0</td>
<td>76.4</td>
<td>75.9</td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

\* Of the 205 enrolled Charité patients, 3 patients had not reached the
24-month evaluation time point at the time of database closure, 1/16/04.
Therefore, the theoretical number of patients due at the 24-month time
point for the Charité group was 202 patients.

The data accountability follow-up rates were calculated as follows Rate
= Actual data / Expected . Except at the Post-Op time point, Rate =
Actual data / Theoretical.

**[Results]{.underline}**

-   **[Primary Endpoint]{.underline}**

**OVERALL SUCCESS**

Individual patient success was defined as a patient with all of the
following conditions:

-   Improvement \>25% Oswestry at 24 months compared to baseline

-   No device failures requiring revision, reoperation or removal

> No pseudarthrosis (control group)

-   Absence of major complication, defined as vessel injury,
    neurological damage, or nerve root injury

-   Maintenance or improvement in neurological status at 24 months, with
    no permanent neurological deficits compared to baseline

The overall success rates for the Charité and the BAK groups were 63%
and 53%, respectively, for the ITT population (p\<0.0001). The overall
success rates for the Completers and Completers In-Window populations
were nearly identical.

  --------------------- ---------------- ---------------- ----------------
  **Overall Success,                                      
  Table 19**                                              

                        **Charité        **BAK Cage**     **p value**
                        Artificial                        
                        Disc**                            

  N                     182              85               

  ITT population        114 (63%)        45 (53%)         \<0.0001

                                                          

  N                     177              78               

  Completers            115 (65%)        46 (59%)         0.0005

                                                          

  N                     158              72               

  Completers In-Window  101 (64%)        42 (58%)         0.0015
  --------------------- ---------------- ---------------- ----------------

  ----------------------------- ----------------- --------------- ---------
  **Success Rates, Table 20**                                     

                                **Charité         **BAK Cage**    **p
                                Artificial Disc**                 value**

  N                             182               85              

  Oswestry success (\>25%       127 (70%)         49 (58%)        0.0540
  improvement)                                                    

  Device failure success (none) 174 (96%)         77 (91%)        0.1632

  Major complication success    180 (99%)         84 (99%)        1.0000
  (none)                                                          

  Neurological deterioration    160 (88%)         74 (87%)        0.8437
  success (none)                                                  
  ----------------------------- ----------------- --------------- ---------

The sponsor performed sensitivity analyses for the primary efficacy
success endpoints (Section 8.4.2.7, Statistics, p.27; Section 8.4.4,
Effectiveness, p.39). These included analyses of the ITT subjects with
non-completers considered to be failures; ITT subjects with any 24-month
follow-up; ITT subjects with 24-month follow-up within the 24-month time
window; "last observation carried forward," or LOCF, for All Randomized
Subjects; LOCF for ITT; LOCF with discontinuations as failures; overall
LOCF for overdue patient. LOCF was performed for All Randomized Patients
and All Randomized Patients with discontinuations considered failures.
For all of these analyses, the overall success rate for the Charité
Artificial Disc Group ranged from 63% to 68%, and the overall success
rate for the BAK Group ranged from 48% to 54% (see Tables 21a and 21b).
An analysis was also performed removing the neurological component of
success, and again showed a higher proportion of success for
non-completers, slightly higher in the Charité Artificial Disc Group.

The overall success rate for the Charité Artificial Disc Group is
sustained over time. A repeated measures model demonstrated that the
success rates for the ITT groups at 6 months, 12 months and 24 months
were 69.2%, 67.6%, and 64.2% for the Charité Group, and 47.8%, 58.8%,
and 54.7% for the BAK Group (see Table 22). An analysis of the time to
sustained response, i.e., the first time when success for the BAK Group
was observed and continued through 24 months, was performed. For the
Charité Group, the times to first response at 6 months, 12 months and 24
months were 44%, 51%, and 63%, and for the BAK Group they were 35%, 41%,
and 53%.

![](media/image1.wmf)

Subgroup and covariate analyses were performed (see Table 23.1). The
following factors were found to be not significant at the 0.15 level:
age, baseline Oswestry score, gender, operative level, use of hormone
replacement therapy, and use of pain medication. The following factors
were found to be associated with the outcome: body mass index (but no
treatment interaction); current activity (better in active patients in
the Charité group, and better in inactive patients in the BAK group);
osteopenia (Charité performed better than BAK; however, this involved
only 15 total patients); and study site.

There were no significant differences in the success rates for the
individual components of the Overall Success definition at 24 months:

**OSWESTRY SUCCESS**

-   Improvement \>25% Oswestry at 24 months compared to baseline

The Oswestry success rates for the Charité and the BAK groups were 70%
and 58%, respectively, for the ITT population (p=0.0540).

+--------------------+---------------+---------------+---------------+
| **Oswestry         |               |               |               |
| Success**          |               |               |               |
|                    |               |               |               |
| **Defined as \>25% |               |               |               |
| Improvement, Table |               |               |               |
| 20.1a**            |               |               |               |
+--------------------+---------------+---------------+---------------+
|                    | **Charité     | **BAK Cage**  | **p value**   |
|                    | Artificial    |               |               |
|                    | Disc**        |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 182           | 85            |               |
+--------------------+---------------+---------------+---------------+
| ITT population     | 127 (70%)     | 49 (58%)      | 0.0540        |
+--------------------+---------------+---------------+---------------+
|                    |               |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 177           | 78            |               |
+--------------------+---------------+---------------+---------------+
| Completers         | 127 (72%)     | 49 (63%)      | 0.1860        |
+--------------------+---------------+---------------+---------------+
|                    |               |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 158           | 72            |               |
+--------------------+---------------+---------------+---------------+
| Completers         | 112 (71%)     | 46 (64%)      | 0.2886        |
| In-Window          |               |               |               |
+--------------------+---------------+---------------+---------------+

**DEVICE FAILURES SUCCESS**

-   No device failures requiring revision, reoperation or removal

-   No pseudarthrosis (BAK Control Group)

The Device Failure success rates for the Charité and the BAK groups were
96% and 91%, respectively, for the ITT population (p=0.0490).

+--------------------+---------------+---------------+---------------+
| **Device Failure   |               |               |               |
| Success**          |               |               |               |
|                    |               |               |               |
| **Defined No       |               |               |               |
| Device Failure,    |               |               |               |
| Table 20.1a**      |               |               |               |
+--------------------+---------------+---------------+---------------+
|                    | **Charité     | **BAK Cage**  | **p value**   |
|                    | Artificial    |               |               |
|                    | Disc**        |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 182           | 85            |               |
+--------------------+---------------+---------------+---------------+
| ITT population:    | 8 (4%)        | 8 (9%)        | 0.1632        |
| Failures           |               |               |               |
+--------------------+---------------+---------------+---------------+
| ITT population:    | 174 (96%)     | 77 (91%)      |               |
| Successes          |               |               |               |
+--------------------+---------------+---------------+---------------+
|                    |               |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 177           | 78            |               |
+--------------------+---------------+---------------+---------------+
| Completers         | 170 (96%)     | 71 (91%)      | 0.1350        |
+--------------------+---------------+---------------+---------------+
|                    |               |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 158           | 72            |               |
+--------------------+---------------+---------------+---------------+
| Completers         | 153 (97%)     | 66 (92%)      | 0.1030        |
| In-Window          |               |               |               |
+--------------------+---------------+---------------+---------------+

**MAJOR COMPLICATIONS SUCCESS**

-   Absence of major complication, defined as vessel injury,
    neurological damage, or nerve root injury

The Major Complications success rates for the Charité and the BAK groups
were 99% and 99%, respectively, for the ITT population (p=1.000).

+--------------------+---------------+---------------+---------------+
| **Complications    |               |               |               |
| Success**          |               |               |               |
|                    |               |               |               |
| **Defined as No    |               |               |               |
| Major              |               |               |               |
| Complication,      |               |               |               |
| Table 20.1a**      |               |               |               |
+--------------------+---------------+---------------+---------------+
|                    | **Charité     | **BAK Cage**  | **p value**   |
|                    | Artificial    |               |               |
|                    | Disc**        |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 182           | 85            |               |
+--------------------+---------------+---------------+---------------+
| ITT population     | 180 (99%)     | 84 (99%)      | 1.0000        |
+--------------------+---------------+---------------+---------------+
|                    |               |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 177           | 78            |               |
+--------------------+---------------+---------------+---------------+
| Completers         | 175 (99%)     | 77 (99%)      | 1.0000        |
+--------------------+---------------+---------------+---------------+
|                    |               |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 158           | 72            |               |
+--------------------+---------------+---------------+---------------+
| Completers         | 157 (99%)     | 71 (99%)      | 0.5290        |
| In-Window          |               |               |               |
+--------------------+---------------+---------------+---------------+

**NEUROLOGICAL SUCCESS**

-   Maintenance or improvement in neurological status at 24 months, with
    no permanent neurological deficits compared to baseline

The Neurological success rates for the Charité and the BAK groups were
88% and 87%, respectively, for the ITT population (p=0.8437).

The sponsor performed subgroup and covariate analyses. The following
were found to be not significant: age (≤45 years v. \>45 years),
baseline Oswestry, gender, operative level, use of hormone replacement
therapy, and use of pain medication. The following were found to be
associated with the outcome as either a main effect or in the
interaction term: body mass index, current activity level, osteopenia,
and study site.

+--------------------+---------------+---------------+---------------+
| **Neurological     |               |               |               |
| Success**          |               |               |               |
|                    |               |               |               |
| **Defined As No    |               |               |               |
| Deterioration of   |               |               |               |
| Neurological       |               |               |               |
| Status, Tables     |               |               |               |
| 20.1a and 29.1**   |               |               |               |
+--------------------+---------------+---------------+---------------+
|                    | **Charité     | **BAK Cage**  | **p value**   |
|                    | Artificial    |               |               |
|                    | Disc**        |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 182           | 85            |               |
+--------------------+---------------+---------------+---------------+
| ITT population     | 160 (88%)     | 74 (87%)      | 0.8437        |
+--------------------+---------------+---------------+---------------+
|                    |               |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 177           | 78            |               |
+--------------------+---------------+---------------+---------------+
| Completers         | 160 (90%)     | 74 (95%)      | 0.3239        |
+--------------------+---------------+---------------+---------------+
|                    |               |               |               |
+--------------------+---------------+---------------+---------------+
| N                  | 158           | 72            |               |
+--------------------+---------------+---------------+---------------+
| Completers         | 144 (91%)     | 68 (94%)      | 0.4422        |
| In-Window          |               |               |               |
+--------------------+---------------+---------------+---------------+

-   **[Secondary Endpoints]{.underline}**

**OSWESTRY DISABILITY INDEX**

The mean Oswestry score by study population, by follow-up time, by
treatment group, and the changes from baseline were analyzed.

Both the Charité and the BAK group patients experienced significant
improvements in their ODI from baseline at the 6-week, 3-month, 6-month,
12-month, and 24-month evaluation timepoints. The Charité group patients
had a significantly greater change in the ODI at the 6-week, 3-month and
6-month time points, although the differences were not significant at
the later timepoints.

+-------------+--------+--------+--------+--------+--------+--------+
| **Oswestry  |        |        |        |        |        |        |
| Disability  |        |        |        |        |        |        |
| Index**     |        |        |        |        |        |        |
|             |        |        |        |        |        |        |
| **ITT       |        |        |        |        |        |        |
| Population, |        |        |        |        |        |        |
| Table       |        |        |        |        |        |        |
| 27.1**      |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
|             | **Base | **6    | **3    | **6    | **12   | **24   |
|             | line** | wk**   | mo**   | mo**   | mo**   | mo**   |
+-------------+--------+--------+--------+--------+--------+--------+
| Charité, n  | 182    | 174    | 168    | 170    | 169    | 177    |
+-------------+--------+--------+--------+--------+--------+--------+
| ODI         | 49.8   | 37.4   | 29.6   | 27.1   | 25.9   | 25.8   |
+-------------+--------+--------+--------+--------+--------+--------+
| Change\*    |        | -22.9  | -39.5  | -45.5  | -48.3  | 48.9   |
+-------------+--------+--------+--------+--------+--------+--------+
| From        |        | \<     | \<     | \<     | \<     | \<     |
| baseline, p |        | 0.0001 | 0.0001 | 0.0001 | 0.0001 | 0.0001 |
+-------------+--------+--------+--------+--------+--------+--------+
|             |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+
| BAK, n      | 85     | 78     | 81     | 76     | 72     | 79     |
+-------------+--------+--------+--------+--------+--------+--------+
| ODI         | 51.7   | 43.7   | 36.7   | 34.8   | 30.9   | 30.1   |
+-------------+--------+--------+--------+--------+--------+--------+
| Change\*    |        | -12.8  | -26.7  | -32.4  | -39.9  | -43.4  |
+-------------+--------+--------+--------+--------+--------+--------+
| From        |        | \<     | \<     | \<     | \<     | \<     |
| baseline, p |        | 0.0001 | 0.0001 | 0.0001 | 0.0001 | 0.0001 |
+-------------+--------+--------+--------+--------+--------+--------+
| Between     |        | 0.0485 | 0.0087 | 0.0126 | 0.1197 | 0.3407 |
| groups, p   |        |        |        |        |        |        |
+-------------+--------+--------+--------+--------+--------+--------+

\*a negative change indicates an improvement in the ODI.

The number of patients who achieved greater than 25% improvement in the
ODI from baseline as also greater in the Charité group patients at the
6-week, 3-month and 6-month time points, but were not significantly
different at the later timepoints.

+-------------+----------+----------+----------+----------+----------+
| **          |          |          |          |          |          |
| Improvement |          |          |          |          |          |
| in Oswestry |          |          |          |          |          |
| Scores from |          |          |          |          |          |
| Baseline**  |          |          |          |          |          |
|             |          |          |          |          |          |
| **(≥25%     |          |          |          |          |          |
| Im          |          |          |          |          |          |
| provement), |          |          |          |          |          |
| Table       |          |          |          |          |          |
| 26.1**      |          |          |          |          |          |
+-------------+----------+----------+----------+----------+----------+
|             | **6 wk** | **3 mo** | **6 mo** | **12     | **24     |
|             |          |          |          | mo**     | mo**     |
+-------------+----------+----------+----------+----------+----------+
| Charité, n  | 174      | 168      | 170      | 169      | 177      |
+-------------+----------+----------+----------+----------+----------+
| Improved    | 80 (46%) | 107      | 121      | 120      | 128      |
|             |          | (64%)    | (71%)    | (71%)    | (72%)    |
+-------------+----------+----------+----------+----------+----------+
|             |          |          |          |          |          |
+-------------+----------+----------+----------+----------+----------+
| Charité, n  | 78       | 81       | 76       | 72       | 79       |
+-------------+----------+----------+----------+----------+----------+
| Improved    | 24 (31%) | 37 (46%) | 41 (54%) | 47 (64%) | 49 (63%) |
+-------------+----------+----------+----------+----------+----------+
|             |          |          |          |          |          |
+-------------+----------+----------+----------+----------+----------+
| Between     | 0.0269   | 0.0091   | 0.0130   | 0.3637   | 0.1860   |
| groups, p   |          |          |          |          |          |
+-------------+----------+----------+----------+----------+----------+

**NEUROLOGICAL STATUS**

+---------------------------+--------------------+--------------------+
| **Neurological Status**   |                    |                    |
|                           |                    |                    |
| **ITT Analysis, Table     |                    |                    |
| 29.1**                    |                    |                    |
+---------------------------+--------------------+--------------------+
|                           | **Charité Group**  | **BAK Group**      |
+---------------------------+--------------------+--------------------+
| N                         | 182                | 85                 |
+---------------------------+--------------------+--------------------+
| No change                 | 131 (77%)          | 58 (76%)           |
+---------------------------+--------------------+--------------------+
| Significantly improved    | 5 (3%)             | 5 (7%)             |
+---------------------------+--------------------+--------------------+
| Slightly improved         | 27 (16%)           | 7 (9%)             |
+---------------------------+--------------------+--------------------+
| Slightly deteriorated     | 7 (4%)             | 3 (4%)             |
+---------------------------+--------------------+--------------------+
| Significantly             | 1 (1%)             | 3 (4%)             |
| deteriorated              |                    |                    |
+---------------------------+--------------------+--------------------+
| Mixed response            | 0                  | 0                  |
+---------------------------+--------------------+--------------------+
| Total                     | 171                | 76                 |
+---------------------------+--------------------+--------------------+
| Missing                   | 11                 | 9                  |
+---------------------------+--------------------+--------------------+

**PAIN VISUAL ANALOG SCALE** (Tables 30.1-31.2)

The sponsor provided the Pain VAS scores for both groups at each
follow-up time point. The mean change from baseline (measured at 6
weeks) varied from -35.9 to -41.1 for the Charité group and from -28.6
to -35.1 in the BAK group. There were 128 (74%) Charité patients who
were Pain VAS successes (≥20mm improvement from baseline) compared to 49
(62%) BAK patients (p=0.0759).

+---------------------------+--------------------+--------------------+
| **Pain VAS**              |                    |                    |
|                           |                    |                    |
| **ITT Analysis, Table     |                    |                    |
| 31.1**                    |                    |                    |
+---------------------------+--------------------+--------------------+
|                           | **Charité Group**  | **BAK Group**      |
+---------------------------+--------------------+--------------------+
| N                         | 182                | 85                 |
+---------------------------+--------------------+--------------------+
| Significant improvement   | 128 (74%)          | 49 (62%)           |
| (≥20mm)\*                 |                    |                    |
+---------------------------+--------------------+--------------------+
| Some Improvement          | 22 (13%)           | 11 (14%)           |
+---------------------------+--------------------+--------------------+
| No change (-3mm to +3mm)  | 3 (2%)             | 6 (8%)             |
+---------------------------+--------------------+--------------------+
| Deterioration (≥3mm)      | 21 (12%)           | 13 (16%)           |
+---------------------------+--------------------+--------------------+
| Total                     | 174                | 79                 |
+---------------------------+--------------------+--------------------+
| Missing                   | 8                  | 6                  |
+---------------------------+--------------------+--------------------+

\* Success = ≥20mm improvement

**QUALITY OF LIFE SF-36** (Tables 32.1-33.2)

For the component SF-36 scores, 99 (73%) Charité patients and 41 (66%)
BAK patients had a 15% or greater improvement in the Physical Composite
Score (PCS) at 24 months, and 68 (50%) and 34 (55%) patients had a 15%
improvement, for the Mental Composite Score (MCS), respectively. These
were not significantly different (p=0.3475 and 0.4959, respectively).

**DISC HEIGHT**

In the Charité group, there were no patients who had a decrease in disc
height greater than 3mm at 24 months. There were 3 patients in the BAK
group who lost more than 3mm in disc height (4%).

**RANGE OF MOTION** (Tables 35.1)

The vertebral range of motion measured on the lateral flexion and
extension views using the Cobb method at the operated level was measured
at 3, 6, 12, and 24 months. At all intervals, the Charité Artificial
Disc demonstrated near-physiologic ROM (mean). The mean ROM was 4.9,
6.0, 7.0 and 7.4 degrees, respectively.

+--------------------+-----------+-----------+-----------+-----------+
| **Vertebral Range  |           |           |           |           |
| of Motion**        |           |           |           |           |
|                    |           |           |           |           |
| **Table 35.1**     |           |           |           |           |
+--------------------+-----------+-----------+-----------+-----------+
|                    | 3 months  | 6 months  | 12 months | 24 months |
+--------------------+-----------+-----------+-----------+-----------+
| N                  | 133       | 163       | 161       | 175       |
+--------------------+-----------+-----------+-----------+-----------+
| Mean (degrees)     | 4.9       | 6.0       | 7.0       | 7.4       |
+--------------------+-----------+-----------+-----------+-----------+
| Standard deviation | 3.89      | 4.56      | 4.92      | 5.24      |
| (degrees)          |           |           |           |           |
+--------------------+-----------+-----------+-----------+-----------+
| Median (degrees)   | 4.4       | 5.2       | 6.3       | 6.9       |
+--------------------+-----------+-----------+-----------+-----------+
| Range, min-max     | 0-19      | 0-20      | 0-20      | 0-22      |
| (degrees)          |           |           |           |           |
+--------------------+-----------+-----------+-----------+-----------+

Normal segmental range of motion is defined as up to 10 degrees of
motion measured on lateral flexion-extension films.

![](media/image2.wmf)

Normal lumbar segmental range of motion has been documented in the
literature. In Pearcy and Shepherd (Pearcy M, Portek I, Shepherd J:
Three-dimensional x-ray analysis of normal movement in the lumbar spine.
*Spine*, 9(3): 294-297, 1984), the radiographically measured range of
motion of the L~4~L~5~ motion segment was 13 degrees of flexion and 2
degrees of extension, with a 16 degree flexion-extension arc (s.d. = 4
degrees). At the L~5~S~1~ motion segment, the range of motion was 9
degrees of flexion and 5 degrees of extension, with a 14 degree
flexion-extension arc (s.d. = 5 degrees). Therefore, the mean range of
motion found in this investigation (4.9 at 3 months up to 7.4 degrees at
24 months) was within the normal range of motion, and the patients at
the extreme ROM (up to a mean of 22 degrees) are still within 2 standard
deviations of the mean. Thus, the Charité patients did achieve
near-normal segmental motion at the operated segments.

The design characteristics of the device allow for 24 degrees of
flexion, 32 degrees of extension, 32 degrees of lateral bending, and 360
degrees of axial rotation. Thus, the clinically demonstrated motion is
within the design parameters for the device.

The lateral bending and axial rotational range of motion were not
reported for this investigation. The normal range of motion reported in
Pearcy and Tibrewal (Pearcy MJ and Tibrewal SB: Axial rotation and
lateral bending in the normal lumbar spine measured by three-dimensional
radiography. *Spine*, 9(6): 582-587, 1984) at the L~4~L~5~ motion
segment was found to be 3 degrees of axial rotation (range 1-5 degrees),
and 6 degrees of lateral bending (range 1-9 degrees). For the L~5~S~1~
motion segment, the normal range of motion was 2 degrees of axial
rotation (range 0-3 degrees), and 3 degrees of lateral bending (range
1-6 degrees). Because these motions were not measured in this IDE study,
no conclusions about the device's ability to restore normal lateral
bending and rotational ranges of motion can be made.

**DEVICE MIGRATION** (Tables 35.1)

There were no device migrations reported for the BAK group. At 3, 6, 12,
and 24 months, there were 2 (1%), 1 (1%), 2 (1%), and 3 (2%) migrations
\>3mm in the Charité group.

**PSEUDARTHROSIS AND RADIOLUCENCIES**

## In the BAK group, there were 2 (3 %) patients with a pseudarthrosis at 6 months, 2 (3%) at 12 months, and 4 (5%) at 24 months (Table 35.1). In the Charité group, a radiolucency was identified in 1 (1%) patient at 12 months and 2 (1%) patients at 24 months; longitudinal ossifications were identified in 1 (1%), 3 (2%), 6 (4%), and 11 (6%) patients at 6 weeks, 6 months, 12 months and 24 months, respectively (Tables 35.1 and 36.1).

**WORK STATUS** (Table 37.1)

For both groups, there were decreases in the number of patients on
short-term disability compared to baseline. At baseline, there were 15
(8%) patients in the Charité group compared to 8 (6%) patients in the
BAK group on short-term disability. At 12 months, there were 1 (1%) and
1 (1%) patient, respectively, and at 24 months there were 1 (1%) and 0
patients, respectively, on short-term disability.

**SUBJECT SATISFACTION** (Table 38.1)

Subject satisfaction was higher for the Charité group patients than the
BAK patients. At 24 months, the difference was significant (p=0.0092).

  ---------------- ------------- ------------- ------------- -------------
  **Patient                                                  
  Satisfaction**                                             

                   12 months                   24 months     

                   Charité Group BAK Group     Charité Group BAK Group

  N                182           85            182           85

  Satisfied        118 (72%)     42 (59%)      129 (73%)     43 (55%)

  Somewhat         33 (20%)      16 (23%)      27 (15%)      20 (26%
  satisfied                                                  

  Somewhat         8 (5%)        6 (8%)        17 (10%)      5 (6%)
  dissatisfied                                               

  Dissatisfied     6 (4%)        7 (10%)       4 (2%)        10 (13%)

                                                             

  Same treatment?                                            

  Definitely YES   123 (74%)     42 (59%)      122 (69%)     40 (52%)

  Probably YES     22 (13%)      12 (17%)      23 (13%)      10 (13%)

  Not sure         14 (8%)       9 (13%)       21 (12%)      12 (16%)

  Probably NOT     2 (1%)        3 (4%)        1 (1%)        5 (6%)

  Definitely NOT   6 (4%)        5 (7%)        10 (6%)       10 (13%)
  ---------------- ------------- ------------- ------------- -------------

## **Adverse Events**

## The sponsor collected adverse event information on all randomized patients ("Safety Population"), and categorized them as follows: typical or unusual (Table 40.1-40.2); severe or life-threatening (Table 41.1-41.2); device-related or not device-related (Table 42.1-42.2); severe and device-related (Table 43.1-43.2); occurring within 2 days of surgery (Table 44.1-44.2); and by date of onset categories (Table 45.1-45.2).

+------------------------------+---------+---------+---------+---------+
| **Adverse Events**           |         |         |         |         |
|                              |         |         |         |         |
| **Table 39**                 |         |         |         |         |
+------------------------------+---------+---------+---------+---------+
|                              | **      |         | **BAK   |         |
|                              | Charité |         | Group** |         |
|                              | Group** |         |         |         |
+------------------------------+---------+---------+---------+---------+
|                              | P       | \%      | P       | \%      |
|                              | atients |         | atients |         |
+------------------------------+---------+---------+---------+---------+
| Patients enrolled            | 205     |         | 99      |         |
+------------------------------+---------+---------+---------+---------+
| **Patients with an adverse   | **156** | *       | **77**  | *       |
| event**                      |         | *76.1** |         | *77.8** |
+------------------------------+---------+---------+---------+---------+
| Pain, back or lower          | 107     | 52.5    | 52      | 52.5    |
| extremity, total             |         |         |         |         |
+------------------------------+---------+---------+---------+---------+
| > Device-related             | 10      | 4.9     | 2       | 2.0     |
+------------------------------+---------+---------+---------+---------+
| > Not Device-related         | 97      | 47.3    | 50      | 50.5    |
+------------------------------+---------+---------+---------+---------+
| Other                        | 46      | 22.4    | 26      | 26.3    |
+------------------------------+---------+---------+---------+---------+
| Neurological, total          | 34      | 16.6    | 17      | 17.2    |
+------------------------------+---------+---------+---------+---------+
| > Device-related             | 3       | 1.5     | 0       | 0       |
+------------------------------+---------+---------+---------+---------+
| > Not Device-related         | 31      | 15.1    | 17      | 17.2    |
+------------------------------+---------+---------+---------+---------+
| Pain (other), total          | 27      | 13.2    | 9       | 9.1     |
+------------------------------+---------+---------+---------+---------+
| > Device-related             | 0       | 0       | 0       | 0       |
+------------------------------+---------+---------+---------+---------+
| > **Not Device-related**     | **27**  | *       | **9**   | **9.1** |
|                              |         | *13.2** |         |         |
+------------------------------+---------+---------+---------+---------+
| Infection, total             | 25      | 12.2    | 6       | 6.1     |
+------------------------------+---------+---------+---------+---------+
| > Device-related             | 1       | 1       | 0       | 0       |
+------------------------------+---------+---------+---------+---------+
| > Not Device-related         | 14      | 11.7    | 6       | 6.1     |
+------------------------------+---------+---------+---------+---------+
| Approach problems            | 18      | 8.8     | 8       | 8.1     |
| (abdominal)                  |         |         |         |         |
+------------------------------+---------+---------+---------+---------+
| Fusion treatment related     | 0       | 0       | 26      | 26.3    |
+------------------------------+---------+---------+---------+---------+
| > Device-related             | 0       | 0       | 1       | 1.0     |
+------------------------------+---------+---------+---------+---------+
| > Not Device-related         | 0       | 0       | 25      | 25.3    |
+------------------------------+---------+---------+---------+---------+
| DDD progression, natural     | 6       | 2.9     | 4       | 4.0     |
| history, total               |         |         |         |         |
+------------------------------+---------+---------+---------+---------+
| > Device-related             | 0       | 0       | 1       | 1.0     |
+------------------------------+---------+---------+---------+---------+
| > Not Device-related         | 6       | 2.9     | 3       | 3.0     |
+------------------------------+---------+---------+---------+---------+
| Prosthesis related, total    | 8       | 3.9     | 1       | 10      |
+------------------------------+---------+---------+---------+---------+
| > Device-related             | 2       | 1.0     | 0       | 0       |
+------------------------------+---------+---------+---------+---------+
| > Not Device-related         | 6       | 2.9     | 1       | 1.0     |
+------------------------------+---------+---------+---------+---------+
| Additional surgery, Index    | 10      | 4.9     | 8       | 8.1     |
| level                        |         |         |         |         |
+------------------------------+---------+---------+---------+---------+
| > Device-related             | 5       | 2.4     | 1       | 1.0     |
+------------------------------+---------+---------+---------+---------+
| > Not Device-related         | 4       | 2.0     | 8       | 8.1     |
+------------------------------+---------+---------+---------+---------+
| Additional surgery, other    | 3       | 1.5     | 3       | 3.0     |
| than index level             |         |         |         |         |
+------------------------------+---------+---------+---------+---------+
| Intraoperative complications | 2       | 1.0     | 3       | 3.0     |
+------------------------------+---------+---------+---------+---------+
| Abnormal bone formation      | 2       | 1.0     | 0       | 0       |
+------------------------------+---------+---------+---------+---------+

**Severe or Life-Threatening Adverse Events:**

There were 30 (15%) severe or life-threatening adverse events in the
Charité group, compared to 9 (9%) in the BAK group.

+--------------------------------+--------+--------+--------+--------+
| **Severe or Life-Threatening   |        |        |        |        |
| Adverse Events**               |        |        |        |        |
|                                |        |        |        |        |
| **Table 41.2**                 |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
|                                | **C    |        | **BAK  |        |
|                                | harité |        | G      |        |
|                                | G      |        | roup** |        |
|                                | roup** |        |        |        |
+--------------------------------+--------+--------+--------+--------+
|                                | Pa     | \%     | Pa     | \%     |
|                                | tients |        | tients |        |
+--------------------------------+--------+--------+--------+--------+
| Patients enrolled              | 205    |        | 99     |        |
+--------------------------------+--------+--------+--------+--------+
| **Patients with severe or      | **30** | **15** | **9**  | **9**  |
| life-threatening AE**          |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
| Pain (back or lower            | 10     | 4.9    | 5      | 5.1    |
| extremities)                   |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
| Other, total                   | 11     | 5.4    | 3      | 3.0    |
+--------------------------------+--------+--------+--------+--------+
| Other, cardiovascular          | 0      | 0      | 1      | 1.0    |
+--------------------------------+--------+--------+--------+--------+
| Infection                      | 3      | 1.5    | 2      | 2.0    |
+--------------------------------+--------+--------+--------+--------+
| Additional surgery, index      | 4      | 2.0    | 0      | 0      |
| level, removal                 |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
| Additional surgery, index      | 1      | \<1.0  | 0      | 0      |
| level, delayed fusion          |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
| Additional surgery, index      | 1      | \<1.0  | 0      | 0      |
| level, reoperation             |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
| Approach problems (abdominal)  | 2      | \<1.0  | 1      | 1.0    |
+--------------------------------+--------+--------+--------+--------+
| Approach problems, hernia      | 1      | \<1.0  | 0      | 0      |
+--------------------------------+--------+--------+--------+--------+
| Approach problems, retrograde  | 1      | \<1.0  | 1      | 1.0    |
| ejaculation                    |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
| Additional surgery, unrelated  | 1      | \<1.0  | 1      | 1.0    |
| to index level                 |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
| Neurological, nerve root       | 1      | \<1.0  | 0      | 0      |
| injury                         |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+

**Device-Related Adverse Events:**

There were 15 (7.3%) device-related adverse events in the Charité group,
compared to 4 (4.0%) in the BAK group. Most of these adverse events were
"device-related" pain (10, or 4.9%, in the Charité group v. 2, or 2%, in
the BAK group). Despite the higher incidence of pain due to the Charité
device, the Charité group still had 74% Pain VAS successes compared to
62% in the BAK group (p=0.0759). Other device-related adverse events
were \<1% in both groups (Charité: nerve root injury, subsidence,
displacement, removal; BAK: nonunion, degeneration at another level).

+--------------------------------+--------+--------+--------+--------+
| **Device-Related Adverse       |        |        |        |        |
| Events**                       |        |        |        |        |
|                                |        |        |        |        |
| **Table 42.2**                 |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
|                                | **C    |        | **BAK  |        |
|                                | harité |        | G      |        |
|                                | G      |        | roup** |        |
|                                | roup** |        |        |        |
+--------------------------------+--------+--------+--------+--------+
|                                | Pa     | \%     | Pa     | \%     |
|                                | tients |        | tients |        |
+--------------------------------+--------+--------+--------+--------+
| Patients enrolled              | 205    |        | 99     |        |
+--------------------------------+--------+--------+--------+--------+
| **Device-related adverse       | **15** | *      | **4**  | *      |
| events**                       |        | *7.3** |        | *4.0** |
+--------------------------------+--------+--------+--------+--------+
| Pain, back                     | 5      | 2.4    | 1      | 1.0    |
+--------------------------------+--------+--------+--------+--------+
| Pain, back and lower           | 5      | 2.4    | 1      | 1.0    |
| extremities                    |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
| Pain, lower extremities        | 2      | \<1.0  | 0      | 0      |
+--------------------------------+--------+--------+--------+--------+
| Nerve root injury              | 1      | \<1.0  | 0      | 0      |
+--------------------------------+--------+--------+--------+--------+
| Collapse, subsidence           | 1      | \<1.0  | 0      | 0      |
+--------------------------------+--------+--------+--------+--------+
| Implant displacement           | 1      | \<1.0  | 0      | 0      |
+--------------------------------+--------+--------+--------+--------+
| Removal of prosthesis          | 1      | \<1.0  | 0      | 0      |
+--------------------------------+--------+--------+--------+--------+

**Adverse Events Onset:**

The time course of adverse events is similar for the Charité and the BAK
groups, although there is a slightly greater incidence of adverse events
after 210 days in the BAK group (additional surgeries at the index
level).

**Major Adverse Events:**

Major adverse events, as defined in the success/failure criteria as
major vessel injury or blood loss (\>1500cc), neurological damage, or
nerve root injury, were infrequent. There were 2 (\<1%) in the Charité
group and 1 (1%) in the BAK group. These were neurological deterioration
(1) and major vessel injury (1), and a major vessel injury (1),
respectively, for the two groups.

**Device Failures:**

Device failures were defined as a reoperation, revision, removal, or
supplemental fixation of the device. There were 10 patients (4.9%) in
the Charité group and 8 patients (8.1%) in the BAK group with device
failures.

+--------------------------------+--------+--------+--------+--------+
| **Device Failures**            |        |        |        |        |
|                                |        |        |        |        |
| **Table 34**                   |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
|                                | **C    |        | **BAK  |        |
|                                | harité |        | G      |        |
|                                | G      |        | roup** |        |
|                                | roup** |        |        |        |
+--------------------------------+--------+--------+--------+--------+
|                                | Pa     | \%     | Pa     | \%     |
|                                | tients |        | tients |        |
+--------------------------------+--------+--------+--------+--------+
| Patients enrolled              | 205    |        | 99     |        |
+--------------------------------+--------+--------+--------+--------+
| **Device failures**            | **10** | *      | **8**  | *      |
|                                |        | *4.9** |        | *8.1** |
+--------------------------------+--------+--------+--------+--------+
| > Reoperation                  | 0      | 0      | 1      | 1.0    |
+--------------------------------+--------+--------+--------+--------+
| > Revision                     | 0      | 0      | 1      | 1.0    |
+--------------------------------+--------+--------+--------+--------+
| > Removal                      | 2      | \<1.0  | 0      | 0      |
+--------------------------------+--------+--------+--------+--------+
| > Supplemental fixation        | 8      | 3.9    | 6      | 6.1    |
+--------------------------------+--------+--------+--------+--------+

The reasons for each device failure and the treatment given are
tabulated below:

+-------+----+----------------+------------------+--------------------+
| **Ch  |    |                |                  |                    |
| arité |    |                |                  |                    |
| Group |    |                |                  |                    |
| D     |    |                |                  |                    |
| evice |    |                |                  |                    |
| Failu |    |                |                  |                    |
| res** |    |                |                  |                    |
|       |    |                |                  |                    |
| *     |    |                |                  |                    |
| *Narr |    |                |                  |                    |
| ative |    |                |                  |                    |
| Summa |    |                |                  |                    |
| ries, |    |                |                  |                    |
| Se    |    |                |                  |                    |
| ction |    |                |                  |                    |
| 8.4   |    |                |                  |                    |
| .6.5, |    |                |                  |                    |
| pp.59 |    |                |                  |                    |
| -70** |    |                |                  |                    |
+-------+----+----------------+------------------+--------------------+
| *     | *  | **Reason for   | **Problem**      | **Treatment**      |
| *Pati | *L | Failure**      |                  |                    |
| ent** | ev |                |                  |                    |
|       | el |                |                  |                    |
|       | ** |                |                  |                    |
+-------+----+----------------+------------------+--------------------+
| 01045 | L~ | Supplemental   | SI joint pain    | Fusion             |
|       | 5~ |                |                  |                    |
|       | S~ |                |                  |                    |
|       | 1~ |                |                  |                    |
+-------+----+----------------+------------------+--------------------+
| 01078 | L~ | Supplemental   | Unresolved pain  | Fusion             |
|       | 4~ |                |                  |                    |
|       | L~ |                |                  |                    |
|       | 5~ |                |                  |                    |
+-------+----+----------------+------------------+--------------------+
| 03016 | L~ | Supplemental   | Pain,            | Fusion             |
|       | 5~ |                | s                |                    |
|       | S~ |                | pondylolisthesis |                    |
|       | 1~ |                |                  |                    |
+-------+----+----------------+------------------+--------------------+
| 03023 | L~ | Removal        | Nerve root       | Removal, fusion    |
|       | 5~ |                | injury           |                    |
|       | S~ |                |                  |                    |
|       | 1~ |                |                  |                    |
+-------+----+----------------+------------------+--------------------+
| 05012 | L~ | Supplemental   | Spondylolysis    | Fusion             |
|       | 5~ |                |                  |                    |
|       | S~ |                |                  |                    |
|       | 1~ |                |                  |                    |
+-------+----+----------------+------------------+--------------------+
| 09014 | L~ | Supplemental   | Pain             | Fusion             |
|       | 4~ |                |                  |                    |
|       | L~ |                |                  |                    |
|       | 5~ |                |                  |                    |
+-------+----+----------------+------------------+--------------------+
| 09022 | L~ | Removal        | Pain             | Removal            |
|       | 4~ |                |                  |                    |
|       | L~ |                |                  |                    |
|       | 5~ |                |                  |                    |
+-------+----+----------------+------------------+--------------------+
| 10013 | L~ | Supplemental   | Pain             | Fusion             |
|       | 4~ |                |                  |                    |
|       | L~ |                |                  |                    |
|       | 5~ |                |                  |                    |
+-------+----+----------------+------------------+--------------------+
| 13008 | L~ | Supplemental   | Pain             | Fusion             |
|       | 4~ |                |                  |                    |
|       | L~ |                |                  |                    |
|       | 5~ |                |                  |                    |
+-------+----+----------------+------------------+--------------------+
| 13012 | L~ | Supplemental   | Pain             | Fusion             |
|       | 5~ |                |                  |                    |
|       | S~ |                |                  |                    |
|       | 1~ |                |                  |                    |
+-------+----+----------------+------------------+--------------------+

"Supplemental" = patient required fusion at the index level.

**Deaths:**

There was one death in the Charité group from an apparent recreational
drug overdose before the 6-week follow-up evaluation. This was unrelated
to the device and procedure.

## **Device Replacements:**

The sponsor provided a description of 5 patients who required Charité
implants replacement during the index procedure, i.e., without an
inciting adverse event (Section 8.7, p.89). In all cases, the implant
was recognized by the surgeon that the implant was either the wrong size
or not in the ideal position. There were no post-operative
complications.

**[Training Cases Results]{.underline}**

Each investigative site was required to enroll their first 5 patients as
training cases. They all received the Charité Artificial Disc. There
were 71 patients enrolled as training cases at 15 investigational sites.
These patients were not included in the ITT analysis by protocol.

  -------------------------------------------- --------------------------
  **Training Cases**                           

  N                                            71

  Early discontinuation                        7 (10%)

  Completed study                              60 (84.5%)
  -------------------------------------------- --------------------------

The demographics were similar to the randomized group: 30 (42%) were
men, 41 (58%) women, mean age 38.5 years. The surgery was performed at
the L~4~L~5~ level in 19 patients, and at the L~5~S~1~ level in 52
patients.

There were 7 early withdrawals: 3 voluntarily withdrew; 2 were
non-compliant; 1 refused follow-up; 1 failed because of pain and the
device was removed.

**Effectiveness:**

The effectiveness appeared to be comparable to the Randomized patients.
All of the effectiveness parameters were either better or comparable to
the Randomized group scores, including the improvement in Oswestry
scores, lack of neurological deterioration, improvement of the Pain VAS,
improvement in the SF-36, and radiographic assessments (lack of loss of
disc height, lack of migration). In addition, the work status improved
from 13% on short-term disability to 3% at 12 months and 2% at 24
months. Patient satisfaction was good: 81% at 12 months and 83% at 24
months (compared to 71% and 73%, respectively, for the Randomized
patients).

**Safety:**

There were higher early (within the first 2 days of surgery) adverse
events in the Training Cases group (33 patients, or 46.5%) than in the
Randomized group (58 patients, or 28.3%). The rates at all other time
periods are similar between groups. There were more device-related
adverse events in the Training Cases group (8 events, or 11.3%) than in
the Randomized group (14 events, or 6.8%).

**Discussion:**

The Training Cases performed well despite having a higher complication
rate. The higher early adverse event rate is not unexpected. The types
and severity of the complications is not different from the Randomized
group.

**[Continued Access Cases Results]{.underline}**

The sponsor was allowed to continue to enroll up to a total of 615
continued access patients. They all received the Charité Artificial
Disc. There were 71 patients enrolled as continued access cases who have
completed the 12-month follow-up evaluation as of 9/03. These patients
were not included in the ITT analysis by protocol.

The demographics were similar to the randomized group: 31 (44%) were
men, 40 (56%) women, mean age 37.7 years. The surgery was performed at
the L~4~L~5~ level in 28 patients, and at the L~5~S~1~ level in 43
patients.

There were 7 early withdrawals: 3 voluntarily withdrew; 2 were
non-compliant; 1 refused follow-up; 1 failed because of pain and the
device was removed.

**Effectiveness:**

The effectiveness appeared to be comparable to the Randomized patients.
All of the effectiveness parameters were either better or comparable to
the Randomized group scores, including the improvement in Oswestry
scores, lack of neurological deterioration, improvement of the Pain VAS,
and improvement in the SF-36. Patient satisfaction was good: 74% at 12
months (compared to 73% for the Randomized patients).

**Safety:**

The early adverse event rate in the Continued Access patient group was
the lowest rate of all the groups: Continued Access 21%, Randomized
group 28%, Training Cases 46%.

**Discussion:**

The Continued Access group performed comparably to the Randomized group
in terms of effectiveness and early adverse events.

**[VALIDITY OF THE BAK CONTROL GROUP]{.underline}**

The BAK Interbody Fusion System is a well-accepted treatment in the
orthopedic community and is a reasonable comparison treatment. Because
it was implanted via an anterior approach, it also minimized the
approach-related variables. The demonstrated presence of segmental
motion at the Charité Artificial Disc-implanted level contrasts well
with the lack of motion at the BAK-fused level. Other variables, such as
device migrations, replacements, removals, and reoperations, also make
these treatments ideally suited as comparison products. Therefore, the
study's control group treatment is a reasonable treatment for this
clinical indication, and the results are comparable to known clinical
studies for the same indication.

**[OTHER CLINICAL INFORMATION]{.underline}**

The sponsor provided several other unpublished reports pertaining to the
Charité Artificial Disc.

-   "French surgeon's report of an explant 9.5 years after insertion"

> This is an analysis report of an explanted Charité Artificial Disc
> ("SB Charite III") removed 9.5 years after the original operation. The
> endplates were found to be in excellent condition---no scratches or
> other damage. The polyethylene core was fragmented into multiple
> pieces. Shear failure occurred between the superior and inferior
> hemispheres of the bi-concave portion.

-   "Explant from Australia"

> Approximately 3 years after implantation, radiographs demonstrated
> metal-on-metal contact of the endplates, and radiographs demonstrate
> osteolysis. The surgeon was not able to remove the implant because of
> "friable and adherent blood vessels and blood loss." Biopsy showed PE
> debris.

## **CLINICAL UTILITY** (Sections 8.8, 8.9, pp.98-100)

The sponsor provided a risk-benefit analysis of the clinical utility of
the treatments in terms of safety and effectiveness, and emphasized that
the Oswestry Disability Index and Pain VAS scores were significantly
improved in the Charité Artificial Disc patients, and the Charité
Artificial Disc preserves segmental motion.

**[DISCUSSION]{.underline}**

There are some general concerns for this product. Although the Charité
Artificial Disc was highly successful in relieving pain, there were a
significant number of patients who did not obtain pain relief: 14% had
no pain relief or had their pain worsen, and an additional 13% had only
partial pain relief. The etiology of their unrelieved pain is not known.
However, it is possible that despite having facet joint arthrosis as an
exclusion criterion, the spinal motion segment is a three-joint entity,
and facet joint degeneration is probably present at least to small
degree in all patients with degenerative disc disease.

The facet joints are synovial joints, lined by hyaline cartilage and
encased in a fibrous capsule. They degenerate in concert with the disc
space. Their primary function is to protect the disc space from shear
and rotational (torsion) forces. The normal facet joints guide the
motion of the functional spinal unit in the sagittal plane, and limit
motion rotation and bending. Their secondary role is to share a portion
of the axial load when standing (0% when sitting). The lumbar facet
joints bear up to 20% of the compressive loads, particularly in
extension. When degenerative changes develop in the disc space, the
facet joints share even more of the load. Facet joints also degenerate
like knee joints, and form typical osteoarthritic pathologic changes.
Degenerated facet joints can be painful. Free nerve endings are also
present in the fibrous capsule of the facet joint. Pain can originate
from the three-joint complex of the disc and the facet joints. Painful
osteoarthritic degeneration of the facet joints was called the "facet
syndrome" in 1933 (Ghormley). It is usually a fairly constant mechanical
back pain and is almost always bilateral. Pure facet syndrome pain is
off the midline, tends to be proximal over the sacroiliac joints, and is
rarely referred to the thighs. In contrast, pain from isolated
degenerative discs tends to be central.

This may be a source of continued pain in patients unsuccessfully
treated with disc replacement surgery. Whether the disc replacement is
able to unload the facet joints sufficiently to effectively treat this
region is unknown. This may be an unaddressed problem of disc
replacement surgery.