July 28, 2004

Mathematical Statistician

Division of Biostatistics, OSB

Final Statistical Review of PMA P040001, St. Francis Medical's X STOP®
Interspinous Process Distraction System (January 7, 2004)

**Objective**

The objective of the clinical study were to evaluate the safety and
effectiveness of the X STOP Interspinous Process Distraction System in
the treatment of neurogenic intermittent claudication secondary to mild
or moderate lumbar spinal stenosis.

**Study Design**

A prospective, randomized, controlled, multi-center clinical study was
conducted. 191 patients (100 X STOP and 91 controls) were enrolled and
treated at 9 investigational sites. The X STOP was compared to
non-operative therapy in the treatment of neurogenic; intermittent
claudication secondary to mild or moderate lumbar spinal stenosis.
Patients randomized to the control group received at least one epidural
steroid injection, nonsteroidal anti -inflammatories (NSAIDs),
analgesics, and physical therapy. The study was designed to prove that
the X STOP is significantly more efficacious than the control utilizing
the Zurich Claudication Questionnaire (ZCQ) as the primary outcomes
measurement. Safety information was measured by an analysis of reported
adverse events and additional surgeries.

**Sample Size**

The definition of study success is that 'the X STOP group has a higher
success rate than the control group. The sponsor anticipated success
rates for the X STOP and control of 60% and 37.5%, respectively. They
found that for a 2-sided test of proportions with a 0.05 significance
level and 80% power that 85 subjects per group were needed. In order to
allow for a drop-out rate of 15%, 200 patients were planned to be
enrolled in the study. ***Note that the sponsor ultimately enrolled 229
patients, even though their IDE was for 200 subjects. Note that they
only treated 191 subjects (100 X STOP and 91 control).***

**Randomization**

Block randomization of the patients, stratified by site, was used with
block sizes of 2. **Note that with a fixed block size of 2 (1 treatment
and 1 control patient for each pair of randomized patients) used by the
company, the randomization assignment of patients could easily be
subverted by the investigators.** That is they could always know the
treatment assignment of the 2nd of the pair if so inclined, and thus,
potentially pick the patient to receive that second assignment. The
sponsor used a call-in center to assign the treatment when each site
called in the patient's information to verify eligibility. The date of
surgery was considered as the treatment date for the X STOP patients and
the date of the initial epidural injection was considered as the
treatment date for the control patients. Masking of patients was not
possible.

**Enrollment**

The sponsor enrolled 229 patients at 9 centers, with the
highest-enrolling center enrolling 45 and treating 36 patients and the
smallest enrolling 9 and treating 6 (page 44). Of these 229 patients,
191 were treated (100 X STOP and 91 control). 14 X STOP and 24 control
patients withdrew or were excluded before treatment. Reasons were
related to health (3 X STOP/2 Control), failure to meet
inclusion/exclusion criteria (1/1), and voluntary withdrawal (16/26).
Eight subjects withdrew after randomization to the control group.
Details are provided below.

Table 1: Patients Enrolled but not Treated

+--------------------------------------------------+---------+---------+
| **Reason for Withdrawal/Exclusion**              | **X     | **Co    |
|                                                  | STOP**  | ntrol** |
+==================================================+=========+=========+
| Health related                                   |         |         |
+--------------------------------------------------+---------+---------+
| Cancer                                           | 1       | 1       |
+--------------------------------------------------+---------+---------+
| Coronary artery bypass surgery                   | 0       | 1       |
+--------------------------------------------------+---------+---------+
| Hand infection with fever                        | 1       | 0       |
+--------------------------------------------------+---------+---------+
| Renal complications w/nephrectomy                | 1       | 0       |
+--------------------------------------------------+---------+---------+
| Failure to meet inclusion/exclusion criteria     |         |         |
+--------------------------------------------------+---------+---------+
| Stenosis at \> 2 levels                          | 1       | 0       |
+--------------------------------------------------+---------+---------+
| Age \< 50                                        | 0       | 1       |
+--------------------------------------------------+---------+---------+
| Patient unable to schedule surgery/treatment     |         |         |
+--------------------------------------------------+---------+---------+
| Work schedule                                    | 1       | 0       |
+--------------------------------------------------+---------+---------+
| Family illness                                   | 1       | 0       |
+--------------------------------------------------+---------+---------+
| Delayed scheduling treatment until study closed  | 0       | 2       |
+--------------------------------------------------+---------+---------+
| Patient voluntarily withdrew from study          |         |         |
+--------------------------------------------------+---------+---------+
| Elected to undergo laminectomy                   | 1       | 4       |
+--------------------------------------------------+---------+---------+
| Elected to forego X STOP implantation            | 7       | 0       |
+--------------------------------------------------+---------+---------+
| Elected to forego epidural injection             | 0       | 4       |
+--------------------------------------------------+---------+---------+
| > Elected to withdraw after randomization to     | 0       | 8       |
| > control group                                  |         |         |
+--------------------------------------------------+---------+---------+
| Elected to withdraw after loss of spouse         | 0       | 1       |
+--------------------------------------------------+---------+---------+
| Patient refused to make/keep appointments        | 0       | 2       |
+--------------------------------------------------+---------+---------+
| **TOTAL**                                        | **14**  | **24**  |
+--------------------------------------------------+---------+---------+

The sponsor performed a series of sensitivity analyses in order to
assess the effect that the exclusion of untreated patients might have
had on estimates of the study success rate. Analyses were performed
based on a) the assumption that all untreated patients would have been
failures, b) the assumption that all untreated patients would have been
successes, c) the use of available data from untreated patients (24
month ZCQ scores were obtained from untreated patients wherever
possible), and d) multiple imputation methods. As shown in **Appendix
F**, these analyses did not materially affect comparison to the control.
Success rates were always statistically significantly higher in the X
STOP group than in the control group.

**Demographic Data**

A total of 191 patients were enrolled in the X STOP clinical trial: 100
patients were treated with the X STOP and 91 received non-Operative
care. Demographic information pertaining to the patients participating
in the study is presented in Table VI. Note that there was very little
difference between the 2 groups with respect to baseline
characteristics.

+--------------------------+---------------+--------------+-----------+
| Table VI: Demographic    |               |              |           |
| Information              |               |              |           |
+--------------------------+---------------+--------------+-----------+
|                          | > X STOP      | Control      | >         |
|                          | > Device      |              | \_p-value |
|                          |               |              |           |
|                          |               |              | p-value   |
+--------------------------+---------------+--------------+-----------+
| > Age (yr.) Mean (Range) | > 70.0        | 69.1         | > 0.513   |
|                          | > \[50-94\]   | \[50-88\]    |           |
+--------------------------+---------------+--------------+-----------+
| > Weight (lbs.) Mean     | > 177.1       | 180.2        | > 0.569   |
| > (Range)                | > \[105-265\] | \[98-293\]   |           |
+--------------------------+---------------+--------------+-----------+
| > Height (in.) Mean      | > 67.3        | 66.3         | > 0.117   |
| > (Range)                | > \[56-74\]   | \[56-75\]    |           |
+--------------------------+---------------+--------------+-----------+
| > Gender: Male           | > 57 (57.0%)  | 46 (50.5%)   | > 0.387   |
| >                        | >             |              |           |
| > Female                 | > 43.(43.0%)  | 45 (49.5%)   |           |
+--------------------------+---------------+--------------+-----------+
| > Spondylolisthesis      | > 35 (35.0%)  | 24 (26.7%)   | > 0.272   |
| > Present                |               |              |           |
+--------------------------+---------------+--------------+-----------+

**Patient Accountability**

Patient accountability data are summarized below in Tables 5 and 6 of
the Clinical Report (page 47 of Volume I of the PMA). Of the 100 treated
patients for the X STOP group, 88 had 2-year follow-ups. Of the 12
patients who didn't, 6 had additional LSS surgery, 4 died, 1 had an
implant removal, and 1voluntarily withdrew. Of the 91 treated control
patients, only 58 had 2-year evaluations. Of the remaining 33 patients,
24 had LSS surgery, 3 died, 1had the procedure aborted, and 1
voluntarily withdrew.

[Table 2: Patient Accountability by Follow-up Visit - X STOP Patient
Group]{.smallcaps}

+-----------------------------------+------+------+------+------+------+
|                                   | **T  | **6  | **6  | **12 | **24 |
|                                   | reat | wk** | mo** | mo** | mo** |
|                                   | ed** |      |      |      |      |
+===================================+======+======+======+======+======+
| Evaluable Patients (Cumulative)   |      |      |      |      |      |
+-----------------------------------+------+------+------+------+------+
| -   Theoretically due             | 100  | 100  | 100  | 100  | 100  |
+-----------------------------------+------+------+------+------+------+
| -   Additional LSS surgery with   |      |      | 2    | 4    | 6    |
|     device removal (reached       |      |      |      |      |      |
|     defined failure endpoint \<   |      |      |      |      |      |
|     24 months)                    |      |      |      |      |      |
+-----------------------------------+------+------+------+------+------+
| Discontinued Patients             |      |      |      |      |      |
| (Cumulative)                      |      |      |      |      |      |
+-----------------------------------+------+------+------+------+------+
| -   Deaths                        |      | 1    | 2    | 2    | 4    |
+-----------------------------------+------+------+------+------+------+
| -   Implant removals              |      | 1    | 1    | 1    | 1    |
+-----------------------------------+------+------+------+------+------+
| -   Lost to follow-up             |      | \-   | \-   | \-   | \-   |
+-----------------------------------+------+------+------+------+------+
| -   Voluntary withdrawal          |      | \-   | 1    | 1    | 1    |
+-----------------------------------+------+------+------+------+------+
| Expected Patients\*               |      | 98   | 95   | 93   | 89   |
+-----------------------------------+------+------+------+------+------+
| Missed visits\*\*                 |      | 4    | 6    | 4    | 0    |
+-----------------------------------+------+------+------+------+------+
| Patients Evaluated                |      | 94   | 88   | 88   | 88   |
+-----------------------------------+------+------+------+------+------+
| Percent Follow-up                 |      | 9    | 9    | 9    | 9    |
|                                   |      | 5.9% | 2.6% | 4.6% | 8.9% |
+-----------------------------------+------+------+------+------+------+

\* Includes patients who voluntarily withdrew from the study in the
total \# of "expected" patients.

\*\*24 month follow-up visits outside of the protocol-defined window are
treated as protocol deviations and are presented in **Attachment 5**
(**Listing 1.5**).

[Table 3: Patient Accountability by Follow-up Visit - Control Patient
Group]{.smallcaps}

+-----------------------------------+------+------+------+------+------+
|                                   | **T  | **6  | **6  | **12 | **24 |
|                                   | reat | wk** | mo** | mo** | mo** |
|                                   | ed** |      |      |      |      |
+-----------------------------------+------+------+------+------+------+
| Evaluable Patients (Cumulative)   |      |      |      |      |      |
+-----------------------------------+------+------+------+------+------+
| -   Theoretically due             | 91   | 91   | 91   | 91   | 91   |
+-----------------------------------+------+------+------+------+------+
| -   LSS Surgery (reached defined  |      | 1    | 13\* | 17   | 24   |
|     failure endpoint \< 24        |      |      |      |      |      |
|     months)\*                     |      |      |      |      |      |
+-----------------------------------+------+------+------+------+------+
| Discontinued Patients             |      |      |      |      |      |
| (Cumulative)                      |      |      |      |      |      |
+-----------------------------------+------+------+------+------+------+
| Deaths                            |      | \-   | 1    | 2    | 3    |
+-----------------------------------+------+------+------+------+------+
| Procedure Aborted                 | 1    | 1    | 1    | 1    | 1    |
+-----------------------------------+------+------+------+------+------+
| Lost to follow-up                 |      | \-   | \-   | \-   | \-   |
+-----------------------------------+------+------+------+------+------+
| Voluntary withdrawal              |      | 2    | 2    | 2    | 5    |
+-----------------------------------+------+------+------+------+------+
| Expected Patients\*\*             |      | 89   | 77   | 72   | 63   |
+-----------------------------------+------+------+------+------+------+
| Missed visits\*\*\*               |      | 17   | 11   | 1    | 0    |
+-----------------------------------+------+------+------+------+------+
| Patients Evaluated                |      | 70   | 64   | 69   | 58   |
+-----------------------------------+------+------+------+------+------+
| Percent Follow-up                 |      | 7    | 8    | 9    | 9    |
|                                   |      | 8.7% | 3.1% | 5.8% | 2.1% |
+-----------------------------------+------+------+------+------+------+

\*One control patient (#817) in this group died secondary to
complications of Parkinson's disease 20 months following laminectomy

\*\* Patients who voluntarily withdrew from the study are included in
the total \# of "expected" patients.

\*\*\*24 month follow-up visits outside of the protocol-defined window
are treated as protocol deviations and are presented in **Attachment 5**
(**Listing 1.5**).

**Data Analysis and Results**

The primary efficacy variable was analyzed using an Intent-to-Treat
(ITT) methodology where the ITT population was defined as all patients
receiving treatment or attempted treatment (i.e., treatment was
initiated but aborted) in the X STOP or control group. Patients who were
enrolled but not treated (i.e., declined to participate or were unable
to participate) were not included.

For all primary analyses, missing data were not imputed. Patients
reaching any endpoint before completing the study that was defined in
the protocol as a treatment failure (e.g., a laminectomy) were included
as failures in the computation of the study success rate, however.

Secondary efficacy variables, safety variables and demographic and
baseline variables were similarly analyzed except that ITT analysis was
not used. Categorical variables were analyzed using the Fisher exact
test. Continuous variables were analyzed using analysis of variance
(ANOVA). Two-sided p-values were calculated and considered to be
statistically significant when p \<0.05.

**Effectiveness Analysis**

As described above, the primary Efficacy variable was ZCQ success at the
24 month follow-up. Additionally, for treatment with the X STOP to be
considered successful, distraction had to be maintained at 24 months,
and there could be no device-related complications or re-operation.

Table VIII below summarizes the clinical results at the 24 month
follow-up. The X STOP group had statistically significantly improved ZCQ
scores over baseline compared to the control group, and a significantly
greater number of X STOP patients were satisfied with their treatment.
Overall treatment success was 45.7% (42/92) for the X STOP group
compared to 4.9% (4/81) for the control group (p\<0.001).

  ---------------- ------- ----------- ----------- ----------- -----------
  Table VIII:                                                  
  Treatment                                                    
  Success by ZQC                                               
  domain at 24                                                 
  Month Follow-up                                              

                   X STOP              Control                 p-value

                   n/N     \%          n/N         \%          

  ZCQ Success Rate                                             
  by Domain                                                    

  Physical         53/93   57.0%       12/81       14.8%       \<0.001
  Function                                                     

  Symptom Severity 56/93   60.2%       15/81       18.5%       \<0.001

  Satisfaction     68/93   73.1%       28/78       35.9%       \<0.001

  Percent of                                                   
  Patients Meeting                                             
  All 3 ZCQ                                                    
  Success Criteria                                             

  ZCQ Success      45/93   48.4%       4/81        4.9%        \<0.001

                                                               
  ---------------- ------- ----------- ----------- ----------- -----------

From the table above for the overall success rate, 8 of the 100 treated
X STOP and 10 of the 91 Control patients have been removed. As presented
by the sponsor and shown by the results in Table 18.5 (Amendment 1),
2-year results for 10 (4 X STOP and 6 Controls) of these patients with
results for over 1-year can be reasonably imputed. As stated by the
sponsor "Variability in success rate estimates can be substantially
reduced if some reasonable imputations are performed. There are 10
\"missing\" patients for whom the two-year outcome can reasonably be
inferred from available data. These are listed below in **Table 18.5**."

> [Table 18.5: Imputed Results for 10 Patients with Missing 24 Month
> Data]{.smallcaps}

  -------------- ------------- -------------- -------------------------------
  **Group**      **Patient**   **Last Visit   **Result (Imputed)**
                               Day**          

  X STOP         0346\*        384            Failed on all ZCQ domains

  X STOP         0718          559            Failed on ZCQ severity

  X STOP         1026          710            Success on all ZCQ domains

  X STOP         1403          382            Failed on ZCQ physical function

  Control        0124          343            Failed on ZCQ severity and
                                              function

  Control        0125          427            Failed on all ZCQ domains

  Control        0501          581            Failed on all ZCQ domains

  Control        0715          559            Failed on ZCQ severity

  Control        0806\*        389            Failed on ZCQ severity and
                                              function

  Control        1210          355            Failed on all ZCQ domains
  -------------- ------------- -------------- -------------------------------

> \* Died prior to two-year visit.

"Patient #1026 would almost certainly have been a success. That patient
showed success on all ZCQ domains at two years and was only treated as
missing because of the absence of two-year radiographs which prevented
the evaluation of maintained distraction. However, one-year radiographs
did indicate that distraction had been maintained."

"The remaining patients were all failures at one year. Of the 88
patients (in both the X STOP and control groups) who were ZCQ failures
at one year and were evaluable at two years, only 4 (4.5%) became
successful at two years. Therefore it is reasonable to impute two-year
failure for these patients."

As can be seen form Table 18.7 below, the remaining 8 patients (4 X STOP
and 4 controls) who were removed from the database didn't have 1-year
follow-ups. In fact all but one where lost to follow-up by 3 months.
Note that 5 of these patients died within the 1^st^ year (3 X STOP and 2
controls).

> [Table 18.7: Available Results for 8 Patients with Missing Data at the
> 24 Month Follow-up]{.smallcaps}

  -------------- ------------- -------------- --------------------------------
  **Group**      **Patient**   **Last Visit   **Result (Imputed)**
                               Day**          

  X STOP         0120\*        73             ZCQ success but incomplete

  X STOP         0508\*        \-             Died of pulmonary edema on Day 2

  X STOP         0803          41             Failed on ZCQ physical function

  X STOP         0834\*        90             Success on all ZCQ domains

  Control        0319\*        45             Success on all ZCQ domains

  Control        0509          \-             No data available - refused to
                                              return

  Control        1014          38             No ZCQ data - worsening pain
                                              scores

  Control        1017\*        192            Failed on ZCQ severity and
                                              function
  -------------- ------------- -------------- --------------------------------

> \* Died prior to two-year visit.

***The sponsor has demonstrated statistical superiority of their device
over the control with respect to their primary endpoint.*** Given the
information in Tables 18.5 and 18.7 above the overall success rates can
be presented as follows:

> [Table of Overall Success Rates with Imputed Results on 10 Patients
> Compared to Lowest Possible & Highest Possible Success
> Rates]{.smallcaps}

  --------------------- ------------------ ---------------- ---------------
                        **X STOP**         **Control**      **p-value**

  Intent-to-Treat       43/100 (43.0%)     4/91 (4.4%)      \< 0.001
  results\*                                                 

  Evaluable results\*\* 43/96 (44.8%)      4/87 (4.6%)      \< 0.001

                                                            
  --------------------- ------------------ ---------------- ---------------

> \* Results for all patients with 1-year data use last observation
> carried forward (see Table 18.5) and patients with less than 1-year
> data (Table 18.7) treated as failures.
>
> \*\* Results for patients with less than 1-year data (Table 18.7)
> excluded.

**Success Rate by Site**

The sponsor also presented success rates by center on page 72, Table 36
(provided below). The center that treated the most patients had an 85%
success rate (17/20) for the X STOP. All other centers had success rates
of 50% or less. In fact the next 2 largest centers had X STOP success
rates of 28% (5/18) and 14% (2/14). In an attempt to dismiss this
discrepancy, they state that the Breslow-Day test for homogeneity was
not statistically significant (p=.474) and used this as evidence that
there was not a significant difference among sites. ***But when the X
STOP success rates among centers is tested, it is found to be highly
significantly different (p\<0.005 for exact Chi-square and Likelihood
tests). Most of this difference is attributable to the significantly
higher success rate at site 2, the site which treated the most patients.
The sponsor addressed this issue in their amendment by claiming that
significant site to site differences are common in clinical trials, that
the X STOP success rate is greater than the control at all sites, and
that the X STOP success rate will still be significantly greater than
the control even if this site is removed.***

From Table 36 (page 72): Success Rates by Investigational Site

  --------------------------------------------------------------------------------
  **Investigational Site Number**      **X                 **Control**   
                                       STOP**                            
  ------------------------------------ --------- --------- ------------- ---------
                                       **n/N**   **%**     **n/N**       **%**

  1                                    5/18      27.8%     1/16          6.3%

  2                                    17/20     85.0%     2/15          13.3%

  3                                    2/14      14.3%     0/14          0.0%

  4                                    5/11      45.5%     0/9           0.0%

  5                                    4/8       50.0%     0/9           0.0%

  6                                    4/9       44.4%     0/8           0.0%

  7                                    2/4       50.0%     0/5           0.0%

  8                                    2/6       33.3%     1/5           20.0%

  9                                    1/2       50.0%     0/1           0.0%
  --------------------------------------------------------------------------------

***Also note on page 191 and 193, it is stated that the principal
investigators from site 2 hold a significant equity interest in the
Company.*** The reason for the discrepancy in success rates is unknown.
Note that in Section V (the Financial Disclosure section) on pages 191
and 193, the sponsor also describes measures taken to minimize bias into
the study at all sites. Investigators didn't administer questionnaires
to patients and quantitative measurements were made by physicians not
involved in the treatment of patients. An independent radiologist
measured the maintenance of distraction in each patient as well as other
anatomical measurements that were analyzed as part of the study results.

**Safety**

Aside from laminectomy (6 X STOP and 24 Control patients), the
peri-operative and treatment related adverse events were minimal in each
group (Table 49, page 86). The sponsor also lists in Table 50 (page 87)
a number of adverse events that they claim are unrelated to the device
and claim are not statistically different from the control. ***Note that
many of the events in the table below occur with greater prevalence in
the X STOP group.***

Table 4: Adverse Events Unrelated to Device or Treatment

+----------------------------+----+----+----+----+----+----+------+
| **Adverse Event**          | *  |    |    | *  |    |    | **p  |
|                            | *X |    |    | *C |    |    | -val |
|                            | ST |    |    | on |    |    | ue** |
|                            | OP |    |    | tr |    |    |      |
|                            | ** |    |    | ol |    |    |      |
|                            |    |    |    | ** |    |    |      |
|                            | ** |    |    |    |    |    |      |
|                            | (N |    |    | ** |    |    |      |
|                            | =  |    |    | (N |    |    |      |
|                            | 10 |    |    | =  |    |    |      |
|                            | 0) |    |    | 9  |    |    |      |
|                            | ** |    |    | 1) |    |    |      |
|                            |    |    |    | ** |    |    |      |
+============================+====+====+====+====+====+====+======+
|                            | ** | ** | *  | ** | ** | *  |      |
|                            | \# | \# | *% | \# | \# | *% |      |
|                            | of | of | ** | of | of | ** |      |
|                            | Ev | Pa |    | Ev | Pa |    |      |
|                            | en | ti |    | en | ti |    |      |
|                            | ts | en |    | ts | en |    |      |
|                            | ** | ts |    | ** | ts |    |      |
|                            |    | ** |    |    | ** |    |      |
+----------------------------+----+----+----+----+----+----+------+
| **Body as a Whole**        |    |    |    |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Accidental injury          | 14 | 11 | 1  | 4  | 4  | 4. | 0    |
|                            |    |    | 1. |    |    | 4% | .110 |
|                            |    |    | 0% |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Cancer                     | 4  | 4  | 4. | 1  | 1  | 1. | 0    |
|                            |    |    | 0% |    |    | 1% | .371 |
+----------------------------+----+----+----+----+----+----+------+
| Weight gain                | 1  | 1  | 1. | 0  | 0  | 0. | 1    |
|                            |    |    | 0% |    |    | 0% | .000 |
+----------------------------+----+----+----+----+----+----+------+
| **Cardiovascular System**  |    |    |    |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Cardiovascular disorder    | 5  | 5  | 5. | 1  | 1  | 1. | 0    |
|                            |    |    | 0% |    |    | 1% | .214 |
+----------------------------+----+----+----+----+----+----+------+
| Peripheral vascular        | 1  | 1  | 1. | 0  | 0  | 0. | 1    |
| disorder                   |    |    | 0% |    |    | 0% | .000 |
+----------------------------+----+----+----+----+----+----+------+
| **Endocrine**              |    |    |    |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Diabetes                   | 1  | 1  | 1. | 0  | 0  | 0. | 1    |
|                            |    |    | 0% |    |    | 0% | .000 |
+----------------------------+----+----+----+----+----+----+------+
| **Gast                     |    |    |    |    |    |    |      |
| rointestinal/Genitourinary |    |    |    |    |    |    |      |
| System**                   |    |    |    |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Gastrointestinal disorder  | 4  | 3  | 3. | 0  | 0  | 0. | 0    |
|                            |    |    | 0% |    |    | 0% | .248 |
+----------------------------+----+----+----+----+----+----+------+
| Genitourinary              | 4  | 4  | 4. | 0  | 0  | 0. | 0    |
| disorder/infection         |    |    | 0% |    |    | 0% | .123 |
+----------------------------+----+----+----+----+----+----+------+
| **Hematologic**            |    |    |    |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Anemia                     | 1  | 1  | 1. | 0  | 0  | 0. | 1    |
|                            |    |    | 0% |    |    | 0% | .000 |
+----------------------------+----+----+----+----+----+----+------+
| **Hepatobiliary**          |    |    |    |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Gallstones                 | 1  | 1  | 1. | 0  | 0  | 0. | 1    |
|                            |    |    | 0% |    |    | 0% | .000 |
+----------------------------+----+----+----+----+----+----+------+
| **Immunologic**            |    |    |    |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Allergy                    | 1  | 1  | 1. | 0  | 0  | 0. | 1    |
|                            |    |    | 0% |    |    | 0% | .000 |
+----------------------------+----+----+----+----+----+----+------+
| **Musculoskeletal System** |    |    |    |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Back, lower                | 21 | 16 | 1  | 7  | 7  | 7. | 0    |
|                            |    |    | 6. |    |    | 7% | .118 |
|                            |    |    | 0% |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Back, upper                | 4  | 4  | 4. | 0  | 0  | 0. | 0    |
|                            |    |    | 0% |    |    | 0% | .123 |
+----------------------------+----+----+----+----+----+----+------+
| Back, unspecified          | 3  | 3  | 3. | 0  | 0  | 0. | 0    |
|                            |    |    | 0% |    |    | 0% | .248 |
+----------------------------+----+----+----+----+----+----+------+
| Extremity, lower           | 16 | 13 | 1  | 5  | 3  | 3. | 0.0  |
|                            |    |    | 3. |    |    | 3% | 18\* |
|                            |    |    | 0% |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Extremity, upper           | 4  | 4  | 4. | 2  | 2  | 2. | 0    |
|                            |    |    | 0% |    |    | 2% | .685 |
+----------------------------+----+----+----+----+----+----+------+
| Groin                      | 1  | 1  | 1. | 2  | 2  | 2. | 0    |
|                            |    |    | 0% |    |    | 2% | .606 |
+----------------------------+----+----+----+----+----+----+------+
| Hip                        | 13 | 11 | 1  | 3  | 3  | 3. | 0    |
|                            |    |    | 1. |    |    | 3% | .052 |
|                            |    |    | 0% |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Rib                        | 1  | 1  | 1. | 0  | 0  | 0. | 1    |
|                            |    |    | 0% |    |    | 0% | .000 |
+----------------------------+----+----+----+----+----+----+------+
| Unspecified                | 1  | 1  | 1. | 0  | 0  | 0. | 1    |
|                            |    |    | 0% |    |    | 0% | .000 |
+----------------------------+----+----+----+----+----+----+------+
| **Nervous System**         |    |    |    |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Headache                   | 1  | 1  | 1. | 0  | 0  | 0. | 1    |
|                            |    |    | 0% |    |    | 0% | .000 |
+----------------------------+----+----+----+----+----+----+------+
| Neurological disorder      | 1  | 1  | 1. | 1  | 1  | 1. | 1    |
|                            |    |    | 0% |    |    | 1% | .000 |
+----------------------------+----+----+----+----+----+----+------+
| Neuropathy                 | 4  | 4  | 4. | 0  | 0  | 0. | 0    |
|                            |    |    | 0% |    |    | 0% | .123 |
+----------------------------+----+----+----+----+----+----+------+
| Neuropsychological         | 5  | 5  | 5. | 1  | 1  | 1. | 0    |
| disorder                   |    |    | 0% |    |    | 1% | .214 |
+----------------------------+----+----+----+----+----+----+------+
| Stroke                     | 1  | 1  | 1. | 1  | 1  | 1. | 1    |
|                            |    |    | 0% |    |    | 1% | .000 |
+----------------------------+----+----+----+----+----+----+------+
| **Respiratory System**     |    |    |    |    |    |    |      |
+----------------------------+----+----+----+----+----+----+------+
| Respiratory                | 3  | 3  | 3. | 1  | 1  | 1. | 0    |
| disorder/infection         |    |    | 0% |    |    | 1% | .623 |
+----------------------------+----+----+----+----+----+----+------+

P-values determined using the Fisher exact test

\* indicating a level of significance \< 0.05

**Laminectomy Data**

The sponsor provided the following results for a statistical comparison
of 36 laminectomy patients with the X STOP patients from their clinical
trial. The laminectomy patients come from control (26) and X STOP (6)
patients who failed this study, 5 control and 2 X STOP patients from the
unwelded study and 7 untreated patients from this study. Of these,
outcomes were available for 36 patients.

ZCQ data were collected for patients in the clinical trial who underwent
laminectomy surgery. Data were also available for patients undergoing
laminectomy from a feasibility study that preceded the Pivotal Clinical
Trial. These ZCQ data are summarized in Table X on page 17 of the PMA.
Mean follow-up for laminectomy patients was 1.2 years (range: 76 days to
2.71 years). According to the sponsor mean improvement scores in symptom
severity and physical function were not significantly different. The
mean satisfaction score for patients undergoing laminectomy was
significantly higher (indicating less satisfaction) than the mean score
in X STOP patient at the 24 month follow-up (p=0.006).

+----------------+------------+---------+---------+---------+--------+
| Table X:       |            |         |         |         |        |
| Outcomes -     |            |         |         |         |        |
| Laminectomy    |            |         |         |         |        |
| Compared to X  |            |         |         |         |        |
| STOP           |            |         |         |         |        |
+----------------+------------+---------+---------+---------+--------+
| > Mean Change  | > L        |         | > X     |         | > p    |
| > Scores       | aminectomy |         | > STOP  |         | -value |
|                | > Group    |         | > P     |         |        |
|                | > (N=316)  |         | atients |         |        |
|                |            |         | >       |         |        |
|                |            |         |  (N=86) |         |        |
+----------------+------------+---------+---------+---------+--------+
|                | > N        | > Mean  | > N     | > Mean  |        |
|                |            | > (SD)  |         | > (SD)  |        |
+----------------+------------+---------+---------+---------+--------+
| > Symptom      | > 36       | > 0.87  | > 86    | > 0.99  | >      |
| > Severity     |            | > 1.07  |         | > 0.87  |  0.532 |
+----------------+------------+---------+---------+---------+--------+
| > Physical     | > 36       | > 0.74  | > 86    | > 0.76  | >      |
| > Function     |            | > 0.81  |         | > 0.79  |  0.898 |
+----------------+------------+---------+---------+---------+--------+
| > Patient      | > 36       | > 2.20  | > 86    | > 1.70  | > 0    |
| > Satisfaction |            | > 1.03  |         | > 0.85  | .006\* |
+----------------+------------+---------+---------+---------+--------+

P-value determined using an ANOVA

According to the sponsor, there were no significant differences in the
proportion of patients achieving a threshold level of improvement
defined as clinically significant in any of the three ZCQ domains (see
Table XI, page 18. When all three ZCQ criteria are combined, 44.4%
(16/36) of laminectomy patients had a successful outcome compared to
45.7% (42/92) of X STOP patients who met all study criteria for
treatment success (p=0.899).

+------------------------------+------+-------+------+------+--------+
| > Table XI: **Treatment**    |      |       |      |      |        |
| > **Success**                |      |       |      |      |        |
+------------------------------+------+-------+------+------+--------+
|                              | >    |       | >    |      | >      |
|                              |  **L |       |  **X |      |  **p-v |
|                              | amin |       | > ST |      | alue** |
|                              | ecto |       | OP** |      |        |
|                              | my** |       |      |      |        |
+------------------------------+------+-------+------+------+--------+
|                              | >    | > \%  | >    | > \% |        |
|                              |  n/N |       |  n/N |      |        |
+------------------------------+------+-------+------+------+--------+
| > Clinically Significant     | > 2  | >     | > 5  | > 6  | >      |
| > Improvement in Symptom     | 1/36 |  58.3 | 6/93 | 0.2% |  0.841 |
| > Severity                   |      | > %   |      |      |        |
+------------------------------+------+-------+------+------+--------+
| > Clinically Significant     | > 2  | >     | > 5  | > 5  | >      |
| > Improvement in Physical    | 3/36 |  63.9 | 3/93 | 7.0% |  0.465 |
| > Function                   |      | > %   |      |      |        |
+------------------------------+------+-------+------+------+--------+
| > Percent of Patients        | > 2  | >     | > 6  | > 7  | >      |
| > Satisfied                  | 2/36 |  61\. | 8/93 | 3.1% |  0.180 |
|                              |      | > %   |      |      |        |
+------------------------------+------+-------+------+------+--------+
| > Treatment Success          | > 1  | >     | > 4  | > 4  | >      |
|                              | 6/36 | 44.4% | 2/92 | 5.7% |  0.899 |
+------------------------------+------+-------+------+------+--------+

**Note that there are problems with using this collection of patients
who failed the pilot and pivotal study as laminectomy comparison group
for the X STOP device. Such a non-randomized comparison could introduce
bias into the comparison which cannot be quantified and thus would make
the statistical results suspect.**

**Sponsor's Conclusions Drawn from the Studies** (SSE, pages 12-13)

"Results of the Pivotal Clinical Trial confirm the safety of the X STOP.
The implant resulted in a low percentage of complications, which
resolved without significant clinical sequelae and no neurological
injuries occurred in the study.

The efficacy of the X STOP was demonstrated by outcomes at the 24 month
follow-up. A significantly greater proportion of X STOP patients
achieved clinically significant improvement in symptom severity and
physical function compared to control patients. A significantly greater
proportion of X STOP patients were also satisfied with their treatment
compared to control patients.

*Symptom Severity*

At the 24 month follow-up, 60.2% of X STOP patients achieved clinically
significant improvement in symptoms compared to 18.5% of patients in the
control group.

*Physical Function*

At the 24 month follow-up, 57.0% of X STOP patients achieved clinically
significant improvement in physical function compared to 14.8% in the
control group.

*Patient Satisfaction*

At the 24 month follow-up, 73.1 % of X STOP patients were satisfied with
their treatment, compared to 35.9% of control patients.

When patients were required to meet all success criteria as defined in
the study protocol, 45.7% of X STOP patient were treatment successes,
compared to 4.9% of control patients. X STOP outcomes are comparable to
results for laminectomy surgery." **Note that these rates excludes
several patients with missing 24 month data (3 who were failures at
1-year, 1 who was a success on all domains but didn't have 2-year
radiographic results, 3 who died before 1 year, and 1 who was lost to
follow-up after day 41).**

According to the sponsor (page 13 of SSED), "The results of this
clinical study demonstrate that the X STOP can offer patients an
alternative after non-operative therapy and epidural injections are no
longer effective and before a decompressive laminectomy is performed.
The X STOP provides a conservative, safe, effective treatment option for
patients with mild to moderate symptoms of lumbar spinal stenosis."

**[Issues of Concern]{.underline}**

1.  Note that with a fixed block size of 2 (1 treatment and 1 control
    patient for each pair of randomized patients) as used by the
    company, the randomization assignment of patients could easily be
    subverted by the investigators. That is they could always know the
    treatment assignment of the 2nd of the pair if so inclined, and
    thus, potentially pick the patient to receive that second
    assignment.

2.  The sponsor presented success rates by center on page 72, Table 36.
    The center that treated the most patients (site \# 2) had an 85%
    success rate (17/20) for the X STOP. All other centers had success
    rates of 50% or less. In fact the next 2 largest centers had X STOP
    success rates of 28% (5/18) and 14% (2/14). In an attempt to dismiss
    this discrepancy, they state (page 72) that the Breslow-Day test for
    homogeneity was not statistically significant (p=.474) and used this
    as evidence that there was not a significant difference among sites.
    But when the X STOP success rates among centers is tested, it is
    found to be highly significantly different (p\<0.005 for exact
    Chi-square and Likelihood tests). Most of this difference is
    attributable to the significantly higher success rate at site \# 2.
    Furthermore, on page 191 and 193 it is stated that the investigators
    at this site, who also happen to be the inventors of the device,
    hold a significant equity interest in the company.

3.  In Table 4 above (also Table 50, page 87 of the PMA), the sponsor
    presents a number of adverse events they claim are unrelated to the
    device and are not statistically different from the X STOP, yet many
    of them which could be related to the device (e.g., lower back,
    lower extremity, hip, etc.) occur much more frequently in the X STOP
    group.

4.  The sponsor provided the results for a statistical comparison of 36
    laminectomy patients with the X STOP patients from their clinical
    trial (see Tables X and XI on pages 16 and 17) and a discussion of
    the results on pages 101-3 of the PMA. The laminectomy patients come
    from control (26) and X STOP (6) patients who failed this study, 5
    control and 2 X STOP patients from the unwelded study and 7
    untreated patients from this study. Of these, outcomes were
    available for 36 patients. They use the results of the patients and
    Tables X and XI to support the contention that X STOP is comparable
    to results from decompressive laminectomy. Note that there are
    problems with using this collection of patients who failed the pilot
    and pivotal study as laminectomy comparison group for the X STOP
    device. Such a non-randomized comparison could introduce bias into
    the comparison which cannot be quantified and thus would make the
    statistical results suspect. If the sponsor wants to make the claim
    that that the X STOP is comparable to laminectomy, they should
    adequately, if possible, address the bias introduced into the
    comparison of the results since the laminectomy subjects are
    comprised of failed patients of 3 studies and the study is not
    randomized.

**[Conclusion]{.underline}**

The sponsor demonstrated that the X STOP device was superior to the
non-operative therapy control with respect to the chosen primary
endpoint and the X STOP device appeared to be reasonably safe when
compared to the control. Note that the observed success rates of 43% for
the X STOP and 4.4% for the control are substantially lower than the
expected success rates of 60% and 37.5% the design of the study was
Powered (sized) for. Issues of the appropriateness of the control group
and the relatively low effectiveness rate for the device should be
addressed clinically. It should be noted that the sponsor randomized
patients by using block sizes of 2 stratified by site which can allow
investigators to potentially subvert the randomization, and thus
potentially bias the study results. In addition, we noted that there
were discrepancies in the success rates among centers. In Table 50 (page
87), the sponsor presents a number of adverse events they claim are
unrelated to the device and are not statistically different from the X
STOP, yet many of them occur much more frequently in the X STOP group.
The comparison of the X STOP patients to the laminectomy patients is
questionable since the study was not randomized and the laminectomy
patients comprise patients from 3 different studies who failed their
assigned treatment.