**SUMMARY MINUTES**

**OF THE**

**ORTHOPAEDICS AND REHABILITATION DEVICES**

**ADVISORY PANEL MEETING**

**OPEN SESSION**

**January 19, 2001**

**9200 Corporate Blvd.**

**Room 20 B**

**Rockville, Maryland**

**Orthopaedics and Rehabilitation Devices Advisory Panel Members**

**January 19, 2001**

Michael J. Yaszemski, M.D., Ph.D.

Mayo Clinic

Panel Chair

Albert Aboulafia, M.D.

Emory University School of Medicine

Voting Member

Edward Y. Cheng, M.D.

University of Minnesota

Voting Member

Maureen Finnegan, M.D.

U.T. Southwestern Medical Center

Voting Member

Stephen Li, Ph.D.

Dana Center

Voting Member

Harry Skinner, M.D., Ph.D.

University of California, Irvine

Voting Member

Floyd Larson, Ph.D.

PaxMed International

Industry Representative

Karen Rue

Arcadian Health Care Alliance

Consumer Representative

Jens R. Chapman, M.D.

Harbor View Medical Center

Consultant, deputized to vote (participation by phone)

Fernando Diaz, M.D., Ph.D.

Wayne State University Health Center

Consultant, deputized to vote (participation by phone)

Richard Simon, Ph.D.

National Cancer Institute

Consultant, deputized to vote

Timme Topoleski, Ph.D.

University of Maryland, Baltimore

Consultant, deputized to vote.

**FDA Participants**

Hany Demian, M.S.

Executive Secretary

Orthopaedics and Rehabilitation Devices Advisory Panel

Celia Witten, Ph.D., M.D.

Director, Division of General, Restorative, and Neurological Devices
(DGRND)

Mark Melkerson, M.S.

Deputy Director, Division of General, Restorative, and Neurological
Devices (DGRND)

Barbara Zimmerman, B.S.

Branch Chief

Orthopedic Devices Branch

Holly Rhodes, B.S.

Reviewer

Orthopedic Devices Branch

Gene Pennello, Ph.D.

Statistician, Division of Biostatistics

Martin Yahiro, M.D.

Medical Officer, Division of General, Restorative, and Neurological
Devices (DGRND)

**OPEN SESSION---JANUARY 19, 2001**

**Hany Demian, Executive Secretary of the Orthopaedics and
Rehabilitation Devices Panel,** called the meeting to order at 9:37 a.m.
and read a statement deputizing temporary voting members Jens Chapman,
M.D., Fernando Diaz, M.D., Ph.D., Timme Topoleski, Ph.D., and Richard
Simon, Ph.D., noting that Dr. Simon was also a voting member on a panel
of the Center for Drugs Evaluation and Research. Mr. Demian read the
conflict of interest statement, noting that waivers had been granted for
Edward Y. Cheng, M.D., Stephen Li, Ph.D., Harry B. Skinner, M.D., Ph.D.,
and Jens Chapman, M.D., who had declared interests in firms potentially
affected by the day's deliberations and that matters involving Dr. Li,
Dr. Chapman, and Michael J. Yaszemski, M.D., Ph.D., had been considered
but their full participation was allowed. He asked the panel members to
introduce themselves, including Drs. Chapman and Diaz, who were
participating by telephone conference.

**Panel Chair Michael J. Yaszemski, M.D., Ph.D.,** noted that the voting
members constituted a quorum and stated that the charge to the panel was
to consider a premarket approval application (PMA) for the Sulzer
Spine-Tech BAK/C Interbody Fusion System intended for the treatment of
cervical degenerative disc disease with radiculopathy.

**Mark Melkerson, M.S., Deputy Director of the Division of General,
Restorative, and Neurological Devices (DGRND),** introduced three new
reviewers in the division, Glenn Steigman, Michelle Mattera, and Sam
Kim, and the new Branch Chief of the Orthopedics Devices Branch, Barbara
Zimmerman.

# OPEN PUBLIC HEARING

There were no requests from the audience to address the panel.

# SPONSOR PRESENTAT ION

**Dan Mans, director of Clinical and Regulatory Affairs at Sulzer
Spine-Tech,** introduced the sponsor representatives and explained the
rationale for the device, noting that although there are several
approaches to cervical spine fusion, the BAK/C device addresses some
deficiencies that exist with current treatments such as morbidity
associated with bone graft harvest. He reviewed the history of the PMA,
noting that the submission was granted expedited processing due to the
potential for clinically meaningful benefits associated with elimination
of autograft harvest.

**Steven Griffith, Ph.D., from Sulzer Spine-Tech Research,** explained
the design rationale and preclinical testing of the device. He listed
the design characteristics and showed the device, which consists of a
threaded hollow porous uncoated titanium cylinder or a hydroxyapatite
(HA) coated version to enhance fusion and osseo-integration. Dr.
Griffith described goals and results of preclinical mechanical strength
and fatigue testing for a minimum design load of 80 pounds and
biomechanical testing done in two separate labs to show cadaveric
flexibility and stability results. He stated that preclinical animal
studies done on goat and sheep models showed bone growth with mature
trabecular bone inside the cage at three months, no HA-related adverse
events, and no device-related fractures, extrusions, or collapse. Dr.
Griffith concluded that the preclinical experimentation demonstrated
high mechanical strength and integrity, positive rigid biomechanical
fixation, bone growth and fusion, and safety with no unanticipated
adverse events.

**Robert Hacker, M.D, a neurosurgeon consultant for the sponsor,**
explained the design of the clinical study and summarized its results.
He listed various treatment options for cervical degenerative disc
disease and stated that the purpose of the study was to demonstrate the
safety and effectiveness of the BAK/C and BAK/C-HA Interbody Fusion
System for the treatment of this disease with radiculopathy. The study
was a prospective, randomized, multicenter equivalence trial intended to
show 1:1:1 randomization, with 578 patients enrolled at 28
investigational sites and a long-term follow-up of more than two years.
Dr. Hacker explained patient selection procedures and listed inclusion
and exclusion criteria. He concluded that the study showed the device is
safe, as demonstrated by a low rate of complications; effective, as
demonstrated by immediate and sustained relief of pain, improved quality
of life, and fusion success rates; and clinically useful as shown by
reducing the need for autograft harvest.

Dr. Hacker explained that study patients were randomized into coated and
uncoated device groups and a control group treated with anterior
cervical discectomy and fusion (ACDF). These groups were further
stratified into one-level and two-level patients. HA coated and uncoated
study cohorts were combined for statistical analysis; Dr. Hacker stated
that statistical presentation would show coated and uncoated devices
perform comparably. He explained patient demographics for one-level and
two-level patients in all groups, noting no significant differences
among the cohorts. Surgical technique consisted of standard anterior
cervical decompression with the Interbody cage in the treatment arm or
bone graft in the control arm.

Study results showed no significant differences between control and
experimental groups in the one-level patients in terms of serious
complications, although some required additional surgery. In the
two-level patient group, there was a statistically significant
difference between device and control group involving the implant
itself, in that the control group showed significantly more graft
collapse. Effectiveness was evaluated for fusion using flexion-extension
radiographs, neck pain using a visual analog scale, radicular pain using
a pain and strength assessment, and function using the SF-36 general
health survey. Fusion results showed comparable or superior results for
the experimental group versus control, as did pain and function scores.
Clinical utility was assessed in terms of surgical variables, donor site
pain, employment status, and patient perception, with most results very
similar for both groups, except for donor site pain and blood loss, both
of which favored the experimental group.

Dr. Hacker concluded that the BAK/C Interbody Fusion system is safe and
effective for use in treating patients with discogenic radiculopathy
from C3-7, with fusion and clinical outcomes comparable or superior to
those of traditional anterior cervical discectomy and fusion. He stated
that the BAK/C provides the distinct benefits of a noncollapsing
columnar support, autograft biology, and elimination of donor site pain.

**Kinley Larntz, Ph.D.,** gave the sponsor's statistical analysis. He
provided an introduction to Bayesian techniques, in which data are
collected over time, and in which Bayesian inference allows probability
statements about model parameters conditional on the data. The BAK/C
Bayesian model provides a linear model for log odds of success for each
outcome and includes a random effect for center outcome success
probability and for center treatment effect. Dr. Larntz showed various
comparisons that can be done on the BAK/C-HA versus control or on one
versus two level patients. He explained multivariate longitudinal
modification, which permits inclusion of 12-month and long-term data in
the same model and gives more precise estimates of long-term effects
while accounting for missing long-term data. He also explained the
protocol definition of equivalence and showed a posterior distribution
example. After explaining study objectives and outcome measures, Dr.
Larntz looked at long-term effectiveness for a restricted cohort, noting
that an intensive effort was made to increase compliance for the
patients due for 24-month follow-up on November 15, 1999, with
compliance at 81.3 % for this cohort.

Dr. Larntz discussed results of these statistical analyses, which showed
that for one-level patients, equivalence criteria were satisfied for all
outcomes and both uncoated and coated devices were superior to control
in fusion, with the uncoated version also superior to control in overall
success. For two-level patients, equivalence was satisfied for the
coated device for function and overall, with an 80% or better
probability of equivalence except for uncoated device radicular outcome.

Dr. Larntz also performed a sensitivity analysis to explore the extent
to which missing data would need to differ from obtained data in order
to change the study conclusion. He stated that this analysis
demonstrated that the missing data are unlikely to affect study
conclusions. Safety analyses using the same delta as the effectiveness
analysis and using a Bayesian analysis for complication incidence and a
Kaplan-Meier method for time to event analysis showed that the BAK/C
device is superior to control in overall complication rate and in
complications requiring additional surgery. Overall, therefore, Dr.
Larntz concluded that the BAK/C and BAK/C-HA devices are safe and
effective at one level for the stated indications. Two-level performance
is similar to one-level performance, but two-level data alone do not
establish equivalence. He reiterated that missing data are unlikely to
affect study conclusions.

In conclusion, **Dan Mans** stated that the device had proven safety and
effectiveness for use as indicated and showed a clinically meaningful
benefit over existing technology by minimizing need for autograft
harvest.

# FDA PRESENTATION

**Holly Rhodes, lead PMA reviewer,** introduced the members of the FDA
review team. She also described the static and fatigue mechanical
testing of the six mm implant, stating that the bench testing indicated
that the device is strong enough to withstand anticipated physiologic
loading. She stated that in vitro flexibility and stability testing were
done on human cadaveric spines at C4-C5 and C6-C7, with no differences
in initial range of motion or stiffness compared to the intact spine,
but data were not stratified based on level of implantation. Ms. Rhodes
also described results of the animal testing in goats, which found no
statistically significant differences in stability between uncoated and
HA-coated devices. Animal testing in sheep assessed fusion rates
radiographically and compared device with autograft (67%), anterior
plate with autograft (100%), and autograft alone (67%). She noted that
in all three groups many deemed radiologically fused were not fused from
a histological standpoint.

**Martin Yahiro, Medical Officer in the DGRND,** gave the FDA clinical
review, noting that the protocol defined overall success as achievement
of radiographic fusion; pain, functional, and radicular success; and
absence of additional surgery. The rate of long-term overall patient
success was 65.9%, 61.1%, and 53% for the one-level BAK/C, BAK/C-HA and
control groups respectively, and 42.1%, 58.6%, and 46.7% respectively
for the two-level BAK/C, BAK/C-HA, and control groups. Radiographic
fusion rates for all groups were good, especially for one-level fusions.
According to the sponsor's Bayesian statistical analysis, the device
group fusion success rates were "superior " to that of control for
one-level fusions but inconclusive for two-level fusions. For overall
success, the results were "superior" for the one-level uncoated device
and equivalent for the coated device one-level and two-level groups, but
inconclusive for the two-level uncoated group. Dr. Yahiro noted,
however, that the FDA raised concerns about the sponsor's definition of
statistical superiority.

FDA concerns with the effectiveness analysis included the fact that
safety and effectiveness analyses were performed on different data sets,
there were missing data, patients were not missing at random, and a
disproportionate number of control patients withdrew following
randomization but prior to surgery. Dr. Yahiro explained these concerns
in detail, noting FDA questions for panel consideration in each area.

Dr. Yahiro summarized the safety evaluation in terms of data on adverse
events associated with use of the device compared to control treatment.
These adverse events were categorized as implant-related,
surgery-related, additional surgeries, and other. He presented the total
number of each of these events, as well as the type for one- and two-
level fusions for BAK/C, BAK/C-HA, and control device groups. According
to the sponsor's Bayesian statistical analysis, the overall complication
rates were equivalent between the one- and two-level BAK/C groups
compared to the control, but the BAK/C-HA one-level and two-level BAK/C
groups had superior overall combination rates compared to control. The
implant related complication rates of the BAK/C and BAK/C-HA groups were
superior to the control for one-level cases. Comparisons between the
BAK/C group for two-level fusions were inconclusive, but showed
equivalency for the BAK/C-HA group compared to control. Again, however,
the FDA had concerns about the definition of superiority.

FDA concerns regarding the safety analysis were that the safety and
effectiveness analyses were performed on different data sets, that the
safety data accountability analysis shows low follow-up rates at six, 12
month and longer follow-up evaluations, that disproportionate control
group withdrawal is a concern, and that there was no sensitivity
analysis to determine effects of missing data on safety conclusions. Dr.
Yahiro described these concerns in detail, noting FDA questions for
panel consideration.

**Gene Pennello, Ph.D., from the Division of Biostatistics,** gave the
statistical review of clinical data, beginning with an explanation of
the trial design. He noted that the effectiveness analysis was made on
the restricted cohort because the rate of follow-up was higher for the
restricted rather than the unrestricted cohort and the restricted cohort
results were slightly less favorable than the unrestricted cohort. He
explained the difference between a Bayesian and non-Bayesian analysis
and defined equivalence and superiority hypotheses, as well as the log
odds scale for probability of success. He also explained the Bayesian
logistic model on success rate for each endpoint, and showed that
exchangeability allows pooling of data across effects. Dr. Pennello
explained his analysis of long-term effectiveness in the restricted
cohort on one-level patients for uncoated versus control, coated versus
control, and uncoated versus coated, which showed that coated and
uncoated are equivalent to control in all endpoints and in some
endpoints superior to control. The coated device was not superior to
uncoated in any of the effectiveness endpoints, in his analysis. For
two-level patients, only two conclusive results could be obtained, in
part because of lower power to detect equivalence. The coated device was
equivalent to control in function and overall success rates.

Dr. Pennello also looked at the effect of missing data on Bayesian
long-term analysis of effectiveness, noting that the missing patients
will appropriately influence the analysis against BAK because of their
long-term prognosis. A sensitivity analysis of the one-level patients
only considers how the conclusions would change if the missing control
patients were more successful and the missing device patients were less
successful than the model would have predicted. It found that for all
endpoints except neck pain, the conclusion of equivalence would be
maintained even if the odds of success among missing patients relative
to non-missing patients was 1000 times greater for control than the
device.

Dr. Pennello noted that safety analyses on the unrestricted cohort only
show an incidence rate with no adjustments for missing data and no
consideration of time to complications. Looking at time to complication
by Kaplan Meier curves shows that the uncoated and coated devices are
superior to control in overall and implant-related complications and
equivalent to control in surgery-related complications and additional
surgeries. The results are inconclusive for other-related complications.
Longer-term complication incidence rates in the unrestricted cohort for
one and two-level patients showed the coated device superior to the
uncoated in implant-related complications. Dr. Pennello observed that
the submission did not include a descriptive table of complications per
person-year by device. He added that clinical utility variables favored
the experimental device only for donor site pain because few patients
with device needed donation of bone harvested from the iliac crest.

Dr. Pennello concluded that for one-level patients, the uncoated and
coated devices are equivalent to control in all safety and effectiveness
endpoints. The two-level data were inconclusive. The one-level
effectiveness results were adjusted for missing data and insensitive to
missing data deviating from the model. For safety the missing data may
not be an issue for surgery-related, implant related, and additional
surgeries. Limitations on the data are that discontinuations were found
disproportionately among controls and low follow-up rates led to
analyses of different cohorts. Also the Bayesian safety analysis does
not consider time to complication.

# Panel Preclinical Review

**Dr. Topoleski** gave the preclinical panel review, noting that five
major preclinical tests were done: ultimate strength, fatigue strength,
stability, a surgical implantation instrumentation study, and two animal
studies. He described the methodology of these tests, stating that he
found them adequate for and specific to the particular implant.

# Clinical Panel Review

**Dr. Diaz** gave the panel clinical review, inc which he concluded that
the only clear benefit in any area is for the one-level patients. He
also found the only objective analysis to be fusion; all other
analytical endpoints are softer. He thought the safety concerns well
presented and well analyzed, and that the procedure is safe. He thought
that graft collapse using the iliac bone harvest was predictable and
that using a patellar allograft might have provided a better comparison.
Problems with the study included the withdrawal of patient from
follow-up and the use of an overall efficacy analysis, which he said
created a wastebasket analysis. His major concern was with the overall
improvement of radicular symptoms, and he speculated about the
beneficial effect of decompression alone versus the effect of fusion.

# Panel Statistical Review

**Dr. Simon** gave the panel statistical review, stating that he would
have liked an analysis to show that the control itself is effective at
eliminating neck pain. His second issue was the number of control
patients who dropped out of the trial, especially two-level patients; he
would have liked a sensitivity analysis in regarding to refusing
randomization. Dr. Simon thought the Bayesian versus non-Bayesian
analysis overemphasized, and he questioned whether enough patients were
available for follow-up.

# DISCUSSION OF FDA QUESTIONS

1)  Did Sulzer Spine-Tech demonstrate effectiveness of the BAK/C with
    and without the HA coating? And 2) Does the one- and two-level
    combined data set apply to two-level patients?

The panel considered questions 1 and 2 in conjunction. Noting problems
in interpreting the data because of the post-randomization dropout rate
of control patients who did not receive the device, the panel agreed
that equivalence in effectiveness was demonstrated for one-level
patients but not for two-level patients.

3)  ***Did Sulzer Spine-Tech demonstrate safety of the BAK/C with and
    without the HA coating?***

The panel expressed concern about needing to look separately at certain
issues involving the coating (such as mechanical testing data after
steam sterilization and other loading modes in vivo), but they agreed
that safety was established.

4)  ***What, if any, long-term questions does the panel think it would
    be important to answer in a post-approval study?***

Although some failed to see benefit in a postapproval study because of
the long time involved to see small effects, others on the panel
suggested possible topics such as radiographic and motion studies to
assess implant longevity, subsidence, effect at other levels such as
C4-C5 and C5-C6, effect on possible revision surgery, adverse events,
changes in hormonal level in postmenopausal women affecting bone
density, and relationship of study outcomes to implant size and level,
spinal stenosis, revision of titanium after 12 months, and the need for
more information on implant in a living, moving body.

5)  ***Please give guidance on how to answer questions regarding a
    potential post\--approval study in terms of assessment parameters,
    study duration, and any other elements of study design.***

The panel suggested five years for study duration and recommended
radiographic and motion studies on the topics given above. Use of the
Odom scale and assessment by a research nurse rather than by surgeon
should be considered. One suggestion was to consider implants with the
HA coating as a subset.

6)  ***Are there any questions which related to the effect of the HA
    coating that the panel believes need to be addressed in a
    postapproval study?***

Some panel members suggested perhaps studying the HA coating group of
patients separately from the uncoated implants. Other questions that
could be addressed include preclinical testing on crackling off and
abrasion of titanium, titanium wear, and effect of steam sterilization
on the coating.

**OPEN PUBLIC HEARING**

There were no requests to address the panel.

**SPONSOR FINAL COMMENTS\
Mr. Mans** suggested that the panel consider approval for one- and
two-levels with a precaution on two-level patient data. This would allow
clinicians to review the data for themselves in the package insert.

**PANEL RECOMMENDATIONS AND VOTE**

**Mr. Demian** read the voting instructions and options. A motion was
made and seconded to recommend the PMA as approvable subject to
conditions. The motion passed. The conditions, each of which passed
individually, were as follows:\
1) That the device be approved for one-level usage only and that the
package insert note that the data for two-level usage provided by the
company were deemed not evaluable.

2\) That a sensitivity analysis be performed on patient drop-out in the
control group at a level the FDA will decide upon.

3\) That a postapproval study as described in discussion of the FDA
questions be performed.

4\) That the sponsor make a distinction in the postapproval study
between coated and non-coated devices and look separately at clinical
variables such as the rate of integration of both devices and different
rates of ingrowth, incorporating European study data.

5\) That further mechanical testing of the HA coating be done

a.  Along the lines of the testing already done on the uncoated device

b.  For all sizes of the device

c.  With fatigue tests as described above

d.  To show results on HA integrity after the sterilization procedure
    recommended by the sponsor, excluding testing data already in the
    master file

e.  Using a test method and loading more relevant to living bodies by
    reproducing loadings in flexion, extension, rotation, and lateral
    movement

The motion to recommend the PMA as approvable subject to the above
specific conditions was made, seconded, and unanimously approved.

Mr. Demian thanked the panel and sponsor representatives, and the
session was adjourned at 2:15 p.m.

I certify that I attended the Open Session of the Orthopaedics and
Rehabilitation Devices Advisory Panel Meeting on January 19, 2001, and
that this summary accurately reflects what transpired.

\_\_\_\_\_[/s/]{.underline}\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Hany Demian, M.S.

Panel Executive Secretary

I approve the minutes of this meeting as recorded in this summary.

\_\_\_\_\_\_\_[/s/]{.underline}\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Michael J. Yaszemski, M.D., Ph.D.

Panel Chair

Summary minutes prepared by

Aileen M. Moodie

9821 Hollow Glen Pl.

Silver Spring, MD 20910

301-587-9722