# SUMMARY MINUTES

**MEETING OF THE ORTHOPAEDICS AND REHABILITATION DEVICES**

**ADVISORY PANEL**

**OPEN SESSION**

# NOVEMBER 21, 2002

## Gaithersburg Holiday Inn

**Gaithersburg, MD**

**Meeting of the Orthopaedics and Rehabilitation Devices Advisory
Panel**

**Attendees**

November 21, 2002

*Chairperson*

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

*Executive Secretary*

Hany Demian, M.S.

*Members*

Maureen A. Finnegan, M.D.

John S. Kirkpatrick, M.D.

Kinley Larntz, Ph.D.

Sanjiv H. Naidu, M.D., Ph.D.

*Consultants*

Albert Aboulafia, M.D.

John Doull, Ph.D.

Hari Reddi, Ph.D.

Andrew Schmidt, M.D.

*Consumer Representative*

Karen Rue

*Industry Representative*

Sally Maher, Esq.

*FDA Representative*

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

CALL TO ORDER

**Executive Secretary Hany Demian** called the meeting to order at 9:32
a.m. He noted that Albert Aboulafia, M.D., John Doull, Ph.D., and Andrew
Schmidt, M.D., had been appointed to temporary voting status. Mr. Demian
then read the conflict of interest statement. Albert Aboulafia, M.D.,
John Kirkpatrick, M.D., Kinley Larntz, Ph.D., and Andrew Schmidt, M.D.,
had been granted waivers for their interests in firms that could be
affected by the panel's recommendations; they could participate fully in
the panel's deliberations. The Agency took into consideration other
matters regarding Maureen Finnegan, M.D., John Kirkpatrick, M.D., Karen
Rue, Andrew Schmidt, M.D., and Michael Yaszemski, M.D., Ph.D., who
reported interests in firms at issue but in matters not related to the
day's agenda; they could participate fully in the panel's deliberations.
Mr. Demian then asked the panel members to introduce themselves.

**Panel Chair Michael Yaszemski, M.D., Ph.D.,** introduced himself and
stated that the purpose of the meeting was to make recommendations on a
PMA for a growth factor soaked in collagen sponge to treat tibial
fractures. He noted that the panel members present constitute a quorum.

# OPEN PUBLIC HEARING

No comments were made.

# SPONSOR PRESENTATION

**Owen Fields, Ph.D.,** **worldwide regulatory affairs, Wyeth
Research,** described InductOs, a combination product consisting of an
absorbable collagen sponge (ACS) soaked with recombinant human bone
morphogenetic protein-2 (rhBMP-2), an osteoinductive protein. The sponge
is manufactured by Integra Life Sciences and is also marketed as the
Helistat sponge; rhBMP-2 is produced by Wyeth. Only the 1.5 mg/mL dosage
of rhBMP-2 is proposed for marketing.

The preclinical research involved both device and drug studies. The
combination product is biochemically identical for all uses. Because the
FDA approved the INFUSE spine fusion product in July 2002 and
information on the manufacture of rhBMP-2 and ACS has therefore already
been provided to the panel, Dr. Fields did not focus on the preclinical
safety program.

**Rod Riedel, Ph.D., project management, Wyeth,** summarized preclinical
studies demonstrating bone induction in animals. Bone induction is
unique to rhBMP-2. The ability of the protein to induce bone growth de
novo provides the rationale for replacing standard therapy components
(e.g., bone graft) or augmenting standard therapy. Preclinical safety
findings found that no toxicity or systemic effects occurred; the drug
is eliminated rapidly, and low systemic exposure occurs. The preclinical
research both in animal models and in vitro demonstrates that the
protein accelerates healing and establishes the safety profile of the
device. The research supports the clinical use of InductOs in fracture
treatment.

**Alex Valentin, M.D., senior director, clinical R&D, Wyeth,** presented
results of the pivotal clinical study, which was a prospective,
randomized, multicenter study involving 450 patients with open tibia
fractures, 300 of whom were treated with the device. Dr. Valentin
presented information on the study rationale, design, patient
characteristics, results, and conclusions. He noted that open fractures
involve the tibia more often than any other bone.

The pivotal study was single blind and designed to use stratified
randomization; patients were not aware of which treatment group they
were in. Both the treating physician and an independent radiological
panel assessed outcomes using the same x-ray films. Union was defined as
at least three or four cortices being breached on two or more views.
Patients were followed for 12 months in 7 visits. Patients receiving
prophylactic bone grafting were excluded because the treatment is rarely
prescribed; therefore, should the product be approved, patients
requiring prophylactic bone grafting should be excluded. Investigators
could use reamed or unreamed nails because there is no international
consensus on which nails work best. Patients randomized to the
experimental group received standard care plus the device in either an
0.75 mg/mL or a 1.5 mg/mL dose. The study demonstrated the superiority
of the 1.5 mg/mL dose compared with the control group.

Dr. Valentin noted that the study is as standardized as possible given
the nature of orthopedic trauma. No consensus exists on the definition
of delayed union or healing; for the study, assessment of delayed union
and healing was based on the prospective collection of signs and
symptoms supporting the investigators' assessment.

Dr. Valentin described the patient demographics and fracture
characteristics and stated that the similarities across groups were
sufficient to permit pooling the data. Patients tended to be white men
in their early 30s; nearly two-thirds of the patients had been involved
in motor vehicle accidents, and about half were smokers. Compared with
the control group, patients in the 1.5 mg/mL experimental group
experienced significantly less treatment failure and fewer
interventions. Significantly more patients in the 1.5 mg/mL group
experienced healing by 26 weeks without secondary intervention to
promote healing, as assessed by the investigator. In addition, patients
in the 1.5 mg/mL group experienced accelerated fracture union at 26
weeks, as assessed by the radiology panel.

In response to FDA concerns that the study subjects were too
heterogeneous, Dr. Valentin stated that no one category influenced study
results and that the homogenous efficacy results justify pooling the
data. Although FDA had expressed concern that the assessments of
outcomes were biased, investigator assessments of treatment success or
failure were corroborated by patient symptoms, reintervention decisions
were made at comparable timepoints across treatment groups, and healed
patients did not regress.

Even though the patients in the study experienced comparatively high
incidence of infections, the rate was comparable across the three groups
and was most common in the patients with the most severe fractures,
suggesting that rhBMP-2 did not increase the likelihood of infection.
Hardware failures were more likely in the control and low-dose groups
and were most common for patients receiving unreamed nails. No ectopic
calcifications were found to be due to rhBMP-2. The incidence of
heterotopic calcifications was low, although patients receiving the
InductOs device experienced a slightly higher, not statistically
significant rate. In addition, antibodies to rhBMP-2 were found in a
small number of patients.

**Marc Swiontkowski, M.D., University of Minnesota Medical School,
Minneapolis,** presented information on the clinical relevance of the
study findings to the U.S. trauma population. Open tibia fractures are
associated with a high rate of delayed union requiring secondary
procedures. The results of the study are applicable to other, less
severe fractures. He pointed out that the pivotal study had a measurable
endpoint, was clinically meaningful, and was consistent with other
trials. The study was conducted using the highest quality design
available and demonstrated that the InductOs device is safe and
accelerates healing in long bones.

# FDA PRESENTATION

**Aric Kaiser, M.S., PMA lead panel reviewer,** described the device,
reviewed the indications for use, and presented the submission history
of the device. He noted that this is the sponsor's second submission;
the sponsor has submitted a reanalysis of the original data to address
earlier deficiencies. FDA is reviewing only the tibia data presented as
a result of the clinical trial. Some outstanding preclinical issues
include the effects of rhBMP-2 on tumor promotion and fetal development.

**Barbara Buch, M.D., CDRH,** presented FDA's clinical review. She noted
several issues concerning the clinical study that related to confounding
variables, patient assessment, endpoints, and data analysis. Many
variables affect fracture healing, the most striking of which is the
nail insertion technique. Statistically significant differences were
found between the control group and the experimental groups. Patients in
the experimental groups were more likely to receive reamed nails; the
difference may be clinically significant. Also, the group receiving the
larger dose of rhBMP-2 had a slightly higher proportion of
large-diameter, unlocked nails. Fracture types were considered
collectively, rather than by fracture type; however, different types of
fractures were dealt with differently. Also, the protocol allowed for
less than a full sponge to be inserted, so not all patients received
same dose; it is unclear how that might have affected the rate of
healing. Although no statistically significant differences were found
between large and small centers, they handle fractures differently and
have different experience levels. Diverse cultural expectations existed
across sites. Half the patients were enrolled in two countries (South
Africa and Germany), and several sites had fewer than 10 patients.
Patient characteristics differed from country to country, and the types
of fractures treated in each country differed. The ability to
extrapolate to U.S. populations was not clearly demonstrated.

Dr. Buch also listed various problems with the clinical assessment
methods. No standardized assessment methods were implemented. The
criteria for radiographic union for independent radiology panel are
problematic. A definition of healed fracture was set forth, but it was
not clear whether all three of the definition's criteria had to be met.
The difference between delayed union and delayed healing is unclear.
Also, it is not clear how the decision to undertake secondary
intervention was made. Finally, use of prophylactic bone graft may be
helpful, but the sponsor excluded those patients. Although treatment
groups received a substance to enhance bone healing, the control group
did not---so was the control group treated comparably?

The primary endpoint had four subgroups, but a combined clinical and
radiological endpoint (CCRE) was used, an analytical method that has not
been validated. The CCRE was composed of subjective assessment plus
objective assessment---that is, two dissimilar assessments, rather than
two radiological assessments. Patients with secondary interventions were
treated differently; they were paired with the results of independent
radiology review at the time the decision to intervene was made.
Treatment of missing data was inconsistent.

With regard to effectiveness, Dr. Buch noted that 6 months may not have
been an appropriate endpoint because the differences between the
investigators' and the radiology panel's assessments were so marked. The
experimental and control groups showed little difference in time to
fracture healing, as determined by the independent radiology panel.

Concerning safety, Dr. Buch pointed out that the rates of authentic
antibody responses are higher than in other studies of this type of
device. Twelve patients (6 percent) had an authentic immune response.
The contribution of the trauma setting to the response and its clinical
significance is not known. Liver and pancreas function tests showed
higher levels of amylase and higher rates of hypomagnesemia in the
experimental group than in the control group, findings of concern
because a patient in a previous study of rhBMP-2 was diagnosed with
pancreatic cancer. Infection rates seem a bit higher than in other
studies.

**Chang S. Lao, Ph.D., Division of Biostatistics, OSB,** presented the
FDA statistical review. One problem is the poolability of the data due
to the heterogeneity among the centers; the sponsor's approach to
analyzing the data is not valid. Survival analysis is required because
patients were censored or lost to follow up. In addition, it is not
clear that the study could be reproduced because so many subjective
judgments were used in determining patient outcomes.

# PANEL DISCUSSION

**Sanjiv Naidu, M.D.,** summarized the preclinical results. He described
several studies using animal models and concluded that not all the
studies demonstrated the effectiveness of rhBMP-2 to promote fracture
healing. The results are equivocal. His "gut feeling," however, is that
the protein does enhance bone formation, but its clinical usefulness
will be hard to demonstrate.

**Maureen Finnegan, M.D.,** presented the panel's clinical review. She
reviewed the problems with the pivotal study design. Many patients
received rods at first intervention, which is not the standard of care
in the United States. Why did several very capable countries contribute
only a few patients to the study? Was the study protocol not the
standard of care in those countries? Did the centers see few open tibial
fractures? If so, she would be concerned about their experience. She
highlighted several differences between the control group and the
experimental group (e.g., the control group had a larger number of
unreamed nails and more patients with multiple fractures). Dr. Finnegan
noted that the sponsor stated that the ACS needs to touch both ends of
the fracture, which suggests that osteoconduction is the primary method
of fracture healing. CCRE has no validation associated with it.

The biggest concern is that BMP antibodies were found among patients in
the experimental group. No one understands what this finding means. The
safety and efficacy of repeat use of the device are unknown. In sum, one
cannot conclude anything from the pivotal study. The product shows
borderline efficacy, but it seems safe. All we know is that the material
does not interfere with healing.

**Kinley Larntz, Ph.D.,** provided the panel statistical review. He
stated that the sponsor's study does show an effect of rhBMP-2.
Nevertheless, there is a question about the poolability of the data. In
the statistical analysis, one must take into account random effects. If
one conducts the analysis using a logit scale, which the sponsors tried
to do, one would find insufficient data to conduct the analysis. Dr.
Larntz would use a Bayesian analysis, which would reveal a significant
effect of rhBMP-2 with respect to the number of reinterventions.

An important aspect of the sponsor's study is the censoring of data. The
censoring with respect to radiological assessment or investigator
assessment was considerable. For example, in radiological assessment,
the rate of censoring at 150 days was 37 percent for the control group,
meaning that there were no data for radiological assessment for 37
percent of those patients after 150 days. For the group receiving 1.5
mg/mL doses of rhBMP-2, the rate was 16 percent. The differences in
censoring rates between the groups is of concern. If we make adjustments
for censoring, there is no difference between the three groups in terms
of radiological assessment. If you adjust for the differences between
reamed and unreamed nails, it reduces the effect of the 1.5 mg/mL dose
on secondary interventions.

# OPEN PUBLIC HEARING

Bill Christianson, Orthopedic Surgical Manufacturer's Association, urged
the panel to focus on the safety and effectiveness of InductOs. He
reviewed the meanings of "safe" and "effective" and noted that the
regulations and the law clearly state that the standard is "reasonable."
The standard is not proof beyond shadow of doubt.

*Question 1: Discuss the adequacy of data from experience treating acute
open tibia fractures stabilized with IM nails to support a more general
indication.*

The panel generally agreed with the sponsor that the indication should
cover long-bone fractures in general, not just tibia fractures. However,
panel members noted that the data may or may not support use in open
tibia fractures and that it may be problematic to extrapolate to other
fractures. More data are needed.

***Question 2:** Discuss the impact of the following on the ability of
the study to collect clinically valid data: (1) definition of standard
of care in view of the multiple confounding factors; (2) clinical
relevance of the rate of secondary interventions required to promote
healing as a primary endpoint; and (3) reliability of interpretation of
terms "union," "healing," "delayed union," and "delayed healing" at
various sites.*

The panel concurred that the standard of care was acceptable with some
caveats: The local standard of care may have affected the choice of
nail, and other differences may have affected the infection rate. In a
global sense, however, the standard of care was met. Other noninvasive
means may have been appropriate additions. Also, because some patients
did not get the full sponge, there was variation in the rhBMP-2 dose
received. The panel also concurred that the study had flaws in the
definitions of union and healing and that the investigators demonstrated
enthusiasm for study material.

**Question 3:** Accounting for trial design, resulting data, and
statistical analyses, discuss the adequacy of effectiveness in terms of
(1) the decrease in number of secondary interventions required to
promote fracture healing and (2) accelerated fracture healing determined
by fracture healing at 6 months assessed by investigator and fracture
union assessed by independent radiologist.

The panel concurred that the device is generally effective, but the
study data are equivocal.

*Question 4: Accounting for trial design and resulting data, discuss
whether or not the sponsor has provided a reasonable assurance of device
safety in view of the rate of authentic antibody response to rhBMP-2 and
to bovine Type I collagen, rate of hardware failure, rate of infection,
and rate of abnormal liver function for lab values.*

The panel agreed that the rate of hardware failure and infections is not
a major concern. Several panel members commented on the nature of the
antibody response---it may warrant looking at patients over time. Trauma
may have an effect. Also, panel members expressed concern about the
relation of the antibody response to tumors. The panel generally
concurred that the device is safe.

# OPEN PUBLIC HEARING

No comments were made

# VOTE

Mr. Demian read the voting instructions. The panel voted 6-1 to approve
the PMA with the following conditions:

1.  Use of the device should be limited to penetrating fractures that,
    in the opinion of the treating surgeon, represent fractures that
    would benefit from device.

2.  Users should be educated about the device.

3.  The labeling should state that the effects of repeated use are
    unknown with respect to antibodies.

4.  Two studies on antibodies should be conducted---a natural history
    study and an animal or human study.

5.  Postmarket surveillance should be conducted to clarify the issue of
    accelerated fracture healing.

6.  The sponsor and FDA should work out the statistics concerning the
    presence of fibula fracture fixation and its effect on endpoints.

When asked to explain the reasons for their votes, panel members
responded that the device is safe, but its effectiveness is only weakly
demonstrated, if at all. Many felt that the sponsor could produce a
better study. The panel member voting not to approve the device did so
because the preclinical data were mixed, the clinical data had too many
confounders, and the x-ray data were not complete; the healing criteria
were varied.

# GENERAL DISCUSSION ON SPINAL DEVICES

# OPEN PUBLIC HEARING

**Dr. Brenda Seidman, Seidman Toxicology Services,** said that FDA's
proposal to require in vivo particle injection studies for spine devices
is problematic. She raised numerous questions concerning the
appropriateness of such a requirement.

**Diane Johnson, vice president, Regulatory Affairs, Spinal Dynamics
Corporation,** requested that the panel consider FDA's position on
durability testing and its relationship to wear-particle testing. She
asked the panel to consider whether simulation testing for disc devices
should reflect activities of daily living or maximum loads and motions,
as sometimes suggested by FDA. She also asked the panel to consider
whether particle size distribution and quantity should be determined
using a load and motion profile associated with activities of daily
living. Finally, she asked whether the generation of particulate due to
nonphysiologic loading necessarily invalidates animal models in terms of
evaluation of the effects of particulate that is generated in the
animal.

**Bailey Lipscomb, Ph.D., vice president, clinical affairs, Medtronic
Sofamor Danek,** raised several issues. First, in clinical trials,
Oswestry pain success should be based on improvement from baseline, with
a goal of 20 percent improvement. Second, neurological status is just
one component of success; fusion, pain, and device criteria also are
important. Currently, anything affecting neurological success affects
the total success rate for studies. A person could have reduced pain and
many sensorimotor improvements, but if one neurological criterion is
reduced, it is counted as failure. The standard is inappropriate. Third,
FDA is requiring unnecessarily large clinical study sizes.

**Richard Jansen, Pharm.D., vice president, regulatory and clinical
affairs, Disc Dynamics, Inc.,** raised three issues. First, in clinical
studies, the radiographic endpoint of motion on flexion and extension
films should be a secondary endpoint; the main endpoint should be
clinical. Patients will consider surgery successful if they have reduced
pain and a return to activities of daily living. Second, the baboon
model is inappropriate for disc nucleus prostheses. The disc base is too
narrow, and the nucleus cavity is too small. Third, spine arthroplasty
devices should not be required to last the life of the patient. Each
type of device must be considered individually.

**Britt Norton, Raymedica, Inc., Bloomington, MN,** spoke about
preclinical testing related to nonfusion spinal devices. The tests used
to evaluate prosthetic nucleus devices must recognize the fundamental
differences between those devices and fusion devices in order to provide
meaningful results. It is important to differentiate between tests that
characterize the materials used in a device and tests that evaluate the
intended function of the device. He raised issues concerning tests for
compression fatigue, durability, and shear testing; migration and
expulsion; creep and stress relaxation; and potential for generating
wear debris.

# FDA PRESENTATION

Dr. Buch presented background on the guidance document for preparation
of IDEs for spinal systems. She stressed that the panel discussion is
not related to approval of a specific device. The current spinal
guidance focuses on fusion devices, and it needs to be updated to
incorporate new devices.

# Panel Reviews

**John S. Kirkpatrick, M.D.,** provided the panel preclinical and
clinical reviews. He noted that the panel is being asked to recommend
tests for unknown devices even though there are no validated test
methods. The panel will ask for companies to satisfy the burden of
safety and effectiveness. The extensive nature of the tests are high,
but compromise is required.

Devices should be tested in all anticipated loads and motions.
Physiologic load needs to be considered seriously. In addition,
mechanical characteristics should include device changes after testing
for durability, wear, debris, plastic deformation, and other changes.
Migration and expulsion tests are important, as are tests for static and
dynamic shear testing, creep, and stress relaxation. Evaluation of
bone--implant interface may be important. For devices intended to
preserve motion, the limits need to be defined; stability testing is the
way to get at that. Failure at the extremes of motion must be
characterized. Biocompatibility and toxicity testing for new materials
and characterization of corrosion, wear, response to debris, and shelf
life all are important. The effects of debris on the spine are unknown,
and animal models provide us with the best guess at present.
Radiographic measures are challenging at best. Investigators should
consider making indications as refined and specific as possible.

Concerning safety, sponsors should consider the revision options after
device failure. Is replacement an option, or is fusion the only option?
All neurological effects should be reported. In summary, nonfusion
devices will generally require more extensive evaluations, longer in
vitro testing, and longer clinical followup. FDA should set forth
exhaustive guidance and adjust requirements to specific device
applications if a sponsor provides an appropriate rationale.

**John Doull, Ph.D.,** provided the panel safety review. Safety boils
down to whether a device has a toxic effect or a physiologic effect.
Dose affects toxicity. Much is known about silicone, asbestos, and
solid-state tumorigenesis. As one reduces the size of the particle, one
reduces the propensity of the material to induce tumor. The kind of
neurological testing one might do to look for particle-size effects does
not have any good animal models. Good models are needed.

# 

***Question 1:** Please comment on the currently recommended preclinical
mechanical, debris, or wear testing to evaluate new materials, device
properties/integrity and wear debris for fusion and non-fusion devices.
Discuss what additional testing, if any, should be added to current
testing recommendations for the following devices: stabilization devices
for non-fusion; intervertebral disc/joint replacements
(cervical/thoracolumbar); devices manufactured out of new materials; and
intervertebral disc nucleus replacements.*

The panel concurred that the guidance adequately specifies the necessary
tests. The problem is that nonfusion devices come in many types of
materials and polymers. Viscoelastic testing is required, and there are
many types of tests. Because the materials are so variable, these issues
should be addressed individually with the device sponsors.

*Question 2: Because of the limitations of the current testing methods
and models, should devices made of new materials and/or those intended
to retain motion be tested for neurotoxicity independent of the type of
material or the amount of wear debris generated? If you suggest that
testing be performed, please describe the testing you recommend.*

The panel concurred that wear-debris testing is important. Members
proposed various types of testing, such as placing particulates in the
area of intended use adjacent to the dura and testing in conventional
modes. Physiologic loading to represent the most vigorous patient type,
instead of maximal loading, would be appropriate. The panel concurred
that it is important to place a barrage of particles at the site of
implantation and study the reaction. Panel members noted that the
manufacturer should not be required to produce particles of a size not
produced under wear conditions and that FDA needs to be careful not to
put too high a burden on manufacturers.

***Question 3a:** Please discuss study designs which may be better
suited to evaluate Non-Fusion spinal devices. In your discussion, please
comment on enrollment criteria, patient populations, controls, success
criteria and goals of the study that would be suitable for these types
of non-fusion spinal devices.*

The panel concurred that it is important to look at the natural history
of nonfusion devices; the devices may affect degenerative changes at
adjacent segments. Investigators need to carefully consider specific
indications for each device. Success should include improvement of pain
and functional capacity. Patient success is multivariate construct.

***Question 3b:** Devices intended to stabilize the spine yet retain
functional motion are expected to have an upper limit of motion beyond
which one would consider the device to be unstable and a lower limit
below which one would consider the device to have inadequate motion or
possibly even consider the segment to be fused. Please discuss the
amount of motion and on what scale, to define a patient as a functional
and clinical success (i.e., a clinically significant improvement in
condition) for each of cervical, thoracic and lumbar levels for
Non-Fusion spinal devices.*

The panel concurred that it was not useful to require an arbitrary level
of motion. If a patient receives a nonfusion device and improves, then
the device is efficacious. The panel concurred that is important to
study a wide range of diagnoses; indications for replacement versus
fusion are important factors in product design. Investigators must
determine whether interventions would affect adjacent deterioration.
Success criteria should include pain level as well as range of motion.

**ADJOURNMENT**

Mr. Demian thanked the participants and adjourned the panel at 4:22 p.m.

> I certify that I attended this meeting of the Orthopaedics and
> Rehabilitation Devices Advisory Panel on November 21, 2002, and that
> these minutes accurately reflect what transpired.
>
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Hany Demian, M.S.
>
> Executive Secretary

I approve the minutes of the November 21, 2002, meeting

as recorded in this summary.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Michael Yaszemski, M.D.

Acting Chairperson

Summary prepared by

Caroline G. Polk

Polk Editorial Services

1112 Lamont St., NW

Washington, DC 20010

\(202\) 265-8271

cpolk@earthlink.net