# SUMMARY MINUTES

**MEETING OF THE ORTHOPAEDICS AND REHABILITATION DEVICES**

**ADVISORY PANEL**

**OPEN SESSION**

# JANUARY 10, 2002 

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

**Attendees**

January 10, 2002

*Acting Chairperson*

Maureen Finnegan, M.D.

*Executive Secretary*

Hany Demian, M.S.

*Members*

Barbara D. Boyan, Ph.D.

Betty Diamond, M.D.

John Doull, Ph.D., M.D.

Edward N. Hanley, M.D.

John Kirkpatrick, M.D.

Leon Lenchik, M.D.

Stephen Li, Ph.D.

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

A. Hari Reddi, Ph.D.

Gene P. Siegal, M.D., Ph.D.

### Guests

John Kostuik, M.D.

Richard K. Miller, Ph.D.

Rocky Tuan, Ph.D.

*Consultants*

Kinley Larntz, Ph.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 9:40 a.m.
He stated that panel consultants Kinley Larntz, Sanjiv Naidu, Leon
Linchik, Gene Siegal, John Kirkpatrick, Barbara Boyan, John Doull, Betty
Diamond, and Hari Reddi had been granted temporary voting status and
that Maureen Finnegan had been appointed acting chairperson for the
duration of the meeting. In addition, Drs. Li, Larntz, Hanley, and
Kirkpatrick had been granted conflict-of-interest waivers for their
interests in firms that could potentially be affected by the outcome of
the panel's deliberations; they therefore could participate fully in the
meeting. Matters involving Drs. Li, Larntz, Finnegan, Boyan, and Siegal
had been considered and were deemed unrelated to the topic at hand;
those members' full participation was therefore permitted. Dr. Hanley
had past involvement in matters related to the day's agenda and could
therefore participate in panel discussions but not vote. Panel guests
Tuan and Kostuik had interests in the firm at issue. Mr. Demian asked
the panelists to introduce themselves and then turned the meeting over
to Acting Chair Finnegan.

Dr. Finnegan stated that that the purpose of the meeting was for the
panel to make recommendations on a premarket approval application (PMA)
for a spinal fusion cage with a growth factor soaked in a collagen
sponge used to treat lumbar degenerative disk disease (DDD). She noted
that the panel members constituted a quorum.

**OPEN PUBLIC HEARING**

Patsy Trisler, senior director, PharmaNet Consulting, stated that
although bone morphogenetic proteins (BMPs) are an important advance, it
is important to be certain that all questions have been addressed in the
approval process. She expressed surprise that the FDA had agreed that
certain nonclinical safety studies could be conducted postapproval. If
transformed cells or other adverse events are seen after the implant has
been released to the market, what is the surgeon to tell the patient?
The panel should give special attention to the potential for off-label
use for the device at issue.

John McCullough, M.D., an orthopedic surgeon from Denver, CO, stated
that he had been a participant in the pilot study of the device. The
success of the device is well established by research. The FDA should
require the device components to be packaged together to help minimize
the potential for off-label use.

Executive Secretary Hany Demian then read eight letters into the record:

-   Regis W. Haid, M.D., The Emory Clinic, Atlanta, GA, asked the panel
    to expedite the approval of the device. He stated that BMP offers a
    significant advantage for physicians and would eliminate the pain,
    complications, and additional expense associated with the harvest of
    autograft iliac crest.

-   David G. Malone, M.D., F.A.C.S., Oklahoma Spine & Brain Institute,
    stated that BMP may lead to excessive bone growth and may cause
    significant neural impingement if placed in a posterior lumbar
    interbody type of device. He stated that if BMP is approved for
    spinal fusion, it would be useful to require that the device be
    placed in such a manner that bone overgrowth cannot protrude into
    the spinal canal.

-   Robert J. Banco, M.D., chief, Spine Section, New England Baptist
    Hospital, wrote that BMP supplants the need for harvesting the iliac
    crest and reduces the risk of associated complications, including
    pain, infection, nerve damage, and possible damage to the muscle and
    vessels.

-   Paul C. McCormick, M.D., professor of clinical neurological surgery,
    Columbia Presbyterian Medical Center, New York, also noted the
    complications associated with the harvesting of autograft. Any
    useful adjunct that can facilitate and enhance spinal fusion would
    be of tremendous benefit to patients.

-   J.J. Abitbol, M.D., California Spine Group, San Diego, CA, said that
    BMPs are a safe new alternative to taking autograft and urged the
    panel to approve their use.

-   John H. Peloza, M.D., Center for Spine Care, Dallas, TX, described
    the different types of bone graft material and their limitations. He
    outlined the advantages of rhBMP-2 and urged the FDA to move it into
    clinical use.

-   Stephen M. Papadopoulous, M.D., Curtis A. Dickman, M.D., and Volker
    Sonntag, M.D., Barrow Neurological Associates, Phoenix, AZ, stated
    that approval of BMP would provide a significant advance for patient
    outcome and satisfaction following spinal fusion.

-   Dr. Douglas Moreau \[sp?\] wrote that he is both a physician and
    patient and has been delaying his own spine surgery pending approval
    of the device. He urged approval of the device.

SPONSOR PRESENTATION

Bailey Lipscomb, Ph.D., vice president, clinical affairs, Medtronic
Sofamor Danek, outlined the main characteristics of the InFUSE Bone
Graft/LT-CAGE Lumbar Tapered Fusion Device (hereafter, the InFUSE
device). The InFUSE device has three components: a metal spinal fusion
device (i.e., cage), an absorbable collagen sponge (ACS), and
recombinant human BMP-2 (rhBMP-2) solution. The cage and the ACS already
have been approved by the FDA. Dr. Lipscomb described how the device is
used and emphasized that the issue before the panel was not the metal
cage or ACS but the safety and efficacy of rhBMP-2 as a replacement for
current bone graft sources.

Gerard Riedel, Ph.D., Wyeth-Genetics Institute, Cambridge, MA,
summarized the sponsor's biological and preclinical safety data. After
describing the manufacturing process of rhBMP-2, he outlined some of its
properties. Endogenous BMP-2 is active in bone repair and embryonic
development and induces bone growth both in humans and in animals. Dr.
Riedel described the cell biology underlying the mechanisms of BMP-2 and
noted that implantation of rhBMP-2 requires a matrix (in this case, ACS)
to deliver the protein to the site and retain it there long enough to
allow bone formation. Dr. Riedel provided data describing the extent to
which ACS augments rhBMP-2 retention at the implantation site.

Dr. Riedel then presented data from implant safety studies; absorption,
distribution, metabolism, and excretion (ADME) studies; and tumor
biology, systemic toxicity, and reproductive toxicity studies. He stated
that the data demonstrate that the device is safe. Results of implant
studies results found no systemic effects. Biodistribution studies in
rats and rabbits found that rhBMP-2 is released slowly from the implant
site and has low systemic availability. ADME studies found that the
protein is cleared rapidly from the circulation---primarily through the
liver---and is rapidly degraded and excreted into urine.

Although some tumors express BMP-2 and have BMP-2 receptors, tumor
biology studies found no evidence that rhBMP-2 initiates tumors. No
cytotoxic or mutagenic activity was found in vitro, and no evidence of
abnormal cell biology was found in implant toxicity studies. In vitro
testing of 51 tumor cell lines resulted in growth promotion in 3 lines
(2 pancreas, 1 prostate) and no effect on the remaining 48. Of 71
primary tumor isolates tested, either no effect or inhibition occurred,
but inhibition was not sufficient for therapeutic use. Following
consultation with FDA, the sponsor has agreed to carry out additional
tumor studies.

Toxicity studies in rat and rabbit models using 1,000 times the human
rhBMP-2 dose found no systemic effect. Reproductive toxicity studies
also found no systemic effects. Riedel summarized additional studies
designed to gain a better understanding of the immune response to
rhBMP-2 that were planned in consultation with FDA.

Scott Boden, M.D., professor of orthopaedic surgery and director of the
Emory Spine Center at the Emory University School of Medicine,
summarized the preclinical and pilot clinical studies on the InFUSE
device. Animal studies found that the fusion rate at 3 or 6 months
followup was considerably greater with cages using the protein than with
cages not using the protein. Biomechanical test results found no
statistical difference in bone stiffness of autograft and rhBMP-2
fusions. Bone strength relative to adjacent bone also showed no
statistical difference for autograft and rhBMP-2 fusions. In primates,
devices using the ACS without rhBMP-2 showed no fusion at 6-month
followup.

Dr. Boden said that the pilot clinical study results revealed
significantly greater rates of fusion as well as lower Oswestry Low Back
Pain Disability Questionnaire pain scores with the InFUSE device than
with autograft. He presented several slides illustrating the differences
in fusion between patients with the InFUSE device and autograft
controls.

Dr. Boden summarized the data by saying that the device is safe: No bone
formation occurred away from the cages. In addition, the device is
effective because it eliminates bone-grafting morbidity and has equal or
better healing success. The bone formed is normal and biomechanically
equal to autograft. CT scan analysis correlated well with histological
analysis of rhBMP-2 bone formation.

Hallet H. Mathews, M.D., an orthopedic surgeon from Richmond, VA,
presented the clinical trial results for the InFUSE device. The study
had a prospective, randomized controlled design and took place at 16
investigational centers. The patients in the treatment group received
the InFUSE device; the control patients (i.e., the *autograft group*)
received cage devices filled with autogenous bone harvested from the
iliac crest. Patients in both groups had similar demographic
characteristics and preoperative medical conditions. A total of 143
patients received the InFUSE device; 136 patients were treated with
autogenous bone graft. Patient follow-up compliance at all postoperative
periods exceeded 90%.

Success was measured in terms of *Overall Success,* a derived variable
encompassing primary safety and effectiveness considerations; it was the
primary endpoint for the entire study for PMA approval purposes. The
variable comprised the effectiveness parameters of fusion, Oswestry
Questionnaire scores, and neurological success. It also was influenced
by two safety considerations: the occurrence of any serious adverse
event possibly associated with the device and the occurrence of a second
surgical procedure classified as failure. The Overall Success rates for
the two treatment groups were statistically equivalent at 24 months. The
primary clinical trial objective was met, thus supporting approval of
the product.

Safety was assessed as a function of the nature and frequency of adverse
events and second surgery procedures and the formation of antibodies to
rhBMP-2 and collagen. The InFUSE group was found to be as safe as the
autograft group.

No statistical differences were found between the two groups for all
categories of adverse events, except for graft-site events and
urogenital complications. Nearly 6 percent of the autograft patients had
a graft site complication, including bone fractures, nerve injuries,
infection, and hematoma. No graft site adverse events occurred for the
InFUSE group because the device eliminates the need to harvest bone
graft. The differences in the urogenital complication rates were mainly
due to urinary retention following surgery; those problems resolved in
all patients prior to their discharge from the hospital. The second
surgery rates for both groups were comparable; no statistical
differences were found for any of the categories of additional surgery.

Both computed tomography (CT) scans and x-rays were used to assess
fusion, and Mathews described the assessment process and criteria. At 24
months following surgery, the InFUSE fusion rate was statistically
equivalent to the autograft rate.

The Oswestry Questionnaire was used to measure the effects of back pain
on a patient's ability to manage everyday life. The mean Oswestry scores
for the two treatment groups were similar at all time periods. In
addition, the 24-month neurological success rates for both groups were
statistically equivalent. Other outcome measures included back pain, leg
pain, disc height maintenance, and general health status as measured by
the SF-36 survey. The 24-month results were comparable for the two
treatment groups; statistical equivalence between treatments was
demonstrated for all but back pain and the mental component summary of
the SF-36.

Another arm of the clinical trial examined the laparoscopic implantation
of the InFUSE device. Dr. Mathews stated that those data augment the
safety profile of the device and support approval of that implantation
method. Compared with the patients in the open study, the hospital stay
for the 134 laparoscopic patients was approximately 2 days shorter on
average, a finding that was statistically significant. Nearly 45 percent
of the laparoscopic patients were treated on an outpatient basis,
compared with virtually none of the patients in the other two groups;
they also returned to work an average of 20 days sooner. The Overall
Success rate at 24 months following surgery for the laparoscopic
patients was greater than 68 percent---nearly 12 percentage points
higher than and statistically superior to that of the autograft rate of
approximately 56 percent.

Dr. Mathews finished by showing slides of CT scans from some of the
study patients. He stated that CT scans are the best method for
detecting new bone formation within cages and determining fusion status.

Bailey Lipscomb, Ph.D., Medtronic Sofamor Danek, concluded by saying
that the sponsor has demonstrated a reasonable assurance of safety and
effectiveness. He addressed the FDA's questions to the panel and noted
that the evidence indicates that rhBMP-2 has either no effect or an
inhibitory effect on tumor cell proliferation. No scientific evidence
suggests that rhBMP-2 transforms a normal cell into a tumor cell.
Neither preclinical animal studies nor human clinical trials have found
problems involving the effects of antibodies to rhBMP-2 on fetal
development. The issue can be adequately addressed through labeling
statements and instructions to female patients of childbearing age.

FDA PRESENTATION

Aric Kaiser, M.S., PMA lead reviewer, described the components of the
InFUSE device and summarized the areas of concern to the FDA:
reproduction and teratogenicity, tumorigenicity, radiographic
effectiveness, instructions for use, and postmarket studies.

Peter L. Hudson, biologist, Division of General, Restorative, and
Neurological Devices, Office of Device Evaluation, Center for Devices
and Radiological Health, listed some of FDA's concerns with the InFUSE
device and said that the sponsor has begun to address those concerns by
adding studies to the postmarket review process. The FDA is particularly
concerned with rhBMP-2's potential to stimulate transformed cells and
the potential for an immune response to rhBMP-2 to cause adverse
effects. The systemic availability of rhBMP-2 is low and that minimal
exposure to the protein occurs outside the implantation site; rhBMP-2 is
rapidly cleared from the body through a renal pathway. The preclinical
evaluations on carcinogenicity, however, are not sufficient to reveal
the protein's effects on tumorigenesis. In the sponsor's studies, no
adverse clinical effects were correlated with positive antibody
formation. The FDA is concerned about the potential for an immune
response to cause adverse effects on embryogenesis and maternal immune
response. Data from studies of BMP knockout mice indicate that fetal
defects are possible. Additional animal studies should be conducted to
investigate the potential of rhBMP-2 antibodies to cause teratogenic
effects and adverse immunologic effects in women. A registry for women
of childbearing age might be useful.

Barbara Buch, M.D., clinical reviewer, highlighted key points from the
FDA's clinical review. She reviewed the sponsor's findings from the
clinical trial and noted that the study was well conducted. The
significance of the antibody findings cannot be determined. Regarding
adverse events, incidents of pain, hematoma, and infection at the donor
site occurred only in the control group. The rates of urogenital,
retrograde ejaculation, and graft site-related adverse events are of
concern: The investigational group had a higher rate of migration and
malpositioning of devices than the control group; the control group had
higher rates of loosening and displacement and subsidence than the
investigational group. The two groups were equivalent in cysts found
inferior to the implant. On the whole, however, the two groups had
equivalent clinical effectiveness and safety; in addition, the InFUSE
device avoids donor-site morbidity. Concerning radiographic
interpretation of the data, one may not be able to extrapolate animal
data to potential human responses.

Telba Irony, Ph.D., mathematical statistician, Division of
Biostatistics, summarized the FDA's statistical analysis. The
experimental treatments (i.e., laparoscopic and open surgery) were
likely to produce results at least equivalent to those of the control
group. Dr. Irony presented a statistical comparison of the use of x-rays
and CT scans in assessing spinal fusions in the sponsor's study and
concluded that sensitivity and specificity were better for CT scans than
for x-rays. In no case was the presence of bridging bone detected by
x-ray and not by CT scan. Less disagreement was found at 24 months than
at 12 months. The relevant endpoint for this PMA is fusion at 24 months.

Rocky Tuan, chief, Cartilage Biology and Orthopedics Branch, National
Institute of Arthritis, Musculoskeletal, and Skin Diseases, described
the biology of BMPs, including their molecular structure and mechanism
of action, biological activity, and issues related to biological
complications. BMP is highly cell specific: The same BMP can do
different things to different cells. During development, BMPs are
crucial for the fetus; ample evidence indicates that if BMP genes are
deleted, it is lethal to the embryo. After birth, BMPs play a role in
fracture repair, spine fusion, defect healing, and osteointegration.
After implantation in a site, distribution of rhBMP-2 is limited; a low
systemic level is found. Much is still not known about tumor induction,
hematological perturbations, teratological effects (particularly whether
they could be transgenerational), and immunoreaction.

Richard K. Miller, Departments of Obstetrics/Gynecology, Environmental
Medicine, and Pathology, University of Rochester Medical Center,
Rochester, NY, presented an overview of teratology and developmental
toxicology. He outlined the minimum requirements for reproductive
toxicity studies and described the process of human risk assessment in
reproductive toxicology. Dr. Miller concluded by describing what
pregnancy registries can do, when they should be constructed, how they
should be designed, and their timing and scope. The window of
opportunity for collecting reports is in the first 5 years of marketing.
Registries are not likely to be useful for agents on the market for an
extended period of time due to the diminution of voluntary reporting.

John Kostuik, M.D., director of spinal surgery, Johns Hopkins
University, discussed issues involving assessment of spinal fusion. CT
scans could be more useful with the sponsor's product than with
autograft. One of the most telling ways to determine fusion is through
the radiolucency around a device---any lucency means nonunion if the
patient still has pain. Bone scans have little value---most fusions are
warm for 24 months; warmth for longer periods than that indicates
pseudarthrosis. The best indication of fusion is the presence of
anterior sentinel graft, but it is unclear how thick that should be.

Panel Preclinical Review---A. Hari Reddi, Ph.D.

Dr. Reddi noted that BMPs are natural substances that are found in
mammals as well as other organisms. BMPs are normal constituents in the
body; excessive worries about teratogenicity are unwarranted.

Panel Clinical Review---John Kirkpatrick, M.D.

Dr. Kirkpatrick observed that DDD is a fairly controversial subject.
Many people have DDD without pain; fusion is for the treatment of back
pain, not the disease. The patient populations in the clinical trial
were similar. Nothing in the sponsor's data indicates a problem, but it
is unclear why bovine antibodies were found in the control group. The
InFUSE device is as safe as using autograft.

Panel Statistical Review---Kinley Larntz, Ph.D.

Dr. Larntz extended his compliments to the sponsor and FDA for the clear
presentation and the quality of the data. The device clearly meets the
criteria set forth in the protocol. Some kind of sensitivity analysis is
needed: A number of measures are scales, and the analysis summarized
outcomes as success or failure. Information is lost when using arbitrary
cutpoints. The laparascopic patients differed in several ways from the
patients in the other two groups---the results should have been adjusted
for the patient populations.

Mr. Kaiser then read the questions before the panel.

PANEL DISCUSSION

Panel members summarized their questions and concerns about the InFUSE
device. Many members extended compliments to the sponsor on the quality
of the research. Company representatives answered each panel member's
questions in turn.

Dr. Li asked whether any agents had passed all in vitro testing but were
later found to have tumorigenetic effects or to create birth defects.
Dr. Riedel said that to the best of his and his colleagues' knowledge,
there was not such an agent. Dr. Miller said that certain estrogens,
such as diethylstilbestrol, fell into that category. Dr. Li asked for
clarification regarding the definition of bridging bone, which the
sponsor answered to his satisfaction. He also asked whether radiographic
evidence was predictive of clinical success or failure. Harry Genant,
M.D., University of California, San Francisco, a paid consultant to the
sponsor, said that radiographic evidence was not strongly correlated
with clinical success. No determination had been made with regard to the
minimum amount or thickness of bridging bone necessary to be considered
clinically relevant. Dr. Riedel added that it was not uncommon to have
persistent symptoms not in accord with radiographic images. Dr. Li asked
whether any animal or other data correlated the amount of bridging bone
and biomechanical measurements; Dr. Riedel provided additional
information on the biomechanical properties of the bone formation in the
animal studies.

Dr. Doull noted that Dr. Hudson had stated that much variability among
species existed in the effects of a given dose of rhBMP-2. In such
situations, intraspecies variability often exists as well. Dr. Riedel
provided additional information, saying that the local concentration
correlates with the efficacy within species, a relationship that is
consistent across all anatomic sites within a species. In assessing
toxicity, the sponsor used as high a concentration as feasible, and no
dose-limiting toxicity was found. Dr. Tuan added that different cell
types respond to rhBMP-2 with different types of dose response and that
it might be useful to give the panel information about the local
concentration of rhBMP-2 at various tissue sites as a function of time.
Dr. Riedel said that animal studies have indicated that consistently,
0.10 percent of the implanted rhBMP-2 becomes systemically
available---the exposure is very low.

Dr. Diamond said that the antibody assay represents arbitrary numbers
and that maternal antibodies can cause prenatal and postnatal problems.
She asked numerous questions about how the dose of rhBMP-2 was
determined as well as several questions about the sponsor's antibody
studies; Drs. Riedel and Boden and Bonnie Roop \[sp?\] of Wyeth-Genetics
Institute provided additional clarification to her satisfaction. Dr.
Diamond indicated that a pregnancy registry seemed like a good idea and
asked how many pregnancies would be needed to produce useful results.
Dr. Lipscomb indicated that in any given year, 2,500 women of
childbearing age would receive the InFUSE implant; of those, 275 would
become pregnant and 2 would develop rhBMP-2 antibodies. Because of the
small numbers, a registry might not be appropriate. Dr. Diamond said
that the small numbers underscored the importance of studying the
effects of antibodies on pregnancy outcomes in animal studies.

Dr. Hanley noted that he had nonvoting status for this meeting. He
stated that radiographic issues do not have great pertinence; the main
issues are those of labeling, indications, and use of the device.

Dr. Siegal asked whether veterinary or human pathologists had been used
in the studies, whether they worked for the company or were independent,
and whether they were experts in bone disease. He noted that two
pancreatic cell lines showed increased proliferation and one patient had
a pancreatic carcinoma---was that coincidence? Through biopsy it should
have been possible to obtain enough cells from the patient who developed
pancreatic cancer to find out whether rhBMP-2 played a role. Dr.
Lipscomb replied that the number of tumors was less than one would
expect in a normal population. Dr. Riedel said that the animal studies
were conducted using a contractor and that he could not recall whether
the histologist was board certified, but he believed he was. Dr. Siegal
also asked why the sponsor could not provide already hydrated rhBMP-2;
Dr. Riedel replied that it was because of technical manufacturing
issues.

Dr. Kirkpatrick asked how complete the data were beyond 24 months. He
also asked for information on the normal expression of BMP in the course
of fusion and what liver impairments would prevent metabolism of the
enzyme. He expressed concerns about how to guard against off-label use.
Dr. Kirkpatrick asked whether the sponsor had identified specific
reasons why patients in the control group developed antibodies to bovine
collagen, and Dr. Boden responded no. Dr. Boden provided clarification
concerning the data beyond 24 months and the follow-up intervals to Dr.
Kirkpatrick's satisfaction

Dr. Finnegan asked for more information about why cases that failed did
so. Dr. Boden indicated that radiographic failure could be observed in
patients who had fused but had reoperation for other reasons. Dr.
Finnegan also asked for clarification concerning the difficulties with
packaging the three components together. Dr. Lipscomb provided
additional information on the sizes of the cages and sponges and how
they are used together.

Dr. Naidu pointed out that an antibody response occurred in only three
patients and that it appeared that hardly any rhBMP-2 crossed the
placental barrier. He reiterated Dr. Reddi's observations that BMPs are
normal substances in the body and stated his belief that the product is
safe and effective. He asked whether the manual would include additional
details regarding perforating the annulus; Dr. Boden indicated that the
manual was already fairly detailed.

Dr. Boyan asked for additional information on mineralization and
assessment using CT versus x-ray---it is difficult to determine whether
something is bone or remineralized collagen early on. Was it possible
for elderly people or people who have multiple experiences with the
device to develop sensitivity to type-1 collagen or rhBMP-2? Judy
O'Grady, regulatory affairs, Integra Life Sciences Corporations (the ACS
manufacturer), noted that in the 21-year history of the ACS, no
immunogenic response or allergic reaction has been seen. Dr. Boyan asked
Dr. Riedel whether any of the animal studies had looked at specific
immunological markers, and he responded that they had not.

Dr. Reddi said that much research in cell lines means nothing for
patients; tumorigenicity studies must be done in living animals. He
asked whether any long-term effects on mice or rats had been studied to
determine any in vivo tumorigenic actions. Dr. Riedel said that none of
the animal models revealed any evidence of abnormal cell events. Dr.
Reddi asked additional clarifying questions concerning the formation of
and role of antibodies to rhBMP-2, which Bonnie Rupp answered to his
satisfaction.

Dr. Lenchik noted that the quality of the CTs varied widely and that
some were uninterpretable. He asked for an explanation of the lower
rates of fusion, as assessed by CT, at 24 months versus 12 months, for
additional information about the need for a posterior anatomical barrier
between the annulus and the cage, and how to treat patients with annular
tears or herniation. Dr. Boden responded that the normal population has
a high frequency of tears and that those conditions all existed in the
clinical trials because they were done with a normal population. No
patients formed bone posterior to the cage outside the confines of the
disk space. Dr. Boden responded that the drop in the apparent fusion
rate at 24 months was due to second surgery criteria. Lenchik asked
whether any quantification was used in radiographic assessment, and Dr.
Boden answered that although a grading system had been created in the
pilot study, it was determined that the scheme was not useful.

Dr. Larntz noted that the patients in the laparascopic group had
differences in baseline variables from the other groups and asked
whether any adjustments to the analysis had been made as a result of
those differences. Dr. Lipscomb described the sponsor's adjustments.

Dr. Rue observed that although women in the study had agreed not to get
pregnant for 16 weeks, six pregnancies occurred. She added that most
pregnancies are unplanned and that most women do not know that they are
pregnant right away; how did the sponsor suggest handling that
situation? She asked whether any patients in the clinical trials had
hepatitis and how that affected the outcome; Dr. Lipscomb provided
additional data in response.

Ms. Maher said that most surgeons know when fusion occurs and that the
issue should be avoided in labeling. With regard to off-label use, she
urged caution about trying to mandate the practice of medicine. Surgeons
know what is needed and will make that determination on their own
regardless of the labeling. Mandating packaging would increase the cost
to the consumer.

Dr. Kostuik asked for clarification concerning the urogenital adverse
events. Dr. Mathews explained that the patients who did not require
autograft had less pain or went home earlier than their InFUSE device or
laparascopic counterparts; as a result, their catheters were removed
earlier, which in turn affected the rate of urogenital problems.

OPEN PUBLIC SESSION

Tushar Patel, Depuy Acromed, a consultant to Striker Biotech and
clinical assistant professor at Yale School of Medicine, raised two
questions: (1) How does one guard against off-label application of the
device? (2) Were any tests done to detect antibodies to rhBMP-2?

Question 1: Discuss the potential for an immune response in the mother
to effectively block BMP-2 expression in the developing fetus.

The panel concurred that information was not sufficient to answer the
question one way or the other. The labeling should perhaps say that
patients should be aware that immune response is a possible issue,
particularly for pregnant women.

## 

Question 2: Discuss the potential that the fetal expression of BMP-2
could restimulate a maternal immune response and cause adverse effects
in the mother.

The panel indicated that it was unclear whether the transplacental model
goes in both directions. Dr. Miller noted that the data from mouse
models suggest that the immune reaction may be only maternal, not fetal.
The panel concurred that postmarket study of the issue should be
encouraged.

**Question 3: Discuss the potential for rhBMP-2 to stimulate growth of
transformed cells.**

The panel agreed that it was not necessary to conduct further studies on
transformed cells and that in vivo data are most important at this
point.

Question 4: Comment on the interpretation of the radiographic findings
at various timepoints in view of presence/resorption rate of ACS,
progression of bone repair in the presence or absence of rhBMP-2, and
the relative ability of bone formed at various timepoints to withstand
applied loads.

The panel noted that ACS is absorbed within 6 weeks, so it has little
bearing on radiographic findings. The loads are shared by the graft and
the titanium cage. The data are insufficient to answer the last part of
the question.

Question 5: Provide suggestions for adequate instructions for use with
respect to radiographic interpretation. Discuss any other specific
training that should be implemented.

Dr. Hanley noted that the question pertains to the normal clinical
practice of medicine and is not specific to any device. Dr. Finnegan
noted that if the cage and the sponge/rhBMP-2 solution were not packaged
together, the amount of rhBMP-2 could be inadequate, overadequate, or
appropriate for a given cage and patient. Ms. Maher noted that packaging
everything together would create additional expense for consumers. Dr.
Boden said that surgeons needed the ability to mix and match. He noted
that the sponge can only hold so much rhBMP-2 and could not see why a
surgeon would try to use two sponges or additional rhBMP-2.

Question 6: FDA believes that additional animal models may be useful for
assessing an immune response effect on fetal growth and development.
Comment on the need for these studies, the types of studies to be
performed, and appropriate animal models.

The panel concurred that studies of antibodies to rhBMP-2 in mouse
models would be appropriate.

Question 7: FDA and the sponsor have agreed to conduct additional
nonclinical studies to evaluate the potential for rhBMP-2 to stimulate
transformed cells. Comment on the need for any other nonclinical
studies, the types of studies to be performed, and appropriate models.

Dr. Reddi stated that additional study of transformed cell lines is
worthless and that simple animal models would be more appropriate. The
panel concurred that study of cell lines was not useful at this point.

Question 8: Comment on the use of ongoing postmarket registry databases
to further assess the potential for congenital abnormalities. If
registries are recommended, discuss the types of data to be captured.

Dr. Larntz noted that registries are difficult to conduct well and that
the number of potential patients would be too small in this case.

VOTE

Dr. Kirkpatrick moved, and Dr. Larntz seconded, that the PMA be approved
with conditions. The panel voted unanimously to approve the PMA with the
following conditions:

-   That the sponsor study rhBMP-2 in systemic administration mouse
    models for antibodies at conception, implantation, and limb bud
    formation time points (postapproval study)

-   That the sponsor study equal dosing and multiple dosing of rhBMP-2
    in mouse models over a long time to complement a large dose at a
    single time (postapproval study)

-   That the sponsor assess the potential of rhBMP-2 to promote growth
    of primary tumor isolates that have been analyzed for rhBMP-2
    receptor expression (postapproval study)

-   That the FDA approve the PMA for tapered cages only.

The panel also considered requiring that the cage and the sponge/rhBMP-2
solution be packaged together and discussed including a condition that
the sponsor conduct postmarket surveillance using a registry. It
ultimately decided not to require those conditions because they would
not address the panel's concerns regarding off-label use and problems
with fetal development. Dr. Larntz summarized the panel's reasons for
approving the PMA with the conditions by saying that it was the panel's
opinion that the device met the criteria for safety and effectiveness
and that the conditions are appropriate to making the device safe and
effective. The panel members concurred with his summary.

**ADJOURNMENT**

The panel adjourned at 5:30 p.m.

> I certify that I attended this meeting of the Orthopaedics and
> Rehabilitation Devices Advisory Panel on January 10, 2002, and that
> these minutes accurately reflect what transpired.
>
> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Hany Demian, M.S.
>
> Executive Secretary

I approve the minutes of the January 10, 2002, meeting

as recorded in this summary.

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

Maureen Finnegan, M.D.

Acting Chairperson

Summary prepared by

Caroline G. Polk

Polk Editorial Services

1112 Lamont St., NW

Washington, DC 20010

\(202\) 265-8271