Douglas J. King
Senior Vice President & President, Spine
Restorative Therapies Group
Medtronic
1800 Pyramid Place
Memphis, TN 38132
[email protected]
www.medtronic.com
Tel 901.344.1329 May 17, 2016
The Honorable Amy Klobuchar
302 Hart Senate Office Building
Washington, DC 20510
Dear Senator Klobuchar:
I am writing in response to your April 14, 2016, letter to Omar Ishrak arising out of the
Minnesota Star Tribune article published April 10, 2016. Medtronic appreciates the opportunity
to address questions raised by the article’s report on adverse events derived from a retrospective
chart review of surgeries involving the use of Infuse®.
Relying on inaccurate and incomplete information, the article suggests this adverse event data
may have changed the product’s safety profile. This suggestion is wrong, and it is regrettable
that the Star Tribune chose to mislead its readers in this way.1 As the presidents of both the
Minnesota Neurosurgical Society and Minnesota Orthopedic Society expressed in a recent Letter
to the Editor, the article presents an unbalanced evaluation of current scientific literature
regarding Infuse.2 These Mayo Clinic surgeons note that the article omitted information from
recent large-scale studies by independent investigators who concluded the use of Infuse does not
increase the risk of complications.3 The Minnesota surgeons worried that the biased presentation
from the Star Tribune might “inappropriately deter patients” from incorporating Infuse into their
surgical plans.4
Infuse is an important option for physicians treating patients requiring spinal surgery for several
FDA-approved indications for use. The North American Spine Society (NASS), the largest
society devoted to spine care for patients, has emphasized the important clinical role for its use
1
Medtronic Responds to Star Tribune Article Regarding INFUSE Bone Graft, April 10, 2016, available at
http://newsroom.medtronic.com/phoenix.zhtml?c=251324&p=irol-newsArticle&ID=2155741, last accessed
5/11/2016.
2
Letter to Editor, Star Tribune, April 27, 2016, available at http://www.startribune.com/readers-write-april27-fools-and-fast-cars-prince-s-death-ignition-interlock-devices-spine-surgery/377192211/, last accessed 5/11/2016.
3
Referring, for example, to Savage, JW, et al., A population-based review of bone morphogenetic protein:
associated complication and reoperation rates after lumbar spinal fusion, Neurosurg Focus 39 (4):E13, Oct. 2015.
4
Letter to Editor, supra n. 2.
The Honorable Amy Klobuchar
May 17, 2016
Page 2
“for spinal fusion surgery in well-selected patients” in which “other alternatives are either not
available or are not likely to lead to successful fusion.”5 With over a decade of clinical
application, Infuse has become one of the most extensively researched biologic agents
commercially available today, with scores of studies published in leading scientific journals, and
is routinely used to improve patients’ lives around the world.
Before responding to your specific questions, we would like to offer the following background
about Infuse and the retrospective chart review. So that you are aware, we have also provided
this information to Sen. Franken in response to a letter from him with similar inquiries.
Infuse is a medical device that includes bone morphogenetic protein (BMP). Among other
indications, it is used in spine surgery to facilitate bone growth (fusion) of adjacent vertebrae. In
2002, the FDA approved the sale and marketing of Infuse for use in anterior spinal fusion
surgeries in the lumbar spine pursuant to its premarket approval (PMA) process. PMA approval
requires the highest level of scrutiny by the FDA.
The Infuse PMA was based on data from prospective randomized clinical trials specifically
structured to allow the comparison of adverse event types and rates between patients who
received the therapy and those who did not. As one would expect, adverse events can be related
to many different factors. Because all surgeries are associated with the risk of complications,
structured clinical trials are necessary to obtain comparative data from which reliable
conclusions may be drawn.6 In the randomized, controlled clinical trials supporting the Infuse
PMA, the adverse events reported for surgeries with Infuse were similar to those that occurred in
surgeries without Infuse.
In 2005, Medtronic approached the FDA about seeking broader indications for more general use
of Infuse and proposed to support the request with information from a retrospective survey of
surgeons relating to their clinical experience with Infuse in a variety of surgical procedures.
Broader indications would have allowed Medtronic to market Infuse more widely and to
communicate safety information to surgeons about the use of Infuse in additional applications.
The retrospective survey was not a structured clinical trial like those undertaken to support the
FDA approval of Infuse. Instead, it sought information contained in medical records of patients
who had undergone surgeries using Infuse between 2002 and 2006, including all adverse events
– whether or not related to Infuse – in over 15 different bodily systems. Unlike a randomized
5
rhBMP-2: NASS Coverage Policy Recommendations, Nov. 5, 2013, at pp. 5, available at
http://www.coloradospineinstitute.com/pdf/NASSCoveragePolicyfor-rhBMP-20140225-Truumees.pdf, last accessed
5/11/2016.
6
Medtronic and other device manufacturers are required to report adverse events where the device may
have caused or contributed to a death or serious injury or, in the case of a malfunction, would be likely to cause or
contribute to a death or serious injury if the malfunction were to recur. Reporting does not constitute a medical
conclusion that the device actually caused the event. See 21 CFR § 803.16. (emphasis supplied)
-2-
The Honorable Amy Klobuchar
May 17, 2016
Page 3
prospective clinical trial, the review did not include a comparison group based on surgeries that
did not use Infuse.
In 2006 and 2007, surgeons participating in the retrospective survey reviewed charts of patients
who had undergone a variety of spinal surgeries using Infuse. The surgeons were asked to report
all complications noted in the patients’ charts, regardless of the source or cause, on a case report
form that requested limited details about the events. The form asked surgeons to report all
adverse events even when the surgeon considered the event unrelated to the use of Infuse. While
sweeping all adverse events into this broad net, the form also asked the surgeons to assess the
severity of any complication as well as its relatedness to either the surgical procedure or the use
of Infuse. Only 122 events, or less than 12% of the total number of the subsequently reported
adverse events, were identified by the surgeons as possibly related to Infuse, and the majority of
those events were considered to be moderate or mild in severity.
When it became clear to Medtronic that this type of retrospective review would not be adequate
to support FDA approval of expanded indications, the survey was stopped and the chart review
forms were placed in storage. The chart review was not properly closed, and no adverse events
identified in the case report forms were reported to the FDA at that time. As you noted, we have
openly acknowledged that the information was processed improperly.
The information collected during the course of the review was rediscovered about five years later
in February 2013. Medtronic Spine promptly took steps to assess the data, and performed a
thorough analysis to identify reportable events and to communicate that information to the FDA.
Members of Medtronic Spine’s Clinical and Quality groups, together with an independent
physician, assessed whether adverse events collected in the chart review would have any impact
on the safety profile of Infuse, comparing the events to historical adverse event data. They found
no new types of adverse events. By the same token, despite the limitations in its quality, the data
revealed no new risks. Adverse events collected in the chart review were not different from the
types previously reported to the FDA in Infuse MDRs, clinical trial adverse event reporting, and
the medical literature from over 225 reported clinical studies of Infuse.
The chart review data did not change the safety profile of Infuse. In fact, the overwhelming
majority of the events were viewed by the reporting surgeons as being not related to Infuse. The
number of events reported as possibly related to Infuse was low and most were considered to be
moderate or mild in severity.
The Company informed FDA about the adverse events identified in the retrospective chart
review in July of 2013 after completing its assessment of the nature of the events and their MDR
reportability. The FDA directed the Company to file individual MDRs immediately for
reportable instances where the case report form indicated the patient had subsequently died, and
advised that the remaining events might qualify for reporting under the FDA’s Alternative
Summary Reporting program. Medtronic Spine immediately submitted four individual MDRs as
directed. In each instance, the reporting surgeon had concluded that the death was not related to
the use of Infuse.
-3-
The Honorable Amy Klobuchar
May 17, 2016
Page 4
On August 2, 2013, Medtronic submitted to the FDA a formal request for approval of summary
reporting of the other adverse events. The Agency subsequently approved the use of summary
reporting of the events in January 2014. The events were submitted to the FDA in February
2014; they were also reported to the FDA in the Infuse Annual Report submitted in July 2014.
According to the Star Tribune, an FDA spokesman stated that the adverse event information
from the retrospective review “didn’t reflect new public health concerns.”
More than two years have passed since Medtronic reported these events to FDA. In December
2015, based on all the Infuse data previously submitted – including the events reported from the
retrospective chart review – the FDA approved new and additional indications for Infuse use
with additional implants. The FDA has not required any labeling changes to add any new risk
information. A copy of the most recently approved label for spinal indications (Instructions for
Use or IFU) is attached.7
You specifically inquired why it took until 2013 to discover the retrospective review information
and what steps have been taken to prevent similar events in the future.
While we regret that events from the retrospective chart review were not reported earlier, we
have no information to suggest the failure to report was intentional. As discussed above, once
this information was identified in 2013, we took prompt action to assess and report it, and are
confident that appropriate policies and training are in place to avoid a repeat of these events in
the future. Patient safety is our primary concern with all our products, and we continue to have
confidence in the safety and effectiveness of Infuse.
Once the retrospective survey data was discovered, Medtronic Spine initiated a corrective and
preventative action (CAPA) to understand why events from the chart review were not reported
earlier.8 The investigation identified several potential contributing factors, including that the
retrospective review was the first chart review of its kind conducted by Medtronic Spine; that the
Spine Clinical Department’s standard operating procedures for reporting adverse events collected
in a post-market chart review lacked clarity; that the suspension and closure of the retrospective
review did not follow a formal, documented process; and that no master list of clinical activities
included the retrospective chart review.
Medtronic business units, including Medtronic Spine, engage in continuous improvement of their
procedures, both as a matter of general policy and in response to particular problems that might
arise. Medtronic Spine has implemented a number of improvements to its internal processes to
7
Approved Instructions for Use for oral maxillofacial, trauma and other spinal indications are available at
infusebonegraft.com.
8
The FDA requires that manufacturers establish and maintain procedures for implementing corrective and
preventive action (CAPA) aimed at addressing identified quality problems, including investigating the cause of
nonconformities relating to product, processes, and the quality system. 21 CFR § 820.100.
-4-
The Honorable Amy Klobuchar
May 17, 2016
Page 5
ensure that all events identified by the Clinical Department involving a marketed device are
reported to the Quality group responsible for MDR reporting. In addition, Medtronic Spine
revised applicable clinical procedures and work instructions, and conducted training of clinical
department personnel on these processes. Medtronic Spine also established a list of all clinical
projects and ensured its internal auditing process covers clinical activities, including the
submission of MDRs. Finally, Medtronic Spine conducted a review of all post-market clinical
studies (including any chart reviews) relating to spinal products over the prior 10 years to assure
proper MDR reporting had occurred.
*
*
*
*
We appreciate your questions and the opportunity to respond to the information contained in and
issues raised by the April 10, 2016 Star Tribune article. Virtually all of this information was
shared with the Star Tribune. The final article, however, omitted many of these facts and
context, which are germane to these events, and we believe presented a misleading view of what
transpired with the retrospective chart review. We appreciate that your inquiry provides an
additional forum to convey the facts and the ensuing actions by Medtronic and the FDA.
Respectfully,
Douglas J. King
Attachment
-5-
0381148 Rev. G
INFUSE® Bone Graft/LT-CAGE® Lumbar Tapered
Fusion Device
INFUSE® Bone Graft/INTER FIX™ Threaded
Fusion Device
INFUSE® Bone Graft/INTER FIX™ RP Threaded
Fusion Device – Reduced Profile
INFUSE® Bone Graft/PERIMETER® Interbody
Fusion Device
INFUSE® Bone Graft/CLYDESDALE® Spinal System
Important Medical Information
INFUSE® Bone Graft/LT-CAGE® Lumbar Tapered Fusion Device Combinations
LT-CAGE® Lumbar Tapered
Fusion Device
Appropriate INFUSE® Bone Graft Kit
Size Reconstituted
(lead diameter, mm
Part #
Kit name (size in cc)
rhBMP-2/ACS
X length, mm)
graft volume
Part #
Medtronic Sofamor Danek USA, Inc.
1800 Pyramid Place
Memphis, Tennessee 38132
Telephone: 800 933 2635 (in U.S.A.)
901 396 3133 (Outside of U.S.A.)
Fax
901 396 0356
The following contains important medical information on the use of INFUSE® Bone Graft with a variety
of Medtronic interbody fusion cages. These interbody fusion devices include the LT-CAGE® Lumbar
Tapered Fusion Device, the INTER FIX™ Threaded Fusion Device, the INTER FIX™ RP Threaded
Fusion Device, the PERIMETER® Interbody Fusion Device, and the CLYDESDALE® Spinal System.
Hereafter in this insert, these cages will be referred to collectively as Medtronic Interbody Fusion
Device.
DESCRIPTION
7510200
Small (2.8)
2.8ml
8941420
14x20
7510100
X Small (1.4)
1.4
14x23
7510200
Small (2.8)
2.8ml
8941423
14x23
7510100
X Small (1.4)
1.4
8941620
16x20
7510200
Small (2.8)
2.8ml
16x23
7510400
Medium (5.6)
5.6ml
7510100+
7510050
X Small (1.4)+
XX Small (0.7)
2.1
8941623
894162016x20
8941626
16x26
7510400
Medium (5.6)
5.6ml
894162316x23
7510100+
7510050
X Small (1.4)+
XX Small (0.7)
2.1
8941823
18x23
7510400
Medium (5.6)
5.6ml
8941826
18x26
7510600
Large Pre-Cut (8.0)
8.0ml
8941826
18x26
7510800
Large II (8.0)
8.0ml
INTER FIX™ Threaded Fusion Device
Part #
890120
Appropriate INFUSE® Bone Graft Kit
Size
(diameter, mm X
Part #
Kit name length, mm)
(size in cc)
12x20
7510100
X Small (1.4)
Reconstituted
rhBMP-2/ACS
graft volume
1.4ml
890125
12x25
7510200
Small (2.8)
2.8ml
890140
14x20
7510200
Small (2.8)
2.8ml
890143
14x23
7510200
Small (2.8)
2.8ml
890146
14x26
7510200
Small (2.8)
2.8ml
890149
14x29
7510200
Small (2.8)
2.8ml
890160
16x20
7510200
Small (2.8)
2.8ml
890189
18x29
7510400
Medium (5.6)
5.6ml
890200
20x20
7510400
Medium (5.6)
5.6ml
890203
20x23
7510400
Medium (5.6)
5.6ml
890206
20x26
7510600 or 7510800
Large (8.0)*
8.0ml
890209
20x29
7510600 or 7510800
Large (8.0)*
8.0ml
890220
22x20
7510600 or 7510800
Large (8.0)*
8.0ml
890223
22x23
7510600 or 7510800
Large (8.0)*
8.0ml
890240
24x20
7510600 or 7510800
Large (8.0)*
8.0ml
INTER FIX™ Threaded Fusion Device
The INTER FIX™ Device consists of a hollow, perforated cylinder with parallel sides and an endcap.
The cage is available in diameters ranging from 12mm to 24mm and in lengths ranging from 20mm to
29mm. The endcaps of the INTER FIX™ cages are sized according to the diameter of the cylinders and
are applied to the open end of the cylinders after they are filled with INFUSE® Bone Graft.
The INTER FIX™ Threaded Fusion Device implants are made from implant-grade titanium alloy
(Ti-6Al-4V) described by such standards as ASTM F136 or its ISO equivalent.
The INTER FIX™ Threaded Fusion Device component is sold separately from the INFUSE® Bone
Graft component; however, these two components must be used together. The package labeling for
the INTER FIX™ Threaded Fusion Device contains complete product information for this component.
INTER FIX™ RP Threaded Fusion Device
The INTER FIX™ RP Device consists of a hollow, perforated cylinder with a single, large, outerradiused groove along the entire longitudinal axis that extends into the inside diameter of the device.
Both ends of the INTER FIX™ RP implant are closed. The cage is available in diameters ranging from
12mm to 24mm and in lengths ranging from 20mm to 29mm.
The INTER FIX™ RP Threaded Fusion Device implants are made from implant-grade titanium alloy
(Ti-6Al-4V) described by such standards as ASTM F136 or its ISO equivalent.
890163
16x23
7510200
Small (2.8)
2.8ml
890166
16x26
7510400
Medium (5.6)
5.6ml
890169
16x29
7510400
Medium (5.6)
5.6ml
890180
18x20
7510400
Medium (5.6)
5.6ml
890183
18x23
7510400
Medium (5.6)
5.6ml
890186
18x26
7510400
Medium (5.6)
5.6ml
* May be either the Large (Pre-Cut) or Large II Kit
INFUSE® Bone Graft/INTER FIX™ and INTER FIX™ RP Threaded Fusion Device Combinations
(INTER FIX™ RP Device with INTER FIX™ Device)
INTER FIX™ and INTER FIX™ RP
Threaded Fusion Devices
Part # of
INTER FIX™
Devices†
Appropriate INFUSE® Bone Graft Kit
Size
(diameter, mm X
Part #
Kit name length, mm)
(size in cc)
Reconstituted
rhBMP-2/ACS
graft volume
890120
12x20
7510100
X Small (1.4)
1.4ml
890125
12x25
7510200
Small (2.8)
2.8ml
890140
14x20
7510200
Small (2.8)
2.8ml
890143
14x23
7510200
Small (2.8)
2.8ml
890146
14x26
7510200
Small (2.8)
2.8ml
890149
14x29
7510200
Small (2.8)
2.8ml
890160
16x20
7510200
Small (2.8)
2.8ml
890163
16x23
7510200
Small (2.8)
2.8ml
890166
16x26
7510400
Medium (5.6)
5.6ml
890169
16x29
7510400
Medium (5.6)
5.6ml
890180
18x20
7510400
Medium (5.6)
5.6ml
PERIMETER® Interbody Fusion Device
890183
18x23
7510400
Medium (5.6)
5.6ml
890186
18x26
7510400
Medium (5.6)
5.6ml
890189
18x29
7510400
Medium (5.6)
5.6ml
890200
20x20
7510400
Medium (5.6)
5.6ml
890203
20x23
7510400
Medium (5.6)
5.6ml
7510600 or 7510800
Large (8.0)*
8.0ml
7510600 or 7510800
Large (8.0)*
8.0ml
7510600 or 7510800
Large (8.0)*
8.0ml
22x23
7510600 or 7510800
Large (8.0)*
8.0ml
22x26
7510600 or 7510800
Large (8.0)*
8.0ml
8.0ml
The PERIMETER® Interbody Fusion Device is offered in a variety of sizes, although only certain sizes
of the PEEK device are approved for use with INFUSE® Bone Graft. These sizes range from 8mm to
20mm in height, 21mm to 28mm in length, and 26mm and 36mm in width. An array of lordosis options
are also available for this device, spanning from 8 degrees to 15 degrees of angulation. The device
is designed with teeth across both the superior and inferior surfaces to allow the implant to grip the
superior and inferior end plates, thus providing expulsion resistance.
890206
20x26
890209
20x29
890220
22x20
The PERIMETER® Interbody Fusion Device component is sold separately from the INFUSE® Bone
Graft component; however, these two components must be used together. The package labeling for
the PERIMETER® Interbody Fusion Device contains complete product information for this component.
890223
890226
890229
22x29
7510600 or 7510800
Large (8.0)*
The CLYDESDALE® Spinal System consists of PEEK cages of various widths and heights, which
include tantalum markers. These devices can be inserted between two lumbar or lumbosacral vertebral
bodies to give support and correction during lumbar interbody fusion surgeries. The hollow geometry of
the implants allows them to be packed with INFUSE® Bone Graft.
890240
24x20
7510600 or 7510800
Large (8.0)*
8.0ml
890243
24x23
7510600 or 7510800
Large (8.0)*
8.0ml
The CLYDESDALE® Spinal System component is sold separately from the INFUSE® Bone Graft
component; however, these two components must be used together. The package labeling for the
CLYDESDALE® Spinal System contains complete product information for this component.
* May be either the Large (Pre-Cut) or Large II Kit
CLYDESDALE® Spinal System
NOTE: The INTER FIX™ Threaded Fusion Device and the INTER FIX™ RP Threaded Fusion
Device may be used together to treat a spinal level. The LT-CAGE® Lumbar Tapered Fusion
Device, the PERIMETER® Interbody Fusion Device, and the CLYDESDALE® Spinal System
implants are not to be used in conjunction with either the INTER FIX™ or INTER FIX™ RP
implants to treat a spinal level.
The PERIMETER® and CLYDESDALE® devices must be used with any supplemental fixation
system cleared for use in the lumbar spine.
INFUSE® Bone Graft Component
INFUSE® Bone Graft consists of recombinant human Bone Morphogenetic Protein-2 (rhBMP-2, known
as dibotermin alfa) placed on an absorbable collagen sponge (ACS). The INFUSE® Bone Graft component induces new bone tissue at the site of implantation. Based on data from non-clinical studies,
the bone formation process develops from the outside of the implant towards the center until the entire
INFUSE® Bone Graft component is replaced by trabecular bone.
rhBMP-2 is the active agent in the INFUSE® Bone Graft component. rhBMP-2 is a disulfide-linked
dimeric protein molecule with two major subunit species of 114 and 131 amino acids. Each subunit
is glycosylated at one site with high-mannose-type glycans. rhBMP-2 is produced by a genetically
engineered Chinese hamster ovary cell line.
rhBMP-2 and excipients are lyophilized. Upon reconstitution, each milliliter of rhBMP-2 solution
contains: 1.5 mg of rhBMP-2; 5.0 mg sucrose, NF; 25 mg glycine, USP; 3.7 mg L-glutamic acid, FCC;
0.1 mg sodium chloride, USP; 0.1 mg polysorbate 80, NF; and 1.0 mL of sterile water. The reconstituted
rhBMP-2 solution has a pH of 4.5; is clear, colorless to slightly yellow; and is essentially free from plainly
visible particulate matter. The concentration of rhBMP-2 is 1.5mg/ml.
The ACS is a soft, white, pliable, absorbent implantable matrix for rhBMP-2. ACS is made from bovine
Type I collagen obtained from the deep flexor (Achilles) tendon. The ACS acts as a carrier for the
rhBMP-2 and acts as a scaffold for new bone formation.
The INFUSE® Bone Graft component is prepared at the time of surgery and allowed a prescribed
amount of time (no less than 15 minutes) before placement inside of the Medtronic Interbody Fusion
Device components. The Instructions for Preparation contain complete details on preparation of the
INFUSE® Bone Graft/Medtronic Interbody Fusion Device.
Various sizes of INFUSE® Bone Graft kits are available based on the internal volume of the Medtronic
Interbody Fusion Device component that is selected. Each kit contains all the components necessary
to prepare the INFUSE® Bone Graft component: the rhBMP-2, which must be reconstituted; sterile
water; absorbable collagen sponge(s); syringes with needles; this package insert; and instructions for
preparation. The number of each item may vary depending on the size of the kit.
If the need arises during surgery, due to the loss or contamination of a sponge or sponges required for
filling one of the LT-CAGE®, INTER FIX™, or INTER FIX™ RP devices, the following is recommended:
if a Large kit was used originally to fill the device(s), use a Small plus an X Small (1.4cc) kit; if a Medium
kit was used originally, use a Small kit; if a Small kit was used originally, use an X Small (1.4cc) kit; and
if an X Small (1.4cc) kit was used originally, use an XX Small (0.7cc) kit.
The tables below list the appropriate INFUSE® Bone Graft kit for the corresponding Medtronic
Interbody Fusion Device component size.
†
he INTER FIX™ Threaded Fusion Device should be used with the corresponding size of the INTER
T
FIX™ RP Threaded Fusion Device
INFUSE® Bone Graft/INTER FIX™ RP Threaded Fusion Device Combinations
(Dual INTER FIX™ RP Devices)
INTER FIX™ RP
Threaded Fusion Device
Part #
Appropriate INFUSE® Bone Graft Kit
Size
(diameter, mm X
Part #
Kit name length, mm)
(size in cc)
Reconstituted
rhBMP-2/ACS
graft volume
9011221
12x20
7510100
X Small (1.4)
1.4ml
9011225
12x25
7510200
Small (2.8)
2.8ml
9011420
14x20
7510200
Small (2.8)
2.8ml
9011423
14x23
7510200
Small (2.8)
2.8ml
9011426
14x26
7510200
Small (2.8)
2.8ml
9011429
14x29
7510200
Small (2.8)
2.8ml
9011620
16x20
7510200
Small (2.8)
2.8ml
9011623
16x23
7510200
Small (2.8)
2.8ml
9011626
16x26
7510400
Medium (5.6)
5.6ml
9011629
16x29
7510400
Medium (5.6)
5.6ml
9011820
18x20
7510400
Medium (5.6)
5.6ml
9011823
18x23
7510400
Medium (5.6)
5.6ml
9011826
18x26
7510400
Medium (5.6)
5.6ml
9011829
18x29
7510400
Medium (5.6)
5.6ml
9012020
20x20
7510400
Medium (5.6)
5.6ml
9012023
20x23
7510400
Medium (5.6)
5.6ml
9012026
20x26
7510400
Medium (5.6)
5.6ml
9012029
20x29
7510400
Medium (5.6)
5.6ml
9012220
22x20
7510400
Medium (5.6)
5.6ml
9012223
22x23
7510400
Medium (5.6)
5.6ml
9012226
22x26
7510600 or 7510800
Large (8.0)*
8.0ml
9012229
22x29
7510600 or 7510800
Large (8.0)*
8.0ml
9012420
24x20
7510600 or 7510800
Large (8.0)*
8.0ml
9012423
24x23
7510600 or 7510800
Large (8.0)*
8.0ml
* May be either the Large (Pre-Cut) or Large II Kit
SINGLE CAGE USE
INTER FIX™
Threaded Fusion Device
Recommended INFUSE® Bone Graft Kit(s)
Size
(lead diameter,
Part #
Kit size mm X length, mm)
Reconstituted
rhBMP-2/ACS
graft volume (cc)
890120
12x20
7510050
XX Small (0.7)
0.7
890125
12x25
7510100
X Small (1.4)
1.4
890140
14x20
7510100
X Small (1.4)
1.4
890143
14x23
7510100
X Small (1.4)
1.4
89014614x26
7510100+
7510050
X Small (1.4)+
XX Small (0.7)
2.1
89014914x29
7510100+
7510050
X Small (1.4)+
XX Small (0.7)
2.1
89016016x20
7510100+
7510050
X Small (1.4)+
XX Small (0.7)
2.1
89016316x23
7510100+
7510050
X Small (1.4)+
XX Small (0.7)
2.1
INFUSE® Bone Graft/INTER FIX™ Threaded Fusion Device Combinations
Single INTER FIX™ RP Device Fill
INTER FIX™
Threaded Fusion Device
Part #
Recommended INFUSE® Bone Graft Kit(s)
Size
(lead diameter,
Part #
Kit size mm X length, mm)
Reconstituted
rhBMP-2/ACS
graft volume (cc)
9011221
12x20
7510050
XX Small (0.7)
0.7
9011225
12x25
7510100
X Small (1.4)
1.4
9011420
14x20
7510100
X Small (1.4)
1.4
9011423
14x23
7510100
X Small (1.4)
1.4
901142614x26
7510100+
7510050
X Small (1.4)+
XX Small (0.7)
2.1
901142914x29
7510100+
7510050
X Small (1.4)+
XX Small (0.7)
2.1
901162016x20
7510100+
7510050
X Small (1.4)+
XX Small (0.7)
2.1
901162316x23
7510100+
7510050
X Small (1.4)+
XX Small (0.7)
2.1
INFUSE® Bone Graft/PERIMETER® Interbody Fusion Device Combinations
The INTER FIX™ RP Threaded Fusion Device component is sold separately from the INFUSE® Bone
Graft component; however, these two components must be used together. The package labeling for the
INTER FIX™ RP Threaded Fusion Device contains complete product information for this component.
The PERIMETER® Interbody Fusion Device consists of PEEK cages of various widths and heights,
which can be inserted between two lumbar or lumbosacral vertebral bodies to give support and
correction during lumbar interbody fusion surgeries. The hollow geometry of the implants allows them
to be packed with INFUSE® Bone Graft.
INFUSE® Bone Graft/INTER FIX™ Threaded Fusion Device Combinations
Single INTER FIX™ Device Fill
Part #
INFUSE® Bone Graft/INTER FIX™ Threaded Fusion Device Combinations
(Dual INTER FIX™ Devices)
LT-CAGE® Lumbar Tapered Fusion Device
The LT-CAGE® Lumbar Tapered Fusion Device component is sold separately from the INFUSE® Bone
Graft component; however, these two components must be used together. The package labeling for the
LT-CAGE® Lumbar Tapered Fusion Device contains complete product information for this component.
Reconstituted
rhBMP-2/ACS
graft volume (cc)
14x20
Medtronic Interbody Fusion Device Component
The LT-CAGE® implants are made from implant-grade titanium alloy (Ti-6Al-4V) described by such
standards as ASTM F136 or its ISO equivalent.
Recommended INFUSE® Bone Graft Kit(s)
Size
(lead diameter,
Part #
Kit size mm X length, mm)
8941423
The INFUSE® Bone Graft/Medtronic Interbody Fusion Device consists of two components containing
three parts – a spinal fusion cage, a recombinant human bone morphogenetic protein, and a carrier/
scaffold for the bone morphogenetic protein and resulting bone. The INFUSE® Bone Graft component
is inserted into the Medtronic Interbody Fusion Device component to form the complete INFUSE® Bone
Graft/Medtronic Interbody Fusion Device. These components must be used as a system for the
prescribed indication described below. The bone morphogenetic protein solution component
must not be used without the carrier/scaffold component or with a carrier/scaffold component
different from the one described in this document. The INFUSE® Bone Graft component must
not be used without the Medtronic Interbody Fusion Device component.
The LT-CAGE® Device consists of a hollow, perforated, machined cylinder with opposing flat sides. The
cage has a tapered design with an angle of 8.8° and is available in diameters ranging from 14mm to
18mm at the narrow end of the taper to 17mm to 22 mm at the wide end of the taper and in lengths
ranging from 20mm to 26mm. There are two holes on each of the two flat sides. On each of the two
rounded aspects, there is a single rounded slot. The implants have a helical screw thread on the outer
surface. One end of the device is closed. The other end is open to be filled with the INFUSE® Bone
Graft component.
LT-CAGE® Lumbar
Tapered Fusion Device
Part #
8941420
CAUTION: Federal (USA) law restricts this device to sale by or on the order of a physician
with appropriate training.
2016-02-03
INFUSE® Bone Graft/LT-CAGE® Lumbar Tapered Fusion Device Combinations
Single LT-CAGE® Device Fill
The tables below describe how to use the X Small (1.4cc) & XX Small (0.7cc) kits to fill smaller single
LT-CAGE®, INTER FIX™, or INTER FIX™ RP devices if the need arises during surgery, due to the
loss or contamination of a sponge or sponges. In addition, information is provided on use of INFUSE®
Bone Graft with certain sizes of the PERIMETER® and CLYDESDALE® devices, which are implanted
at a single device per level.
PERIMETER® Interbody Fusion Device
Appropriate INFUSE®
Reconstituted
Bone Graft Kit
rhBMP-2/ACS
Footprint,
Size
Kit name
graft volume
Part #
Part #
Lordosis (height)
(size in cc)
MEDIUM, 8 deg 3492308
8mm
7510100
X Small (1.4)
1.4
3492310
10mm
7510100
X Small (1.4)
1.4
349231212mm
7510100+
X Small (1.4)+
2.1
7510050
XX Small (0.7)
3492314
14mm
7510200
Small (2.8)
2.8
3492316
16mm
7510200
Small (2.8)
2.8
349231818mm
7510200+
Small (2.8)+
3.5
7510050
XX Small (0.7)
349232020mm
7510200+
Small (2.8)+
3.5
7510050
XX Small (0.7)
LARGE, 8 deg
3493308
8mm
7510100
X Small (1.4)
1.4
349331010mm
7510100+
X Small (1.4)+
2.1
7510050
XX Small (0.7)
3493312
12mm
7510200
Small (2.8)
2.8
3493314
14mm
7510200
Small (2.8)
2.8
349331616mm
7510200+
Small (2.8)+
3.5
7510050
XX Small (0.7)
349331818mm
7510200+
Small (2.8)+
4.2
7510100 X Small (1.4)
349332020mm
7510200+
Small (2.8)+
4.2
7510100 X Small (1.4)
LARGE, 12 deg 3493412
12mm
7510200
Small (2.8)
2.8
3493414
14mm
7510200
Small (2.8)
2.8
349341616mm
7510200+
Small (2.8)+
3.5
7510050
XX Small (0.7)
349341818mm
7510200+
Small (2.8)+
3.5
7510050 XX Small (0.7)
349342020mm
7510200+
Small (2.8)+
4.2
7510100 X Small (1.4)
XL, 8 deg
7510200+
Small (2.8)+
349431010mm
3.5
7510050 XX Small (0.7)
349431212mm
7510200+
Small (2.8)+
4.2
7510100 X Small (1.4)
3494314
14mm
7510400
Medium (5.6)
5.6
349431616mm
7510400+
Medium (5.6)+
6.3
7510050 XX Small (0.7)
349431818mm
7510400+
Medium (5.6)+
7.0
7510100 X Small (1.4)
349432020mm
7510600 or
Large (8.0) or
8.0
7510800 Large II (8.0)
INFUSE® Bone Graft/CLYDESDALE® Spinal System Combinations
Appropriate INFUSE®
CLYDESDALE® Spinal System
Reconstituted
Bone Graft Kit
rhBMP-2/ACS
Lordosis,
Size
Kit name
graft volume
Part
#
Part
#
Width (height X length)
(size in cc)
0 deg, 18 mm
2969840
8 x 40mm
7510100
X Small (1.4)
1.4
2969845
7510100+
X Small (1.4)+
8 x 45mm
2.1
7510050 XX Small (0.7)
2969850
8 x 50mm
7510200
Small (2.8)
2.8
2969855
8 x 55mm
7510200
Small (2.8)
2.8
2969040
7510100+
X
Small
(1.4)+
10 x 40mm
2.1
7510050 XX Small (0.7)
2969045
10 x 45mm
7510200
Small (2.8)
2.8
2969050
7510200+
Small (2.8)+
10 x 50mm
3.5
7510050
XX Small (0.7)
2969055
7510200+
Small (2.8)+
10 x 55mm
3.5
7510050 XX Small (0.7)
2969240
12 x 40mm
7510200
Small (2.8)
2.8
2969245
7510200+
Small (2.8)+
12 x 45mm
3.5
7510050 XX Small (0.7)
2969250
7510200+
Small (2.8)+
12 x 50mm
4.2
7510100 X Small (1.4)
2969255
7510200+
Small (2.8)+
12 x 55mm
4.2
7510100 X Small (1.4)
2969440
14 x 40mm
7510200
Small (2.8)
2.8
2969445
7510200+
Small (2.8)+
14 x 45mm
4.2
7510100 X Small (1.4)
2969450
7510200+
Small (2.8)+
14 x 50mm
4.2
7510100 X Small (1.4)
2969455
14 x 55mm
7510400
Medium (5.6)
5.6
2969640
16 x 40mm
7510200+
Small (2.8)+
3.5
7510050
XX Small (0.7)
2969645
7510200+
Small
(2.8)+
16 x 45mm
4.2
7510100 X Small (1.4)
2969650
16 x 50mm
7510400
Medium (5.6)
5.6
2969655
16 x 55mm
7510400
Medium (5.6)
5.6
6 deg, 18 mm
2968840
8 x 40mm
7510100
X Small (1.4)
1.4
2968845
7510100+
X Small (1.4)+
8 x 45mm
2.1
7510050 XX Small (0.7)
2968850
7510100+
X Small (1.4)+
8 x 50mm
2.1
7510050 XX Small (0.7)
2968855
8 x 55mm
7510200
Small (2.8)
2.8
2968860
8 x 60mm
7510200
Small (2.8)
2.8
2968040
7510100+
X Small (1.4)+
10 x 40mm
2.1
7510050 XX Small (0.7)
INFUSE® Bone Graft/CLYDESDALE® Spinal System Combinations
Appropriate INFUSE®
CLYDESDALE® Spinal System
Reconstituted
Bone Graft Kit
rhBMP-2/ACS
Lordosis,
Size
Kit name
graft volume
Part #
Part #
Width (height X length)
(size in cc)
6 deg, 18 mm
7510100+
X Small (1.4)+
2968045
10 x 45mm
2.1
(cont.)
7510050 XX Small (0.7)
2968050
10 x 50mm
7510200
Small (2.8)
2.8
2968055
7510200+
Small (2.8)+
10 x 55mm
3.5
7510050 XX Small (0.7)
2968060
7510200+
Small (2.8)+
10 x 60mm
3.5
7510050 XX Small (0.7)
2968240
7510100+
X Small (1.4)+
12 x 40mm
2.1
7510050 XX Small (0.7)
2968245
12 x 45mm
7510200
Small (2.8)
2.8
2968250
7510200+
Small (2.8)+
12 x 50mm
3.5
7510050 XX Small (0.7)
2968255
7510200+
Small
(2.8)+
12 x 55mm
4.2
7510100
X Small (1.4)
2968260
7510200+
Small (2.8)+
12 x 60mm
4.2
7510100
X Small (1.4)
2968440
14 x 40mm
7510200
Small (2.8)
2.8
2968445
7510200+
Small (2.8)+
14 x 45mm
3.5
7510050
XX Small (0.7)
2968450
7510200+
Small (2.8)+
14 x 50mm
4.2
7510100
X Small (1.4)
2968455
7510200+
Small (2.8)+
14 x 55mm
4.2
7510100
X Small (1.4)
2968460
14 x 60mm
7510400
Medium (5.6)
5.6
2968640
7510200+
Small (2.8)+
16 x 40mm
3.5
7510050
XX Small (0.7)
2968645
7510200+
Small (2.8)+
16 x 45mm
4.2
7510100
X Small (1.4)
2968650
7510200+
Small
(2.8)+
16 x 50mm
4.2
7510100
X Small (1.4)
2968655
16 x 55mm
7510400
Medium (5.6)
5.6
2968660
7510400+
Medium (5.6)+
16 x 60mm
6.3
7510050
XX Small (0.7)
6 deg, 22 mm
2926840
8 x 40mm
7510100
X Small (1.4)
1.4
2926040
7510100+
X Small (1.4)+
10 x 40mm
2.1
7510050
XX Small (0.7)
2926240
7510100+
X Small (1.4)+
12 x 40mm
2.1
7510050
XX Small (0.7)
2926440
14 x 40mm
7510200
Small (2.8)
2.8
2926640
7510200+
Small (2.8)+
16 x 40mm
3.5
7510050
XX Small (0.7)
2926845
7510100+
X Small (1.4)+
8 x 45mm
2.1
7510050
XX Small (0.7)
2926045
7510100+
X Small (1.4)+
10 x 45mm
2.1
7510050
XX Small (0.7)
2926245
12 x 45mm
7510200
Small (2.8)
2.8
2926445
7510200+
Small (2.8)+
14 x 45mm
3.5
7510050
XX Small (0.7)
2926645
7510200+
Small (2.8)+
16 x 45mm
4.2
7510100
X Small (1.4)
2926850
7510100+
X Small (1.4)+
8 x 50mm
2.1
7510050
XX Small (0.7)
2926050
10 x 50mm
7510200
Small (2.8)
2.8
2926250
7510200+
Small (2.8)+
12 x 50mm
3.5
7510050
XX Small (0.7)
2926450
7510200+
Small (2.8)+
14 x 50mm
4.2
7510100
X Small (1.4)
2926650
7510200+
Small (2.8)+
16 x 50mm
4.2
7510100
X Small (1.4)
2926855
8 x 55mm
7510200
Small (2.8)
2.8
2926055
7510200+
Small (2.8)+
10 x 55mm
3.5
7510050
XX Small (0.7)
2926255
7510200+
Small (2.8)+
12 x 55mm
4.2
7510100
X Small (1.4)
2926455
7510200+
Small
(2.8)+
14 x 55mm
4.2
7510100
X Small (1.4)
2926655
16 x 55mm
7510400
Medium (5.6)
5.6
2926860
8 x 60mm
7510200
Small (2.8)
2.8
2926060
7510200+
Small (2.8)+
10 x 60mm
4.2
7510100
X Small (1.4)
2926260
7510200+
Small (2.8)+
12 x 60mm
4.2
7510100
X Small (1.4)
2926460
14 x 60mm
7510400
Medium (5.6)
5.6
2926660
7510400+
Medium (5.6)+
16 x 60mm
6.3
7510050
XX Small (0.7)
12 deg, 22 mm
2922040
10 x 40mm
7510100
X Small (1.4)
1.4
2922240
7510100+
X Small (1.4)+
12 x 40mm
2.1
7510050
XX Small (0.7)
2922440
14 x 40mm
7510200
Small (2.8)
2.8
2922640
7510200+
Small (2.8)+
16 x 40mm
3.5
7510050
XX Small (0.7)
2922045
7510100+
X Small (1.4)+
10 x 45mm
2.1
7510050
XX Small (0.7)
2922245
12 x 45mm
7510200
Small (2.8)
2.8
2922445
7510200+
Small (2.8)+
14 x 45mm
3.5
7510050
XX Small (0.7)
2922645
7510200+
Small
(2.8)+
16 x 45mm
4.2
7510100
X Small (1.4)
2922050
10 x 50mm
7510200
Small (2.8)
2.8
2922250
7510200+
Small (2.8)+
12 x 50mm
3.5
7510050
XX Small (0.7)
2922450
7510200+
Small (2.8)+
14 x 50mm
4.2
7510100
X Small (1.4)
2922650
7510200+
Small (2.8)+
16 x 50mm
4.2
7510100
X Small (1.4)
2922055
10 x 55mm
7510200
Small (2.8)
2.8
2922255
7510200+
Small (2.8)+
12 x 55mm
3.5
7510050
XX Small (0.7)
2922455
7510200+
Small
(2.8)+
14 x 55mm
4.2
7510100
X Small (1.4)
2922655
16 x 55mm
7510400
Medium (5.6)
5.6
2922060
7510200+
Small (2.8)+
10 x 60mm
3.5
7510050
XX Small (0.7)
7510200+
Small (2.8)+
2922260
12 x 60mm
4.2
7510100
X Small (1.4)
2922460
7510200+
Small (2.8)+
14 x 60mm
4.2
7510100
X Small (1.4)
2922660
16 x 60mm
7510400
Medium (5.6)
5.6
No warranties, express or implied, are made. Implied warranties of merchantability and fitness for a
particular purpose or use are specifically excluded.
INDICATIONS
The INFUSE® Bone Graft/Medtronic Interbody Fusion Device is indicated for spinal fusion procedures in
skeletally mature patients with degenerative disc disease (DDD) at one level from L2-S1. DDD is defined as
discogenic back pain with degeneration of the disc confirmed by patient history and radiographic studies.
These DDD patients may also have up to Grade I spondylolisthesis or Grade 1 retrolisthesis at the involved
level. Patients receiving the INFUSE® Bone Graft/Medtronic Interbody Fusion Device should have had
at least six months of nonoperative treatment prior to treatment with the INFUSE® Bone Graft/Medtronic
Interbody Fusion Device.
The following interbody devices and surgical approaches may be used with INFUSE® Bone Graft:
•The LT-CAGE® Lumbar Tapered Fusion Device, implanted via an anterior open or an anterior
laparoscopic approach at a single level.
•The INTER FIX™ or INTER FIX™ RP Threaded Fusion Device, implanted via an anterior open
approach at a single level.
•Certain sizes of the PERIMETER® Interbody Fusion Device implanted via a retroperitoneal anterior
lumbar interbody fusion (ALIF) at a single level from L2-S1or an oblique lateral interbody fusion
(OLIF) approach at a single level from L5-S1.
•Certain sizes of the CLYDESDALE® Spinal System, implanted via an OLIF approach at a single
level from L2-L5.
CONTRAINDICATIONS
• The INFUSE® Bone Graft/Medtronic Interbody Fusion Device is contraindicated for patients with a
known hypersensitivity to recombinant human Bone Morphogenetic Protein-2, bovine Type I collagen,
or to other components of the formulation.
• The INFUSE® Bone Graft/Medtronic Interbody Fusion Device should not be used in the vicinity of a
resected or extant tumor, in patients with any active malignancy, or patients undergoing treatment
for a malignancy.
• INFUSE® Bone Graft/Medtronic Interbody Fusion Device should not be used in patients who are
skeletally immature (<18 years of age or no radiographic evidence of epiphyseal closure).
• The INFUSE® Bone Graft/Medtronic Interbody Fusion Device should not be used in pregnant women.
The potential effects of rhBMP-2 on the human fetus have not been evaluated.
• The INFUSE® Bone Graft/Medtronic Interbody Fusion Device should not be implanted in patients
with an active infection at the operative site or with an allergy to titanium, titanium alloy, or polyetheretherketone.
WARNINGS
• In an experimental rabbit study, rhBMP-2 has been shown to elicit antibodies that are capable
of crossing the placenta. Reduced ossification of the frontal and parietal bones of the skull was
noted infrequently (<3%) in fetuses of rabbit dams immunized to rhBMP-2; however, there was
no effect noted in limb bud development. There are no adequate and well-controlled studies in
human pregnant women. Women of child bearing potential should be warned by their surgeon of
potential risk to a fetus and informed of other possible orthopedic treatments.
.
• Women of childbearing potential should be advised that antibody formation to rhBMP-2 or its
influence on fetal development has not been completely assessed. In the clinical trial supporting
the safety and effectiveness of the INFUSE® Bone Graft/LT-CAGE® Lumbar Tapered Fusion
Device, 2/277 (0.7%) patients treated with INFUSE® Bone Graft component and 1/127 (0.8%)
patients treated with autograft bone developed antibodies to rhBMP-2. The effect of maternal
antibodies to rhBMP-2, as might be present for several months following device implantation,
on the unborn fetus is unknown. Additionally, it is unknown whether fetal expression of BMP-2
could re-expose mothers who were previously antibody positive. Theoretically, re-exposure may
elicit a more powerful immune response to BMP-2 with possible adverse consequences for the
fetus. However, pregnancy did not lead to an increase in antibodies in the rabbit study. Studies
in genetically altered mice indicate that BMP-2 is critical to fetal development and that a lack of
BMP-2 activity may cause neonatal death or birth defects. It is not known if anti-BMP-2 antibodies
may affect fetal development or the extent to which these antibodies may reduce BMP-2 activity.
• INFUSE® Bone Graft should not be used immediately prior to or during pregnancy. Women of
childbearing potential should be advised not to become pregnant for one year following treatment
with the INFUSE® Bone Graft/Medtronic Interbody Fusion Device.
• The safety and effectiveness of the INFUSE® Bone Graft/Medtronic Interbody Fusion Device in
nursing mothers has not been established. It is not known if BMP-2 is excreted in human milk.
General
• The INFUSE® Bone Graft/Medtronic Interbody Fusion Device should not be used in patients suspected of having a malignancy at the site of application.
• The safety and effectiveness of the use of the INFUSE® Bone Graft component with other spinal
implants, implanted at locations other than the lower lumbar spine, or used in surgical techniques
other than anterior open (LT-CAGE®, INTER FIX™, INTER FIX™ RP, and PERIMETER® Devices),
anterior laparoscopic (LT-CAGE® Device), or oblique lateral (PERIMETER® and CLYDESDALE®)
approaches have not been established.
• The implantation of the INFUSE® Bone Graft/LT-CAGE® Lumbar Tapered Fusion Device using
an anterior laparoscopic surgical approach is associated with a higher incidence of retrograde
ejaculation (10.5%, 6/57 male patients) when compared to implantation using an anterior open
surgical approach (6.4%, 5/78 male patients). Both of these rates are greater than that for a control
group implanted using an open anterior approach who did not receive INFUSE® Bone Graft (1.5%,
1/68 male patients). In the randomized study of the anterior open surgical approach, retrograde
ejaculation occurred in the INFUSE® Bone Graft group in 17.6% (3/17) of the male patients who
underwent the surgery with a transperitoneal approach, as compared to 3.2% (2/ 61) of the males
with a retroperitoneal approach. In the control group, the retrograde ejaculation rate was 7.6%
(1/13) in the males with a transperitoneal approach, as compared to 0% (0/55) in the males with a
retroperitoneal approach. With the two treatment groups pooled, retrograde ejaculation occurred in
13.3% (4/30) of the males who underwent a transperitoneal approach and in 1.8% (2/116) of the
males who underwent a retroperitoneal approach. This difference is statistically significant (p=0.017,
Fisher exact test). Male patients should be informed of this potential risk prior to considering the use
of INFUSE® Bone Graft.
• The safety and effectiveness of the use of INFUSE® Bone Graft implanted in the cervical spine has
not been established. This product is only approved for use in the lumbar spine as indicated above.
– When anterior cervical spinal fusions were performed using the INFUSE® Bone Graft component,
some cases of edema have been reported within the first postoperative week. In some of these
cases, this swelling has been severe enough to produce airway compromise, sometimes requiring emergency surgery.
− In a clinical trial comparing single-level anterior cervical fusion using INFUSE® Bone Graft to a
control that did not use INFUSE® Bone Graft, 16.4% of patients treated with INFUSE® Bone
Graft reported dysphagia, compared to 7.3% of control patients. Most of the dysphagia events
occurred within the first four weeks after surgery, and most of these events were classified as
non-serious (e.g., non-life-threatening events not requiring hospitalization). While dysphagia may
occur following anterior cervical procedures, it may occur more frequently or to a greater extent
in the presence of INFUSE® Bone Graft.
−When anterior cervical fusions were performed using INFUSE® Bone Graft, the radiographic
appearance of anterior heterotopic ossification (HO) was noted in some patients, most commonly
observed anterior and superior to the treated level. In some of the cases of severe HO, adjacentlevel fusion and reduced motion were also noted. HO may occur more frequently or to a greater
extent with the use of INFUSE® Bone Graft.
Bone Formation
• Posterior bone formation outside of the disc space was observed in some patients when degenerative disc disease was treated by a posterior lumbar interbody fusion procedure. Although it was not
clearly associated with key clinical outcome measures (e.g., leg pain) in most of the cases, bone
formation outside of the disc space is not desirable and may potentially lead to nerve compression,
requiring surgical intervention.
• Inappropriate use of the product, such as preparing it differently than prescribed, compressing the
rhBMP-2/ACS implant more than necessary, or overfilling the volume intended for new bone formation, may change the concentration of the rhBMP-2, which may inhibit the ability of the rhBMP-2/
ACS to convert to bone and/or cause complications. Such use of the rhBMP-2/ACS implant may
result in radiographic evidence of resorption. These findings may be asymptomatic or symptomatic.
A sheep model developed to test the hypothesis that volume overfilling and/or hyperconcentration
of the rhBMP-2 solution results in radiographic evidence of bone resorption has preliminarily been
evaluated and appears to be supportive of the hypothesized mechanism.
• Placement of rhBMP-2/ACS can cause initial resorption of trabecular bone that may be transient.
• Device migration has been reported with use of rhBMP-2/ACS in spinal fusion surgery. Device
migration has been reported in the presence and absence of bone resorption.
• Nerve compression associated with heterotopic bone formation has been reported in patients
undergoing spine surgery with rhBMP-2/ACS. Surgical intervention may be required to address the
symptoms.
Fluid Collection/Edema
• The formation of fluid collections (sometimes encapsulated) in some cases resulted in nerve compression and pain, which may require clinical intervention (aspiration and/or surgical removal) if
symptoms persist. Many of these reports have occurred when rhBMP-2/ACS was used in conjunction with unapproved approaches/devices or in a manner inconsistent with the instructions for use.
• While there are currently anecdotal and literature evidence to suggest that volume overfilling and/
or hyperconcentration of the rhBMP-2 solution may lead to fluid formation and/or edema, animal
models for scientifically evaluating these events do not presently exist.
PRECAUTIONS
PHYSICIAN NOTE: Although the physician is the learned intermediary between the company and the
patient, the important medical information given in this document should be conveyed to the patient.
!USA
FOR US AUDIENCES ONLY
General
• The safety and effectiveness of repeat applications of the INFUSE® Bone Graft component has not
been established.
• The INFUSE® Bone Graft/Medtronic Interbody Fusion Device should only be used by surgeons who
are experienced in spinal fusion procedures and have undergone adequate training with this device
for anterior laparoscopic, anterior open, and/or oblique lateral procedures.
• Two Medtronic Titanium Threaded Interbody Fusion Device components (i.e., LT-CAGE® Lumbar
Tapered Fusion Device, INTER FIX™ Threaded Fusion Device, or INTER FIX™ RP Threaded
Fusion Device) should be implanted side by side at the surgical level whenever possible. Only one
PEEK PERIMETER® or CLYDESDALE® device may be implanted at the surgical level.
•Unless marked sterile and clearly labeled as such in an unopened sterile package provided by
the company, any Medtronic Interbody Fusion Devices and/or instruments used in surgery must
be sterilized by the hospital prior to use according to the sterilization instructions provided in the
product-specific package insert.
•When using the device(s) at spinal levels between L2 and L4, the potential impact of anatomical
structures (e.g., the aorta) on implant placement must be considered.
•The formation of exuberant or heterotopic bone growth at the upper lumbar levels (L2- L4) may have
a deleterious impact on certain neurovascular structures (e.g., the aorta and sympathetic nerve
chain).
•The safety and effectiveness of the device at spinal levels L2- L4 or in patients with up to Grade 1
retrolisthesis has not been established.
• The INFUSE® Bone Graft/Medtronic Interbody Fusion Device is intended for single use only.
Discard unused product and use a new device for subsequent applications.
• Prior to use, inspect the packaging, vials, and stoppers for visible damage. If damage is visible, do
not use the product. Retain the packaging and vials and contact a Medtronic representative.
• Do not use after the printed expiration date on the label.
Hepatic and Renal Impairment
• The safety and effectiveness of the INFUSE® Bone Graft/Medtronic Interbody Fusion Device in patients
with hepatic or renal impairment has not been established. Pharmacokinetic studies of rhBMP-2 indicate
that the renal and hepatic systems are involved with its clearance.
Geriatrics
• Clinical studies of the INFUSE® Bone Graft/LT-CAGE® Lumbar Tapered Fusion Device did not
include sufficient numbers of patients 65 years and older to determine whether they respond differently
from younger subjects.
Bone Formation
• The safety and effectiveness of the INFUSE® Bone Graft/Medtronic Interbody Fusion Device has
not been demonstrated in patients with metabolic bone diseases.
• The potential for heterotopic or undesirable exuberant bone formation exists.
Antibody Formation/Allergic Reactions
• The safety and effectiveness of the INFUSE® Bone Graft/Medtronic Interbody Fusion Device has
not been demonstrated in patients with autoimmune disease.
• The safety and effectiveness of the INFUSE® Bone Graft/Medtronic Interbody Fusion Device has
not been demonstrated in patients with immunosuppressive disease or suppressed immune systems resulting from radiation therapy, chemotherapy, steroid therapy, or other treatments.
Immunogenicity
• As with all therapeutic proteins, there is a potential for immune responses to be generated to the
INFUSE® Bone Graft component. The immune response to the INFUSE® Bone Graft components was
evaluated in 349 investigational patients and 183 control patients receiving lumbar interbody fusions.
- Anti-rhBMP-2 antibodies: 2/349 (0.6%) patients receiving the INFUSE® Bone Graft component
developed antibodies vs. 1/183 (0.5%) in the control group.
- Anti-bovine Type I collagen antibodies: 18.1% of patients receiving the INFUSE® Bone Graft
component developed antibodies to bovine Type I collagen vs. 14.2% of control patients. No
patients in either group developed anti-human Type I collagen antibodies.
- The presence of antibodies to rhBMP-2 was not associated with immune mediated adverse events
such as allergic reactions. The neutralizing capacity of antibodies to rhBMP-2 is not known.
• The incidence of antibody detection is highly dependent on the sensitivity and specificity of the
assay. Additionally, the incidence of antibody detection may be influenced by several factors,
including sample handling, concomitant medications, and underlying disease. For these reasons,
comparison of the incidence of antibodies to the INFUSE® Bone Graft component with the incidence
of antibodies to other products may be misleading.
ADVERSE EVENTS
The INFUSE® Bone Graft/LT-CAGE® Lumbar Tapered Fusion Device was implanted in 288 investigational patients and compared to 139 control patients who received the LT-CAGE® Lumbar Tapered
Fusion Device filled with iliac crest autograft. The investigational patients were implanted with the
device via either an open anterior surgical approach or a laparoscopic anterior surgical approach. The
control patients were implanted via the open anterior surgical approach only.
Adverse event rates presented are based on the number of patients having at least one occurrence for
a particular adverse event divided by the total number of patients in that treatment group. Because no
control subjects were evaluated at the 48- and 72-month time points, the reported events at these time
points are only from the investigational subjects.
considered to have an elevated immune response if the preoperative test was negative (titer < 50) and
postoperative test was positive (titer > 50) or if the preoperative test was positive and the postoperative
test was positive with a three-fold higher titer than the preoperative test.
ADVERSE EVENTS
(INFUSE® Bone Graft/LT-CAGE® Device data combined from all clinical trial experience with the device)
Surgery
Postoperative
(1 day < 4 Weeks)
6 Weeks
(> 4 Weeks < 9 Weeks)
3 Months
(> 9 Weeks< 5 Months)
6 Months
(> 5 Months < 9 Months)
12 Months
(> 9 Months < 19 Months)
24 Months
(> 19 Months < 30 Months)
Complication
Inves.
Control
Inves.
Control
Inves.
Control
Inves.
Control
Inves.
Control
Inves.
Control
Inves.
Control
Anatomical/Technical
Difficulty
11
3
0
0
0
0
0
0
0
0
0
0
0
0
Back and/or Leg Pain
0
0
12
4
11
5
12
5
15
4
20
7
8
12
Cancer
0
0
0
0
0
0
0
1
0
0
1
0
1
0
Cardio/Vascular
1
0
6
5
5
2
1
3
2
1
4
2
1
1
Death
0
0
0
0
0
0
0
0
0
1
0
0
0
0
Dural Injury
0
0
0
0
0
0
0
1
0
0
0
0
0
0
Gastrointestinal
1
0
40
22
2
0
5
1
7
1
10
3
7
5
Graft Site Related
0
0
0
8
0
0
0
0
0
0
0
0
0
0
Implant
Displacement/
Loosening
0
0
1
1
3
0
1
0
0
0
0
0
0
0
Infection
0
0
19
9
8
4
5
1
5
1
3
0
0
2
Malpositioned Implant
5
0
0
0
0
0
0
0
0
0
0
0
0
0
Neurological
0
0
8
5
7
3
5
2
6
2
13
4
6
8
Non-Union*
0
0
0
0
0
0
0
0
1
2
4
0
1
1
Non-Union**
0
0
0
1
0
1
2
0
3
4
4
6
1
1
Other
5
6
18
11
9
2
3
4
11
4
15
8
20
8
Other Pain
0
0
3
1
2
1
4
2
6
1
10
8
11
3
Respiratory
0
0
3
2
1
0
0
0
1
0
0
1
0
1
Retrograde
Ejaculation
0
0
5
1
4
0
1
0
0
0
2
0
0
0
Spinal Event
0
0
1
2
1
0
6
2
10
4
10
8
9
2
Subsidence
0
0
3
2
2
0
1
0
1
0
0
0
0
0
Trauma
0
0
4
5
5
3
11
7
14
5
28
11
20
8
Urogenital
0
0
24
5
3
0
2
3
6
3
3
1
7
2
Vascular Intra-Op
15
5
0
0
0
0
0
0
0
0
0
0
0
0
Vertebral Fracture
0
0
1
0
0
0
0
0
0
0
0
0
0
0
# of Patients Reporting &
Total Adverse Events
(Through 24-Month Reporting
Window)
Investigational#
Control#
(%of288)
(%of139)
TotalEvents
TotalEvents
11(3.8)
3(2.2)
11
3
70(24.3)
33(23.7)
78
37
2(0.7)
1(0.7)
2
1
17(5.9)
12(8.6)
20
14
0(0.0)
1(0.7)
0
1
0(0.0)
1(0.7)
0
1
56(19.4)
27(19.4)
72
32
0(0.0)
8(5.8)
0
8
Any Adverse Event
48 Months
(>30 Months< 60 Months)
72 Months
(>60 Months< 84 Months)
Total #
(% of 134)
Total Events
0(0.0)
0
23(17.2)
24
4(3.0)
4
7(5.2)
7
2(1.5)
2
0(0.0)
0
14(10.4)
17
0(0.0)
0
Total #
(% of 140)
Total Events
0(0.0)
0
18(12.9)
21
1(0.7)
1
4(2.9)
4
0(0.0)
0
0(0.0)
0
6(4.3)
8
0(0.0)
0
5(1.7)
5
1(0.7)
1
0(0.0)
0
0(0.0)
0
36(12.5)
40
5(1.7)
5
39(13.5)
45
6(2.1)
6
10(3.5)
10
62(21.5)
81
31(10.8)
36
5(1.7)
5
11(7.9)1
12
30(10.4)
37
7(2.4)
7
68(23.6)
82
41(14.2)
45
14(4.9)
15
1(0.3)
1
16(11.5)
17
0(0.0)
0
23(16.5)
24
3(2.2)
3
13(9.4)
13
37(26.6)
43
13(9.4)
16
4(2.9)
4
1(1.4)2
1
17(12.2)
18
2(1.4)
2
34(24.5)
39
13(9.4)
14
5(3.6)
5
0(0.0)
0
4(3.0)
4
0(0.0)
0
12(9.0)
12
0(0.0)
0
0(0.0)
0
22(16.4)
29
15(11.2)
20
1(0.7)
1
0(0.0)
0
9(6.7)
9
0(0.0)
0
21(15.7)
23
2(1.5)
2
1(0.7)
1
0(0.0)
0
3(2.1)
3
0(0.0)
0
5(3.6)
5
0(0.0)
0
0(0.0)
0
17(12.1)
18
11(7.9)
12
1(0.7)
1
0(0.0)
0
8(5.7)
8
0(0.0)
0
20(14.3)
22
3(2.1)
3
0(0.0)
0
0(0.0)
0
228(79.2)
117(84.2)
84(62.7)
64(45.7)
Some of the reported adverse events required surgical interventions subsequent to the initial surgery.
The number of subjects requiring a second surgical intervention was 10.4% (30/288) in the investigational groups and 13.7% (19/139) in the control group. The majority of supplemental fixations were
due to painful non-union.
Through the 24-month adverse event reporting window, urogenital events occurred with greater
frequency in the investigational groups (14.2%) compared to the control group (9.4%). Retrograde
ejaculation rates were greater in the investigational groups (11 subjects) compared to the control group
(1 subject), with the majority of events occurring in the early postoperative period.
The incidence of adverse events that were considered device related, including implant displacement/
loosening, implant malposition, and subsidence, was greater in the investigational groups compared
to the control group. The rates of these events were low, however, and may be partially attributed to
a learning curve associated with the laparoscopic surgical approach. The rate of non-union requiring
secondary surgery in the investigational groups was comparable to that of the control group. One death
was reported – a control group subject with cardiovascular disease.
Potential Adverse Events
The following is a list of potential adverse events that may occur with spinal fusion surgery with the
INFUSE® Bone Graft/Medtronic Interbody Fusion Device. Some of these adverse events may have
been previously reported in the adverse events table or have been reported to the manufacturer:
•
•
•
•
•
•
Allergic reaction.
Anaphylactic reaction.
Bone fracture.
Bone resorption, which may be transient.
Bowel or bladder problems.
Cessation of any potential growth of the operated portion of the spine. Loss of spinal mobility or
function.
• Change in mental status.
• Damage to blood vessels and cardiovascular system compromise.
• Damage to internal organs and connective tissue.
•Death.
• Development of respiratory problems.
• Disassembly, bending, breakage, loosening, and/or migration of components.
• Dural tears.
• Elevated erythrocyte sedimentation rate.
• Encapsulated fluid collection.
• Erythematous tissue.
• Fetal development complications.
• Foreign body (allergic) reaction.
• Gastrointestinal complications.
•Hematoma.
• Heterotopic and/or exuberant bone formation.
• Incisional complications.
•Infection.
•Inflammation.
• Insufflation complications.
•Itching.
• Localized edema (swelling).
• Neurological system compromise.
• Non-union (or pseudarthrosis), delayed union, mal-union.
•Pain.
• Postoperative change in spinal curvature, loss of correction, height, and/or reduction.
• Retrograde ejaculation.
• Scar formation.
•Seroma.
• Tissue or nerve damage.
Note: Additional surgery may be necessary to correct some of these potential adverse events.
CLINICAL RESULTS
Clinical data to support the safety and effectiveness of the INFUSE® Bone Graft/LT-CAGE® Lumbar
Tapered Fusion Device were collected as part of a prospective, multi-center pivotal study that consisted of randomized and non-randomized arms. The randomized arm contained two groups, one
investigational and one control. The control group was implanted with the LT-CAGE® Lumbar Tapered
Fusion Device filled with iliac crest autograft bone, while the investigational group was implanted with
the INFUSE® Bone Graft/LT-CAGE® Lumbar Tapered Fusion Device. In both cases, the surgical
approach was an open anterior approach. The non-randomized arm contained only an investigational
group, where subjects were implanted with the INFUSE® Bone Graft/LT-CAGE® Lumbar Tapered
Fusion Device through a laparoscopic anterior approach. The control group from the randomized arm
was used as the control for the non-randomized arm.
Neither the investigators nor the subjects were blinded to the treatment. Subject blinding was not possible due to the second surgical site resulting from the need to collect the iliac crest grafts. The potential
for investigator bias in the clinical outcome parameters was reduced by having the subjects rate their
outcome using objective self-assessments. The radiographic outcome parameters were performed by
independent radiologists who were blinded to treatment. These were the only radiographic evaluations
used for determining radiographic success.
The indication studied was degenerative disc disease (DDD) accompanied by back pain with or without
leg pain at a single level between L4 and S1 confirmed by history and radiographic studies.
Clinical and Radiographic Effectiveness Parameters
Patients were evaluated preoperatively (within 6 months of surgery), intraoperatively, and postoperatively at 6 weeks, 3, 6, 12, and 24 months and biennially thereafter until the last subject enrolled in
the study had been seen for their 24-month evaluation. Complications and adverse events, devicerelated or not, were evaluated over the course of the clinical trial. At each evaluation time point, the
primary and secondary clinical and radiographic outcome parameters were evaluated. Success was
determined from data collected during the initial 24 months of follow-up. Antibodies to rhBMP-2 and
bovine Type I collagen were assessed preoperatively and at 3 months postoperatively. Antibodies to
human Type I collagen were assessed if the antibody response to bovine Type I collagen was positive.
Sixty-six (66) subjects were considered to have an authentic elevated antibody response to bovine
Type I collagen – 18 open surgical approach investigational subjects, 32 laparoscopic surgical
approach investigational subjects, and 16 control subjects. No subjects had positive responses to
human Type I collagen.
An evaluation was performed on the impact of a positive antibody response on overall success and
fusion success. There was very little difference in overall and individual success when antibody status
was taken into consideration.
During the course of the study, six pregnancies were reported – one in the control group and five in
the investigational groups. Two of the four pregnancies that occurred in the laparoscopic approach
group resulted in first trimester miscarriages. The other three pregnancies in the investigational groups
resulted in live births with no reported complications. None of the pregnant subjects had antibody
responses to rhBMP-2 or Type I collagen (bovine or human) that were detectable to the limits of the
sensitivity of the assay.
Through the 24-month adverse event reporting window, three cases of cancer were diagnosed – two
in the investigational group and one in the control group. One investigational subject was found to
have pancreatic cancer while another was diagnosed with breast cancer. A control subject was also
found to have breast cancer. No additional information is available on these subjects (e.g., BMP-2
receptor expression).
Post-Approval Study
A total of 145 investigational subjects were evaluated out to six years (72 months) after the initial surgery in a post-approval study. The patient population was obtained from participants in both the open
and laparoscopic arms of the IDE clinical trial. Control subjects from the IDE study were not followed in
the post-approval study. Based on criteria from the IDE study, information pertaining to the safety and
effectiveness of the product was obtained at four and six years post-implantation, including adverse
events, an independent radiographic assessment of fusion, and an assessment of pain and function.
The table below summarizes the clinical and radiographic data evaluated during the post approval
study, as well as the overall success rate at each time point.
Overall Success Rates – Post Approval Study
Variable
4-Year Evaluation
6-Year Evaluation
Overall Success
60.6% (77/127)
60.4% (84/139)
Oswestry Pain Improvement
81.5% (106/130)
79.0% (109/138)
Fusion
98.3% (117/119)
98.5% (128/130)
Neurological Status
73.3% (96/131)
81.2% (112/138)
(Maintenance or Improvement)
HOW SUPPLIED
INFUSE® Bone Graft component is supplied in various kit sizes containing all the components necessary to prepare this portion of the device (i.e., the collagen sponge(s), a vial with the lyophilized
growth factor, a vial with sterile water for reconstituting the growth factor, syringes, and needles). The
Medtronic Titanium Threaded Interbody Fusion Device component is supplied in a variety of sizes,
which must be properly selected based on a specific patient’s anatomy.
STORAGE CONDITIONS
Store the INFUSE® Bone Graft component at room temperature [15-30 degrees Centigrade (59 to 86°
F)]. The Medtronic Interbody Fusion Device component should also be stored at room temperature.
DOSAGE AND ADMINISTRATION
The INFUSE® Bone Graft component is prepared immediately prior to use from a kit containing all
necessary components. Once prepared, the INFUSE® Bone Graft component contains rhBMP-2 at a
concentration of 1.5 mg/mL.
The size of the INFUSE® Bone Graft component kit and the volume of INFUSE® Bone Graft component to be implanted are determined by the internal volume of the Medtronic Interbody Fusion Device
components that are utilized. The patient’s anatomy will determine the size of the Medtronic Interbody
Fusion Device components to be used. Surgical technique manuals for the INFUSE® Bone Graft with
the specific Medtronic Interbody Fusion Devices referenced in this package insert are available and
will provide more information on templating to determine the appropriate size Medtronic Interbody
Fusion Device component.
* Non-union adverse events that have not resulted in a second surgery.
** Non-union adverse events that have resulted in a second surgery.
1
Percent of 140 males.
2
Percent of 70 males.
The reported rates of several adverse events were high but similar in both the investigational and
control groups. These events included back and leg pain, neurological events, gastrointestinal events,
spinal events, cardiovascular events, and infection.
There were three subjects who had positive antibody responses to rhBMP-2 – one subject in each of
the study groups. The rates of positive antibody response to rhBMP-2 were 0.7% in the open surgical
approach investigational group and 0.8% in the laparoscopic surgical approach investigational and
open surgical approach control groups. While there is a theoretical possibility that antibodies to rhBMP-2
could neutralize endogenous BMP-2, thereby interfering with subsequent bone healing, this was not
observed during the course of the study.
Primary and secondary clinical and radiographic effectiveness outcome parameters were evaluated
for all treated subjects at all follow-up evaluation time points identified above. The primary clinical
parameters assessed were of pain, function, and neurological status. The secondary clinical outcome parameters assessed were general health status, back and leg pain, donor site pain (control
subjects only), patient satisfaction, and patient global perceived effect of the treatment. The primary
radiographic outcome parameter consisted of evaluations of fusion, while the secondary radiographic
assessment was disc height.
Fusion was evaluated at 6, 12, and 24 months post-op using plain radiographs (AP, lateral, and flexion/
extension films) and high resolution thin-slice CT scans (1mm slices with 1mm index on axial, sagittal,
and coronal reconstructions). Fusion was defined as the presence of bridging bone connecting the
inferior and superior vertebral bodies; a lack of motion on flexion/extension (≤ 3mm of translation and
< 5° of angulation); and no evidence of radiolucencies over more than 50% of either implant. Fusion
success was defined as the presence of all of these parameters plus the lack of a second surgical
intervention resulting from a non-union. All assessments were made from the plain films except for the
assessment of bridging bone, which was made using the CT scans only if bridging bone could not be
visualized on the plain film.
Pain and function were measured using the Oswestry Low Back Pain Disability Questionnaire.
Success was defined as a 15-point improvement in the Oswestry score from the pre-op baseline score.
Only store the components in this INFUSE® Bone Graft kit in the manner described on the package, only
mix the components in the manner described in the directions, only add the reconstituted rhBMP-2 to
the ACS carrier provided in the manner described, and only use in the quantity and indication specified
in the package insert. Any other storage, mixture, or administration may cause unanticipated adverse
events.
DIRECTIONS FOR USE
The INFUSE® Bone Graft component is prepared at the time of surgery in the surgical suite by
reconstituting the lyophilized rhBMP-2 with sterile water (see Instructions for Preparation) and then
uniformly applying the reconstituted rhBMP-2 solution to the ACS. The INFUSE® Bone Graft component is then inserted into the Medtronic Interbody Fusion Device component. The complete device is
then implanted through an anterior surgical approach (including ALIF and OLIF, see the appropriate
Surgical Technique manual). If the INFUSE® Bone Graft component is not used within two hours after
reconstitution, it must be discarded.
The INFUSE® Bone Graft component must not be sterilized by the hospital. The Medtronic Interbody
Fusion Device component, if not supplied sterile, should be sterilized before insertion of the INFUSE®
Bone Graft component. Please refer to the specific Medtronic Interbody Fusion Device package insert
for information on packaging, cleaning/decontamination, and sterilization of this component and its
instruments.
PRODUCT COMPLAINTS
A total of 143 open approach investigational and 136 control patients were enrolled in the randomized
arm of the study and received the device. A total of 134 subjects were enrolled in the non-randomized
arm of the study and received the device. For the majority of the demographic parameters, there were
no differences in pre-op demographics across the three populations.
Any health care professional (e.g., customer or user of this system of products) who has any complaints or who has experienced any dissatisfaction in the product quality, identity, durability, reliability,
safety, effectiveness, and/or performance should notify the distributor or Medtronic. Further, if any
of the implanted INFUSE® Bone Graft/Medtronic Interbody Fusion Device component(s) ever “malfunction,” (i.e., do not meet any of their performance specifications or otherwise do not perform as
intended), or are suspected of doing so, the distributor should be notified immediately. If any Medtronic
product ever “malfunctions” and may have caused or contributed to the death or serious injury of a
patient, the distributor should be notified immediately by telephone, fax, or written correspondence.
When filing a complaint, please provide the component(s) name and number, lot number(s), your
name and address, the nature of the complaint, and notification of whether a written report from the
distributor is requested.
Surgical Results and Hospitalization
DEVICE RETRIEVAL EFFORTS
Neurological status consisted of measurements of four parameters – motor, sensory, reflexes, and
straight leg raise (SLR). Neurological status success was defined as maintenance or improvement of
the pre-op baseline score for each parameter. Overall neurological status success required that each
individual parameter be a success for that subject to be counted as a success.
Patient Demographics and Accountability
Surgical and Hospitalization Information
Investigational Open Control Open Surgical Approach
Surgical Approach
Mean Operative Time (hrs)
Mean EBL (ml)
Hospitalization (days)
Investigational
Laparoscopic
Surgical Approach
1.6*
2.0
1.9
109.8*
153.1
146.1
3.1
3.3
1.2*
Should it be necessary to remove an INFUSE® Bone Graft/Medtronic Interbody Fusion Device, please
call Medtronic prior to the scheduled surgery to receive instructions regarding data collection, including
histopathological, mechanical, and adverse event information.
©2016 MEDTRONIC SOFAMOR DANEK USA, Inc. All rights reserved.
INFUSE® Bone Graft in combination with LT-CAGE®, INTER FIX™, INTER FIX™ RP, PERIMETER®, or
CLYDESDALE® devices incorporate technology developed by Gary K. Michelson, M.D.
EXPLANATION OF SYMBOLS
!USA
*Statistically different from control
Clinical and Radiographic Effectiveness Evaluation
Individual subject success was defined as success in each of the primary clinical and radiographic
outcome parameters. Success for these parameters included:
1.The presence of radiographic fusion;
2.An improvement of at least 15 points from the baseline Oswestry score;
3.Maintenance or improvement in neurological status;
4.The presence of no serious adverse event classified as implant-associated or implant/surgical
procedure-associated; and
5.No additional surgical procedure classified as “Failure.”
Study success was expressed as the number of individual subjects categorized as a success divided
by the total number of subjects evaluated. The table below describes the success rates for the individual primary outcome parameters and overall success. All success rates were based on the data
from the 24-month follow-up evaluation, and posterior probabilities of success were calculated using
Bayesian statistical methods.
Posterior Probabilities of Success at 24 Months
Investigational Open
Control Open
Primary
Surgical Approach
Surgical Approach
Outcome
Variable
Posterior Mean
Posterior Mean
(95% HPD Credible Interval) (95% HPD Credible Interval)
Investigational Laparoscopic
Surgical Approach
Posterior Mean
(95% HPD Credible Interval)
Fusion
92.8% (88.5%, 96.9%)
88.1% (82.6%, 99.3%)
93.0% (87.9%, 97.5%)
Oswestry
71.0% (63.4%, 78.7%)
70.9% (63.1%, 79.1%)
83.0% (75.6%, 90.5%)
Neurologic
81.0% (74.5%, 87.9%)
81.7% (74.9%, 88.7%)
89.0% (83.1%, 94.8%)
Overall Success
57.1% (49.2%, 65.7%)
56.7% (48.3%, 65.0%)
68.0% (59.3%, 76.5%)
The probability (also called the posterior probability) that the 24-month overall success rate for the
investigational groups was equivalent to the 24-month success rate for the control group was 99.4%
for the open surgical approach investigational group and almost 100% for the laparoscopic surgical
approach investigational group.
For a future patient receiving the INFUSE® Bone Graft/LT-CAGE® Lumbar Tapered Fusion Device
via the open anterior surgical approach, the chance (the predictive probability) of overall success at
24 months would be 57.1% for the open surgical approach. Given the results of the trial, there is a
95% probability that the chance of success ranges from 49.2% to 65.7%. For a future patient receiving
the INFUSE® Bone Graft/LT-CAGE® Lumbar Tapered Fusion Device via the anterior laparoscopic
surgical approach, the chance of overall success at 24 months would be 68.0%. Given the results of
the trial, there is a 95% probability that the chance of success ranges from 59.3% to 76.5%. For a
future patient receiving the control treatment, the chance of overall success at 24 months would be
56.7%. Given the results of the trial, there is a 95% probability that the chance of success ranges from
48.3% to 65.0%.
Safety and Immune Response Evaluation
The assessment of safety consisted of an evaluation of the reported adverse events, as well as an
evaluation of antibodies to rhBMP-2, bovine Type I collagen, and human Type I collagen. The complete list of complications, adverse events, and subsequent interventions is described in the Adverse
Events section above. The presence of antibodies was assessed at the pre-op and 3-month post-op
visits using ELISA. If there was a positive response to bovine Type I collagen, the serum was also
tested for antibodies to human Type I collagen. The screening ELISA cutpoint for positive antibody
responses was set to 5 times the standard deviation of sera from normal human donors. Subjects were
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