Bone Graft Options - Pathways to Market

Bone Grafting Options
Pathways to Market
An overview of how bone grafts
are classified and the pathways
to bring them to market.
Bone Grafting Options | pathways TO MARKET
Categorization of Bone Grafts
Introduction
The incorporation of bone grafts
into bone healing procedures has
become an important component of
surgical success. Similar to implants
and instruments, bone grafts may
be recognized as medical devices.
Depending on their classification,
they are required to pursue a defined
regulatory pathway and provide a
specific level of evidence to gain U.S.
Food and Drug Administration (FDA)
approval. This brochure provides
an overview of medical device
classifications and the regulatory
pathways involved in bringing
a bone graft to market.
Bone Grafting Options
Synthetic
Allograft
Bone Morphogenetic Protein
Ceramic
Mineralized
Tissue
Biocomposite
Demineralized
Tissue
rhBMP
Examples:
Examples:
Examples:
Examples:
Examples:
Actifuse®
Novabone®
chronOS™
Formagraft®
Mozaik™
Vitoss®
MASTERGRAFT® Family
Traditional Allograft
PLEXUR P®
Biocomposite
PLEXUR M®
Biocomposite
Accell®
DBX®
Osteocel® Plus
OP-1® Putty/Implant
INFUSE® Bone Graft
MAGNIFUSE® Bone Graft
XPANSE® Bone Insert
PROGENIX® Family
GRAFTON® Family
Pathways to Market
510(k)
Human Cellular and
Tissue Product (HCT/P)*
Humanitarian Device
Exemption (HDE)
Premarket Approval
(PMA)
Regulated as a Medical
Device
Yes
No
Yes
Yes
FDA Submission Required
Yes
No
Yes
Yes
Required Proof
Substantial equivalence to
predicate device
None
Safety and
probable benefit
Safety and clinical efficacy
in large pivotal clinical trial
Required Study Design
Varies: Typically bench
testing or preclinical data
None
Varies: Typically retrospective Clinical: Large pivotal IDE
clinical data to pilot IDE
Medical Device Classification
Class II
None
Class III
Class III
Product Class (Example)
Ceramic/Synthetic
Actifuse®, Vitoss®,
MASTERGRAFT® Family
Formulated DBM
Accell®, DBX®,
PROGENIX® Family
GRAFTON® Family
MAGNIFUSE® Bone Graft
Biocomposite
PLEXUR P® Biocomposite
PLEXUR M® Biocomposite
Mineralized Tissue
Traditional Allograft
Demineralized Tissue***
Osteocel® Plus
Trinity® Evolution™
XPANSE® Bone Insert
rhBMP-7
OP-1® Putty, and OP-1®
Implant
rhBMP-2
INFUSE® Bone Graft
Clinical Function
Typically combined with
autogenous bone
Actively induces de novo bone
without the need for autograft***
(Used in less challenging healing environments)
(Used in more challenging healing environments)
Development Costs
$Thousands
$Thousands
$Millions
Time to Market
3–6 months
Immediate
Minimum 2 years
Approximately 6–8 years
Requires Institutional Review
Board (IRB) Approval for
Commercial Use
No
No
Yes
No
$Tens of Millions
*Tissue therapies (Human Cellular and Tissue Products, or HCT/Ps) are not regulated as medical devices. There is no regulatory submission or
clearance required for commercial distribution. Tissue manufacturers must only register with the FDA and comply with Good Tissue Practices.
**These DBMs are primarily fresh frozen allograft and also have a demineralized component. They are classified as HCT/Ps.
***BMPs have been tested as an autograft alternative in multiple clinical studies for certain indications in spine, orthopedic trauma, and dental.1–4
Bone Grafting Options | pathways TO MARKET
Categorization of Bone Grafts continued
FDA Device Regulations
On May 28, 1976, an amendment to
the Federal Food, Drug, & Cosmetic
Act (FD&C) gave the FDA authority
to regulate medical devices. They
are evaluated in a classification
system based on design complexity,
manufacturing process, performance
standards, safety, and efficacy.
»» Class I Devices—minimal user risk;
simple in design (e.g., elastic bandages)
»» Class II Devices—510(k) submission
to show that the device is
substantially equivalent to a predicate
device marketed prior to 1976 (e.g.,
synthetic, DBM, biocomposite)
»» Class III Devices—PMA or HDE
submission; more data are required
for FDA to evaluate safety and efficacy
(PMA) or safety and probable benefit
(HDE) (e.g., INFUSE® Bone Graft: PMA;
OP-1® Putty: HDE)
Role of the Package Insert
A package insert (PI) is an FDA-regulated
document that generally accompanies
a medication or medical device, and
includes additional information about
that product. The intent of the PI is to
provide physicians and patients detailed
information on the risks and benefits of
a medical therapy. In the U.S., the FDA
determines the requirements for
package inserts.
Package inserts follow a standard FDA
format for every medication and include
the same types of information.
»» Description—includes the name
When selecting a bone grafting
option, two sections of the PI provide
clear insight into the technology’s
composition and intended usage per
the regulatory pathway*:
»» Indications for Use—uses for which
Pathway to Market and Package Insert: Together They Tell the Story
PMA
HDE
HCT/P
510(k)
Product Class
(Example)
Description
of the product, formulation,
administration, and active ingredients
the product has been FDA-approved
or cleared, and guidance as to how
the technology should be used in a
clinical application
*Approved technologies will also have
detailed information in their package inserts
about the therapeutic results shown in
clinical trials.
Package Insert
Indications for Use
Ceramic/Synthetic
Vitoss®
Actifuse®
MasterGraft® Family
Porous ceramic (e.g., HA, TCP,
calcium sulphate), collagen, and
various blends of these materials
Fill bony voids or gaps that are not intrinsic to the stability of the bony
structure. Some have approval as an autograft extender
Formulated DBM
Accell®
DBX®
Progenix® Family
GRAFTON® Family
Human demineralized bone matrix
combined with some type of carrier
(e.g., glycerol, sodium hyaluronate)
to provide handling characteristics
Fill bony voids or gaps that are not intrinsic to the stability of the bony
structure. Some have approval as an autograft extender
Biocomposite
PLEXUR P®
Biocomposite
PLEXUR M®
Biocomposite
Combination of mineralized tissue
with some type of polymer or other
synthetic material
Fill bony voids or gaps that are not intrinsic to the stability of the bony
structure. Some have approval as an autograft extender
Mineralized Tissue
Traditional Allograft
Aseptic or terminally sterilized
donor bone. Comes in many shapes
and sizes
Homologous use for the repair, replacement, or reconstruction
of musculoskeletal defects
Demineralized Tissue†
Osteocel® Plus
XPANSE® Bone Insert
Demineralized bone, and/or ground
bone matrix
Homologous use for the repair, replacement, or reconstruction
of musculoskeletal defects
rhBMP-7
OP-1® Putty
OP-1® Implant
rhBMP-7, collagen, and CMC
(carboxymethylcellulose) powder
1) OP-1® Putty is indicated as an alternative to autograft in compromised
patients requiring revision posterolateral lumbar spine fusion, for whom
autologous bone and bone marrow harvest are not feasible or are not
expected to promote fusion
2) OP-1® Implant is indicated as alternative to autograft in recalcitrant
long bone nonunions where use of autograft is unfeasible and alternative
treatments have failed
rhBMP-2
INFUSE® Bone Graft
rhBMP-2 on an absorbable
collagen sponge
1) INFUSE® Bone Graft/LT-CAGE® Device is indicated for spinal fusion in
skeletally mature patients with degenerative disc disease (DDD) at one level
from L2–S1, who may also have a Grade 1 spondylolisthesis or retrolisthesis.
It is to be implanted via an anterior open or anterior laparoscopic approach
2) INFUSE® Bone Graft is indicated for treating acute, open tibial shaft fractures
that have been stabilized with IM nail fixation. INFUSE® Bone Graft must be
applied within 14 days of initial fracture and used on skeletally mature patients
3) INFUSE® Bone Graft is indicated as an alternative to autologous bone graft
for sinus augmentations, and for localized alveolar ridge augmentations for
defects associated with extraction sockets
These DBMs are primarily fresh frozen allograft and also have a demineralized component. They are classified as HCT/Ps.
†
www.medtronic.com
Please see the package insert for the complete list of indications,
warnings, precautions, adverse events, clinical results, definition of
DDD, and other important medical information. The package insert
also matches the sizes of those sized devices that are indicated for
use with the appropriate INFUSE® Bone Graft kit.
CAUTION: Federal (USA) law restricts this device to sale by or on the order of a
physician with appropriate training or experience.
BRIEF SUMMARY OF INDICATIONS, CONTRAINDICATIONS,
WARNINGS, AND PRECAUTION FOR INFUSE® BONE GRAFT FOR
CERTAIN ORAL MAXILLOFACIAL AND DENTAL REGENERATIVE USES
INFUSE® Bone Graft is indicated as an alternative to autogenous bone graft for
sinus augmentations, and for localized alveolar ridge augmentations for defects
associated with extraction sockets.
The INFUSE® Bone Graft consists of two components – recombinant human
Bone Morphogenetic Protein-2 (rhBMP-2) placed on an absorbable collagen
sponge (ACS). These components must be used as a system for the
prescribed indication. 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 the package insert.
INFUSE® Bone Graft 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 and 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, in pregnant
women, or patients with an active infection at the operative site.
There are no adequate and well-controlled studies in human pregnant women.
In an experimental rabbit study, rhBMP-2 has been shown to elicit antibodies
that are capable of crossing the placenta. Women of child bearing potential
should be warned by their surgeon of potential risk to a fetus and informed of
other possible dental treatments. The safety and effectiveness of this device has
not been established in nursing mothers. Women of child-bearing potential
should be advised to not become pregnant for one year following treatment
with this device.
INFUSE® Bone Graft has not been studied in patients who are skeletally
immature (<18 years of age or no radiographic evidence of
epiphyseal closure).
Please see the package insert for the complete list of indications,
warnings, precautions, adverse events, clinical results, and other
important medical information.
BRIEF SUMMARY OF INDICATIONS, CONTRAINDICATIONS, AND
WARNINGS FOR: INFUSE® BONE GRAFT
INFUSE® Bone Graft is indicated for treating acute, open tibial shaft fractures
that have been stabilized with IM nail fixation after appropriate wound
management. INFUSE® Bone Graft must be applied within 14 days after the
initial fracture. Prospective patients should be skeletally mature.
INFUSE® Bone Graft consists of two components – recombinant human
Bone Morphogenetic Protein-2 solution and a carrier/scaffold for the bone
morphogenetic protein solution and resulting bone. These components
must be used as a system. 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.
INFUSE® Bone Graft 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 and should
not be used in the vicinity of a resected or extant tumor, in patients with
an active malignancy or patients undergoing treatment for a malignancy.
INFUSE® Bone Graft should also not be used in patients who are skeletally
immature, in patients with an inadequate neurovascular status, in patients
with compartment syndrome of the affected limb, in pregnant women, or in
patients with an active infection at the operative site.
There are no adequate and well controlled studies in human pregnant women.
In an experimental rabbit study, rhBMP-2 has been shown to elicit antibodies
that are capable of crossing the placenta. Women of child bearing potential
should be warned by their surgeon of potential risk to a fetus and informed
of other possible orthopedic treatments. The safety and effectiveness of this
device has not been established in nursing mothers. Women of child-bearing
potential should be advised to not become pregnant for one year following
treatment with this device.
Please see the package insert for the complete list of indications,
warnings, precautions, adverse events, clinical results, and other
important medical information.
CAUTION: Federal (USA) law restricts this device to sale by or on the order of a
physician with appropriate training or experience.
References:
1. Burkus, et al. Anterior Lumbar Interbody Fusion Using rhBMP-2 With Tapered Interbody Cages. J Spinal Disorders. 2002; 15(5): 337-349.
Medtronic
Spinal and Biologics Business
Worldwide Headquarters
2600 Sofamor Danek Drive
Memphis, TN 38132
1800 Pyramid Place
Memphis, TN 38132
(901) 396-3133
(800) 876-3133
Customer Service: (800) 933-2635
For more information visit
www.myspinetools.com
2. Boyne PJ, Lilly LC, et al. De Novo Bone Induction by Recombinant Human Morphogenetic Protein-2 (rhBMP-2) in Maxillary Sinus Floor Augmentation. J Oral Maxillofac Surg.
2005; 63:1693-1707.
3. Fiorellini JP, Howell TH, et al. Randomized Study Evaluating Recombinant Human Bone Morphogenetic Protein-2 for Extraction Socket Augmentation. J Periodontol. 2005; 76(4): 605-613.
4. Friedlaender, et al. Osteogenic Protein-1 (Bone Morphogenetic Protein-7) in the Treatment of Tibial Nonunions: A Prospective, Randomized Clinical Trial Comparing rhOP-1 with Fresh Bone
Autograft. J Bone Joint Surg Am. 2001; 83-A Suppl 1(Pt 2): S151-S158.
Vitoss® and Vitoss® Foam are registered trademarks of Orthovita, Inc.
Novabone® is a registered trademark of NovaBone Products, LLC
Pro Osteon® 500R is a registered trademark of BIOMET®
Healos® is a registered trademark of DePuy Spine, Inc., a Johnson & Johnson company
Mozaik™ and Accell® are trademarks of Integra Life Sciences Corporation
Formagraft® is a registered trademark of NuVasive, Inc.
Osteocel® is a registered trademark of Osiris Therapeutics, Inc., but is distributed by NuVasive, Inc.
Trinity® is a registered trademark of Orthofix Holdings, Inc.
DBX® is a registered trademark of Musculoskeletal Transplant Foundation
OP-1® Putty and OP-1® Implant are registered trademarks of Olympus Biotech Corp.
Actifuse® is a registered trademark of ApaTech
chronOS™ is a trademark of Synthes, Inc.
PRO-STIM™ is a trademark of Wright Medical Technology
MLITBGOPTM11 ©2011 Medtronic Sofamor Danek USA, Inc. All Rights Reserved. PMD001227-2.0 UC201203648IE
BRIEF SUMMARY OF INDICATIONS, CONTRAINDICATIONS, AND
WARNINGS FOR: 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
The INFUSE® Bone Graft/Medtronic Titanium Threaded Interbody Fusion Device
is indicated for spinal fusion procedures in skeletally mature patients with
degenerative disc disease (DDD) at one level from L2-S1, who may also have
up to Grade I spondylolisthesis or Grade 1 retrolisthesis at the involved level.
The INFUSE® Bone Graft/ LT-CAGE® Lumbar Tapered Fusion Device is to be
implanted via an anterior open or an anterior laparoscopic approach. INFUSE®
Bone Graft with either the INTER FIX™ or INTER FIX™ RP Threaded Fusion
Device is to be implanted via an anterior open approach.
The INFUSE® Bone Graft/Medtronic Titanium Threaded Interbody Fusion Device
consists of two components containing three parts– a metallic spinal fusion
cage, a recombinant human bone morphogenetic protein and a carrier/scaffold
for the bone morphogenetic protein and resulting bone. These components
must be used as a system for the prescribed indication described
above. 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 Titanium Threaded Interbody Fusion
Device component.
NOTE: The INTER FIX™ Threaded Fusion Device and the INTER FIX™ RP Threaded
Fusion Device may be used together to treat a spinal level. LT-CAGE® Lumbar
Tapered Fusion Device implants are not to be used in conjunction with either
the INTER FIX™ or INTER FIX™ RP implants to treat a spinal level.
The INFUSE® Bone Graft/Medtronic Titanium Threaded 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 and 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; in patients who are skeletally
immature; in pregnant women; or in patients with an active infection at the
operative site or with an allergy to titanium or titanium alloy.
There are no adequate and well-controlled studies in human pregnant women.
In an experimental rabbit study, rhBMP-2 has been shown to elicit antibodies
that are capable of crossing the placenta. Women of child bearing potential
should be warned by their surgeon of potential risk to a fetus and informed
of other possible orthopedic treatments. The safety and effectiveness of this
device has not been established in nursing mothers. Women of child-bearing
potential should be advised to not become pregnant for one year following
treatment with this device.

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