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This policy addresses the use of blood-derived growth factors, including recombinant platelet-derived growth factors and platelet-rich plasma (PRP), as a treatment of wounds or other miscellaneous non-orthopedic conditions, including but not limited to treatment of diabetic ulcers, pressure ulcers, and ulcers related to venous stasis.
A variety of growth factors have been found to play a role in wound healing, including platelet-derived growth factors (PDGF), epidermal growth factor, fibroblast growth factors, transforming growth factors, and insulin-like growth factors. Autologous platelets are a rich source of PDGF, transforming growth factors (that function as a mitogen for fibroblasts, smooth muscle cells, osteoblasts), and vascular endothelial growth factors. Recombinant PDGF has also been extensively investigated for clinical use in wound healing.
Autologous platelet concentrate suspended in plasma, also known as platelet-rich plasma (PRP), can be prepared from samples of centrifuged autologous blood. Exposure to a solution of thrombin and calcium chloride degranulates platelets, releasing the various growth factors in the polymerization of fibrin from fibrinogen, creating a platelet gel. The platelet gel can then be applied to wounds or may be used as an adjunct to surgery to promote hemostasis and accelerate healing. In the operating room setting, PRP has been investigated as an adjunct to a variety of periodontal, reconstructive, and orthopedic procedures. For example, bone morphogenetic proteins are a type of transforming growth factors, and thus PRP has been used in conjunction with bone-replacement grafting (using either autologous grafts or bovine-derived xenograft) in periodontal and maxillofacial surgeries.
Platelet-rich plasma is distinguished from fibrin glues or sealants, which have been used for many years as a surgical adjunct to promote local hemostasis at incision sites. Fibrin glue is created from platelet-poor plasma and consists primarily of fibrinogen. Commercial fibrin glues are created from pooled homologous human donors; Tisseel® (Baxter) and Hemaseel® are examples of commercially fibrin sealants. Autologus fibrin sealants can be created from platelet-poor plasma. This policy does not address the use of fibrin sealants.
A recombinant PDGF product, becaplermin gel (Regranex®, McNeil Pharmaceutical) has been approved by the U.S. Food and Drug Administration (FDA). The labeled indication is as follows:
"Regranex Gel is indicated for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. When used as an adjunct to, and not a substitute for, good ulcer care practices including initial sharp debridement, pressure relief and infection control, Regranex Gel increases the complete healing of diabetic ulcers. The efficacy of Regranex Gel for the treatment of diabetic neuropathic ulcers that do not extend through the dermis into subcutaneous tissue or ischemic diabetic ulcers has not been evaluated." In 2008, the manufacturer added this black box warning to the labeling for Regranex, "An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of Regranex Gel in a post-marketing retrospective cohort study. Regranex Gel should only be used when the benefits can be expected to outweigh the risks. Regranex Gel should be used with caution in patients with known malignancy."
Blood products such as PRP are regulated by the Center for Biologics Evaluation and Research (CBER). CBER is responsible for regulating human cells, tissues, and cellular and tissue-based products. The regulation process for these products is described in FDA’s 21 CFR 1271 of the Code of Federal Regulations. Under these regulations, certain products including blood products such as PRP are exempt and therefore, do not follow the traditional FDA regulatory pathway. To date, FDA has not attempted to regulate activated PRP.
Augment Bone Graft (Wright Medical) is composed of recombinant PDGF with a conductive scaffold of beta tricalcium phosphate. In August 2013, FDA rejected Wright Medical’s premarket application for use in ankle/foot arthrodesis, expressing concern that “the population enrolled was predominantly low risk and, therefore, may not have warranted the use of either autograft or Augment Bone Graft.” In October 2013, FDA agreed to hold a dispute resolution panel with Wright Medical. Augment Bone Graft is currently available outside of the U.S.
There are numerous PRP preparation systems on the market today with FDA clearance. For example, Aurix™ System (previously AutoloGel™; Cytomedix) and SafeBlood® (SafeBlood Technologies) are two (2) related but distinct autologous blood-derived preparations that can be prepared at the bedside for immediate application. Both Autologel and SafeBlood have been specifically marketed for wound healing. Other devices may be used in the operating room setting, such as Medtronic Electromedic, Elmd-500 autotransfusion system, the Plasma Saver device, or the Smart PreP device. The Magellan Autologous Platelet Separator System (Medtronic) includes a disposable kit designed for use with the Magellan Autologous Platelet Separator portable tabletop centrifuge. BioMet Biologics received marketing clearance through the FDA's 510(k) process for a gravitational platelet separation system (GPS®II), which uses a disposable separation tube for centrifugation and a dual cannula tip to mix the platelets and thrombin at the surgical site. Filtration or plasmapheresis may also be used to produce platelet-rich concentrates. The use of different devices and procedures can lead to variable concentration of active platelets and associated proteins, increasing variability between studies of clinical efficacy.
Related medical policies -
POLICYRecombinant platelet-derived growth factor (i.e., becaplermin) may be considered medically necessary when used as an adjunct to standard wound management for the following indications:
Appropriate candidates for becalpermin gel for treatment of neuropathic diabetic ulcers should meet ALL of the following criteria:
Appropriate candidates for becalpermin gel for the treatment of pressure ulcers should meet ALL of the following criteria:
Patients are typically treated once daily for up to 20 weeks or until complete healing. Application of the gel may be performed by the patient in the home.
Other applications of becaplermin are considered investigational, including, but not limited to ischemic ulcers, ulcers related to venous stasis, and ulcers not extending through the dermis into the subcutaneous tissue.
Use of autologous blood-derived preparations (i.e. platelet-rich plasma) is considered investigational for the treatment of acute or chronic wounds, including surgical wounds and non-healing ulcers.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY4/1993: Approved by Medical Policy Advisory Committee (MPAC) as Growth Factors for Wound Healing. ICD-9 diagnosis 707.1 added
5/2000: Comprehensive revision with medically necessary indications approved by MPAC; policy renamed
2/11/2002: Investigational definition added
5/2/2002: Type of Service and Place of Service deleted
11/2002: Reviewed by MPAC; indications expanded to include venous stasis and pressure ulcers, FEP exception added, Sources updated, Code Reference updated, 707.1 5th digit added, ICD-9 diagnosis 459.81, 707.0 added covered codes, HCPCS S0157 added covered codes, non-covered table added, HCPCS S9055 added non-covered codes
9/2/2003: Code Reference section updated, ICD-9 diagnosis code range 250.60-250.63, 250.80-250.83 listed separately
10/20/2004: Code Reference section updated, ICD-9 diagnosis code 707.0 deleted effective 9/30/2004, ICD-9 diagnosis code 707.0 5th digit effective 10/1/2004
5/18/2006: Policy revised. Revisions approved by Medical Policy Advisory Committee (MPAC)
6/26/2006: Code reference section updated, ICD-9 diagnosis codes 440.23, 440.24, 454.0, 454.2, 459.81 deleted from medical policy.
1/25/2007: Policy description reviewed and updated. Name of policy changed from Platelet-Derived Growth Factors for Wound Healing to Recombinant and Autologous Platelet-Derived Growth Factors as a Primary Treatment of Wound Healing and Other Miscellaneous Conditions
5/9/2007: Policy reviewed, no changes
7/10/2008: Policy reviewed, statement concerning black box warning added to description
9/17/2008: Annual ICD-9 updates effective 10-1-2008 applied
3/19/2010: Description section was updated to include language about the Magellan® Autologous Platelet Separator System and BioMet Biologics platelet separation system (GPSII); Policy Statement section was revised for clarity; Code Reference section was revised to remove ICD-9 diagnosis codes 249.60 - 249.61, 250.60 - 250.63 and descriptions were revised for ICD-9 diagnosis codes 707.23 and 707.24.
06/21/2011: Policy reviewed; no changes.
05/09/2012: Policy reviewed; no changes.
08/07/2013: Policy reviewed; no changes to policy statement. Deleted outdated references from the Sources section.
07/22/2014: Policy title changed from "Recombinant and Autologous Platelet-Derived Growth Factors as a Primary Treatment of Wound Healing and Other Miscellaneous Conditions" to "Recombinant and Autologous Platelet-Derived Growth Factors as a Treatment of Wound Healing and Other Conditions." Policy description updated. Medically necessary policy statement revised to remove "When used according to the FDA-labeled indication; i.e.," from the list of indications and add "Pressure ulcers extending into the subcutaneous tissue." Investigational policy statements regarding autologous blood-derived preparations revised to state that the use of autologous blood-derived preparations (ie, platelet-rich plasma) is considered investigational. This includes, but is not limited to, use in the following situations: treatment of acute or chronic wounds including non-healing ulcers; adjunctive use in surgical procedures; primary use (injection) for other conditions such as epicondylitis (ie, tennis elbow), plantar fasciitis, or Dupuyten contracture.
09/01/2015: Code Reference section updated for ICD-10.
09/17/2015: Policy title changed from "Recombinant and Autologous Platelet-Derived Growth Factors as a Treatment of Wound Healing and Other Conditions" to "Recombinant and Autologous Platelet-Derived Growth Factors as a Treatment of Wound Healing and Other Non‒Orthopedic Conditions." Policy description and policy sections updated to remove orthopedic applications of platelet-rich plasma from the policy. Policy description also updated regarding PRP preparation systems and to add a link to the Orthopedic Applications of Platelet-Rich Plasma medical policy. Investigational policy statement revised to state that the use of autologous blood-derived preparations (i.e. platelet-rich plasma) is considered investigational for the treatment of acute or chronic wounds, including surgical wounds and non-healing ulcers. Removed the following statements: This includes, but is not limited to, use in the following situations: Adjunctive use in surgical procedures; Primary use (injection) for other conditions such as epicondylitis (i.e. tennis elbow), plantar fasciitis, or Dupuytren's contracture. Policy Guidelines section updated to add medically necessary and investigative definitions.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.01.16
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.