Autologous Blood-Derived Products for Chronic Non-Healing Wounds

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CMS covers autologous platelet-rich plasma (PRP) only for patients who have chronic non-healing diabetic, pressure, and/or venous wounds and when all the following conditions are met: The patient is enrolled in a clinical research study that addresses the following questions using validated and reliable methods of evaluation. Clinical study applications for coverage pursuant to this National Coverage Determination (NCD) must be received by August 2, 2014. The clinical research study must meet the requirements specified below to assess the effect of PRP for the treatment of chronic non-healing diabetic, pressure, and/or venous wounds. The clinical study must address: Prospectively, do Medicare beneficiaries that have chronic non-healing diabetic, pressure, and/or venous wounds who receive well-defined optimal usual care along with PRP therapy, experience clinically significant health outcomes compared to patients who receive well-defined optimal usual care for chronic non-healing diabetic, pressure, and/or venous wounds as indicated by addressing at least one of the following: complete wound healing; ability to return to previous function and resumption of normal activities; or reduction of wound size or healing trajectory, which results in the patient’s ability to return to previous function and resumption of normal activities? The study of PRP must adhere to the following standards of scientific integrity and relevance to the Medicare population: The principal purpose of the research study is to test whether PRP improves the participants’ health outcomes. The research study is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use. The research study does not unjustifiably duplicate existing studies. The research study design is appropriate to answer the research question being asked in the study. The research study is sponsored by an organization or individual capable of executing the proposed study successfully. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46. All aspects of the research study are conducted according to appropriate standards of scientific integrity set by the International Committee of Medical Journal Editors (http://www.icmje.org). The research study has a written protocol that clearly addresses, or incorporates by reference, the standards listed here as Medicare requirements for coverage with evidence development (CED). The research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options. The research study is registered on the ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors (http://www.icmje.org). However, a full report of the outcomes must be made public no later than three (3) years after the end of data collection. The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary. The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. Consistent with §1142 of the Social Security Act (the Act), the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions. Any clinical study undertaken pursuant to this NCD must be approved no later than August 2, 2014. If there are no approved clinical studies on or before August 2, 2014, this CED will expire. Any clinical study approved will adhere to the timeframe designated in the approved clinical study protocol.

Decision Memo: To: Administrative File: CAG-00190R3 Autologous Blood-Derived Products for Chronic Non-Healing Wounds (Third Reconsideration) From: Louis Jacques, MD Director, Coverage and Analysis Group Tamara Syrek Jensen, JD Deputy Director, Coverage and Analysis Group James Rollins, MD, MSHA, PhD Director, Division of Items and Devices Medical Officer Lisa Eggleston, RN, MS Analyst Cheryl Gilbreath, PharmD, MBA, RPh Analyst Rosemarie Hakim, PhD Epidemiologist Leslye K. Fitterman, PhD Epidemiologist Subject: Decision Memorandum for CAG-00190R3 Autologous Blood-Derived Products for Chronic Non-Healing Wounds Date: August 2, 2012 I. Decision CMS covers autologous platelet-rich plasma (PRP) only for patients who have chronic non-healing diabetic, pressure, and/or venous wounds and when all the following conditions are met: The patient is enrolled in a clinical research study that addresses the following questions using validated and reliable methods of evaluation. Clinical study applications for coverage pursuant to this National Coverage Determination (NCD) must be received by August 2, 2014. The clinical research study must meet the requirements specified below to assess the effect of PRP for the treatment of chronic non-healing diabetic, pressure, and/or venous wounds. The clinical study must address: Prospectively, do Medicare beneficiaries that have chronic non-healing diabetic, pressure, and/or venous wounds who receive well-defined optimal usual care along with PRP therapy, experience clinically significant health outcomes compared to patients who receive well-defined optimal usual care for chronic non-healing diabetic, pressure, and/or venous wounds as indicated by addressing at least one of the following: complete wound healing; ability to return to previous function and resumption of normal activities; or reduction of wound size or healing trajectory, which results in the patient’s ability to return to previous function and resumption of normal activities? The study of PRP must adhere to the following standards of scientific integrity and relevance to the Medicare population: The principal purpose of the research study is to test whether PRP improves the participants’ health outcomes. The research study is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use. The research study does not unjustifiably duplicate existing studies. The research study design is appropriate to answer the research question being asked in the study. The research study is sponsored by an organization or individual capable of executing the proposed study successfully. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46. All aspects of the research study are conducted according to appropriate standards of scientific integrity set by the International Committee of Medical Journal Editors (http://www.icmje.org). The research study has a written protocol that clearly addresses, or incorporates by reference, the standards listed here as Medicare requirements for coverage with evidence development (CED). The research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options. The research study is registered on the ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. The research study protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors (http://www.icmje.org). However, a full report of the outcomes must be made public no later than three (3) years after the end of data collection. The research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary. The research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility. Consistent with §1142 of the Social Security Act (the Act), the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions. Any clinical study undertaken pursuant to this NCD must be approved no later than August 2, 2014. If there are no approved clinical studies on or before August 2, 2014, this CED will expire. Any clinical study approved will adhere to the timeframe designated in the approved clinical study protocol. II. Background A. Wound Etiology and the Wound Healing Process Wound healing is a dynamic, interactive process that involves multiple cells and proteins. There are three progressive stages of normal wound healing, and the typical wound healing duration is about four weeks. While cutaneous wounds are a disruption of the normal anatomic structure and function of the skin, subcutaneous wounds involve tissue below the skin's surface. Wounds are categorized as either acute or chronic. In acute wounds, the normal wound healing stages are not yet completed but it is presumed they will be resulting in orderly and timely wound repair. However, in a chronic wound, the wound has failed to progress through the normal wound healing stages and repair itself within a sufficient time period. A wound is a disruption of normal anatomic structure and function and can range from a simple scratch to an interruption that goes through tissue and muscle down to bone. Acute wounds are wounds of relatively new onset that heal in an orderly fashion, first by reestablishing epithelial integrity, then by laying down new collagen to strengthen the damaged tissue. The result is re-establishment of anatomic and functional integrity. Fortunately, most wounds are acute wounds that heal rapidly and uneventfully. The process of wound healing involves an integrated series of cellular, physiologic, biochemical, and molecular events. The stages of wound healing are defined as inflammatory, proliferative, and remodeling. The inflammatory phase is characterized by platelet accumulation, coagulation, and leukocyte migration into the wound site. During this phase, the platelets adhere to collagen to form a vascular plug and the leukocytes, along with macrophages, begin removing cellular debris and bacteria. This inflammatory phase occurs during the first three to four days after a wound presents. The cellular interactions in this phase help to provide a temporary stable wound environment. The proliferative phase, also termed fibroblastic, is characterized by the regeneration of epidermis, angiogenesis, and the proliferation of fibroblast that forms collagen. Angiogenesis, the formation of a new vascular supply, is important for allowing the nutrition required in the healing process to invade the wound area. Collagen formation plays a prominent role in wound healing and there are over 20 different types of collagen in the human body. Type III collagen, which is part of the granulation tissue, is produced by fibroblasts during the proliferative phase. The re-epithelialization helps to restore the cutaneous barrier. All of these physiologic events normally occur during the 10 to 14 day period after a wound presents. The third and final phase of wound healing, the remodeling phase, takes place from a period of months up to two years (Bhanot & Alexi 2002). This phase is characterized by collagen synthesis and degradation. The type III collagen is replaced by type I collagen that is instrumental in decreasing the wound size through contraction. Contractile forces are produced by contractile proteins as well as the presence of type I collagen that ultimately results in scar formation. At the end of remodeling, the resulting scar tissue is approximately only 80% the strength of normal skin (Bhanot & Alexi 2002). The stages of wound healing are sequential in the normal healing process of acute wounds. Many chronic wounds fail to complete all the stages of normal wound healing (Loots et al. 1998). When the healing process fails to progress properly and the wound persists for longer than one month, it may be described as a chronic wound. In chronic wounds, the healing process is disrupted by some underlying abnormality that prolongs the inflammatory phase, resulting in poor anatomic and functional outcome. Common underlying abnormalities include diabetes, abnormal external pressures and arterial or venous circulatory insufficiency. Since the etiology of wounds varies, the most effective therapy may vary as well. For example, the etiology of a pressure ulcer relates to unrelieved pressure on the skin, whereas the origin of a diabetic ulcer has other etiologies. Therefore, it is difficult to generalize the findings from studies on therapy from one type of ulcer to another type. According to the "Guidance for Industry-Chronic Cutaneous Ulcer and Burn Wounds-Developing Products for Treatment," the Food and Drug Administration (FDA) states that "Wounds differ pathophysiologically, making it difficult-if not impossible-to generalize results obtained from a trial conducted in patients with one type of wound to those with another wound type. Separate safety and efficacy data should be submitted for each wound type for which an indication is sought" (FDA 2000). Wound care must be directed at providing an environment in which the body can effectively carry out the healing process. Conventional or standard therapy for chronic wounds involves local wound care as well as systemic measures. Standard care considerations to promote wound healing include debridement or removal of necrotic tissue, wound cleansing and dressings that promote a moist wound environment. Systemic treatments include the use of antibiotics to control infection and optimizing nutritional status. Early concepts in wound management involved soaking the wound in antiseptics to kill bacteria and then covering the wound with a dry dressing. As the biology of wound healing has become better understood, a variety of wound care strategies and products have been developed to help aid the healing process. Various new dressings such as alginates, hydrogels, films, and foam products are now used. Additionally, newer techniques such as negative pressure dressings, radiant heat, electrical stimulation and hyperbaric oxygen are also being investigated. There are other conventional therapeutic modalities that may be applied to certain subgroups of patients depending on their type of wound. Specific conventional therapies for venous ulcers include the use of compression devices aimed at decreasing venous stasis. Patients that have pressure ulcers require frequent repositioning to redistribute the pressure that is causing the ulcers. Appropriate glucose control for diabetic foot ulcers and establishing adequate circulation for arterial ulcers have been used in addition to ulcer-specific therapies. The multitude of wound care regimens demonstrates the complexity of wound care management and the lack of a unified, proven, universal treatment strategy. Knowledge of the pathophysiology of healing combined with realistic patient outcomes will help guide the clinician in choosing the wound care treatment plan. Authors reported that no single wound dressing is sufficient for all types of wounds and few are ideally suited for the treatment of a single wound through all phases of healing (Lait & Smith 1998). Some wound care specialists have proposed that chronic wounds do not heal due to a lack of vital growth factors that are believed to be deficient in chronic wounds (Belden 1999). Several authors have proposed that this deficiency is due to repeated trauma, ischemia, and infection that increases the level of pro-inflammatory cytokines, increases the level of matrix metalloproteinases, decreases the presence of tissue inhibitors of metalloproteins, and lowers the level of growth factors (Payne et al. 2001). B. Role of Platelets and the Development of Platelet-rich Plasma Originally, it was thought that platelets were important only for clot formation. However, it is now clear that platelets contain a large number of growth factors. The exact number and purpose of all of the growth factors is not known. Four growth factors are most frequently cited (Atri et al. 1990). The first is the platelet-derived angiogenesis factor that causes new capillary formation from the existing microvasculature (Knighton et al. 1982). Platelet-derived epidermal growth factor and platelet factor 4 (considered to be a chemoattractant for neutrophils) have also been identified. The fourth type is platelet-derived growth factor (PDGF), which is a potent fibroblast mitogen and chemoattractant. With this knowledge, a system was developed in 1985 to obtain multiple growth factors from platelets and started treating patients at the University of Minnesota. A retrospective study based on the first patients treated with PDGF was published in 1986 (Knighton et al. 1986). The first prospective trial was then conducted and the results were published (Knighton et al. 1990). Dr. Knighton obtained a patent in 1992 on products released from platelets (i.e., platelet releasate) that are used for tissue repair. Procuren Solution® produced by CuraTech (which later became Curative Health Services) was available throughout the United States through 150 wound care centers starting in 1986. Marketing of Procuren Solution® ceased in 2001. However, various PDGF products, which contain multiple proteins like Procuren but do not contain cells like PRP, are in use for patient care. In 1997, FDA approved the biologics license application of Ortho-McNeil Johnson Pharmaceuticals, Inc. to market Regranex® (becaplermin) Gel 0.01%. The recombinant human platelet-derived growth factor-BB (rhPDGF-BB) was approved for the treatment of lower extremity diabetic neuropathic ulcers that extend into subcutaneous tissue or beyond and have an adequate blood supply. It was not approved for superficial ulcers that do not extend through the dermis into subcutaneous tissue or ischemic diabetic ulcers. This decision memorandum is primarily focused on autologous products, and since becaplermin is not an autologous product, it is not addressed in this memorandum. PRP is produced in an autologous or homologous manner. Autologous PRP is comprised of blood from the patient who will ultimately receive the PRP. Alternatively, homologous PRP is derived from blood from multiple donors. Blood is donated by the patient and centrifuged to produce an autologous gel that has been used in the treatment of acute wounds as well as chronic, non-healing cutaneous wounds that persist for 30 days or longer and fail to properly complete the healing process. Autologous blood derived products for chronic, non-healing wounds include: PDGF products (such as Procuren®), and PRP products (such as AutoloGel™). In an attempt to improve the healing process, wound specialists have become more interested in autologous PRP produced by an apheresis process first developed by Charles Worden in 1998. In this process, autologous blood (blood donated by the patient) is centrifuged to produce a concentrate high in both platelets and plasma proteins. Individual growth factors are not identified or separated during this process. Additives are used to change the consistency of the product. Autologous PRP has been used for a variety of purposes such as an adhesive in plastic surgery and filler for acute wounds. It is also now being used on chronic wounds. PRP is different from earlier products in that it contains whole cells including white cells, red cells, plasma, platelets, fibrinogen, stem cells, macrophages, and fibroblasts and is used by physicians in a clinical or surgical setting. PDGF does not contain cells and was previously marketed as a product to be used by patients at home. Both PDGF and PRP gels are derived from the patient's own blood. PRP is frequently administered as a spray, or a gel. Other systems and protocols have been used to administer PRP. In this decision memorandum as in previous ones, CMS is evaluating PRP as a service, and not a specific system for administrating PRP. III. History of Medicare Coverage In 1992, CMS issued a national non-coverage determination for platelet-derived wound healing formulas intended to treat patients with chronic, non-healing wounds. On December 15, 2003, CMS issued a national non-coverage determination for use of autologous PRP for the treatment of chronic non-healing cutaneous wounds except for routine costs when used in accordance with the clinical trial policy defined in section 310.1 of the National Coverage Determinations Manual. On April 27, 2006, CMS issued an NCD to correct the erroneous potential for local coverage of becaplermin, printed in section 270.3 of the National Coverage Determinations Manual, entitled “Blood-Derived Products for Chronic Non-Healing Wounds.” CMS deleted the erroneous sentences and inserted the correct statement that “Coverage for treatments utilizing becaplermin, a non-autologous growth factor for chronic non-healing subcutaneous wounds, will remain nationally non-covered under Part B based on §1861(s)(2)(A) and (B) because this product is usually administered by the patient.” On March 19, 2008, CMS issued a non-coverage determination for the use of autologous blood-derived products for the treatment of acute wounds where PRP is applied directly to the closed incision site, and for dehiscent wounds. Current non-coverage for chronic, non-healing cutaneous wounds was maintained. A. Current Request On October 4, 2011, Cytomedix submitted a formal request to reopen and revise section 270.3 of the Medicare National Coverage Determinations Manual, which addresses Autologous Blood-Derived Products for Chronic Non-Healing Wounds. They stated that PRP is the prevalent blood-derived therapeutic product used for treating chronic non-healing wounds. Cytomedix submitted new studies and requested that CMS re-evaluate the coverage of autologous PRP gel for the treatment of the following chronic wounds: diabetic, pressure, and/or venous ulcers. Alternatively, Cytomedix requested that CMS cover PRP gel through an NCD with data collection as a condition of coverage; and requested that this would provide a practical means by which CMS could obtain the necessary data to evaluate the performance of PRP gel and to confirm the outcomes presented in their request. B. Benefit Category For an item or service to be covered by the Medicare program, among other things, it must meet one of the statutorily defined benefit categories outlined in the Act. There is no specific Medicare benefit category for autologous blood-derived products for treatment of chronic non-healing wounds. However, these services, at a minimum, fall within the benefit categories of physician’s service (§1861(s)(1) of the Act) and “incident to” a physician’s service (§1861(s)(2)(A) of the Act). This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service. IV. Timeline of Recent Activities Date Action November 9, 2011 CMS formally opened a third reconsideration of the national coverage analysis on Autologous Blood-Derived Products for Chronic Non-Healing Wounds. The initial 30-day public comment period opened. December 9, 2011 The initial public comment period closed. February 7, 2012 CMS had a conference call with Cytomedix, the requestor, and its physician representatives, who discussed an overview of a trial that was pending submission for publication. The results of this trial were not available during this call. May 9, 2012 Proposed decision posted. Second public comment period opened. June 8, 2012 Second public comment period closed. June 26, 2012 CMS had a meeting with Cytomedix, the requestor, and its research representatives, who discussed an overview of their potential methods for conducting a prospective controlled clinical research study. V. FDA Status The AutoloGel™ System has been cleared by the FDA under Section 510(k). It is important to note that the FDA has only issued a 510(k) device clearance for the equipment in the AutoloGel™ System, to manufacture a gel that can be used to promote moisture retention at a wound site. The gel is intended for use in conjunction with standard of care procedures as one component of a more comprehensive wound management plan. This clearance does not represent a premarket or biological license approval for the PRP gel produced by this device. The device has not been cleared or approved to produce a biologicallyactive wound healing agent. According to FDA documents a “510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent (SE), to a legally marketed device (21 CFR 807.92(a)(3)) that is not subject to premarket approval (PMA). Submitters must compare their device to one or more similar legally marketed devices and make and support their substantial equivalency claims. A legally marketed device, as described in 21 CFR 807.92(a)(3), is a device that was legally marketed prior to May 28, 1976 (preamendments device), for which a PMA is not required, or a device which has been reclassified from Class III to Class II or I, or a device which has been found SE through the 510(k) process. The legally marketed device(s) to which equivalence is drawn is commonly known as the "predicate." Although devices recently cleared under 510(k) are often selected as the predicate to which equivalence is claimed, any legally marketed device may be used as a predicate.” (FDA 2010) Cytomedix’s 510(k) submission to FDA described the AutoloGel™ System as “a device consisting of a tabletop centrifuge… and a wound dressing convenience kit…comprised of legally-marketed products…” Their Indications for Use enclosure, included in FDA’s clearance letter, states the device “is intended to be used at point-of-care for the safe and rapid preparation of PRP gel from a small sample of a patient’s own blood. Under the supervision of a healthcare professional, the PRP gel produced by the AutoloGel™ System is suitable for exuding wounds, such as leg ulcers, pressure ulcers and for the management of mechanically or surgically-debrided wounds.” The posted 510(k) summary concluded, “Based on the clinical performance information, it can be concluded that AutoloGel is substantially equivalent to the marketed wound dressing IPM Wound Gel.” (510(k) BK060007 Sponsor-provided 510(k) summary and FDA-issued clearance letter) It is also important to emphasize that the clinical data summarized in the 510(k) clearance show the wound response rate based on ulcer size and the recommended duration of use. All of the wounds that closed in this trial were less than 7.0cm 2 at the start of PRP administration and responded within 8.5 weeks of the first application. This trial did not evaluate the safety or effectiveness of repeat courses of PRP gel applications. VI. General Methodological Principles In general, when making NCDs under §1862(a)(1)(A), CMS evaluates relevant clinical evidence to determine whether or not the evidence supports a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or improves the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for Medicare beneficiaries. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary under §1862(a)(1)(A) of the Act. A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A. Public comments sometimes cite the published clinical evidence and provide CMS with useful information. Public comments that provide information based on unpublished evidence, such as the results of individual practitioners or patients, are less rigorous and, therefore, less useful for making a coverage determination. CMS uses the initial comment period to inform the public of its proposed decision. CMS responds in detail to the public comments that were received in response to the proposed decision when it issues the final decision memorandum. VII. Evidence A. Introduction This section provides a summary of the evidence that CMS considered during the review. There were a number of systematic reviews and meta-analyses found in the medical literature that investigated the use of PRP in patients with acute as well as chronic wounds. Though results of both types of wounds were reported, the primary focus of this NCD is the effects of PRP on chronic wounds. A number of prospective studies such as comparative studies, and cohort studies, as well as retrospective studies were also found. They also were reviewed for this analysis. B. Discussion of Evidence Reviewed 1. Question and Outcomes Is the evidence sufficient to determine that Medicare beneficiaries who have chronic non-healing diabetic, pressure, and/or venous wounds that receive PRP therapy experience clinically significant health outcomes as indicated by at least one of the following: complete wound healing, or ability to return to previous function and resumption of normal activities? The ultimate goal for patients with chronic wounds is complete healing and improved quality of life. These are the primary outcome measures. A number of secondary outcome measures exist, and they may also be important to patient well-being. Wounds may, depending on their anatomic location and severity, limit range of joint motion and ambulation. Ideally, a wound would be completely cured and would not recur. Avoidance of infection and elimination of pain are essential in the recovery process. Chronic wounds that are malodorous may be embarrassing for a patient and thus can lead to social isolation. Improvement in these outcomes should culminate in increased activity that will lead to resumption of normal activities and improved quality of life. 2. External Technology Assessment CMS did not request an external technology assessment (TA) on this topic. On June 15, 2012, the Cochrane database, the NICE database, the Blue Cross/Blue Shield TEC database, and the Canadian Agency for Drugs and Technologies in Health database were searched using the terms “wound care,” “platelet gel,” “platelet lysate,” “platelet-derived wound healing factor” and “platelet-rich plasma.” No technology assessments were found. AHRQ released a TA dated March 8, 2005 titled “Usual Care in the Management of Chronic Wounds: A Review of the Recent Literature.” This technology assessment presented a broad review of the products, techniques, and protocols used in wound management but did not address autologous PRP specifically except to state that growth factors “show promise but need further, more rigorous evaluation.” (AHRQ 2005) AHRQ also released a TA dated May 26, 2009, which evaluated the use of Negative-Pressure Wound Therapy; however, this TA did not address the use of PRP in patients with chronic non-healing diabetic, pressure, and/or venous wounds. Currently, AHRQ is performing a TA on Skin Substitutes for Treating Chronic Wounds. We will determine whether the use of PRP is addressed in this TA when it is publicly available. 3. Internal Technology Assessment Literature search methods The reviewed evidence was gathered from articles submitted by the NCD requester, submitted during the public comment period, and from a literature search of Pub Med, Cochrane Library, EMBASE as well as other sources, such as the TRIP Database, performed by CMS staff. Search terms used to review the medical literature include the following: platelet-rich plasma, platelet-rich plasma gels, PRP, PRP gel(s), autologous plasma rich in platelets, autologous platelet gel, autologous platelet-rich plasma gel, preparation rich in growth factors (PRGF), platelet-rich and platelet poor plasma, platelet gel, autologous platelet lysate, platelet releasate, platelet derived growth factors (PDGF), autologous platelet-derived wound healing factors (PDWHF), wounds, chronic wounds, chronic non-healing wounds, dehiscence wounds, diabetic ulcers, venous ulcers, and pressure ulcers. Only sources provided in English were used. The following terms are considered synonymous to PRP: platelet releasate, platelet lysate, PDWHF, and PDGF. The NCD requesters provided the full text of 149 articles as part of the reconsideration materials. We also received a number of full text articles as well as references to articles from commenters during the initial comment period, much of which were duplications of full text articles submitted by the requester. Using the above mentioned search terms, over 8,000 citations were identified. Neither the Cochrane Library review nor EMBASE provided any additional studies, but the Cochrane Library currently has posted a protocol for a systematic review of autologous PRP for the treatment of chronic wounds. A large number of these articles were excluded from this evaluation because they were clinical summary review articles that do not provide primary evidence (e.g., Akingboye et al. 2010, Everts et al. 2006, Peitramaggiori et al. 2006); addressed the use of PRP in only acute wounds (e.g., Almdahl et al. 2011, Englert et al. 2006, Fanning et al. 2007, Trowbridge et al. 2005 ); discussed PRP usage in conjunction with other treatment modalities (e.g., Cervelli et al. 2010, Gurvich et al. 2008, Klayman et al. 2006); discussed PRP used in orthopedic procedures (e.g., Christgau et al. 2006, Jenis et al. 2006, Simon et al. 2004); discussed PRP usage in dental procedures (e.g., Babbush et al. 2003, Griffin et al. 2004, Marx 2004); or discussed the use of PRP in ear, nose and throat (ENT) procedures (e.g., Kassolis et al. 2005, Pomerantz et al. 2005, Steigmann et al. 2005). The medical literature also had a large number of studies that reported outcomes as a percentage of wound surface healing and as healing trajectory (Anitua et al. 2007, van Rijswijk & Polansky 1994, Benigni et al. 2007, Carter et al. 2011, Coerper et al. 2008, Phillips et al. 2000, Robson et al. 2000, Sheehan et al. 2003, Snyder, et al. 2010, van Rijswijk et al. 2011, van Rijswijk and Polansky 1994, de Leon et al. 2011, Frykberg et al. 2010, Sell et al. 2010). Some of these studies were designed to show that reduction in chronic wound size over a specified period of time was a good predictor of complete healing. Though these articles are of interest, they do not address the key outcomes, complete healing and/or the patient’s ability to return to previous function and resumption of normal activity, which CMS considers pertinent clinical health outcomes in patients with chronic wounds. Therefore, these studies were not persuasive in this analysis and were excluded. Other studies were excluded because they were duplicate studies, cost-effectiveness studies, case studies/series, reported outcomes not of interest to CMS, used freeze-dried PRP preparations or allogenic PRP frozen platelets, used homologous PRP, or were animal studies. The following tables with summaries of the literature analysis can be found in Appendix B: Table 1: Partial List of Excluded Studies Table 2: Randomized Clinical Trials (RCTs) Table 3: Other Prospective Studies Table 4: Retrospective Studies Systematic Review/Meta-Analysis In a review of the medical literature, there were ultimately three pertinent systematic reviews/meta-analyses found addressing, at least tangentially, the use of PRP in the treatment of patients with chronic wounds. In the proposed decision memorandum, we included mention of a fourth meta-analysis performed by Margolis et al. (1999); since it did not include an exploration of PRP, we have therefore removed it from this final memorandum. Carter MJ, Fylling CP, Parnell LK. Use of platelet-rich plasma gel on wound healing: a systematic review and meta-analysis. Eplasty. 2011;11:e38. Using RCTs and comparative groups, Carter et al. performed a systematic review on the use of autologous platelet-rich plasma (intervention group) compared to standard wound care (control group) in cutaneous wounds. The systematic review looked at articles published between 2001 and 2011. Outcomes of interest included healing information such as complete or partial wound healing, time to heal, healing trajectory, velocity or rate, and wound size reduction. The assessment included publications from peer-reviewed journals (which included articles, brief articles, case studies or letters to the editor), as well as materials presented at scientific meetings (e.g., abstracts, posters). Eligible studies included investigations of patients with cutaneous ulcers or wounds (including dehisced wounds, open surgical wounds, acute or chronic wounds) that were treated with activation-processed PRP. Patients with mixed origin wounds, subsets of different wound types, surgical wounds treated with PRP prior to closure and opening, and surgical wounds treated with PRP were also included in the analysis. Inclusion eligibility required PRP studies to have a control treatment group (e.g. placebo, wound care treatment). Non-inferiority trials that involved two types of PRP treatments were also eligible for the study. To avoid methodological confounding, studies in which the investigational group received other treatments were eligible provided that the control group also received the same treatment or care. Excluded studies were those that focused on burns, dental or jaw treatment, bone fractures, orthopedic injections, plastic surgery, or those that used homologous/allogenic PRP procedures, lysates, freezing or freeze-dried techniques to produce PRP “fibrin glue.” Wound healing parameters (e.g., wound area reduction, healing rate, comparisons of clinically significant healing events) used as outcome measures, were reviewed unadjusted or adjusted for other covariates and factors using both baseline and final outcomes as well as repeated measures statistics. Sources used to obtain studies included the Cochrane Library, Scopus, CINAHL, Pub Med database as well as the clinicaltrial.gov database, using specific search terms. Study quality was assessed using a method reported by Downs and Black (modified by Carter et al.) that evaluated quality of study data reporting, the generalizability of the study, the potential for bias and confounding, and the power of the study to discriminate the effect sizes of the outcomes. Outcomes were categorized by type, and for each one the pre-treatment and post-treatment numbers, median, or mean values were extracted. Numbers needed to treat (NNT) were calculated and, in cases where protocol analyses were used, the data was updated to reflect an intent-to-treat (ITT) analysis. A fixed-effect model was used to calculate the 95% confidence interval and P values, but if inconsistencies arose, a random effects model was employed. The GRADE classification system was used to compare PRP treatments against standard care treatments. Statistical pooling was carried out on studies that had high homogeneity on: (1) complete wound healing; (2) superficial infection; and (3) reduction in pain, and RCTs were pooled separately from other comparative studies. Statistical heterogeneity was assessed using the I 2 (inconsistency) statistic. Based on the eligibility criteria, 21 studies (which consisted of 12 RCTs, three cohort studies, five comparative studies, and one retrospective analysis) as well as three systematic reviews were identified and used (qualitative synthesis). After further refinement of the studies, the authors found the following: Four RCTs were found and based on tools used to assess quality, they were all found to have serious limitations (Driver et al. 2006, Friese et al. 2007, Anitua et al. 2008, Saldalamacchia et al. 2004). Of these, two reported results statistically significant for complete wound healing and improved healing time in patients treated with PRP compared to patients treated with saline gel or no topical treatment (Driver et al. 2006, Friese et al. 2007). Two of the four RCTs showed statistically significant differences in wound size reduction in patients receiving PRP compared to subjects who received saline gauze or no topical treatment (Anitua et al. 2008, Saldalamacchia et al. 2004). However, these studies did not report any correlation between wound size reduction and the patient's ability to return to previous function or resumption of normal activities. Using propensity scores, a non-RCT comparative study reported that platelet releasate was more effective than standard care in the treatment of diabetic foot ulcers (1.14-1.59) (Margolis et al. 2001). A historical cohort study reported that PRP patients required significantly fewer days to complete healing compared to patients in the control group treated with hyaluronic acid-dressings (Mazzucco 2004). Meta-analyses were also performed based on research design, type of wound (e.g., chronic versus acute), and outcomes (e.g., complete healing, pain reduction, reduction in infection rate). The first meta-analysis found that the same four RCTs above met their criteria in evaluating chronic healed wounds (Anitua et al. 2007, Driver et al. 2006, Friese et al. 2007, Saldalamacchia et al. 2004). No evidence of significant heterogeneity was noted amongst the studies. Of the four studies, two failed to reveal any statistical difference between patients receiving PRP treatment compared to patients that received saline gel or no topical treatment. When assessing the four studies using a fixed-effect model, the results revealed findings that were significantly in favor of PRP therapy compared to control therapies of saline gauze, saline gel, or not topical treatment (Z = 2.54, P = 0.01). The authors indicate that this was due to the statistical weight of one study that was presented at a medical conference but was not published as a peer-reviewed article. A meta-analysis for RCTs in acute wounds with primary closure was not performed because only two studies were found. Another meta-analysis, using a random-effects model was performed to evaluate reduction in infection in acute wounds. The researchers found two articles that met their criteria (Everts et al. 2006, Trowbridge et al. 2005). Results revealed that superficial infections in acute wounds with primary closure was favorable, but were not statistically significant when compared to no topical treatment (Z = 1.42, P = 0.16). The final meta-analysis, again using the random effects model, was performed to evaluate acute wounds with primary closure for postoperative pain (Yoo et al. 2008, Buchwald et al. 2008, Englert et al. 2004). Study findings again revealed that the results were in favor of PRP therapy, but were not statistically significant when compared to saline spray or topical treatment (Z = 0.90, P = 0.37). Martinez-Zapata MJ, Marti-Caarvajal A, Sola I, Bolivar I, et al. Efficacy and safety of the use of autologous plasma rich in platelets for tissue regeneration: a systematic review. Transfusion. 2009;49(1):44-56. Using data sources such as MEDLINE, EMBASE, Cochrane registry of controlled trials, and the Science Citation Index, Martinez-Zapata and associates performed a systematic review to determine the safety and tissue regeneration ability of platelet-rich products. Peer-reviewed publications from 1945 to 2006 were reviewed. Inclusion criteria included RCTs that assessed the safety and/or efficacy of PRP for healing and regeneration of hard and soft tissues in any and all medical or surgical procedures. A random-effects model was used by the authors to calculate risk ratios for binary outcomes, and sensitivity analysis was performed if a high degree of heterogeneity was noted amongst the studies. Though 20 RCTs met the inclusion criteria of the study, only seven studies (six parallel designs and one crossover design) addressed the use of PRP in cutaneous ulcers, and only two studies (one parallel and one split design) addressed the use of PRP in surgical wounds. In studies that evaluated PRP use in patients with cutaneous wounds, Jadad scores were used to assess quality: three studies were considered high quality, three studies were of moderate quality and one study was low quality. Four of the RCTs included patients with chronic ulcers of different etiologies, two studies addressed patients with chronic venous ulcers, and one study addressed patients with diabetic foot ulcers. Six of the seven studies used “complete ulcer epithelialization” as an outcome (the other study used a different definition for healing); combining these six studies resulted in a total of 122 patients in the intervention group and 105 patients in the control group (Knighton et al. 1990, Krupski et al. 1991, Stacey et al. 2000, Senet et al. 2003, Weed et al. 2004, Driver et al. 2006). Results of these combined studies revealed that complete ulcer epithelialization was not statistically significant between the intervention group and the control group (relative risk [RR], 1.40, range 0.85-2.31). Because of the high degree of heterogeneity found between studies (I 2 = 56.8%), a sensitivity analysis was performed, and results were similar to the principle analysis which revealed no statistically significant difference between the two groups (RR, 1.23, range 0.90 - 1.41). Similarly, the authors found two studies that evaluated the use of PRP in patients with surgical wounds (Powell et al. 2001, Englert et al. 2005). Both studies acknowledged only one treatment session with PRP therapy, and based on Jadad quality scores, both studies were considered of low quality. Outcomes for this group of studies included pain, swelling and redness. Results of the analysis revealed that though the experimental group had better relief in pain, redness and swelling compared to the control group, the degree of improvement was not statistically significant. The authors concluded that in the treatment of skin ulcers PRP can increase the percentage of recovery but not statistically significantly, and for the treatment of surgical wounds, there was not a statistically significant difference in the outcomes (e.g., pain, redness, swelling, etc.) when compared to the control group. Villela DL, Santos VL. Evidence on the use of platelet-rich plasma for diabetic ulcer: a systematic review. Growth Factors. Apr 2010;28(2):111-6. Villela and Santos performed a systematic review to evaluate the use of PRP for the topical treatment of chronic diabetic leg ulcers. Using procedures adopted by the Cochrane Collaborative, articles were retrieved from the following sources: Cochrane, Lilacs, CINAHL, EMBASE, and the Pub Med databases, using July of 2008 as an ending date. Specific inclusion criteria (e.g., clinical trials, complete articles, articles from national and international journals) as well as exclusion criteria (e.g., abstracts, studies using platelet-poor-plasma in combination with PRP; studies using a recombinant or single growth factor) were used in the retrieval of articles. Specific search terms were also used. To evaluate the study quality and evidence, the authors used the scale to assess the grade of recommendation and level of evidence (SGRLE) and the scale to assess control of variables (SACV). The authors acknowledged that there was no scale to assess the intrinsic and extrinsic variables that interfere with chronic wound healing. The Jadad (Oxford) scale was used to assess study quality in cases where RCTs were evaluated. Meta-analysis was performed according to the classification of the results, and both fixed-effects as well as random-effects models were used, depending on the degree of heterogeneity between studies. There were 18 studies found that met criteria; seven were RCTs and three were cross-sectional clinical studies. When looking at study quality based on the three scales, collectively they were moderate. Only four studies were methodologically similar (Driver et al. 2006, Knighton et al. 1990, Holloway et al. 1993, Steed et al. 1992). A meta-analysis of these four studies was performed. When graphing the four studies individually on a Forest plot, two studies (Holloway et al. 1993, Knighton et al. 1990) reported the best outcome for the treatment group (80% and 81% had healed wounds; CI 2.05-48.5 and 3.65-150 respectively), while the other two studies (Driver et al. 2006, Steed et al. 1992) failed to reveal a difference between the control and treatment group (CI 0.78-10.57 and 0.83-186 respectively). When the four studies were analyzed together, it revealed a trend towards the occurrence of healing and it remained higher in the PRP group compared to the control group (CI 2.94- 20.31). These findings were replicated in both the fixed effect as well as the random effects models. After reviewing results, the authors did acknowledge that it is practically impossible to establish a reference value of platelet concentration in PRP necessary to produce healing because each study reported different methods of preparation and concentrations of PRP. In conclusion, the authors note that there was scientific evidence regarding favorable outcomes when using PRP in the treatment of diabetic ulcers, but this is tempered by the knowledge that all studies used different preparations of PRP. Prospective Studies A number of prospective studies were identified that evaluated the use of PRP in patients with chronic wounds. These include RCTs (Table 2), as well as other types of prospective studies (Table 3). A number of parameters are captured in the analysis. Most of these prospective studies were randomized, double blind, placebo controlled studies (N = 9), though some prospective trials were open-label trials without control groups. The number of participants in these studies ranged from 13 to 97. Randomized Clinical Trials There were nine RCTs identified that addressed the use of PRP in patients with chronic wounds. Of these, only the study performed by Knighton appeared in the meta-analyses performed by Villela and Martinez-Zapata. The primary outcome of interest in all of these studies, including the RCTs as well as the meta-analyses, was complete wound healing. Complete wound healing was defined as documentation of 100% epithelialization of the wound confirmed by inspection, photography, tracings or planimetry, which is a three dimensional measurement of the wound. Driver VR, Hanft J, Fylling CP. Beriou JM. A Prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage. 2006;52(6):68-87. The objective of this study was to evaluate the safety and incidence of complete wound healing as well as wound recidivism rates among healed wounds in the treatment of non-healing diabetic foot ulcers. To be eligible for the study, participants must have type I or type II diabetes, be between the ages of 18 and 95, and must have an ulcer that lasted for at least four weeks. A total of 72 patients met the inclusion criteria, including 40 participants in the intervention group (PRP gel) and 32 participants in the control group (saline gel). The mean age in intervention group was 56.4 years, while the mean age in the control group 57.5 years (reported as not statistically significant). The percentage of males in the intervention and control groups were 80%/81.4 respectively (reported as not statistically significant). Patients received treatment with either PRP gel or saline gel twice weekly. An Intent-to-Treat Analysis (ITT) was performed, and of the 72 participants, 13 of 40 patients (32.5%) in the PRP gel and nine of 32 patients (28.1%) in the control group had completely healed wounds after 12 weeks (P = 0.79). Because the authors felt that the ITT analysis results did not reflect previous clinical outcomes, an independent audit was performed. This resulted in the elimination of 32 participants due to protocol violations and failure to complete treatment. The final analysis was based on 19 patients in intervention group and 21 patients in control group. Based on this new per-protocol analysis, 13 of 19 (68.4%