Autologous Blood-Derived Products for Chronic Non-Healing Wounds

During the public comment period earlier this year upon the posting of the initial tracking sheet, I submitted a comment in my capacity as the lead author on the paper published in the September 2019 issue of Advances in Skin and Wound Care entitled "Aurix Gel Is an Effective Intervention for Chronic Diabetic Foot Ulcers: A Pragmatic Randomized Controlled Trial". [Then, as now, I have no financial disclosures.] I commented at that time that subjects enrolled at St. Luke's Wound and Hyperbaric Clinic where I serve as Medical Director made up the largest component of the population in the randomized but pragmatic study of Aurix conducted under Coverage with Evidence Development. As I also commented then, my experience with Aurix specifically as an autologous PRP product over my 5+ years of usage fully supports its coverage by CMS for Medicare beneficiaries. Therefore, I commend CMS for issuing its proposal approving coverage of autologous PRP for chronic wounds as a favorable step that should provide true benefit to Medicare beneficiaries. As I've indicated, my experience with autologous PRP is with Aurix which is a topically applied platelet derived hematogel. I'm also aware of at least one other autologous PRP product, 3C Patch, with an approved indication for chronic wounds and other comments submitted here speak favorably to its effectiveness. But, I think this raises an important point that CMS should strongly consider. In the same way that I am approached by vendors with, for example, a amniotic tissue product who show me clinical data from a different amniotic product and claim that the efficacy is the same and to which I reply that I think seeing data on their product is important, I am concerned about what appears to be a blanket approval by CMS of all autologous PRP products.

I believe CMS properly acknowledges that wound healing is a complex biological process and what supports and controls an effective wound healing outcome therefore becomes as much a matter of science as clinical considerations. And, if the biology (science) controls the process, then CMS should be careful of providing coverage to PRP products that do not have underlying clinical data in support of their effectiveness in wound care. I'm aware that the 3C Patch is a different product than Aurix but that the two products share an FDA clearance in wound care. I'm equally pleased that 3C Patch's apparent effectiveness would mean two wound care specific autologous PRP products covered by Medicare offering benefit to patients. However, my concern is with the non-trivial number of autologous PRP products which have usage today in various orthopedic and even sports medicine applications that would apparently be covered under CMS' proposed decision. The wound care field is today overly burdened with products lacking clinical evidence; CMS would be doing an ultimate disservice to wound care patients by approving coverage for products lacking evidence of clinical success in wounds. For make no mistake, a covered product will be a used product and Medicare budgetary resources will be consumed by their use. And, I strongly suspect that PRP lacking evidence of wound care effectiveness will in fact prove not to be effective and the overall impression of autologous PRP in wound care will suffer. I was under the impression that the historical lack of coverage of autologous PRP for Medicare beneficiaries with chronic wounds over now four cycles of reconsideration was a function of the uneven and disparate data supporting clinical effectiveness. CMS now appears to be setting aside differentiated data for the two products with the most robust clinical evidence (as your own proposed decision memo indicates) and suggesting that each and every autologous PRP product should receive coverage. My five years of direct day-to-day clinical experience with Aurix has unequivocally shown me that patients otherwise and seemingly unable to establish a positive healing trajectory in a long-standing chronic wound can frequently and quickly experience dramatic and significant improvement in the underlying wound. There would be no excuse for confounding a clinical appreciation for any effective autologous PRP product by summarily allowing products with no supporting clinical evidence in wounds to be covered.

In conclusion, the entirely reasonable threshold in the wound care space - where too many wounds are in a chronically non-healed state already - should be an FDA clearance specific to wound care based on clinical data. The mantra of the past year in this time of the Covid pandemic has been "follow the science". CMS should do similarly here and provide important Medicare coverage to a patient population with a large unmet medical need based on data backed by science and clinical experience. With that data in hand, clinicians will welcome additional products that bring benefit to their patients.

https://www.cms.gov/medicare-coverage-database/staticpages/public-comment.aspx?commentID=32973&ReportType=nca

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On behalf of the members of the American Podiatric Medical Association (APMA), the national organization representing the vast majority of the nation’s estimated 15,000 doctors of podiatric medicine (DPMs), also known as podiatric physicians and surgeons, we appreciate the opportunity to offer our support for the National Coverage Decision (NCD) for Autologous Blood-Derived Products for Chronic Non-Healing Wounds. APMA is a member of the Alliance of Wound Care Stakeholders (the Alliance) and supports the comments that the Alliance has submitted.

APMA, as a member of the Alliance, also has a vested interest in this coverage determination as many of our members use these products to treat their patients with chronic nonhealing wounds. This coverage determination consequently addresses policies that provide treatment options that are critical for their patients’ care.

While APMA supports Medicare’s decision to provide coverage for the use of autologous platelet-rich plasma (PRP) for patients with chronic non-healing wounds, there is one area which we believe needs to be addressed to improve the NCD.

APMA feels that some of the policy language should be modified. CMS states that there will be national coverage for autologous PRP for “chronic non-healing diabetic wounds,” and local MACs will have the authority to cover autologous PRP for “all other chronic non-healing wounds.” We agree with this language. However, CMS further states that autologous PRP is non-covered when used for the treatment of “chronic, non-healing, cutaneous wounds.” APMA disagrees with this statement and recommends deleting it from the policy. PRP has been used on chronic non healing cutaneous wounds and CMS utilized several studies in this coverage decision in which patients had “cutaneous” wounds.

Thank you for the opportunity to comment on this NCD. We welcome the opportunity to discuss these issues further, and if you need additional information, please contact APMA’s Director of Health Policy, Scott Haag, JD, MSPH, at slhaag@apma.org or (301) 581-9233.

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Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Medicare & Medicaid Services
Mail Stop # S3-02-01
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: Proposed Decision Memo for Autologous Blood-Derived Products for Chronic Non-Healing Wounds (CAG-00190R4)

Dear Ms. Jensen:

On behalf of Reapplix A/S (Reapplix), the manufacturer of the 3C Patch® System, I am pleased to submit comments on the above-referenced Proposed Decision Memo (hereinafter, the “Memo”).

The 3C Patch® System is a single use medical device used to prepare an autologous platelet-rich plasma (PRP) gel from the patient’s peripheral blood by centrifugation, without any reagents. Under the supervision of a healthcare professional, the PRP gel produced by the 3C Patch® System is topically applied for the management of exuding cutaneous wounds, such as leg ulcers, pressure ulcers, and diabetic ulcers and mechanically or surgically-debrided wounds.¹ On August 14, 2014, CMS approved for coverage under CED a randomized controlled trial investigating the use of the 3C Patch® (hereinafter, the “RCT”).² After Reapplix reported favorable results from the RCT,³ CMS approved a follow-up claims-based trial for the 3C Patch®.⁴

In general, Reapplix strongly supports the proposal to provide national coverage for autologous PRP for “chronic non-healing diabetic wounds,” and to give local MACs the authority to cover autologous PRP for “all other chronic non-healing wounds.” This proposal is consistent with the available evidence, including the RCT, and Reapplix encourages CMS to finalize this aspect of the Memo as proposed.

However, Reapplix does have concerns about certain technical aspects of the operative National Coverage Determination (NCD) language provided in Appendix B of the Memo. As a result, Reapplix recommends that CMS modify the Memo as follows:

1. Modify the description of “PRP” to clarify that the 3C Patch® System would be covered under the NCD. The Memo proposes coverage for “autologous PRP.” Given the Memo’s favorable characterization of the RCT, we understand CMS intends for the 3C Patch® System to be one type of “autologous PRP” covered under the NCD.

   The Memo currently describes “PRP” as a product that “contains whole cells including white cells, red cells, plasma, platelets, fibrinogen, stem cells, macrophages, and fibroblasts.” We are surprised by the inclusion of “macrophages” and “fibroblasts” in this description, as these cells are not part of whole blood. The 3C Patch® System produces a PRP gel comprised of components from whole blood – primarily fibrin, thrombocytes, and leukocytes, but also red cells, stem cells, monocytes, and fibrocyte precursors.

   We are concerned that if a Medicare Administrative Contractor (MAC) interprets the NCD to require a PRP product to produce PRP that includes all of the elements referenced in the Memo’s current description, the 3C Patch® System would not be eligible for coverage. To clarify that CMS intends to cover PRP produced by systems like the 3C Patch® System, we encourage CMS to modify its description of “PRP” to read as follows:

   The PRP is different from previous products in that it contains whole cells including white cells, red cells, plasma, platelets, fibrinogen, stem cells, macrophages and fibroblastsfibrocyte precursors.

   The “clean” version of this language reads as follows:

   The PRP is different from previous products in that it contains whole cells including white cells, red cells, plasma, platelets, fibrin, stem cells, and fibrocyte precursors.
2. Recommended deletion of non-coverage language for “cutaneous” wounds. As outlined above, the Memo proposes national coverage for autologous PRP for “chronic non-healing diabetic wounds,” and to give local MACs the authority to cover autologous PRP for “all other chronic non-healing wounds.” However, the Memo also states that autologous PRP is non-covered when used for the treatment of “chronic, non-healing, cutaneous wounds” (emphasis added).

   Excluding all “cutaneous” wounds from coverage would be inconsistent with clinical evidence supporting the use of the 3C Patch® System and other autologous PRP systems, as the underlying studies were not limited to subcutaneous wounds. For example:

   • Clinical data supporting the 3C Patch® System. In the CED-approved RCT, researchers divided the wounds treated with the 3C Patch® System into “superficial”, “down to tendon” and “down to bone” groups.⁵ The “superficial” wound population included patients whose wounds did not extend into the subcutaneous tissue.
   • Clinical data relied upon by CMS in the Memo. Several of the studies CMS relied upon in the Memo included patients with “cutaneous” wounds, such as the following:
     • Gude (2019): Included patients with “any wound severity (Wagner 1-4)”⁶
     • Karimi (2016): Included patients “having a DFU in grades 1 or 2 (according to the Wagner classification system for DFU”)⁷
     • Milek (2017): Included “37 patients… with degree I stage C and 13 patients with degree II stage C” on the University of San Antonio scale⁸

We understand that CMS would like to exclude coverage for the most superficial wounds. However, we would not recommend requiring the use of any particular grading methodology due to inconsistencies in patient assessment. In light of the above, we urge CMS to revise the language denying coverage for autologous PRP for the treatment of “cutaneous” wounds and replace it with language identifying wounds as non-covered if they are limited to the epidermis at initiation of treatment. (We would recommend adding the modifier “at the initiation of treatment” to avoid disruptions in coverage as wounds heal.)

For your reference, we have attached a redlined version of the draft NCD language, which illustrates our proposed edits.

Please contact me at 202.756.8794 (or by e-mail at pradensky@mwe.com]) if you have any questions regarding this request. We look forward to working with you and your staff on this request.

Sincerely yours,

Paul Radensky, M.D., J.D.

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A. General

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 4 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, in where the normal wound healing stages are not yet completed but it is presumed they will be, resulting in orderly and timely wound repair, or chronic, in where a wound has failed to progress through the normal wound healing stages and repair itself within a sufficient time period.

Platelet-rich plasma (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 for treatment of 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 includes both: (1)platelet derived growth factor (PDGF) products (such as Procuren), and (2) PRP (such as AutoloGel).

The PRP is different from previous products in that it contains whole cells including white cells, red cells, plasma, platelets, fibrinogen, stem cells, macrophages, and fibroblasts fibrocyte precursors.

The PRP is used by physicians in clinical settings in treating chronic, non-healing wounds, open, cutaneous wounds, soft tissue and bone. Alternatively, PDGF does not contain cells and was previously marketed as a product to be used by patients at home.

B. Nationally Covered Indications

Effective for services performed on or after [Month/XX][Day/XX][20XX], the Centers for Medicare & Medicaid Services (CMS) will cover autologous platelet-rich plasma (PRP) for the treatment of chronic non-healing diabetic wounds under section 1862(a)(1)(A) of the Social Security Act (the Act).

C. Nationally Non-Covered Indications

• Autologous PDGF for the treatment of chronic, non-healing cutaneous wounds.
• Autologous PRP for the treatment of chronic, non-healing, cutaneous wounds limited to the epidermis at the initiation of treatment.
• Becaplermin, a non-autologous growth factor for chronic, non-healing subcutaneous wounds.
• Autologous PRP for the treatment of acute surgical wounds when the autologous PRP is applied directly to the closed incision, or for dehiscent wounds.

D. Other

Coverage of autologous PRP for the treatment of all other chronic non-healing wounds will be determined by local Medicare Administrative Contractors (MACs) under section 1862(a)(1)(A) of the Act.

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1 510(k) Summary – BK170002 (Apr. 3, 2017), https://www.fda.gov/media/104546/download.
2 Autologous Platelet-rich Plasma (Jan. 30, 2020), https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence- Development/Autologous-Platelet-rich-Plasma (identifying “Leucopatch® System in the Management of Hard-To-Heal Diabetic Foot Ulcers” (NCT02224742) as an approved study).
3 See Game F, Jeffcoate W, Tarnow L, Jacobsen JL, et al. LeucoPatch system for the management of hard-to-heal diabetic foot ulcers in the UK, Denmark, and Sweden: an observer-masked, randomized controlled trial. Lancet Diabetes Endocrinol 2018;6(11):870-878.
4 Autologous Platelet-rich Plasma (Jan. 30, 2020), https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence- Development/Autologous-Platelet-rich-Plasma (“Reapplix 3C Patch® System for the Treatment of Diabetic Foot Ulcers: A Medicare Claims Study” (NCT03997526) as an approved study).
5 See Game F, Jeffcoate W, Tarnow L, Jacobsen JL, et al. LeucoPatch system for the management of hard-to-heal diabetic foot ulcers in the UK, Denmark, and Sweden: an observer-masked, randomized controlled trial. Lancet Diabetes Endocrinol 2018;6(11):870-878.
6 Gude W, Hagan D, Abood F, Clausen P. Aurix gel is an effective intervention for chronic diabetic foot ulcers: a pragmatic randomized controlled trial. Adv Skin Wound Care 2019;32(9):416-426.
7 Karimi R, Afshar M, Salimian M, Sharif A, et al. The effect of platelet rich plasma dressing on healing diabetic foot ulcers. Nurs Midwifery Stud 2016;5(3):e30314.
8 Milek T, Baranowski K, Zydlewski P, Ciostek P, et al. Role of plasma growth factor in the healing of chronic ulcers of the lower legs and foot due to ischaemia in diabetic patients. Adv Dermatol Allergol 2017:34(6):601-606.

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Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
BalDmore, MD 21244-1850

Laurie M. Rappl, PT, DPT, CWS
Title: Physical and Certified Wound Specialist
205 Staffordshire Way
Simpsonville, SC 29681

Re: Proposed Decision Memo for Autologous Blood-Derived Products for Chronic Non-Healing Wounds (CAG-00190R4)

Date: January 20, 2021

Dear Ms. Jensen,

In this letter I would like to provide some suggestions for clarificaton of some items in the proposed decision and also share some additional published data to complement the extensive positive outcomes shown in the Coverage Decision Memo.

As a wound care clinician who used autologous platelet rich plasma (PRP) on patients for nearly 2 decades, I have consistently seen improved healing, positive change in healing trajectory, reduced pain, reduced exudate, and improvement in patient's wellbeing. I am pleased that the published, peer-reviewed literature is finally demonstrating enough data so that CMS can propose a positive coverage decision for using this advanced technology for the treatment of diabetic wounds. Clinically I have seen the same positive outcomes in venous and especially pressure ulcers so I respectfully request that they would be included in this positive decision.

In reviewing the excellent exhaustive literature review that the Coverage and Analysis Group conducted, it was commented that even with the variety of study designs among the publications there was a consistent trend of PRP treated wounds having better outcomes than non-PRP treated wounds especially in diabetic wounds. The trend is there also in venous and pressure ulcers. While the critique documented flaws in most of the studies, the overwhelming consistency of positive outcomes with PRP demonstrated its efficacy. It is commendable that CMS noted in the proposed decision, “Given the myriad logistical challenges, the different approaches, and extent to which the trials addressed the challenges, it is notable that all the above trials consistently reported favorable outcomes for increased healing with PRP.”

Clarifications

The following are several areas to help clarify statements in the Proposed Decision Memo for Autologous Blood-Derived Products for Chronic Non-Healing Wounds (CAG-00190R4):

Background Section and Memo Appendix B:

Food and Drug Administration (FDA) Status

The PRP product AutoloGel renamed Aurix has two FDA clearances. The initial one was for the centrifuge that produced the PRP, the later one was for the end-product, the PRP gel that was produced by the entire AutoloGel System including the centrifuge, reagents, formula for producing the gel, dressings, and the application to wounds. This latter clearance ensured that there was consistent standardized formulation of the PRP gel that was applied to the wounds and used in the AutoloGel/Aurix studies. The two FDA Clearances for AutoloGel/Aurix (Autologous Platelet Rich Plasma) are:

Additional Data for Considera(on - See also Appendices

The Coverage and Analysis Group (CAG) was not only interested in the rate of wound healing but also “the reduction of wound size or healing trajectory as an intermediary towards a final endpoint of a patient's ability to return to previous function and resumption of normal activities.” While the studies did not document “a patient's ability to return to previous function and resumption of normal activities”, several studies definitely documented the reduction of wound size or healing trajectory in a short period of time

Frykberg, R. G., Driver, V. R., Carman, D., Lucero, B., Borris-Hale, C., Fylling, C. P., et al. (2010). Chronic wounds treated with a physiologically relevant concentration of platelet-rich plasma gel: a prospective case series. Ostomy Wound Management, 56(6), 36-44.
Key Points

• Number of patients = 49, Number of wounds = 65
• Mean previous duration without healing = 47.8 weeks
• All etiologies (n=65 wounds): In 2.8 weeks with 3.2 AutoloGel applications
  • 89.2% of the wounds had 62% volume reduction
  • 84.6% of the wounds had 50.9% area reduction
  • 100% of the wounds had 77.8% undermining reduction
  • 100% of the wounds had 45.8% sinus tract/tunneling reduction
• Pressure ulcers (n=17 wounds) : In 2.8 weeks with 3.2 AutoloGel applications
  • 85.7% of the wounds had 58% volume reduction
  • 76.2% of the wounds had 49% area reduction
  • 100% of the wounds had 66.7% undermining reduction
  • 100% of the wounds had 38.9% sinus tract/tunneling reduction
• Venous ulcers (n=11 wounds) : In 2.8 weeks with 3.2 AutoloGel applications
  • 93.8% of the wounds had 61.5% volume reduction
  • 93.8% of the wounds had 47.7% area reduction
  • No wounds with undermining, sinus tracts/tunneling
• Diabetic ulcers (n=10 wounds): In 2.8 weeks with 3.2 AutoloGel applications
  • 85.7% of the wounds had 75.4% volume reduction
  • 85.7% of the wounds had 67.2% area reduction
  • 100% of the wounds had 77.3% undermining reduction
  • 100% of the wounds had 69.1% sinus tract/tunneling reduction

Rappl LM. (2011) Effect of platelet rich plasma gel in a physiologically relevant platelet concentration on wounds in persons with spinal cord injury. Intl Wound Journal. 8(2), 187-195.
Key Points

• Number of spinal cord injured (SCI) patients = 20, Number of wounds = 20 (largest wound if patient had multiple wounds)
• 18/20 of the wounds were pressure ulcers. 2/20 were lower leg ulcers.
• Mean previous duration without healing = 79.4 weeks
• All etiologies: In 3.4 weeks with 4 AutoloGel applications
  • 90% of the wounds had 67.3% volume reduction
  • 90% of the wounds had 53.8% area reduction
  • 75% of the wounds had 47% undermining reduction
  • 100% of the wounds had 26.1% sinus tract/tunneling reduction
• These positive outcomes occurred even though the patient's hemoglobin and hematocrit were below normal.
• The article by Carter et al, 2011 cited and detailed on page 8 of this commentary is a comparative run in article that demonstrates the change in the wounds from non-healing to healing. This Rappl observational study corroborates this acDon of change.
• In SCI wounds with a mean duration of 79.4 weeks, 90% rapidly iniDated robust healing with AutoloGel.

de Leon J, Driver VR, Fylling CP, Carter MJ, Anderson C, Wilson J, et al. (2011) The clinical relevance of treating chronic wounds with an enhanced near-physiological concentration of platelet rich plasma (PRP) gel. Advances in Skin and Wound Care, 24(8), 357-368.
Key Points

• Number of patients = 200, Number of wounds = 285
• Mean previous duration without healing = 48.1 weeks
• All etiologies: In 2.2 weeks with 2.8 AutoloGel applications
  • 90.5% of the wounds had 63.6% volume reduction
  • 86.3% of the wounds had 47.5% area reduction
  • In 1.8 weeks with 2.5 AutoloGel applications:
    • 89.4% of the wounds had 71.9% undermining reduction
    • 85.7% of the wounds had 49.3% sinus tract/tunneling reduction
• Pressure ulcers (n=142 wounds) : In 2 weeks with 2.6 AutoloGel applications
  • 90.8% of the wounds had 61.0% volume reduction
  • 88.0% of the wounds had 46.8% area reduction
  • 90.9% of the wounds had 66.5% undermining reduction
  • 94.1% of the wounds had 39.0% sinus tract/tunneling reduction
• Venous ulcers (n=32 wounds) : In 2.1 weeks with 2.4 AutoloGel applications
  • 93.8% of the wounds had 56.6% volume reduction
  • 87.5% of the wounds had 40.2% area reduction
  • 100% of the wounds had 100% undermining reduction
  • No wounds with sinus tracts/tunneling
• Diabetic ulcers (n=41 wounds): In 3.4 weeks with 4.0 AutoloGel applications
  • 87.9% of the wounds had 74.0% volume reduction
  • 90.2% of the wounds had 60.2% area reduction
  • In 1.8 weeks with 2.5 AutoloGel applications:
    • 100% of the wounds had 77.8% undermining reduction
• In 2.5 weeks with 2.3 AutoloGel applications:
  • 100% of the wounds had 80.0% sinus tract/tunneling reduction
• Overall, in wounds that had been present for 48.1 weeks, 97% of them responded positively with a fast-healing trajectory which corroborates with the Carter et al, 2011 run-in study cited and detailed on page 8 of this commentary.
• The mean area reduction per day varied by wound size with the largest wounds having the largest reduction (1.59 cm2/day); medium wounds (0.189cm2/day); and small wounds (0.068 cm2/day). The differences between small and medium and small and large wounds were significant (p = 1.0 x 10-14, and p = 1.0 x 10-250, respectively)
• Deeper wounds had the same positive healing trajectory as shallow wounds.
• These succeeding 210 wounds had the same positive healing trajectory as the initial 65 wounds in the registry (Frykberg, 2010) indicaDng consistency in outcomes.
Patients with low lab values (n = 32) had the same positive healing trajectory as those patients with higher lab values (n = 33).
• Medicare beneficiaries (n = 111 wounds) had the same positive healing trajectory as non-Medicare beneficiaries (n = 135 wounds).

Glover JL, Weingarten MS, Buchbinder DS, Poucher RL, Deitrick GA, Fylling CP. A four-year multicenter retrospective study of topical multiple growth factor therapy for chronic wounds. Adv Wound Care 1997;10(1):27-32.

Results complement

Gude W, Hagan D, Abood F, et al. Aurix Gel is an effective intervention for chronic diabetic foot ulcers: A pragmatic randomized controlled trial. Adv Skin Wound Care. 2019 Sep;32(9):416-426.

The randomized clinical trial conducted under the CED program published by Gude et al, 2019 and thoroughly abstracted in the Proposed Decision Memo, Internal Technology Assessment was a prospective study of the use of PRP plus usual and customary care (UCC) versus UCC alone in the average wound seen in outpatient wound care centers; there were no inclusion/exclusion restrictions, all wounds were enrolled. Previous to that study, a retrospective study by Glover et al, 1997 summarized below was conducted over 4 years at 39 outpatient wound care centers on the use of Procuren (platelet releasate – the predecessor method of processing autologous blood derived products) plus UCC then called comprehensive wound care versus UCC alone. Wound healing and limb salvage was studied in 3,830 patients, only the largest wound for each patient was included in the study so 3,830 wounds were followed. This large retrospective data set conducted in sites similar to the Gude CED prospective study complements the Gude results.

Glover is a retrospective study that was conducted to evaluate wound healing rates and limb salvage. A standardized, customized database was uDlized to gather data on patients treated for chronic wounds of various etiologies during a 52-month period in 39 hospital-affiliated ambulatory wound care centers. A total of 3,830 patients were studied. Wound healing and limb salvage rates in 2,811 patients treated with a comprehensive wound care (CWC) regimen plus autologous topical multiple growth factor therapy—platelet releasate (PR)—was compared to 1,019 patients who received only a CWC regimen. There was no staDsDcal significance between the two groups except that the CWC + PR wounds were more severe (P=0.00032) and had larger wound volume (P=0.00004).

Overall healing rates were higher in the CWC + PR group relaDve to the CWC group (65.7%/50.8%; P< 0.00001), respecDvely; amputation rates were lower for CWC + PR than for CWC patients (4.1%/7.6%; P=0.00005). Healing rates per eDology were higher for the CWC + PR group vs. the CWC group:

Diabetic amputation rates were lower in the CWC + PR group, 6.0%, than in the CWC group 13.3% (P=0.00012).

In diabetic wounds of increasingly greater severity (demonstrated by incremented wound grades), the rate of healing was higher and the rate of amputation lower in the CWC + PR group vs. the CWC group:

No clinically significant adverse events were observed. The study concluded that CWC + PR produced higher rates of wound healing and increased limb salvage for all wounds.

Venous Wounds
Regarding venous wounds, the CAG stated: “All of the studies invesDgaDng venous wounds showed either an increase rate of healing wounds, or a reduction in the size of the wounds.” Rather than transferring the decision to the local MACs, with this additional data demonstrating the quick change in healing trajectory of venous ulcers when treated with PRP, I would recommend that venous wounds be included in the proposed positive coverage decision. Delaying this decision would just delay non-healing for Medicare beneficiaries.”

Pressure Wounds
Regarding pressure wounds, the CAG stated: “We must be mindful that because of the small number of studies and participants, we are not able to definiDvely say the PRP does not work in this patient group.” In the additional data posted above, pressure wounds responded positively to the PRP treatment and changed from a month or year-long stagnant non-healing status to a positive healing trajectory in 2 – 4 weeks. These studies were not designed to go all the way to healing otherwise that data would have been available. But this significant change in healing trajectory has not been accomplished by other wound treatment modalities in the literature. Rather than transferring the decision to the local MACs, with this additional data demonstrating the quick change in healing trajectory of pressure wounds when treated with PRP, I would recommend that pressure wounds be included in the proposed positive coverage decision. Delaying this decision would just delay non-healing for Medicare beneficiaries.”

Summary

In summary, I would like to recommend that the Proposed Decision Memo for Autologous Blood-Derived Products for Chronic Non-Healing Wound (CAG-00190R4) include coverage for diabetic, venous, and pressure wounds.

Thank you for this opportunity to share some clarification and additional data with the Coverage and Analysis Group. I sincerely appreciate your careful consideration of this new information. Please contact me if you have any questions.

Sincerely,

Dr Laurie Rappl, PT, DPT, CWS
Physical Therapist and CerDfied Wound Specialist
lrappl630@gmail.com
864-915-5679

Appendices

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NUO THERAPEUTICS, INC.
8285 El Rio, Suite 150
Houston, TX 77054

January 20, 2021

Tamara Syrek Jensen, J.D.
Director, Coverage and Analysis Group (CAG)
Centers for Medicare & Medicaid Services (CMS)
7500 Security Blvd.
Baltimore, MD 21244-1850

Re: Comments to Proposed Decision Memorandum for Autologous Blood-Derived Products for Chronic Non-Healing Wounds (CAG-00190R4)¹

Dear Ms. Syrek Jensen:

In its 2012 final decision memo in response to Nuo Therapeutics Inc.’s (“Nuo”) third reconsideration request and in the Proposed Decision Memo (“PDM”) issued December 21, 2020, CMS notes that in assessing whether to cover autologous PRP for the treatment of chronic, non-healing wounds, “[c]omplete wound healing was the primary outcome of most importance to CMS.”²

Nuo has demonstrated with increasingly compelling evidence that Aurix (f/k/a AutoloGel)³ markedly improves complete healing of chronic, non-healing wounds. Nuo’s CED study⁴ was the culmination of a 20-year effort seeking a favorable Medicare coverage determination. The positive results of that study prompted Nuo to submit a fourth reconsideration request on May 9, 2019. CMS responded to Nuo’s request on June 13, 2019 and advised that CMS needed to postpone action on the request due to internal capacity restraints. CMS noted, however, that this delay was not meant to minimize the importance of the request. Rather, CMS wrote, “it only reflects the limitations of our available resources.”

On behalf of the multitude of Medicare beneficiaries suffering daily from the debilitating effects of chronic, non-healing DFUs, VUs, and PLUs, Nuo is grateful to CMS for agreeing to Nuo’s fourth reconsideration request, especially in light of the significant additional strains on CMS’ resources stemming from the COVID-19 pandemic. In addition, Nuo commends CMS for commissioning AHRQ to conduct a technology assessment (MYOE59) of the field (the “AHRQ-TA”).

Most importantly, Nuo appreciates CMS’ preliminary determination, as reflected in the Proposed Decision Memo, to both (i) authorize coverage of autologous PRP for the treatment of chronic non-healing DFUs and (ii) allow local MACs to determine whether to cover the use of autologous PRP for treatment of any other chronic non-healing wounds. To assure that CMS’ primary goal of “complete wound healing” is achieved, Nuo offers this single substantive comment regarding the proposed coverage language in Sections B and D of “Appendix B” to the Proposed Decision Memo:

As detailed below, there are three primary reasons coverage should be limited to FDA-cleared devices having an indication as being suitable for the management of exuding cutaneous wounds, such as leg ulcers, pressure ulcers, and diabetic ulcers and mechanically or surgically debrided wounds (hereinafter, a “chronic wound management indication”):

1. RCTs Using FDA-Cleared Devices Having A Chronic Wound Management Indication Have Produced Favorable Outcomes For Complete Healing While Those Cleared Exclusively For Bone Grafts And Other Orthopedic Procedures Have Failed To Demonstrate Complete Or Improved Healing.

In its notice in the Federal Register of August 7, 2013, entitled “Revised Process for Making National Coverage Determinations,” CMS stated that “generally we will not accept coverage for a device or pharmaceutical that has not been approved or cleared for marketing by the FDA for at least one indication.”⁶ The Proposed Decision Memo and the AHRQ-TA concur in this assessment, with both explicitly stating: “If a medical device is labeled or promoted for manufacturing PRP for the purpose of administering the device output to a patient, then the device would require FDA approval or clearance for that use prior to marketing in the U.S.” (PDM at 7; AHRQ-TA at 19).

The Proposed Decision Memo states that “CMS is evaluating PRP as a service, and not a specific system for administering PRP.” (PDM at p.5). Based on the above guidance from CMS, however, coverage for the service of administering autologous PRP for the treatment of a chronic non-healing wound cannot realistically be separated from the delivery system which must be FDA-cleared “for that use prior to marketing in the United States.” (Emphasis added). The AHRQ-TA listed ten FDA-cleared devices that currently produce autologous PRP for clinical use at the patient’s point of care. (AHRQ-TA at 19, Appendix Table M). Notably, the only indication carried by eight of these ten devices is the mixing of PRP “with autograft and/or allograft bone prior to application to an orthopedic site” and none carry a chronic wound management indication. By way of contrast, the devices marketed by Nuo and Reapplix each carry an indication exclusively for use in chronic wound management.

It is instructive to compare these two different cleared indications to appreciate the magnitude of the differences at issue. The vast majority of autologous PRP devices with marketing clearance for orthopedic procedures have the following indication for use:

In some instances, the indication includes an explicit disclaimer regarding its use, such as:

In contrast, the chronic wound management indication for Nuo’s Aurix system and Reapplix’s 3C Patch are identical and state:

Both the AHRQ-TA and the Proposed Decision Memo establish that the only two FDA-cleared devices bearing a chronic wound management indication (i.e., those marketed by Nuo and Reapplix) are effective in achieving the primary outcome of complete healing of DFUs. (PDM at 35) (“Of the trials, the Game [Reapplix] study followed by the Gude [Nuo] study appeared to have the strongest methods for assessing ulcer healing (see the table); both specifically addressed diabetic foot ulcers.”). By comparison, seven of the eight FDA-cleared devices bearing an indication only for orthopedic procedures have never even undertaken a randomized controlled trial (“RCT”) or observational study to assess whether their autologous PRP system actually heals DFUs or other chronic wounds. And the sole FDA-cleared device (the Biomet-GPS) evaluated in an RCT to assess the effectiveness of the autologous PRP generated on the management of chronic wounds found “no statistical difference on complete wound healing” or healing trajectory. (AHRQ-TA at Appendices H-5 and J-1, citing the Kakagia RCT).

This disparity in effectiveness between FDA-cleared PRP delivery systems having a chronic wound management indication and those bearing only an indication for orthopedic procedures strongly supports Nuo’s recommendation that Sections B and D of “Appendix B” to the Proposed Decision Memo should be revised to limit coverage to services performed using FDA-cleared devices that have a chronic wound management indication.

Narrowing the proposed coverage to FDA-cleared devices carrying a chronic wound management indication is also entirely appropriate—both logically and clinically—given (i) the heterogeneity of PRP formulations, preparations, dosages, and frequency of applications and (ii) the summary of findings in the AHRQ-TA and the Proposed Decision Memo, both of which chronicle the array of autologous PRP formulations that have proven ineffective in improving the healing rate or healing trajectory of chronic wounds. (See AHRQ-TA at Appendix J (Summary of Findings); PDM at Appendix D (Summary of Evidence)). Indeed, seven of the 11 RCTs summarized at Appendix J to the AHRQ-TA (excluding the three RCTs using Nuo’s Aurix or Reapplix’s 3C Patch) reported no significant difference between the outcomes of chronic wounds treated with PRP and the control arm.

Similarly, the summary of evidence in the Proposed Decision Memo indicates that none of the systematic reviews included any meta-analysis of the subject data because of the lack of standardization and heterogeneity of PRP formulations and delivery protocols. Further, the value of the Karimi and Milek studies was questioned by AHRQ, which noted that (i) “the [Karimi study] reported conflicting and potentially anomalous results in different sections of the paper” and (ii) it had to “double check” the Milek study because of the miniscule 0.019 cm2 average wound size in that study. (AHRQ’s “Research Review Disposition of Comments Report,” Responses to Peer Reviewers ## 9, 10).⁷

2. Substantial Precedent From The Medicare National Coverage Determinations Manual Supports Limiting Coverage To FDA-Cleared Devices Having A Specific Indication For Chronic Wound Management.

In other national coverage determinations, CMS has found it appropriate to limit coverage of medical items or services to those performed using FDA-approved or cleared devices that carry a specific indication:

• Section 20.7 of the manual limits coverage of percutaneous transluminal angioplasty “to procedures performed using an FDA-approved CAS stents and FDA-approved or -cleared embolic protection devices.”


• Section 250.5 of the manual limits coverage for dermal injections for the treatment of facial lipodystrophy syndrome those “using dermal fillers approved by the Food and Drug Administration for this purpose.”


• Section 260.7 of the manual limits coverage for lymphocyte immune globulin preparations to ones “indicated for the management of allograft rejection episodes in renal transplantation.” This section further notes that “other forms of lymphocyte globulin preparation which the FDA approves for this indication in the future may be covered under Medicare.”

Here, too, it would be entirely appropriate for the proposed amendment to section 270.3 of the National Coverage Determinations Manual to limit coverage of autologous PRP services to those using an FDA-cleared device that carries a chronic wound management indication.

3. The Risks From Expanding Coverage Beyond FDA-Cleared Devices With A Chronic Wound Management Indication Are Significant.

Sensing an open-ended business opportunity, PRP device companies marketing FDA-cleared devices with indications only for use in orthopedic procedures have presumed that the final coverage will enable them to market their devices in the chronic wound space. If true, this would be a very unfortunate result that would likely forever tarnish this nascent therapy for the management of chronic wounds since no RCT has ever concluded such devices are effective in the management of chronic wounds. Indeed, the only RCT to assess the effectiveness of an FDA-cleared orthopedic device on chronic wounds found no difference in complete healing or improved healing trajectory between the PRP applications and the control arm. (AHRQ-TA at Appendices H-5 and J-1, citing the Kakagia RCT).

Opening the barn doors by authorizing coverage of any FDA-cleared device that produces autologous PRP, regardless of whether it carries a chronic wound management indication will invariably result in large and well-resourced companies marketing their existing PRP devices into the chronic wound arena despite no study showing the output from such devices is effective in healing chronic wounds. As Nuo proposes in the attached redline at Exhibit A hereto, the final coverage decision should exclude from coverage any FDA-cleared device for production of autologous PRP that lacks a chronic wound management indication. Private insurers and chronic wound management providers have long been reluctant to use FDA-cleared autologous PRP therapies for chronic wound management in light of CMS’ long-standing national coverage determination denying or significantly circumscribing coverage. If PRP devices indicated exclusively for orthopedic procedures are granted coverage, the likely unsatisfactory clinical outcomes from those devices will further dissuade an already skeptical market from adopting this proven, pragmatic therapy.⁸ The end-result is a predictable one: misconceptions of the value of autologous PRP for chronic wound management will continue; untold resources will be wasted on ineffective PRP therapies; and—worst of all—large portions of the ever-growing chronic wound-ridden Medicare population will unnecessarily suffer from these often debilitating wounds and the related amputations and untimely deaths that too often follow in their wake.⁹

Where appropriate, CMS has limited nationwide coverage to FDA-cleared devices having specific indications. Such limitation is appropriate here, too.

Nuo is available to review its comment with CMS and closes by again expressing its deep gratitude to CMS for advancing Nuo’s fourth reconsideration request with due speed and deliberation.

Sincerely,

David Jorden
Chief Executive Officer

B. Nationally Covered Indications

Effective for services performed on or after [Month/XX][Day/XX][20XX], the Centers for Medicare & Medicaid Services (CMS) will cover autologous platelet-rich plasma (PRP) for the treatment of chronic non-healing diabetic wounds under section 1862(a)(1)(A) of the Social Security Act (the Act) where the PRP is produced using an FDA-cleared device having an indication of being suitable for the management of exuding cutaneous wounds, such as leg ulcers, pressure ulcers, and diabetic ulcers and mechanically or surgically debrided wounds.

. . .

D. Other

Coverage of autologous PRP for the treatment of all other chronic non-healing wounds will be determined by local Medicare Administrative Contractors (MACs) under section 1862(a)(1)(A) of the Act where the PRP is produced using an FDA-cleared device having an indication of being suitable for the management of exuding cutaneous wounds, such as leg ulcers, pressure ulcers, and diabetic ulcers and mechanically or surgically debrided wounds.

1 Capitalized terms used herein and not otherwise defined shall have the meanings set forth in the Proposed Decision Memo.
2 CMS Decision Memo for Autologous Blood-Derived Products for Chronic Non-Healing Wounds (CAG-00190R3) at 27; PDM at 8.
3 Section A of “Appendix B” to the Proposed Decision Memo references “AutoloGel” as one of the autologous blood derived products available for chronic, non-healing wounds. Nuo requests that this reference instead be changed to “Aurix (f/k/a AutoloGel).” In October 2014, Nuo rebranded AutoloGel under the name Aurix.
4 Warren Gude MD, Dan Hagan DPM DABPS, Ferial Abood MD, and Peter Clausen PhD, Aurix Gel is an Effective Intervention for Chronic Diabetic Foot Ulcers: A Pragmatic Randomized Controlled Trial, ADVANCES IN SKIN & WOUND CARE, September 2019; 32:416-25.
5 A redline version of Nuo’s suggested changes to Sections B and D of “Appendix B” to the Proposed Decision Memo is attached hereto as Exhibit A.
6 78 Fed. Reg. 48164, 48165 (August 7, 2013).
7 Found at https://www.ahrq.gov/sites/default/files/wysiwyg/research/findings/ta/comments/prp-wound-care-comments.pdf
8 Warren Gude MD, Dan Hagan DPM DABPS, Ferial Abood MD, and Peter Clausen PhD, Aurix Gel is an Effective Intervention for Chronic Diabetic Foot Ulcers: A Pragmatic Randomized Controlled Trial, ADVANCES IN SKIN & WOUND CARE, September 2019; 32:416-25.
9 The AHRQ-TA opened with the following statement regarding the prevalence of chronic wounds within the Medicare population and the cost burden of these wounds on the Medicare system: Chronic wounds are a common chronic medical condition with a high impact on the aging population, with chronic wounds or infections affecting nearly 15 percent of Medicare beneficiaries with a healthcare burden of $28 to $96 billion United States (US) dollars per year. (AHRQ-TA at 1).

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I have been in the full-time practice of wound management for 30 years and am a nationally recognized expert in the field. I have extensive clinical experience with several different autologous PRP formulations both inside and outside of IRB approved clinical trials. I applaud CMS’ determination in the Proposed Decision Memo, to both authorize coverage of autologous PRP for the treatment of chronic non-healing diabetic foot ulcers (DFUs) and allow local MACs to decide whether to cover the use of autologous PRP in other chronic non-healing wounds. However, I am concerned about the way that “autologous PRP” will be defined in this policy.

Nearly 3 decades ago I began using various autologous blood preparations in hopes of healing refractory wounds. None of them worked. I had given up on the concept until I began treating patients with what was originally called Autologel (Cytomedix, now Nuo). It remains the only product able to close deep tunnels and undermining in wounds – in addition to its ability to heal otherwise refractory ulcers. It is unfortunate that poor decisions by the leadership of the company impacted the success of studies performed under CED. I have also used the “3-C patch” by Reapplix with great success. I have no affiliation with either aforementioned company. My concern is that all autologous products are not created equal. Some of them have demonstrated their clinical effectiveness and some have not.

I urge CMS to specify that coverage of autologous PRP for the treatment chronic non-healing wounds be limited to services performed using devices cleared by the FDA for the production of autologous PRP with an indication for the management of cutaneous wounds. There are many PRP products currently approved for other indications (e.g orthopedics) that have no data to support their use in open wounds and are not FDA cleared for this purpose, but which will nonetheless be used in the treatment of wounds under this new coverage policy. Also, Medicare will be billed for “homemade” PRP preparations which, had they worked, would have made the investment in devices for PRP delivery unnecessary.

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January 20, 2021

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, Maryland 21244-1850

RE: Autologous Blood-Derived Products for Chronic Non-Healing Wounds - (CAG-00190R4)

Dear Director Syrek Jensen:

On behalf of the Alliance of Wound Care Stakeholders (“Alliance”), I am pleased to submit comments in support of the National Coverage Decision (NCD)for Autologous Blood-Derived Products for Chronic Non-Healing Wounds. The Alliance is a nonprofit multidisciplinary trade association representing physician specialty societies, clinical and patient associations whose mission is to promote evidenced-based quality care and access to products and services for people with chronic wounds. The Alliance has a vested interest in this coverage decision as some of our clinical association members have used these products successfully to treat their patients with chronic nonhealing wounds. They have informed us that they are pleased that the Agency determined a positive coverage decision for these products since that will give them an additional choice of treatment options for their patients.

The Alliance applauds and supports Medicare’s decision to provide coverage for the use of autologous platelet-rich plasma (PRP) for patients with chronic non-healing wounds. However, we believe that there are certain aspects of the coverage decision which need to be modified.

CMS states that there will be national coverage for autologous PRP for “chronic non-healing diabetic wounds,” and the local MACs will have the authority to cover autologous PRP for “all other chronic non-healing wounds.” We agree with this language. However, CMS further states that autologous PRP is non- covered when used for the treatment of “chronic, non-healing, cutaneous wounds.” The Alliance disagrees with this statement and recommends deleting it from the policy. PRP has been used on chronic non healing cutaneous wounds and in fact CMS utilized several studies in this coverage decision in which patients had “cutaneous” wounds. The Alliance recommends deleting this sentence from the policy .

Furthermore, there is some language in the policy that is not clinically accurate. The policy states, “The PRP is different from previous products in that it contains whole cells including white cells, red cells, plasma, platelets, fibrinogen, stem cells, macrophages, and fibroblasts.” This is not accurate. Blood does not contain macrophages and fibroblasts. Therefore, the Alliance recommends that the language be modified to read: “The PRP is different from previous products in that it contains whole cells including white cells, red cells, plasma, platelets, fibrinogen, stem cells, monocytes, and fibrocyte precursors.”

On behalf of the Alliance of Wound Care Stakeholders, we appreciate the opportunity to submit these comments in support of the National Coverage Decision on Autologous Blood-Derived Products for Chronic Non-Healing Wounds. Please contact me if you have any questions regarding our endorsement of this policy as well as our recommendations to modify the language.

Sincerely,

Marcia Nusgart R.Ph.
Executive Director

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As a pharmacist with 35 years experience in hospital and long term care I applaud CMS’ recent proposed decision to cover Autologous PRP (A-PRP) product for chronic wounds.

I had commented in April this would be a significant addition to the therapeutic armamentarium. I respectfully offer these considerations which I believe will enhance the policy. 

1. I am concerned that the current decision will lead to overuse by non-effective A-PRP systems The AHRQ study shows some A-PRP systems are clinically appropriate for managing chronic wounds, while other PRP systems or devices are indicated for orthopedic procedures.Thus, CMS’ patients will be better served by covering only those PRP systems that are FDA approved for wound management. 

2. I am concerned that covering diabetic wounds nationally but leaving PU & VUs to local decision will further the disparity among ethnic groups, which the AHRQ study clearly shows now occurs. 

Clinical Pharmacy recognizes patients respond differently to drugs and when a patient fails to respond to one drug we quickly change to an alternate drug. Similarly, CMS should cover A-PRP for all 3 three wound etiologies.

Discontinue coverage when a patient fails to respond after an initial treatment window of 30-90 days.

Thank you for your consideration,
Phillip Wright, RPh

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January 20, 2021

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

Re: Proposed Decision Memo for Autologous Blood-Derived Products for Chronic Non-Healing Wounds (CAG-00190R4)

Dear Ms. Jensen:

AABB appreciates the opportunity to submit comments in response to the Proposed Decision Memo for Autologous Blood-Derived Products for Chronic Non-Healing Wounds. AABB is an international, not-for-profit association representing institutions and individuals involved in transfusion medicine and cellular therapies. The association is committed to “improving lives by making transfusion medicine and biotherapies safe, available and effective worldwide.” AABB works toward this vision by developing and delivering standards, accreditation and educational programs that focus on optimizing patient and donor care and safety. AABB individual membership includes physicians, nurses, scientists, researchers, administrators, medical technologists, and other health care providers. AABB’s accreditation program started in 1958, and since 1995 AABB has served as a deemed accrediting organization for the Centers for Medicare & Medicaid Services (CMS) for transfusion medicine, blood donor activity, cellular therapy services, immunohematology reference laboratories and molecular testing laboratories.

AABB appreciates that CMS relied on an extensive review of clinical evidence for the coverage determination analysis. We recommend that CMS recognize in its decision memo for autologous platelet-rich plasma (PRP) for the treatment of chronic non-healing wounds standards-setting and accreditation organizations, including AABB, to ensure the safety and quality of these treatments.

For example, AABB has an established standards and accreditation program that supports improved outcomes for patients receiving PRP. The AABB Standards for Perioperative Autologous Blood Collection and Administration (Perioperative Standards) covers all elements of collecting, manufacturing, and administering PRP. Additionally, these Standards are written by experts and include guidance on the collection, storage, transport, testing, processing, administration, and patient outcomes for these products. The Perioperative Standards also contain requirements that focus on the clinical care of the patient, including any special conditions that should be considered for optimal patient outcomes after treatment.

We encourage CMS to work with AABB to ensure product quality and patient safety for treatment options utilizing blood and blood products. Thank you for the opportunity to provide feedback. If you have any questions, please contact Susan Leppke at sleppke@aabb.org or 301.547.3962.

Sincerely,

Debra BenAvram
Chief Executive Officer
AABB

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As I understand in my review of the AHRQ Technology Assessment and CMS proposed decision, there are two types of devices in the field that produce PRP; 1 type is indicated by FDA 510K clearance for use in orthopedics and other surgical settings and 1 type is indicated for use in chronic wounds.

Providing coverage for products or treatment systems that lack clinical evidence for efficacy in wound treatment can have unintended consequence of economically incentivizing usage “Off label”.

In my experience when the medical community is free to utilize pharmaceutical products for treatment not FDA indicated it often proves to be a waste of valuable resources. In fact it is often the most heated discussion in medical staff Pharmacy & Therapeutics committees.

I believe it is in the best of interest of CMS, patients and the providers to assure that coverage is only extended to those products which demonstrate clinical efficacy through proven clinical evidence such as FDA clearance or approval for use in chronic wounds.

Additionally, given my experience in the long term care setting we see many patients who suffer from pressure ulcers that are often treated topically or superficially given the unavailability of product to conforming to the hidden an often cavernous undermining of Wagner II & IV wounds. CMS would well serve the patient to provide national determination to cover Autologous PRP for these wounds.

Thus would provide for treatment as a first defense to bring closure to the undermining or at least significant reduction to the would volume, thereby allowing for PRP or alternate treatments to then close the superficial wounds as they have advance healing down to a Wagner grade I or II.

Thank you for your consideration of making PRP a part of healing for treating professionals

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I am writing in support of coverage for PRP methods for healing open chronic wounds, specifically those that have an evidence base such as an FDA indication. My specific interest is in pressure ulcers. [PHI Redacted] Throughout these comments I will make most reference to one PRP, Aurix, as that is the one with which I am experienced. I once worked for the company but for 5 years have had no affiliation with them in any way.

[PHI Redacted]

Closed pressure ulcers, especially on the ischium of persons in wheelchairs, are fragile and prone to breaking down again. [PHI Redacted]

Others experience - I published a peer-reviewed article on the use of Aurix on 20 wounds in persons with SCI.1 18 of the 20 wounds were pressure ulcers and on average were more than 1.5 years old.

90% of the wounds decreased 67% in volume in 3.5 weeks.
90% of the wounds decreased 53% in area in 3.5 weeks.
75% of the wounds decreased 47% in undermining.

These outcomes are extremely significant on pressure ulcers in persons with SCI. While this report is not an RCT, it does provide results to be considered along with other studies that include pressure ulcers.

At one time I worked for Nuo Therapeutics (Aurix). These dramatic results were almost commonplace as I helped clinicians learn how to use and apply Aurix. Only lack of reimbursement prevented more patients from escaping long term bedrest and quickly closing these wounds to resume their lifestyles.

Evidence Questions - In your consideration you note that your evidence questions relate to a) complete wound healing, b) reduction in size with no specification as to area or volume, and c) return to function. These do not capture the benefits of Aurix or PRP for these patients. Aurix was used to do the difficult work of filling in tunnels, undermining and depth, none of which appear to be captured in your questions and all of which are difficult to measure. After these difficult areas are filled, clinicians opt for simpler modalities like dressings which don’t require a blood draw, spin, and cell extraction. Therefore Aurix and PRP may not be credited as answering all of your evidence questions although it literally laid the very foundation for all three questions.

PRP involves a blood draw which is uncomfortable for many patients, can be difficult to accomplish if the patient is difficult to draw and the clinician is not well-practiced, and is more time-consuming for the clinician to perform. Therefore, PRP is used to fill in tunnels, undermining and depth, but when the wound is filling in well and closing quickly clinicians will opt for an easier method of treatment. Wounds are seldom treated through to complete closure with PRP. In these cases, wound surface area would not show progress with PRP, but volume and depth will. Since PRP is used for depth and subcutaneous wound filling, using volume or depth is a better measure of progress with PRP than wound area.

2 External Technology Assessments related to PU - In your consideration you note “No studies evaluated the outcome of complete wound closure”. This is not evidence that PRP does not help to close pressure ulcers. As stated above, the visible outcome of complete wound closure is not in the literature because PRP is often not used to complete closure. If a wound has closed to the point that its surface area is very small, closure can happen with simple dressings which are certainly less complicated than blood draw, spin, and cell extraction required for PRP. Forgive my repetition but it is a critical point in assessing effectiveness of this product.

In this section you note “Evidence was insufficient to estimate an effect of autologous platelet-rich plasma on wound area”. Again, wound area is a poor marker to use to look for evidence for PRP because PRP fills in depth which must happen before area can close.

Section on Analysis - Evidence Review Summary - You note, “Given the myriad logistical challenges, the different approaches, and extent to which the trials addressed the challenges, it is notable that all the [above] trials consistently reported favorable outcomes for increased healing with PRP.” That is the most remarkable finding; all trials were favorable for wound healing while using various other measures.

Plea for Access - Please do not leave the coverage of evidence-based devices and PRP for pressure ulcers up to the individual MACs. Please allow national coverage for pressure ulcers. There are dozens of products covered for diabetic ulcers, and for venous ulcers, and precious few for pressure ulcers. Patients with pressure ulcers are languishing in bed for months and years. Aurix is an extremely viable option, and will cut their healing time and medical costs short. Pressure ulcer patients do not have the numbers, the population saturation, or the advocacy organizations such as the American Diabetes Association that other wounds have, but their needs are every bit as serious and their wounds are at least as life altering as others. They need access to another modality for successful healing.?

Different centrifuges and methods of making PRP yield dramatically different end products, as many authors have written over the last several years and as recently as Everts et al, 2020.2 These different end products yield different “PRP’s”, just as generic drugs will often have different or no effects compared to the tested brand name drugs and generic versions of any drug differ from each other. Rather than waste valuable Medicare dollars on any and all products that brand themselves as PRP, I strongly encourage you to limit coverage to those products that have stood the test of extensive and critical clinical usage, documentation, and publication.

Thank you for reading all of the way through these lengthy comments.

Laurie M. Rappl, PT, DPT, CWS
Doctorate in Physical Therapy, Certified Wound Specialist
T-12 paraplegic

1 Rappl LM. Effect of platelet rich plasma gel in a physiologically relevant platelet concentration on wounds in persons with spinal cord injury. Int Wound J. 2011;8(2):187-95.
2 Everts P, Onishi K, Jayaram P, Lana JF, Mautner K. Platelet-rich plasma: new performance understandings and therapeutic considerations in 2020. Int J Mol Sci. 2020;21(20).

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Re: Reapplix 3C Patch
Using the Reapplix 3C Patch we were able to demonstrate significant healing in chronic wound patients with diabetic foot ulcers despite numerous comorbidities. This included patients with chronic wounds greater than 5 years and had previously failed numerous other modalities including Negative Pressure Wound Therapy, surgeries, multiple dressing types, amniotic grafts and hyperbaric oxygen therapy. Healing with the 3C Patch was demonstrated despite ongoing patient non-compliance with offloading and diabetes control attempts. Although there was more progress with diabetic foot ulcers compared to venous ulcers, there was improvement demonstrated in both groups. Based on its mechanism of action I would like CMS to consider expanding the 3CPatch indications to include other difficult to heal etiologies including ulcers related to delayed effects of radiation, pyoderma gangrenosum and morphea.

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Platelet Rich Plasma (PRP) is a true "trunk to bed" modality. As a mobile wound company that services thousands of wounds a week to aging or underserved populations in numerous states covering 6 MACS and 12 different Place of Service codes, modalities that do not need refrigeration or a temperature controlled environment are important and valuable. When we do not have access to advanced wound healing modalities, we incur the cost by spending healthcare dollars elsewhere. Weekly transportation costs to and from appointments to transport patients that can be treated in their own environment, if allowed is costly and time consuming, often requiring the patient to sit on the same problem wound for hours at a time to get to and from those appointments. Patients congregating while waiting on appointments can expose the already weak and wounded to a wide variety of viruses, bacteria, and other potential human-spread issues unnecessarily. PRP allows clinicians to perform this wound healing modality at the bedside from the comfort of the patient's place of residence without transporting them or requiring them to sit on the wound or even develop new wounds while sitting. This relatively painless, minimally invasive modality is a vital tool that can save so many using the power of their own blood with an FDA approved PRP medium/activator. The evidence supports using this modality when warranted and CMS has the opportunity to champion this modality by supporting it through CPT codes and assigning a Relative Value Unit (RVU) for the purposes of reimbursement.

Please be mindful when assigning a reimbursement amount, that the providers must incur the cost of the centrifuge, activator kit, and the time it takes to draw blood, spin it down, etc. Many skin substitutes/CTPs reimbursement take in to consideration the cost of the skin substitute/CTP and CMS should make the same consideration when evaluating the reimbursement of PRP.

The Quality of Life improvement from PRP is worth the effort and reimbursement CMS is considering that will allow many patients the ability to return to a better Quality of Life and/or increase in heal rates. Please allow this modality to be covered as an advanced modality for fee for service providers to be paid, reimbursed, and allowed to use across many Place of Service Codes in all the MACs for our complex wound patients suffering from a litany of co-morbid medical conditions, polypharmacy, and many other barriers preventing them from healing. PRP is an excellent choice with limited reasons for restrictions in both payment, accessibility, and adoption in to the NCD, should CMS wisely choose to allow it and reimburse appropriately.

Because PRP is applied under clean technique (versus sterile), the following Place of Service codes should be considered for this modality: 05 Indian Health Service Free-Standing Facility, 06 Indian Health Service Provide-based Facility, 11 Office, 12 Home, 13 Assisted Living Facility, 14 Group Home, 15 Mobile Unit, 19 Off Campus-Outpatient Hospital, 21 Inpatient Hospital, 22 On-campus Outpatient Hospital, 31 Skilled Nursing Facility (Excluded from Consolidated Billing), 32 Nursing Facility, 33 Custodial Care Facility, 34 Hospice, 54 Intermediate Care Facility, 61 Inpatient Rehab Facility, 62 Outpatient Rehab Facility, and 72 Rural Health Clinic. The number of place of service codes that are potentially appropriate for this modality show the versatility and ease of accessibility this product has to offer. I await your careful consideration.

Respectfully and with anticipation,

Martha R Kelso
Chief Executive Officer
Wound Care Plus, LLC

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As a medical practice that specializes only in wound medicine, we have been following the studies and reimbursement guidelines over the years related to platelet-rich plasma (PRP). We are very pleased to see the Centers for Medicare and Medicaid Services (CMS) propose new coverage guidelines. Although we have not participated in the CMS recognized studies, we have created our very own case studies that have had tremendous results on all wound types, but especially diabetic ulcerations, venous ulcerations, pressure ulcerations, and non-healing surgical wounds.

The focus of our comments is related to avoiding vendor product dependency for administering PRP to patients such as Nuo Therapeutics that submitted the formal request for coverage. It has been our experience that preparing and administering PRP to patients does not require the use of a specific vendor’s product.

Our utilization of this modality would have been much greater had there been coverage, as we have had to charge $600 per treatment to cover the costs of supplies and provider time. We feel strongly that forcing physician practices to utilize a specific vendor for a simple procedure will result in higher overall costs, and further limit the use of the overall modality of PRP on patients that can benefit from it. As such, we have submitted our organization’s policy and protocol below with references to serve as an example of preparing and administering PRP without the use of a vendor specific product.

Policy Statement:
MedCentris will provide advanced wound therapies that are current to standards of care, effective, and appropriate in the treatment of a specific condition and within best practices by industry standards.

Purpose:
The purpose of this policy is to describe the procedure of constructing and applying a Platelet Rich Plasma Graft as an adjunct therapy for wound healing by using components of the patient’s own blood to replicate one's own healing process for tissue repair. Platelet Rich Plasma Grafts is used to activate wound healing for a variety of wounds and /or tissue defects. The PRP graft construction is explained within and proprietary to MedCentris.

Scope:
This policy will apply to all MedCentris staff who undertake the decision making for the use of PRP as a part of a comprehensive wound treatment plan and those who participate in obtaining, processing and application of Platelet Rich Plasma grafts. Physicians and Advanced Practitioners will prep wound sites and apply PRP grafts. Nurse and advanced wound medicine techs with demonstrated competency working with PRP and will assist with prep of blood product and supplies.

Policy:
The Platelet Rich Plasma procedure is an accepted advanced wound therapy in the treatment of chronic wounds. PRP grafts will be utilized as adjunctive wound therapy when specific conditions exist to indicate justification of its use. MedCentris recognizes that each patient and condition effecting the wound is unique and is to be evaluated and treated on an individual basis. This policy is a guide for advanced providers and should not be used to replace clinical judgment but rather to compliment it. The procedure portion of this policy is the expected method of graft construction and application once a patient has been deemed appropriate for the procedure.

PRP procedures may not be covered by insurance and fees for service must be discussed with patient prior to procedure. An Advanced Beneficiary Notice (ABN) may be required. Current fee for service can be obtained from clinic manager or billing department. See the Guide to PRP Payment and Charge Entry that follows.

PRP grafts will be indicated only when standard wound therapy is maintained and conditions promoting healing are optimized and a comprehensive wound management plan of care is in place. Including:

• Assess the entire patient (Historical H&P plus current workup)
• Appropriate laboratory and diagnostics have been resulted and reviewed
• Characterize the wound
• Ensure adequate tissue oxygenation/blood flow
• Offload the wound
• Ensure adequate nutrition
• Treat infection
• Debride all necrotic tissue
• Remove foreign bodies
• Biopsy suspicious wounds
• Provide a moist wound environment
• Standard documentation for wound management and wound care procedures

Indications: Pre-Platelet Rich Plasma Graft Procedure

• The wound has been present without a reduction in volume for (4) weeks (unresponsive to standard advanced wound therapy or post previous Platelet Rich Plasma procedure); or
• In a traumatic or acute wound, presenting with a concern for exposed structure or inhibited “normal” repair processes, indicating the immediate need to seal, preserve bone or soft tissue, and initiate or improve immediate re-granulation, adhesion, or repair.

Absolute Contraindications

• Thrombocytopenia
• Active tumor in wound bed
• Pregnancy
• Allergy to bovine products if bovine thrombin is to be used
• Septicemia
• Local infection at the site of the procedure

Relative Contraindications:

• Platelet count < 105 per microliter
• Hemoglobin level < 10 gr/dl
• Platelet dysfunction or other blood disorder
• Anticoagulation therapy
• Consistent use of NSAIDS within 48 hours of procedure
• Patient weight less than 100 lbs
• Recent fever or illness
• Corticosteroid injection at treatment site within 1 month
• Cancer or metastatic dx– especially hematopoietic or of bone

Procedure: Activation of Platelets in Platelet Rich Plasma (PRP) using reconstituted Thrombin Materials:

• General purpose centrifuge
• White top tubes (Max 6 tubes). Can use saline cavity fill method to determine amount of PRP needed for tunnels and cavities. (For this method fill a 5 or 10 ml syringe with saline, drip saline into the wound until the fluid is at skin level, the amount of fluid required to fill the void is the amount of PRP you will want to harvest.)
• 21-gauge needle and vacutainer for venipuncture.
• Test tube rack
• Sterile container for preparation of PRP if needed. (sterile specimen contained for example)
• Thrombin, reconstituted to 10% thrombin solution as instructed on vial/package insert
• 3- 1 ml (TB) syringes (one for withdrawing thrombin, one for PRP prep, one for PRP injection)
• 2- 10 ml syringes
• 2- small gauge needles for PRP injection
• Collagen (sheet)
• Stoma paste
• Occlusive dressing material
• ABD or other suitable absorptive secondary dressing, and tape
• Sterile 2x2 gauze

Method:

• Draw blood using a 21-gauge needle or larger
• Draw appropriate amount of white top tubes (each tube collects 5 ml of blood and yields approx. 2.5 ml of PRP)
• Place the tubes in the centrifuge to produce PRP, 3500 rpm for 10 min
• Once spun, retain one tube of PRP to be drawn up and injected into the periwound/wound.

Construction of the graft:

• With THROMBIN: To activate the PRP using thrombin, add 10% thrombin solution at a ratio of 1:5 or 0.2ml thrombin solution to 1 ml PRP to the PRP using a syringe for up to 10 ml of PRP or a sterile container for amounts larger than 10 ml. Once gently mixed, the activated complex should then be delivered via the syringe or pipette to the wound promptly.
• determined by the Provider that thrombin activation is not required, the PRP can be added to sheet collagen (example: Promogran, Fibracol) to form a gelatinous patch which can be place into the wound bed.

Site preparation and application of the graft:

• Periwound should be cleansed with cholraprep and wound debrided as indicated prior to PRP application.
• Withdraw PRP from a tube. Inject this PRP into the tissue surrounding the wound and into the wound base with a small gauge needle. Distribute the PRP around and into the surrounding tissue.
• Next, prep the periwound with skin barrier prep or benzoin to protect the peri-wound.
• Use stoma paste to build a dam around the wound margins. (hint: wet gloved fingers to keep stoma paste from sticking to gloves). May also want to windowpane the wound with transparent film or protective dressing. It is normal to have drainage therefore the periwound must be protected to prevent moisture associated skin damage.
• When ready to place the prepared PRP graft (see graft construction above), place the graft into the wound bed paying special attention to filling tunnels or undermining. Fill the wound bed to the skin level. If additional fill is needed use retained PRP to back fill over the graft.
• For large area wounds, the spray method may be used to distribute the PRP over the wound bed. (For the spray method, load a 10 ml syringe with large bore needle or open end TB syringe (no needle) and gently spray the PRP across the wound bed to distribute a thin layer over the large area surface area, top this with collagen soaked with remaining PRP)
• Photograph the PRP graft on the wound, and then again after primary dressing is applied to document the procedure.
• Apply primary dressing over the PRP patch inside the stoma paste. Common primary dressing types include: additional sheet Collagen, plain gauze, or silicone contact layer.
• Cover the site with occlusive transparent film dressing or wound vac drape.
• Poke small holes in the occlusive dressing using a needle to allow for slow drainage release onto outer absorptive dressing, usually an ABD pad that can be changed as needed without disturbing the graft and primary dressing.
• Cover the entire dressing with an absorptive type of dressing such as ABD pads or other absorbent dressing.

Post Application Care:

• Maintain the primary dressing for 5 to 7 days. The outer secondary absorptive dressing can be changed as needed for drainage collection, leaving the primary dressing undisturbed.
• Post procedure patient instructions should include how to poke additional holes in the dressing should drainage become excessive, and how to change the outer absorptive dressing as needed.
• Watch for signs of infection. Inform the patient that an odor around day 3-5 is not a sign of infection alone but a natural results of the process as the platelets degrade in the wound bed.
• At first dressing change, clean peri-wound with normal saline. Gently rinse and lightly pat exudate from the wound bed, do not wipe or scrub the wound bed. The provider will determine if debridement is necessary and the degree/level. It is usually best not to disturb the granulation but rather protect and support its maturation.
• Document and photograph wound response.
• Providers will determine need for repeat application of PRP based on wound response. PRP can be performed weekly.
• When PRP series is complete, the provider will determine appropriate next course of treatment and dressing selection to preserve new tissue and promote treatment goals.

Acknowledgment of other methods of obtaining platelet rich plasma grafts:
MedCentris recognizes other methods of producing Platelet Rich Plasma Grafts and intends to follow the hosting facilities accepted method.

• For facility-based practice other than a MedCentris facility, use an activation kit for PRP acceptable to the facility you are practicing in.
• Follow activation kit manufacturer’s instruction and process

Reference and resources
1.) Clinical & Quality Management MEDICAL POLICY Copyright 2015, Proprietary Information of UCare Page 2 of 8 “Platelet Rich Plasma”
2.) Emerging trends in Wound Care Platelet Rich Plasma (PRP) Uchenna Nwaneri MD Jyoti Dharod CCP Baltimore Perfusion Conference 2013 pg. 31

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DFUs and VLUs dominate the spectrum of chronic wounds. Considering the risks for infection, gangrene, amputation and life-altering complications for a patient ailing with a chronic open wound, it is of paramount importance that implementation of products with proven efficacy to the long-term successful treatment of these ulcers be undertaken.

A medical device that prepares an autologous combined leucocyte, platelet and fibrin patch* from autologous blood by an automated 20-min process that involves centrifugation, coagulation and compaction is now available. The formed Patch consists of three-layers: fibrin, platelets and leukocytes, which is placed topically on the prepared wound¹.

This case series document the usage of the IWGDF recommended² patch on wounds non-responsive to best available care in a podiatric clinical setting. 5 patients with a total of 6 wounds; 4 DFU, 1 traumatic wound and 1 VLU were all found non-responsive to available treatments. Wound ages ranged from 9-84 months. The patients have had a diverse selection of active treatments, including enzymatic debridement, growth factor (PDGF), living cell constructs, amniotic products and HBOT without wound closure.

Patches were applied either weekly or bi-weekly dependent on wound status. 6 of 6 wounds healed completely with an average of 6,2 patch application (range 3-9) over an average of 8,2 weeks (range 6-12).These data support the clinical effect of the patch, previously found in a large (n=269) RCT on hard-to-heal DFUs3, in a US clinical setting.

In summary, we find that the automated user-friendly production using this system and application of the patch to non-healing wounds worked well in the ambulatory setting and is an efficacious, innovative and tolerated product addition to the cost-effective line on the dizzying array of available wound treatment products in the marketplace today.

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Dear Sir or Madam,

I was given a chance to use Reapplix 3 C patch in my office as a trial on patients with severe, chronic non healing Diabetic ulcer. The wounds we used this product on closed in 6 months of weekly application. One specific pt that received the product, had the ulcer on his heel for over 3 years and weekly debridement and application of other expensive products had zero effect. The wound on that pt closed completely in 6 months and since then I have only seen him twice a year for DM foot assessments. It is a great tool to add to any office setting has a lower reimbursement, it is very effective. I would love to be able to use this on many of my DM. venous, or vascular ulcers. Thank you for you time and consideration

Dr. Yousefpour

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Comments are also being submitted via email in a more readable format:

Thank you for the opportunity to comment on CMS’ Proposed Decision (CAG-00190R4) to cover autologous platelet-rich plasma (PRP) for the treatment of chronic non-healing diabetic wounds, and to allow coverage of autologous PRP for treatment of all other chronic non-healing wounds to be determined by local Medicare Administrative Contractors (MACs).

In my role as Medical Director for CMS’ Unified Program Integrity Contractor for the Midwest Region (UPIC-MW), assessing medical evidence as it applies to the nexus between Medicare beneficiaries and guidance documents (NCDs, LCDs, rules/regulations, etc.) is a fundamental part of my role.

Additionally, anticipating how a request, rule, proposal or approval is likely to impact care delivery; current behavior; and the potential for fraud, waste and abuse; is a basic tenet of my responsibility.

It is primarily from these two perspectives that I provide comment.

My 15+ years as a practicing (still-board-certified) emergency physician, 8 years as Chief Medical Officer, and 5+ years as a hospital CEO also inform my comments to some degree.

Summary Comments
The following bullet points are a summary of the narrative that follows. For full contextual rationale and supporting links, please see the corresponding narrative (internal document links to each Section are embedded in the outline; each subsection contains a link back to this Summary Comments section heading).

Medical Evidence

1. Since the initiation of the Coverage with Evidence Determination (CED) in 2012, reputable compilations of medical evidence, as well as wound-based journals, have shown that high-quality, peer-reviewed randomized controlled trials (RCTs) involving the use of autologous platelet-rich plasma (PRP) for chronic non-healing diabetic wounds have not been published.
2. Randomized controlled trials (RCTs) published through 2016 were determined to be “low-quality evidence” by the Cochrane Review with results that “may” show a benefit only for non-healing diabetic foot ulcers. The Journal of Wound Care has published only one small RCT (55 patients) related to autologous PRP vs standard treatment of diabetic wounds since that time.

Coverage with Evidence Determination Requirements

1. The Nuo Therapeutics study was not well-designed to meet the requirement of determining whether autologous PRP was better than standard therapy because “standard therapy” was not standardized across the 28 sites that submitted data.
2. Study results are likely to be impacted significantly by the fact that patients treated with autologous PRP started with wounds that were 26.4% smaller than controls. This “head start” effect is likely to be amplified by the relatively small size of the study.
3. Several typically underrepresented subpopulations were not well-represented. Notably, women, blacks, and Hispanics were disproportionately low in the study, which is likely to impact generalizability.
4. Results are not effectively generalizable to the Medicare diabetic population based on the Nuo Therapeutics study (or current evidence overall) as >50% of Medicare ages are not represented in the data; diabetic women are underrepresented by half; black diabetics are underrepresented by nearly half; diabetic Hispanics aren’t represented at all; and all diabetics with cognitive impairment and multiple other clinical criteria are not represented in the results at all.

Potential Impact of Approving Proposed Decision Memo

1. CAG-001940R4 does not contain the specific clinical inclusion and exclusion criteria that arguably allowed the clinical studies to achieve results.
   1. Absence of any clinical parameters other than “chronic non-healing diabetic ulcer” (not defined) has a very high probability of resulting in Medicare waste and abuse.
   2. Length of use could be extreme based on current wording.
2. Coverage of “all” chronic non-healing diabetic wounds, when research has evaluated only diabetic foot ulcers, and has shown only poor-quality evidence that autologous PRP “may” result in improved healing, might set an unwelcome precedent for the level of evidence required in future coverage determinations.

Recommendation

1. Continue autologous PRP as a non-covered device per the NCD; alternatively
2. Add clinical requirements to the Decision Memo, which could be drawn directly from the inclusion and exclusion criteria used to support approval of CAG-001940R4.

Medical Evidence for Topical Platelet Rich Plasma in Chronic Non-healing Wounds
Since the inception of the Coverage with Evidence Determination (CED) in 2012, minimal additional evidence in support of the effectiveness of autologous PRP for treatment of chronic non-healing wounds (CNHWs) has been published.

This assertion is supported in that the only “new” evidence submitted by Nuo Therapeutics in support of its request was [a] its own article (discussed later); [b] one letter and report from Indian Health Service (referencing data on 44 patients from 8/1/04 – 7/31/05) and [c] a 2015 abstract from Journal of British Surgery (which addressed 15 patients and was neither a randomized, controlled trial nor did it address diabetic foot ulcers).

Reputable Compilations of Evidence (Cochrane Database and UpToDate):

1. The Cochrane Database of Systematic Reviews evaluated the literature on this question (5/25/16) and concluded that the only evidence for PRP was low quality evidence from two small randomized controlled trials (RCTs) showing that it “may improve the healing of foot ulcers associated with diabetes.” Based on evidence (10 studies, 442 participants) “it is unclear whether PRP influences the healing of other chronic wounds.”

   Authors further noted that studies were underpowered to detect treatment effects (if they existed) and studies were at high or unclear risk of bias. They reiterated their 2012 comment (from a previous review of literature on this topic) that “adequately powered clinical trials are needed.”

2. UpToDate, a clinical resource written, reviewed and edited by physicians across specialties, for use by physicians in the clinical setting, includes multiple specialty Society recommendations and evolving research in its summaries. None of its summaries addressing treatment of chronic wounds includes the use of topical platelet-rich plasma (accessed 1/12/21). This is notable, as UpToDate summaries typically reference clinically relevant research articles even when the strength of evidence is technically very low quality and the sample size is small.

   The UpToDate wound treatment summary included information from, and links to, current Society Guidelines (most recent was updated in 2020, though many had not been updated by the Societies for much longer) across the United States, Canada, Europe, the United Kingdom, Australia/New Zealand, Japan and International Consortiums.

Wound-based Sources (Journal of Wound Care, Burns and Trauma, Mayo Clinic):

1. The Academy of Physicians in Wound Healing (APWH) cites the Journal of Wound Care (JWC) as “the leading source of tissue viability research and information.”

   Subsequent to the Cochrane Review cited earlier, JWC published 2 small RCTs using autologous PRP to treat wounds (one with 55 patients/diabetic foot ulcers published in 2017 ; one with 69 patients/”other” chronic wounds published in 2019 ).

   In the diabetic foot ulcer study, PRP-treated wounds healed more quickly, though all wounds in both treatment and control groups healed completely. In the other study, PRP-treated wounds showed more rapid wound size reduction but also showed more frequent microbial contamination. Neither was adequately powered to draw significant conclusions, and neither addressed patient functional status.

   Other articles involving autologous PRP in JWC since the Cochrane Review were either not controlled trials (1) or did not involve chronic wounds.

2. Burns and Trauma, Volume 8, 2020, published an article of laboratory-based wound research noting that autologous PRP has been suggested for wound healing but “evidence for its use in patients with acute and chronic wounds remains insufficient.” Results noted that “PRP strongly improved skin wound healing [in laboratory rats with inflicted wounds], which was associated with regulation of local inflammation, enhancement of angiogenesis and re-epithelialization,” among other effects.

   The authors concluded that “[o]ur data provide a preliminary theoretical foundation for the clinical administration of PRP in wound healing and skin regeneration .”

3. Mayo Clinic site (noted by APWH as a Resource) was searched for “platelet-rich plasma.” This produced 144 results, none relating to research or treatment of CNHW, but many involving injection of PRP into tendons or joints.

CMS Requirements from the CED vs Results of Nuo Therapeutics’ Published Study
In its Decision Memo dated 8/2/12 (CAG-00190R3), CMS required any clinical study under the CED to address at least one of three outcomes and adhere to thirteen (13) “standards of scientific integrity and relevance to the Medicare population.”

The required outcomes were “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. (emphasis added)

Notably, no published study appears to have addressed the second or third bullet point. While several of the small studies mentioned have noted reduction in wound size and/or improved healing trajectory, studies have not addressed the patient’s ability to return to “previous function and resumption of normal activities.”

Three of CMS’ requirements for scientific integrity and relevance to the Medicare population included (paraphrased):

• Research study design is appropriate to answer the research question being asked in the study (criterion d);
• Study protocol must explicitly discuss subpopulations, particularly those that are traditionally underrepresented in clinical studies (criterion l); and
• Study protocol explicitly discusses how results are/are not expected to be generalizable to the Medicare population (criterion m).

Collectively, then, my comments in this section will address the extent to which it appears Nuo Therapeutics’ research, and medical literature in general, met CMS’ goals as summarized below:

1. A research study designed to answer the question of whether autologous PRP leads to complete wound healing significantly better than usual and customary (UCC) wound care;
2. Results from the study showing that wounds treated with autologous PRP did heal statistically better than UCC;
3. The extent to which underrepresented subpopulations were addressed; and
4. The extent to which generalizability to the Medicare population was addressed.
Design

I. Study Design
The Nuo Therapeutics study was described as a “pragmatic” randomized controlled trial, with 129 patients, conducted in 28 sites across the country, which resulted in an average of approximately four (4) patients per site.

In the usual and customary care (UCC) arm, the treatment provided was left to the discretion of the provider and the patient. Thus, the relatively standard treatment of Aurix was compared against a potential potpourri of treatments, some of which may have been inherently more effective than others.

While both study arms allowed for advanced treatments (and, therefore, variability in treatment even in the Aurix arm), comparing the relative standardization of the Aurix + UCC arm to the unstandardized UCC arm might only be answering the question of whether standardized care leads to faster/better healing than unstandardized care.

II. Results: Was “Complete Wound Healing” Statistically Better?
The Nuo Therapeutics results documented a 12-week healing rate of 48.5% (32 patients) in the Aurix group vs. 30.2% (19 patients) in the UCC group.

The first is that patients in the Aurix group started with wounds that were 26.8% smaller than patients in the control group. Thus, patients in the “treatment” group had a significant “head start” toward complete healing within 12 weeks, since they were more than a quarter of the way there before treatment ever started.

The second consideration is the very small sample size. The study was underpowered to draw general conclusions.

III. Underrepresented Subpopulations
Authors discussed their difficulty in recruiting patients to this study, and the reasons therefor. Demographic and key comorbidity data of study participants, compared to 2017-18 CMS data for Medicare beneficiaries, is significant, as noted below. Underrepresented subpopulations were not well-addressed.

Metric	Study	Medicare pts w/ diabetes, unless otherwise stated
Age (Aurix/UCC-only)	64.7/66.9	Only 48.4% of general Medicare beneficiaries were 65-74 years
Male	77.5%	56%
Female	22.5%	44%
White	86%	77%
Black	7%	12.9%
Asian	1.5%	2.25%
Other ethnicity	5.4%	3.9%
Hispanic	N/A	2.8%
No other comorbidities except diabetes	26.4%	< 5%

IV. Generalizability to the Medicare Population
At least three significant issues exist in trying to generalize the Nuo Therapeutics study to the Medicare population.

1. Demographics of the study population are not a good representation of the Medicare or Medicare diabetic population (as noted in the table above);
2. Cognitive impairment was a specific exclusionary criterion, making cognitively impaired diabetics completely unrepresented in the data; and
3. Small study size and significant disparity of wound starting size make applicability to any population questionable.

The remaining medical literature on this topic does not fill these gaps.

Specific, and probably significant, issues with generalizability, include the following:

• Diabetics who are female, black, cognitively impaired or Hispanic are significantly underrepresented in the study (or not represented at all);
• The study population (both arms) included 26.4% of patients whose only medical condition was diabetes; fewer than 5% of Medicare patients with diabetes were reported to have only diabetes;
• Therapeutic response in patients outside a narrow age range (i.e. more than half the Medicare population) is unknown and was not addressed;
• Results are not applicable to an unknown number of Medicare beneficiaries who were excluded from the study but would not be excluded from coverage based on clinical criteria (e.g. hemoglobin <10.5, malignancy near the wound, albumin <2.5, and others as noted below).

Comments Regarding Potential Impact of Finalizing Proposed Decision CAG-00190R4
First, as previously discussed, existing evidence is insufficient to demonstrate statistically significant complete healing of diabetic wounds using autologous PRP. Evidence supporting improved “complete healing” has not advanced significantly since the comprehensive Cochrane Review in 2016, inclusive of the Nuo Therapeutics study published in 2019, for the reasons discussed.

While data in these small studies supports that autologous PRP may be beneficial for a subset of patients with diabetic foot ulcers (based on lengthy exclusion criteria, discussed below), that subset hasn’t been defined.

The Nuo Therapeutics study only addressed diabetic foot ulcers; it did not address all non-healing diabetic ulcers as proposed for coverage by the Decision Memo (nor did other studies do so). Additionally, the study had multiple inclusion and exclusion criteria based on the target population and the criteria’s potential to impact clinical outcomes.

Exclusion criteria included:

• Presence of another wound that could interfere with treatment of the index ulcer;
• Cognitive impairment;
• Infection;
• Malignancy in the wound area;
• Patient on chemotherapy;
• Serum albumin of less than 2.5 gm/dL;
• Platelet count of less than 100 x 109/L; and
• Hemoglobin less than 10.5 g/dL

Neither arm of the study included a patient who met one of the criteria above.

However, the Proposed Decision Memo

1. Allows coverage for all types of chronic non-healing diabetic wounds (though no study has addressed diabetic wounds other than in the feet);
2. Does not include any clinical criteria for coverage; and
3. Does not include any clinical exclusions from, or limitations of, coverage.

In addition to the clinical and programmatic concerns, approval of this Proposed Decision Memo for “all” types of chronic non-healing diabetic wounds, when evidence only exists for diabetic foot ulcers, might set a very unwelcome precedent for the level of evidence required to meet coverage criteria in the future.

Recommendation
While my recommendation, based on evidence to date, is to continue autologous PRP as a non-covered device, should CMS decide to finalize the Proposed Decision Memo, one reasonably expected outcome is as follows.

Covering all types of diabetic wounds, with no specificity re coverage criteria (such as were present in the studies), based on clinical studies of diabetic feet whose outcomes depended on explicit exclusionary criteria, is likely to result in an explosive utilization of autologous PRP for any and all wounds in diabetics, irrespective of the condition of the patient or the wound.

Also, with no length of use criteria, the autologous PRP utilization may well go on for months, particularly if there is a concomitant financial incentive for the provider (e.g. net profit, high wRVU, etc.).

While it is understandably desirable in many instances to leave such criteria development to the providers and/or to the MACs, those who would take advantage of the lack of criteria will easily have well over a year to do so prior to implementation of such criteria.

Thus, from the perspective of someone who routinely reviews records for fraud, waste and abuse, my strong commentary would be that if CMS chooses to finalize this Proposed Decision Memo despite the significant evidentiary and generalizability gaps, now would be the time to introduce at least some of the basic protections against fraud, waste and abuse by including clinical use indications and exclusion criteria. These indications could be drawn directly from the inclusion and exclusion criteria in the studies CMS uses to support its decision.

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Tamara Syrek Jensen
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244-1850

RE: National Coverage Analysis for Autologous Blood-Derived Products for Chronic Non-Healing Wounds (CAG-00190R4)

Dear Ms. Syrek Jensen,

Terumo Blood and Cell Technologies is a global leader in blood component, therapeutic apheresis, cellular and autologous biologic technologies. As innovators for over 40 years in cell separation, we are committed to providing autologous biologic technologies that deliver consistently reproducible results that clinicians and healthcare organizations have come to trust. Through our service and support, we enable physicians to use cutting-edge technologies, increase patient access to autologous therapies and continue to advance next-generation technology.

We appreciate the opportunity to submit a final comment on the Centers for Medicare & Medicaid Services’ (CMS) National Coverage Analysis for Autologous Blood-Derived Products for Chronic Non-Healing Wounds. We support CMS’ thorough decision to revise the National Coverage Determination for Blood-Derived Products for Chronic Non-Healing Wounds (270.3) to establish Medicare coverage for the use of autologous platelet-rich plasma (PRP) for patients with chronic non-healing diabetic wounds, pressure wounds and venous wounds.

We applaud Medicare’s decision to provide coverage of PRP for chronic non-healing wounds. This will not only improve wound care for Medicare beneficiaries but will also lower the cost of care for CMS and improve the quality of life for patients. Terumo Blood and Cell Technologies is thankful to be part of the discussion and for the ability to submit a final comment on this important National Coverage Analysis. We look forward to any future collaboration with CMS to expand access to Medicare beneficiaries. Please do not hesitate to contact us with any questions.

Terumo Blood and Cell Technologies Health Economics & Market Access Team
us.marketaccess@terumobct.com

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