Response to Comments: Skin Substitutes for the Treatment of Diabetic Foot Ulcers and Venous Leg Ulcers (DL)

Comments were received from The American Association of Tissue Banks (AATB) which included a review of the history of skin grafts, the FDA regulations for skin substitutes, and role of amniotic membrane products as a barrier to promote wound healing. They go on to state “all amnion products in sheet form and split-thickness skin/decellularized dermis products when labeled and marketed as wound coverings or barriers should be considered in compliance with relevant FDA regulations, should not require a TRG letter, and should be covered under the LCD.” 

Thank you for your review and comments. The definition of skin substitute graft (consistent with the AMA CPT Codebook) is defined as non-autologous human skin (dermal or epidermal, cellular and acellular) grafts (eg. Homograft, allograft), non-human skin substitute grafts (eg xenograft) and biological products that form a sheet scaffolding for skin growth (2023 CPT Codebook p.95). This surface is not intended to be removed, but grows into place or serves as surface for new skin to grow in. This was detailed in the B&C article, but to clarify further a definition section has been added to the LCD.

The American Association of Tissue Banks (AATB) states requiring TRG letter is burdensome.

To be considered reasonable and necessary for use as a skin graft substitute a product must function as a sheet scaffolding for skin growth. The TRG letter is one of several items that may distinguish products that are coverings or barriers from those that have additional indications as promotion of wound healing through function as skin scaffolding. A section has been added to the LCD to explain the process used to distinguish products and determine if they will be covered per LCD. The TGR letter does not need to be submitted with each claim, but once to the MAC for consideration of the product.

Multiple letters were received from the American Podiatric Medical Association (APMA) and podiatric providers. The letter summarized the scope of the problem of wound care in terms of volume and dollars and that diabetic foot ulcers and venous leg ulcers are among the most common types of wounds with high morbidity and mortality. They support the covered indication and limitation sections of the proposed LCD. They disagree with the limitation of 4 applications stating it is no consistent with current literature or recommendations. Supporting literature was referenced. They also state that this limitation constrains providers from treating the most severe wounds and this limitation does not adhere to some product’s FDA labeling citing Apligraf as an example.

A letter from a local podiatric group in Ohio expressed concerns the limitation would negatively impact the ability to heal the more complex wounds that they treat in their practice period they state that the algorithm which they use to determine the most cost effective and timely wound management plan for each case has been published but no supporting literature was provided with the comment.

Since several of the cited studies had protocols that changed the product on a scheduled basis it is unclear how many applications were necessary vs. changed due to protocol requirements. Zeken compared 2 products to standard wound care with one product requiring 2.5 changes over a 12-week period and the other 6 applications within 12 weeks and limited by small sample size. It is possible the less frequent applications were due to the shorter time to healing and higher success rates reported with this product.

This evidence highlights the challenge within the current literature as there is a lack of standardized protocols or consistency in when these products need to be changed. It is also unclear if some products are superior to others in reducing the frequency of applications, as well as rate and success of wound healing. Regardless, in most cases use of 4 or more products was the exception unless the protocol required changes at specific intervals. While the commenter claims this limitation would restrict providers in treating the most complex wounds there is insufficient evidence that this would impact care because it has yet to be determined which (if any) are of these products offer superior result to high quality standard wound care or when re-application is indicated. However, products used as skin substitute grafts to develop a skin scaffolding for regrowth typically will not require frequent applications as this would disrupt the healing process.

The Apligraf label states the wound should be inspected and the dressing (not skin substitute) should be changed at least once a week during the immediate post application period. Additional applications of allograph may be necessary, but healing tissue or adherent graft should not be disrupted or additional applications of Apligraf should not be applied over areas where it is adherent. It also warns that the safety and effectiveness has not been established for patients receiving greater than five device applications of the product which aligns with the frequency limitation in the LCD. (https://www.accessdata.fda.gov/cdrh_docs/pdf/P950032c.pdf)

A comment states concern with lack of a consistent and accurate definition of what is a chronic non-healing wound. They stayed a chronic non-healing wound should be defined as 30 days or 4 weeks which is already standardized and used by CMS and other A/B MACs. They expressed concern that the policy states that a wound not healed within 1-3 months may be considered chronic and the application of a skin substitute graph as an advanced treatment modality may be considered. They feel that this 1–3-month range is too long and ambiguous. 

A definition section has been added to the LCD and chronic wound defined as lack of healing for 30 days or longer. This is consistent with what was included in the covered indications section of the LCD.

A commenter states that the term “wound” should not be used in the policy and that only diabetic foot and venous leg ulcer should be utilized

The term wound was replaced with ulcer where appropriate throughout policy.

A commenter express concerns with omission of ICD codes for diabetic ulcers above the ankle.

The ICD-10 codes have been updated.

A commenter states there is no evidence basis for a 6-week time frame for smoking cessation before using a skin substitute and suggest that the provider is required to counsel on smoking cessation and impact on wound healing but not a specified time frame requirement.

We agree there is no evidence to support this requirement and it has been revised.

A comment express concerns about a requirement for venous diagnosis to implement treatment, numbers used to for the measurement of HgA1C and ABI of 0.9 lacks reference. No evidence is submitted.

There are multiple references cited within the LCD that provide reference ranges for measurement of HgA1C and ABI, however the policy does not set a specific requirement, but that their underlying provider has accessed the underlying disease process and management is optimal management is pursued as this is a key factor in successful wound healing. See the Covered Indication Section. 

A commenter expresses concern regarding the inability to switch products during treatment. They state that this would limit treatment options for the clinician and inhibit a patient from receiving the best optimal treatment. They state that providers sometimes will use one product to initiate granulation and then use a second product to close the wound. No evidence was submitted to support this.

We agree there is lack of evidence regarding switching products. In most cases if products are healing there is not an indication to change products. SMEs have shared examples of clinical situations that change of product may be indicated therefore this restriction was removed from the policy. However, the total number of applications per wound is limited to 4 regardless of a change in product during the treatment course.

A commenter expresses concern that some sheet products that are currently covered are no longer on the covered list.

A section has been added to the LCD to explain the process for products to be designated as covered or non-covered. Some products were relocated to non-covered list as they were determined to not meet the definition of skin scaffolding for wound healing. 

The Alliance of Wound Care Stakeholders submitted multiple comments. They asked if retrospective studies were being considered, a list of additional ICD10 for consideration, lack of consistent definition of chronic non-healing wound, concerns regarding limitations in frequency and changing applications, a statement CPTs are not surgical supplies, smoking timeframe, pack size requirements, and terminology concerns. The also opine the policy is not evidence based. 

See comments #1, 3, 4, 6, 7 &9. There was no literature submitted to support these comments.

CGS references RCT and higher quality studies when available. In situations where there is a lack of available evidence retrospective studies may be reviewed understanding the limitations of the study design.

Reference to surgical supplies has been removed.

We support the purchase of the smallest package size to reduce wastage. Since this language is regarding purchasing and not clinical aspect it has been move to the Billing and Coding Article.

Adjunct therapy has been replaced with advance therapy unless it is references as adjunctive therapy as it is commonly referred in the literature and guidance.

A definition section has been added for clarity. ‘Skin substitute’ will be retained which aligns with literature and the CPT coding (2023).

Regarding the Alliance’s comments that the policy is not evidence based: In areas where there is a paucity of evidence a service is considered investigational or experimental. The overall body of evidence to support skin substitute grafts is weak with a lack of high-quality studies, standard practices, huge variability in products and lack of consistency in care across providers. Additional investigation is clearly needed to understand the role of these products on a broader scale. This is best summarized by the AHRQ technology assessment of 22 RCTs revealing significant challenges within this literature, inadequate data, and a lack of robust, well controlled studies. In head-to-head comparative studies, 5/6 did not show a substantial difference between skin substitutes and outcomes measured up to 12 weeks follow-up. Most studies published since that time are low quality, lack comparative groups and at risk of bias with industry sponsorship. However, a limited coverage criteria has been created based on the limited, but consistent reports of improvement despite the limitations in this evidence guided by expert opinions from societal guidance in a condition where there are limited treatment options and the sequalae of these conditions have high morbidity and mortality.

ICD-10 codes have been updated.

The APMA expressed concerns with the use of RT and LF modifiers and that it does not align with CPT guidance

Thank you for bringing this to our attention. The billing and coding article has been updated.

Multiple ICD-10 codes were requested to be added to the B&C article. Several of these codes refer to the thigh, calf, ankle, heel and midfoot, other lower leg or lower extremity

See Comment #10.

Comments on behalf of the Musculoskeletal Transplant Foundation were made in relation to one of their products AlloPatch® Pliable (HCPCS Code Q4128), donated human allograft dermis. They object to placement of this product in non-covered Group 3 Codes

A section has been added to the LCD to explain the process for products to be designated as covered or non-covered. Some products were relocated to non-covered list as they were determined to not function as a skin scaffolding for wound healing. The intended use of Q4128 is a protective covering/barrier which does not meet the definition within the policy. 

ProgenaMatrix comment letter states “appropriate number of applications to achieve this benefit may vary significantly depending on wound characteristics. We therefore believe that the strict limits that have been proposed of a maximum of four applications per twelve weeks, with no product switching and no skin substitute treatment in the succeeding twelve weeks, may be overly restrictive in many cases.” They reference the work of Armstrong et al with Medicare Limited Dataset evidence of variability in wound healing rates. This work was not published at the time of the draft LCD.

Thank you for your comments. The Armstrong paper has now been published and has been added to the LCD. Armstrong (2021) evaluated large propensity-matched cohorts to assess outcomes in patients receiving advanced treatment (AT) with skin substitutes for lower extremity diabetic ulcers (LEDUs) versus no AT (NAT) for the management of LEDUs. This study used the Medicare Limited Dataset (1 October 2015 through 2 October 2018) to provide a retrospective analysis. The average number of applications used was found to be 3.7. Based on the available data, the limitation language will be revised in the finalized LCD to indicate that greater than four applications of a skin substitute graft or CTP within the episode of skin replacement surgery (defined as 12 weeks from the first application of a skin substitute graft or CTP) will not be considered medically reasonable and necessary. Product change within the episode of skin replacement surgery is allowed but in situations where more than one specific product is used, it is expected that the number of applications or treatments will still not exceed four. While we agree there is variability in wound healing the Armstrong (2021) paper did not define parameters for use despite this being one of the groups used to classify response. This was the smallest cohort in the study and the only that used an average of >4 applications. It is not clear if “parameters” group requires applications change at specified intervals, based on wound healing or other factors. Also, why this group required a great number of applications as compared to other much larger group. The mean for the application changes in this overall paper was 4 or less applications. The paper is limited by retrospective design, lack of standardized protocol, and risk of bias.

Multiple commenters expressed the concern about the inability to switch products or use additional applications. Multiple providers discussed state not all CTP products are designed to carry a wound to closure, and some perform better at depth fill while others epithelization. No supporting evidence was submitted with any of the comments. 

See Comments #3&9.

A Ohio orthopedic surgeon comments in support of Apligraf and PuraplyAM and that more than 4 applications are sometimes needed. They state since Apligraft cannot be used in setting of exposed bone or tendon they use PuraplyAM until the tissues is not exposed and then switches to Apligraft which in her experience has more efficient healing due to living cells. No supporting literature was provided. 

See Comment #3 & 9.

A letter was provided by Molecular Biologicals in support of LCD. They support the limitation of 4 applications within a 12-week period stating the current standard of care has yielded approximately 1/3 of wounds not healing and other treatment modalities must be considered to improve outcomes. They provide application for HCPCS for two products, Keramatrix and Keragel, and request coverage. HCPSC application and literature was provided. 

Thank you for your support of the policy. The product Keramatrix and Keragel are classified as Hydrogels (A6248) are beyond the scope of this LCD and address in the Surgical Dressing LCD L33831.

MIMEDX submitted comments regarding frequency of applications, evidence to support their products (Armstrong 2021) to support frequency of applications, concern with TGR letter requirement, size and wastage, and documentation requirements. The comment letter states that CGS focused on narrow subset of literature to determine frequency recommendations. 

See Comments #2, 3, 9 & 15.

CGS reviewed a broad range of literature including all literature cited within the comment letter. Many published papers did not report the frequency of application changes, the indications for reapplication or the outcomes of this practice. Additionally, some papers including several of the RCT provided report a standard protocol in which the products were required to be changed as part of the protocol. This leads to a great deal of ambiguity regarding the appropriate frequency of the products. Utilizing the currently published literature the current evidence supports the frequency limits stated in the LCD.

The documentation requirements have been edited. 

Comments from LifeNet advocate for Q4201 to be placed in the covered. They state a RCT is underway.

See Comment # 10. Please submit the RCT if published in peer-reviewed journal for further consideration. Q4201 does not meeting the definition outlined in the LCD because the FDA indication is for use as a covering or barrier and remains in Group 3.

See Comment #3 & 10. Product Q4210 does not meet the definition outlined in the LCD as the HCPCS application states it is to be used as wound barrier and therefore remain in Group 3.

See Comment #3 & 10. Product Q4210 does not meet the definition outlined in the LCD as the HCPCS application states it is to be used as wound barrier and therefore remain in Group 3.

Comments received were regarding Q4244 with the TGR letter, literature, and product information. 

Thank you for providing the necessary components to evaluate if Q4244 is indicated for use as a covering for wounds and does not meet definition for skin scaffolding therefore remain in Group 3.

Bioventus supports limitations of the number of CPT applications which “achieve higher value of care at a lower cost while patients benefit with less out of pocket cost as providers are incentivized to choose CTP products requiring the fewest number of applications among those products that are proven effective in wound healing rates with the least chance for wound reoccurrence. This solution also incentivizes manufacturers to bring innovative products to the marketplace that improve patient outcomes with fewer applications and reduce downstream costs of wounds that go on to require amputations and/or transfers to sites with higher acuity of care.” However, they feel 4 is too restrictive and should be problematic for larger wounds (>25sq cm) or difficult to heal due to co-morbidities. They estimate 30% of wounds will require >4 applications or more than 12 weeks of care. They encourage use of KX modifier to identify wounds that require additional applications or extended duration to avoid denials, appeals or delay in care. They also comment on adjust B&C language from RT/LT modifier to sum of all wounds. Another comment was on not requiring TDR information in patient’s charts. They requested change from skin substitute terminology and not to call them surgical supplies. They also request that use of the products outside of DFU and VLU is not addressed in this LCD be added. They also request product A2008 to Group 2.

See comment #1-4 & 9-12. Thank you for your through and thoughtful comments. Application of skin substitute grafts for wound care indications other than for DFU or VLU are not addressed by this LCD and have as been added to the LCD. The TDR letter is not required to be in each patient record but submitted to MAC for review upon consideration of adding or changing a products Group. The product A2008 meets the definition added to the policy and has been relocated to Group 2 because the FDA indication is for wound management including ulcers and meet definition of skin scaffolding.

Commenter states PuraPly, PuraPly AM, and PuraPly XT should be included in the covered group. They oppose the utilization limit of four applications. They state they have conducted their own analysis and products are being used appropriately so a cap is not necessary (unpublished). They list guidelines that do not include reference to number of applications for support. They also request extension of coverage beyond 12 weeks if indicated. They express concern on limitations for underlying conditions and smoking. They object to requiting TDR letter.

See Comment # 2, 3, 8, 9, & 10. If additional literature is published that address utilization it can be submitted through reconsideration process. Q4195, Q4196, & Q4197 under the name FortaDerm and PuraPly are indicated as a barrier in the 501K Summary therefore remain in Group 3.

Comments are regarding frequency limitations for products to 4, switching products, concerns with glycemic control, modifiers language, and ICD-10 codes to add and advocating removing ICD-10 list. Clinical examples were included but no published literature was submitted.

See Comments 3, 6, 8, 9, 12 & 13.

Comments are regarding frequency limits of applications to 4 in 12 weeks and switching products. They included an unpublished case series that reported on a combination of products that resulted in healing of complex wound. They propose “MLM Biologics requests that all skin subs go through the appropriate regulatory process to be eligible to receive a reimbursement code from CMS, and that all Q-Codes be treated consistently for reimbursement purposes. We request that the current non-transparent MUE value assignments be based on a clearly defined metric that can be shared directly with manufacturers and providers. We also suggest that there be a capped total price increase of no more than 20% annually to prevent price gauging that creates significant practice economic benefits driving economic versus outcomes-based utilization. MLM understands the production economics associated with skin subs and would suggest that grafts in excess of $500 per sq cm not be reimbursed.”  

Thank you for your comments and ideas. See Comments #3 & 9. MUE and pricing caps are not determined by the MACs or within local coverage determinations. 

“We agree with CGS proposed assignment of HCPCS codes to Group 2 who meet the necessary FDA regulatory requirements and criteria. We agree with the recommendation by CGS in the ‘Analysis of Evidence’ section of the LCD that the manufacturer of the particular skin substitute graft or CTP product obtain the appropriate information and send to the Medicare Administrative Contractors along with evidence-based literature, if available.” 

Thank you for your support of the LCD.

Comments were received regarding the limitation of 4 skin substitutes in 12 weeks and advocated for 10 applications within 12 weeks. They provided a table of payer specific policies. They suggest that if the limitation remains at four there is a prior authorization process to obtain authorization for additional applications. Also requested removal of documentation requirements #8 and 9 in the billing and coding article which is the FDA regulatory requirements. 

Thank you for your comments and suggestions. See Comment #3. The documentation requirements have been edited. Thank you for the references regarding payer specific coverage policies however many of these policies are retired and outdated. Prior Authorization topics are not determined by the Medicare Administrative Contractors.

The commenter suggests postponing implementation of the proposed LCD to align the reimbursement policy with CMS 2023 Medicare physician fee schedule final rule that delays policy changes for skin substitutes. They state this would advocate access reduce inequities, complications, and stifle innovation. They suggest removal of the four-application cap and establish utilization limits based on evidence. They suggest evaluation of products beyond TGR letter. Finally, they request moving Q4103 to covered list. Reference list to support products was included.

See comments # 2, 3, 14, 15, 17, 23 & 28. Coverage and reimbursement are not the same therefore delaying coverage determination for reimbursement information would not be necessary, however the 2023 fee schedule has been released at the time of this publication. We certainly agree the optimal strategy for determining utilization limitations for these products would be based on evidence, however there is a paucity of evidence, and the currently available evidence was utilized in the development of the current limitations as explained in comment #3. The TGR letter is one of multiple items reviewed. In consideration of which products meet the definition of skin substitute this process is now explained in the LCD (Comment #14). The cited literature has been added to the LCD. The commenter stated that retrospective paper should not be included in the LCD however also suggests the LCD should be aligned with the retrospective paper by Couture et al. It is preferable not to utilize retrospective papers in LCD due to their inherent low quality however given the lack of high-quality studies the currently available evidence has been included and the Couture paper added to the LCD. Product Q4103 meets the definition within the LCD and has been moved to the Group 2 list.

The commenter expresses concern about the four applications over 12-week limitation, the switching of skin grafts during the 12-week episode of care, the definition of failed response and request Q4299, Q4257 and Q4258 to be added to the covered list. These products do not meet the definition required for Group 2 as they are indicated for use as a wound covering or barrier and therefore remain on group 3

See comments # 3, 4, 9 & 14. Thank you for pointing out the discrepancy between the definition of failed response. We agree this should be consistent and based on the evidence-based guidelines therefore the policy has been updated. The requested products do not meet the definition required for Group 2 per LCD and therefore remain in group 3. 

An Ohio provider submitted a letter regarding concerns with the limitation of applications to four, definition of chronic non healing wound, incorrectly describing the application of skim substitutes as adjunct therapy rather than advanced therapy, admitted coverage products in the LCA, inappropriate use of the term wound, and inability to switch products.

Thank you for your comments. No submitted literature was included. See comments 3, 4, 5, 9, 10, 14 and 17.

Comments were received with accolade for appropriate designation of their products. They oppose the limitation of four applications within 12 weeks, and they reference an observational trial published in the Journal of Wound Care using Artacent Wound and stated that weekly and biologically applications were included in this trial (paper was submitted with comments). They suggested not to include ICD 10 codes. They suggested ensuring consistency in the coverage section with duration of conservative wound care.

See Comment #3, 4, and 6. The submitted paper was added to LCD.

A Kentucky provider expressed concern with utilization limitations, smoking cessation, hemoglobin A1C requirements, and switching products.

See comment #3, 7-9.

They request removing the utilization parameters and limitations and to provide clear and consistent standards for 361HCT/P based skin substitutes. The support frequency restrictions within the policy. The provide recommendations on cost caps. They request Q4256 be placed on the Group 2 covered list. 

Thank you for your comments please see responses # 3,9,10,14,17 & 18. We do consider cost -analysis in local coverage determination decisions. Q4256 is indicated for wound healing and functions as skin scaffolding per definition and has been relocated to Group 2. 

Comments were received regarding frequency of applications and to request placement of Q4120 to Group 2 list. 

See comment #3 & 10. Three articles were included to support use of dehydrated amniotic membranes for use in wound healing. Thank you for articles which included small RCT (25-31 subjects), retrospective reviews and case series on a variety of products (did not include Q4120). The indication for Q4120 is for use as wound covering or barrier therefore does not meet the definition required for Group 2.

The B&C list was revised based on comments and to align consistently with definition that was added to the policy.

The following were placed in the Group 2 list since they met the definition outlined in the LCD: A2001, A2008, A2013, A2015, A2016, A2018, A2019, A2021,Q4128, Q4168 & Q4256.

The following products were relocated to Group 3 for one or more of the following reasons: did not meet definition of skin substitute graft, requires regular replacement (does not function as scaffolding for new skin growth), or the product indication is for use as a wound covering or barrier and therefore does not meet the defined criteria in the policy: A2014, Q4137, Q4157, Q4159, Q4160, Q4165, Q4169, Q4170, Q4178, Q4180, Q4182, Q4183, Q4186, Q4188, q4190, Q4194, Q4199, Q4204, Q4205, Q4209, Q4214, Q4226, Q4227, Q4229, Q4232-Q4255, Q4259-Q4258