Hyperbaric Oxygen (HBO) Therapy (Section C, Topical Oxygen)

Tamara Syrek-Jensen, Esq., Director
Coverage and Analysis Group (GAG)
The Centers for Medicare and Medicaid Services (CMS)
7500 Security Blvd.
Baltimore, MD 21244

February 10, 2017

RE: Proposed Decision Memo for Hyperbaric Oxygen (HBO) Therapy (Section C, Topical Oxygen) (CAG-00060R)

Dear Ms. Syrek-Jensen,

This letter constitutes AOTI’s public comments relating to the Proposed Decision Memo for Hyperbaric Oxygen (HBO) Therapy (Section C, Topical Oxygen) (CAG-00060R) published by CMS last month.

We would like to firstly applaud CMS for conducting a very complete and thoughtful review of the different types of Topical Oxygen devices available in the marketplace and the published clinical evidence as to their respective efficacy.

We would like to break our public comments down into three sections:

AOTI agrees with CMS’s conclusion that “the evidence on chronic wound healing from topical oxygen therapies has increased over the past few years, CMS believes a national non-coverage decision is no longer appropriate.”

AOTI also agrees with CMS’s statements that “blinding may be difficult to apply to all aspects of wound care research”. However, like CMS, AOTI believes that this should not be used as an excuse not to conduct well designed double-blinded placebo-controlled RCTs with appropriate run-in periods on Standard of Care (SOC) on Topical Oxygen devices.

We strongly support CMS’s analysis that “the lack of formal run in periods in most of the studies makes it difficult to determine if the wounds under investigation would have closed with the SOC alone or truly required a more elaborate intervention.” Further, we concur with the statement that “The standard of care chosen should be reported in the investigation with sufficient detail to allow a consistent and uniform application across all study locations and all treating providers. We also believe it is necessary to apply a run-in period within the bounds of the investigation to determine if the wound is truly persistent under appropriate conditions of treatment. The rationale for this is to distinguish those wounds that will heal with compliance to appropriate standard of care from those wounds that require more elaborate interventions to that include greater control of the Standard of Care with appropriate run-in periods.”

AOTI commends CMS on recognizing our currently ongoing study as an example of a well-designed wound care study protocol, namely; “we found at least one (1) randomized, double-blinded, parallel group, sham-controlled, multi-center study of topical oxygen applied for ninety (90) minutes, five (5) days per week on ClinicalTrials.gov. This investigation is actively recruiting at the time this analysis is being written (https://clinicaltrials.gov/ct2/show/NCT02326337)”.

As noted earlier, AOTI agrees with CMS’s conclusion that “the evidence on chronic wound healing from topical oxygen therapies has increased over the past few years, CMS believes a national non-coverage decision is no longer appropriate.” Given that studies conducted over the last several years have strengthened the evidence base for this class of therapies, we believe that a reasonable option to local coverage would be for CMS to consider providing national coverage under the Coverage with Evidence Development policy mechanism. This approach would be more likely than local coverage to stimulate additional high quality clinical studies of topical oxygen therapies, and more rapidly identify those that provide meaningful benefits to Medicare beneficiaries. This rationale seems to be supported by CMS’s statement on ongoing evidence development: “Ongoing research in the US and Europe and pending publications may provide additional evidence that may support a request to reconsider a national determination in the future.”

Based on this and specific comments in the CMS proposed decision memo about the desirable features of clinical studies of these technologies, we believe that AOTI’s ongoing clinical trial meets all of the CMS requirements for eligible CED studies. Our randomized, double-blinded, parallel group, sham-controlled, multi-center study protocol has been developed in conjunction with some of the world’s leading diabetic foot experts to incorporate the most rigorous experimental design, including explicit standard of care control with appropriate run-in period, which we believe meets the criteria outlined by CMS for CED studies. We have included our study protocol to our public comment for your consideration. [1] We would plan to submit this protocol for formal review by CMS should the final decisoin memorandum offer CED as a mechanism for Medicare coverage.

AOTI also agrees with CMS’s decision to separate Topical Application of Oxygen from NCD 20.29 by creating a new NCD 270.7, "Topical Oxygen for Chronic Non-Healing Wounds".

However, AOTI would like to request that CMS further delineate within section 270.7 - Topical Oxygen for Chronic Non-Healing Wounds of the National Coverage Determinations Manual between the two distinct Topical Oxygen techniques that CMS outlines in its discussion, namely; Intermittent and Continuous flow. AOTI believes that such clarification would further aid future coverage determinations at either the Local or National level. Consistent with CMS’s description contained within the background section of the proposed decision manual, with a minor correction to incorporate the intermittent pressure range applied by our devices, we suggest that such delineation may be worded as follows:

We appreciate your time and consideration of our public comments and accompanying attachments.

Please feel free to contact me at 760-672-1920 if you have any questions or need additional information.

Sincerely

Dr. Michael S. Griffiths
CEO and Medical Director
AOTI Ltd.

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In response to the proposed decision published on January 12, we would like to submit additional evidence for your consideration. The results from a recently completed, double-blind study demonstrating positive results for patients with chronic wounds who received Continuous Diffusion of Oxygen (CDO) therapy using the TransCu O2® System by EO2 Concepts® (EO2) has been accepted for publication in the Journal of Diabetes Science and Technology (2017 Symposium/Special Issue, DOI: 10.1177/1932296817695574). Since the final copyedit has been approved, yet not published (the article is awaiting online publication within the next few days), specific results are not contained in this response. The title of the study is “A Prospective, Randomized, Double-Blind Multicenter Study Comparing Continuous Diffusion of Oxygen Therapy to Sham Therapy in the Treatment of Diabetic Foot Ulcers”, hereafter referred to simply as the CDO Study. Details of the protocol for the CDO Study can be found on clinicaltrials.gov under the identifier NCT01645891.

SUMMARY OF OUTCOMES

The CDO Study enrolled and randomized 100 subjects with DFUs to receive either active CDO therapy using an active device, or an otherwise fully operational sham (placebo) device that provided moist wound therapy (MWT) without delivering oxygen. Patients were followed until closure or 12 weeks, whichever was sooner. Patients, family members treating physicians and independent evaluators were blinded to the study arm. All patients received identical offloading, dressings and follow-up.

There were no significant differences in assessed descriptive characteristics between the treatment arms. A significantly higher proportion of people healed in the active arm compared to sham. This relative effect became greater in more chronic wounds. Patients randomized to the active device experienced significantly faster rates of closure relative the to sham.

The results of this study suggest that continuously diffused oxygen over a wound leads to significantly higher rates of closure, and faster time to closure, compared to similarly treated patients receiving standard therapy with a sham device. Furthermore, the relative efficacy appears to improve the more the therapy may be needed (more chronic and larger wounds).

HOW THIS NEW CITATION MEETS THE STUDY CRITERIA IN THE STUDY CRITERIA IN THE CMS PROPOSAL

The following points were made in the context of CAG-0060R. The discussion following each point describes how the CDO Study met the stated criteria set forth in the proposal.

1) Outcome Measures - Full Wound Closure
Full closure is stated as being the most objective and clinically meaningful endpoint. The primary endpoint of the CDO Study is defined as full closure with no weeping and is independently verified by a blinded observer through digital photography with planimetric analysis. The CDO Study demonstrated statistically significant closure.

2) Outcome Measures – Systematic Use of Photographic Verification
The CDO Study employed digital planimetric analysis of photos taken at all visits, verified by an independent reviewer for wound size and full closure. These measurements were used to verify inclusion criteria during the run-in period (wound size and rate of wound closure), rate of wound closure during the study, and verification of full closure.

3) Study Design – Double-Blind with Allocation Concealment
The CDO study treated all patients identically through the use of a placebo device. This enabled double-blind comparison in which neither the patients nor the clinicians knew who received a placebo device and who received the active device, thus avoiding observer bias. It can further be termed as fully blinded, since not only were the patients and clinicians blinded, the family members, investigators, and sponsor were also unaware of which treatment was being received. Everyone was blinded except the third party biostatistician who established the randomization tables and device identifiers. The CDO Study has thereby eliminated what is commonly referred to as the placebo effect, in which patients respond better to treatment because they believe they are receiving a more beneficial treatment.

4) Run-In Period
The use of run-in periods within the bounds of the investigation to ensure consistent and uniform application across study locations and treating providers is discussed. Monitoring wound closure rates during the run-in period also allows for differentiating between wounds that are truly persistent, or chronic, and wounds that will likely heal when treated in compliance with standard of care. The CDO Study employed a defined two week run-in period with defined standard of care at each study site. The wounds were monitored for closure rates based on planimetric traces of the wounds over this time frame. Those exceeding a maximum closure rate of 50% in two weeks, or 30% in either week, measured as percentage wound area reduction, were excluded from the study. For subjects that qualified, outcomes were further analyzed for effect of the closure rate of wounds during the run-in period, with statistically significant results presented.

5) Sample Size
The CDO Study was designed to be adaptive and utilize the results from a planned interim analysis to statistically power the full sample size of the study (n=100, 50 active and 50 sham). The final study results demonstrated statistical significance in both the primary outcome of full wound closure and rate of wound closure.

6) Generalizability – Study Population and Cut Points
The inclusion criteria of the CDO Study included targeting the diabetic population under coverage by Medicare (diabetic with higher minimum age of 30 years old). Cut points were included to evaluate the impact of wound size and chronicity on the primary outcome of full wound closure.

7) Standard of Care
It is stated that the standard of care applied to all wounds should be well described and standardized. The CDO Study was designed to meet these requirements with the highest rigor possible: double-blind with a sham device and standardized offloading and treatment regimens. All subjects received identical treatment devices, dressings, offloading and care. The only difference between the active and sham arms was that the oxygen in the active arm flowed to the wound bed, whereas the oxygen in the sham arm circulated within the device (did not go the wound bed). As mentioned above, a run-in period was also used to ensure consistent and uniform application across study locations and treating providers.

We submit the results of the rigorous CDO Study, now accepted for publication in the Journal of Diabetes Science and Technology, as meeting the proposed criteria in the January 12, 2017 CMS Proposal CAG-0060R as being a representative study to be considered for full publication in NCD 270.7. Furthermore, we submit that this CMS analysis, together with the other case studies published on CDO therapy using EO2 devices, validate the common findings in the CDO Study for the treatment of broad range of chronic and acute wounds, and thus appropriate for Medicare reimbursement.

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I. INTRODUCTION

The Centers for Medicare & Medicaid Services (“CMS” or “you”) is currently soliciting comments regarding its proposed decision in its first reconsideration of Section C, Topical Application of Oxygen, of the National Coverage Determination (“NCD”) for Hyperbaric Oxygen Therapy (20.29) on January 12, 2017 (the “Proposed Decision”). GWR Medical, Inc. (“GWR” or “we”) appreciates the opportunity to submit comments. [FN 1: GWR is a provider of Topical Oxygen for the healing of open wounds. Our device delivers oxygen directly to the wound surface using GWR’s FDA-approved O2Boot® or O2Sacral® devices. Topical Oxygen is an adjunct therapy in chronic wound management and treatment. The intended population for the O2Boot and O2Sacral devices is patients with open chronic wounds such as: skin ulcerations due to diabetes, venous stasis ulcers, post-surgical infections, gangrenous lesions, decubitus ulcers, amputations/infected stumps, skin grafts, burns, and frostbite.]

We support your proposal to remove Section C from NCD 20.29 and create NCD 270.7. Not only is it unclear as to why this paragraph was added in 2002, but CMS has not reexamined coverage for Topical Oxygen since 2002 and there has been an abundance of evidence demonstrating the clinical efficacy of Topical Oxygen wound treatment since then. In fact, we believe that there is sufficient evidence demonstrating that Topical Oxygen is a safe and effective wound care treatment and that NCD 270.7 should provide coverage for Topical Oxygen rather than leave the decision to individual local contractors. We urge CMS to carefully consider the information discussed below, which makes evident that sufficient clinical information exists for CMS to provide coverage for Topical Oxygen wound treatment as reasonable and necessary for the treatment of illness or injury among the Medicare beneficiary population.

CMS opened the reconsideration request to reconsider Section C of NCD 20.29 in its entirety and solicited comments regarding the clinical efficacy of Topical Oxygen. GWR responded timely to the August 11, 2016 comment deadline, including a substantial package of supporting documents that demonstrated the following points (referred to herein as the “August 11th Comment”):

• Topical Oxygen treatment is not the same as Hyperbaric Oxygen treatment.
• Topical Oxygen is safe and effective for FDA-cleared indications.
• Topical Oxygen has historically received inconsistent scrutiny among federal agencies (i.e., FDA and CMS).
• Sufficient clinical information exists for CMS to provide coverage for Topical Oxygen as reasonable and necessary for the treatment of illness or injury. In fact, according to the FDA Maude Database records of adverse event reporting, Topical Oxygen is safer than negative pressure wound therapy and systemic hyperbaric wound treatment.
• NCD 20.29 is not applicable to Topical Oxygen and it would be more appropriate for CMS to consider a separate NCD for Topical Oxygen.

Though we do not restate all of our original arguments here or incorporate all of the attachments, we believe that they are still applicable and reassert all of the points made in our August 11th Comment.

Oxygen treatment for wounds first emerged in the 1960s. Since then, a number of different definitions and descriptions have been used by government agencies, health care institutions, and scientific literature to characterize the differences between the multiple oxygen treatment modalities; some of which overlap. As we discussed in our August 11th comment, while experts agree on the definition of hyperbaric oxygen therapy, several definitions of Topical Oxygen exist. However, any difference between the various definitions of Topical Oxygen technology is belied by the FDA’s classification of all five technologies into one regulation. To this end, we recommend that CMS clarify the definition of Topical Oxygen for Chronic Non-Healing Wounds in NCD 270.7. We propose the following definition that is aligned with the FDA’s regulation:

• Topical Oxygen wound treatment uses a device that is intended to surround a patient’s limb and apply humidified oxygen topically at a pressure slightly greater than atmospheric pressure to aid healing of chronic skin ulcers such as bedsores. [FN 2: See 21 C.F.R. § 878.5650.]

FDA has classified all Topical Oxygen devices, whether an inflatable plastic chamber to surround the wound area and affected extremity with oxygen, or a cannula that continuously diffuses oxygen over the wound area under a moist dressing, under this single medical device regulation. The only regulation applicable to technology intended to deliver oxygen directly to a wound, without also raising the oxygen content of circulated blood (i.e., as with HBO), is 21 C.F.R. § 878.5650. Although the mechanical action of HBO includes the effects of both respirated oxygen and Topical Oxygen, there does exist this separate FDA regulation for Topical Oxygen as an independent treatment.

We believe that the extensive use of GWR’s Topical Oxygen devices across the country over the past twenty years and successful treatment of chronic wounds serves as a basis for Medicare coverage. Nationwide, groups that cover the use of our Topical Oxygen devices include the Department of Veterans Affairs, Department of Defense, managed care organizations, third party administrators, and state Medicaid programs. In addition, state workers’ compensation programs also cover the use of our Topical Oxygen devices.

The use of GWR’s Topical Oxygen devices was recently analyzed and the results submitted for publication in the peer-reviewed journal, Advances in Wound Care. We expect a peer review decision on this manuscript soon and will provide a copy to CMS for your review as soon as possible. Below, please find a summary of the study. We welcome the opportunity to discuss these findings and respond to any questions you may have.

In this manuscript, Angie Purvis, PhD and Karen Copeland, PhD, perform statistical testing of retrospective data collected between January 1, 2007 and July 18, 2016. This manuscript represents a data set of 4,127 total wounds from 3,462 patients, collected over 9.5 years to evaluate patient outcomes following Topical Oxygen. These records represent 4,127 wounds from male and female patients in the age range of 4 years old to 105 years old. To our knowledge, this is the largest data set ever analyzed with regard to Topical Oxygen efficacy. In fact, most of the data regarding clinical efficacy of Topical Oxygen comes from controlled studies in a clinical setting.

The results of this review demonstrate healing and amputation rates similar to those reported in controlled clinic studies. Topical Oxygen was associated with a healing rate of 59.4% and an amputation rate was 2.4%. We believe that this real-world evidence is of substantial scientific value because it not only analyzes a much larger data set than any controlled clinical study, but also focuses on real life outcomes; the positive results were experienced by real people in the home treatment setting, on a large scale.

The patient records reviewed for this manuscript were extracted from GWR’s database (as described in our August 11th Comment). At the time data was reviewed for inclusion in the study, the database contained records corresponding to a total of 10,980 wounds. All 10,980 records were reviewed against the inclusion criteria for this study: (1) wounds that were at least 1 cm2; (2) wounds that were treated with at least one separate modality prior to Topical Oxygen; (3) patient completed Topical Oxygen for a minimum of two weeks; (4) wound was no longer receiving Topical Oxygen; and (5) record included all data elements to be analyzed. [FN 3: The data elements analyzed include the following variables: patient age, patient gender, primary payor type, diagnosis/ICD-9 code, wound(s) location, wound(s) age, treatment duration, dimensions of the wound(s) before and after Topical Oxygen, and the reason for ending Topical Oxygen.] All cases that met the inclusion and exclusion criteria were selected for study.

Chronic wounds treated with Topical Oxygen showed a low rate of amputation (2.4%), regardless of site, wound age, wound starting size, and other clinical variables. The results showed the rate of healing was 59.4% and complete healing was cited as the most frequent reason (39.2%) for ending Topical Oxygen. The results of this study demonstrate improved patient outcomes and improved quality of life when chronic wounds are treated with Topical Oxygen.

It is clear, from real-world use and results, that Topical Oxygen supports complete wound closure or helps reduce the size of the wound to allow resumption of standard wound care. Although these authors did not have access to data regarding pain reduction as these wounds healed, the 2013 Tawfick study you cited in your Proposed Decision measured pain as an endpoint in a cohort of patients with refractory venous ulcers who were treated with Topical Oxygen. After only 13 days of treatment, the patients receiving Topical Oxygen reported a decrease from 8 to 3 on the pain numerical ranking scale. Therefore, we believe that Topical Oxygen not only has a positive impact on chronic wound healing, reduces the rate of amputation, but it also leads to better quality of life for patients with chronic wounds and reduces the pain associated with the wounds.

In our August 11th Comment, we provided a summary of relevant scientific literature and clinical information that demonstrates that Topical Oxygen is a reasonable and necessary treatment of an illness or injury and should be covered under Medicare. However, your Proposed Decision focuses on only a limited number of these resources. In fact, the Proposed Decision outlines your literature search method, which appears to be insufficient as it does not refer to several scientific studies that positively demonstrate the physiology of wound healing and the effectiveness of Topical Oxygen (i.e., increased oxygen in a chronic wound stimulates a resumption of the wound healing cascade) and, without explanation, did not consider studies that focus on animal subject or that were completed prior to 2006. We urge CMS to carefully consider all of the important resources and evidence developed since Section C was added to NCD 20.29 in 2002. We believe that these support full national Medicare coverage of Topical Oxygen at this time. We again include here a short description of the resources not included in your Proposed Decision.

Wound healing is a complex process involving a complex series of biologic responses to stimulate cell migration leading to tissue repair and wound closure. This sequence (known as the wound healing cascade) consists of removal of debris, control of infection, clearance of inflammation, angiogenesis, deposition of granulation tissue, contraction, remodeling of the connective tissue matrix, and maturation. If wounds fail to undergo this sequence, then the wound may become a chronic wound.

As noted in the references discussed here, one of the major issues for chronic wounds is the lack of oxygen to support the healing process. This condition, known as hypoxia, may be the result of vascular insufficiency which reduces blood flow to the wound site and increased oxygen demand due to the open wound. We are including references from a variety of clinical experiences including randomized clinical trials, cohort studies and clinical case series. These various studies document that Topical Oxygen can support complete wound healing, help reduce the size of the wound to allow resumption of standard wound care, may help reduce pain, support important and clinically meaningful changes to the local wound environment (such as increased growth factors expression, reduced inflammation, antimicrobial effect and angiogenesis), and importantly, assist the patient’s ability to return to previous function and resumption of normal activities.

For example, in a randomized clinical trial (Heng, 2000), 40 patients (with 79 ulcers) were treated with either Topical Oxygen or the standard of care. The study measured the percentage of wound healing in each group and measured the capillary density of wound tissues during the healing process. The results showed that 90% of the wounds healed in the Topical Oxygen group compared to 22% in the standard wound care controls. The study also reported that the size of ulcers (at 4 weeks) was significantly smaller with Topical Oxygen-treated wounds, but larger with standard of care treated wounds. The study also found that capillary density of tissue evaluated under high power microscopy was significantly higher in Topical Oxygen treated wounds than in standard wound care wounds (P < 0.001). [FN 4: Heng, M.C.Y., Harker, J., Csathy, G., Marshall, C., Brazier, J., Sumampong, S., and Paterno Gomez, E. “Angiogenesis in Necrotic Ulcers Treated with Hyperbaric Oxygen.” Ostomy Wound Management 46.9 (2000): 18-38, 30-32. ATTACHMENT 1 (August 11th Comment, Attachment 26, Resource 8).]

An important study in 2005 (Fries, 2005) demonstrated that Topical Oxygen can transfer oxygen into the wound tissue, enabling the oxygen state of the wound to rise, and that the oxygen state goes down with the withdrawal of the device. These researchers demonstrated that this form of oxygen therapy is able to modify the oxygen state of the wound tissue. [FN 5: Fries, R.B., Wallace, W.A., Roy, S., Kuppusamy, P., Bergdall, V., Gordillo, G.M., Melvin, W.S., and Sen, C.K. “Dermal Excisional Wound Healing in Pigs Following Treatment with Topically Applied Pure Oxygen.” Mutation Research 579 (2005): 172-181. ATTACHMENT 2 (August 11th Comment, Attachment 27, Resource 2).]

Another study (Rao, 2016) examined the effect of Topical Oxygen on the hind limb wounds of rats under ischemic conditions. Here, researchers compare twelve injured rats treated with Topical Oxygen to twelve injured control rats. The results demonstrated that Topical Oxygen improved ischemic healing: wound healing time was shorter in the Topical Oxygen group than the control group; would healing rate and granulation tissue formation in the Topical Oxygen group showing significant improvement on days 3, 7, and 14; the accumulation of collagen fiber in the Topical Oxygen group improved when compared to the control group on day 7; and, many more new vessels were found in the Topical Oxygen group than the control group on day 7. [FN 6: Rao, C., Xiao, L., Liu, H., Li, S., Lu, J., Li, J., and Gu, S. “Effects of Topical Oxygen Therapy on Ischemic Wound Healing.” The Journal of Physical Therapy Science 28.1 (2016): 118-123. ATTACHMENT 3 (August 11th Comment, Attachment 26, Resource 13).]

A retrospective review of case studies (Kalliainen, 2003) demonstrated that Topical Oxygen (GWR’s device) had no detrimental effects on wounds and showed beneficial indications in promoting wound healing. Researchers analyzed the results of Topical Oxygen by collecting data from seven surgeons who treated 58 wounds in 32 patients, with Topical Oxygen with follow-up ranging from 1 to 8 months, over the course of 9 months. Researchers noted that upper extremity and trunk wounds were most responsive to Topical Oxygen. [FN 7: Kalliainen, L.K., Gordillo, G.M., Schlanger, R., and Sen, C.K. “Topical Oxygen as an Adjunct to Wound Healing: A Clinical Case Series.” Pathophysiology 9 (2003): 81-87. ATTACHMENT 4 (August 11th Comment, Attachment 26, Resource 10).]

Similarly, in a cohort study comparing Topical Oxygen to HBO (Gordillo, 2008), wound healing was evaluated at 12 weeks. Overall, HBO did not result in statistically significant improvements in wound size in the given population over the time monitored in this study. However, Topical Oxygen did significantly improve wound size. Furthermore, among three oxygen-edge tissue biopsies, Topical Oxygen was associated with higher vascular endothelial growth factor (VEGF) expression in healing wounds. [FN 8: Gordillo, G.M., Roy, S., Khanna, S., Schlanger, R., Khandelwal, S., Phillips, G., and Sen, C.K. “Topical Oxygen Therapy Induces Vascular Endothelial Growth Factor Expression and Improves Closure of Clinically Presented Chronic Wounds.” Clinical and Experimental Pharmacology and Physiology 35.8 (2008): 957-964. ATTACHMENT 5 (August 11th Comment, Attachment 26, Resource 5).]

You stated in the Proposed Decision that you did not find any relevant evidence-based guidelines. We turn your attention, again, to this article by Gordillo, titled, “Evidence-Based Recommendations for the Use of Topical Oxygen Therapy in the Treatment of Lower Extremity Wounds.” Here, Dr. Gordillo and her colleagues outline a set of relevant evidence-based guidelines for Topical Oxygen. [FN 9: Gordillo, G.M. and Sen, C.K. “Evidence-Based Recommendations for the Use of Topical Oxygen Therapy in the Treatment of Lower Extremity Wounds.” The International Journal of Lower Extremity Wounds 8.2 (2009): 105-111. ATTACHMENT 6 (August 11th Comment, Attachment 26, Resource 6).]

In addition to the emerging clinical evidence for the use of Topical Oxygen in the treatment of chronic wounds, recent publications highlight the importance of oxygen in the wound healing process. For example, a recent review article (Eisenbud, 2012) focuses on the role of oxygen in wound healing, the author indicates that there are important roles of oxygen in wound healing. These roles include:

• Energy source to fuel biochemical reactions and cellular function
• Nutrient essential to the synthesis and crosslinking of collagen
• Cofactor that is manufactured into signaling molecules such as nitric oxide and hydrogen peroxide
• Substrate for generation of reactive oxygen species (ROS) that combat wound colonization and infection
• Essential signaling component that turns on and off genes that encode proteins critical to the healing cascade
• Deliberate hyperoxygenation recruits endothelial progenitor cells to the wound, increases (VEGF), and promotes angiogenesis [FN 10: Eisenbud, D.E. “Oxygen in Wound Healing: Nutrient, Antibiotic, Signaling Molecule, and Therapeutic Agent.” Clinics in Plastic Surgery 39 (2012): 293-310. ATTACHMENT 7 (August 11th Comment, Attachment 26, Resource 4).]

The antimicrobial effects of oxygen are also noted in the article by Gordillo (Gordillo, 2009). The author cites evidence that oxygen is a rate-limiting substrate for the production of reactive oxygen species (ROS) that serve as a disinfectant and as intracellular signaling molecules that orchestrate the wound healing response. In particular, at the wound-site, ROS are generated from oxygen by almost all wound-related cells. Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) is the enzyme that generates ROS for signal transduction necessary to promote healing. In phagocytic cells at the wound site, the ROS produced by NADPH oxidase are used to kill bacteria. [FN 11: Gordillo et al., supra note 9.]

Another scientific publication reviews the positive effects of oxygen on the wound healing process and provides an overview of the benefits of HBO and Topical Oxygen (Sen, 2009). The article provides a relatively comprehensive overview of the oxygen-dependent pathways involved in wound healing, as well as a review of the supporting scientific literature. The author also includes a brief comparison of HBO and Topical Oxygen, concluding that Topical Oxygen is preferred when the “goal is to correct hypoxia of the superficial tissue” rather than increase “supraphysiological levels of tissue pO2.” [FN 12: Sen, C.K. “Wound Healing Essentials: Let There Be Oxygen.” Wound Repair and Regeneration 17.1 (2009): 1-18. ATTACHMENT 8 (August 11th Comment, Attachment 26, Resource 14).]

All of the studies discussed here and in our August 11th Comment demonstrate that (1) the clinical effectiveness of Topical Oxygen is supported by results of recent clinical trials, and (2) Topical Oxygen is a beneficial treatment alternative for chronic wounds. The recent publications highlight the scientific evidence that increased oxygen in a chronic wound stimulates a resumption of the multiple factors wound healing cascade. These effects are documented in a number of clinical evaluations and are manifested in as important and clinically meaningful changes to the local wound environment (such as increased growth factors expression, reduced inflammation, anti-microbial effect and angiogenesis).

As you noted in your Proposed Decision, FDA reclassified the Topical Oxygen chamber for extremities from a Class II to a Class II device in 2011. In light of FDA’s regulations, we urge CMS to consider Topical Oxygen devices for full Medicare coverage at this point rather than allowing local, and potentially inconsistent, coverage determinations. This action would also finally align CMS and FDA processes, definitions, and clinical experience.

FDA’s decision to reclassify these devices was based primarily on the data presented in three, then recent, studies. [FNs 13 – 16: Proposed Rule: Reclassification of the Topical Oxygen Chamber for Extremities, 71 Fed. Reg. 17,390 (Apr. 6, 2006). ATTACHMENT 9 (August 11th Comment, Attachment 4); Heng, M.C.Y., Harker, J., Bardakjian, V.B., and Ayvazian, H. “Enhanced Healing and Cost-Effectiveness of Low-Press Oxygen Therapy in Healing Necrotic Wounds: A Feasibility Study of Technology Transfer.” Ostomy Wound Management 46.3 (2000): 52-60, 62. ATTACHMENT 10 (August 11th Comment, Attachment 26, Resource 7); Heng et al., supra note 4; Kalliainen et al., supra 7.] FDA’s primary role as a government agency is to ensure that all drugs, biologics, and devices available in U.S. commerce are safe and effective for their intended therapeutic uses. With respect to devices, the manufacturer of a medical device must demonstrate to FDA that the device is safe and effective for its intended use when used in conjunction with general controls alone (Class I) or with general and special controls (Class II), otherwise the device will be classified as a Class III. [FN 17: 21 U.S.C. § 360c(a)(1)(A)–(B) (2012); see also 21 C.F.R. § 860.7(c)(1) (“After considering the nature of the device and the rules in this section, the Commissioner will determine whether the evidence submitted or otherwise available to the Commissioner is valid scientific evidence for the purpose of determining the safety or effectiveness of a particular device and whether the available evidence, when taken as a whole, is adequate to support a determination that there is reasonable assurance that the device is safe and effective for its conditions of use.”).] Class III is reserved for devices (1) for which insufficient information exists that general or special controls will provide reasonable assurance of safety and effectiveness, and (2) which are substantially important in preventing impairment of health or which present an unreasonable risk of death. [FN 18: 21 U.S.C. § 360c(a)(1)(C); see also 21 C.F.R. § 860.7(g)(1) (“It is the responsibility of each manufacturer and importer of a device to assure that adequate, valid scientific evidence exists, and to furnish such evidence to the Food and Drug Administration to provide reasonable assurance that the device is safe and effective for its intended uses and conditions of use. The failure of a manufacturer or importer of a device to present to the Food and Drug Administration adequate, valid scientific evidence showing that there is reasonable assurance of the safety and effectiveness of the device, if regulated by general controls alone, or by general controls and performance standards, may support a determination that the device be classified into class III.”).]

In making its determination in 2011, the FDA relied on twenty years of clinical information (much of which was excluded by CMS in its literature review when it limited the date range to 2006 – present) regarding Topical Oxygen devices, the “agency’s Medical Device Reports,” and comments from the public regarding the clinical information. [FN 19: Proposed Rule: Reclassification of the Topical Oxygen Chamber for Extremities, supra note 13.] After considering all of the evidence, FDA determined that sufficient evidence had been provided to demonstrate that general and special controls would ensure safe and effective use of Topical Oxygen devices and thus released a final rule formally reclassifying Topical Oxygen devices from Class III to Class II. [FN 20: Final Rule: Reclassification of the Topical Oxygen Chamber for Extremities, 76 Fed. Reg. 22,805 (Apr. 25, 2011). ATTACHMENT 11 (August 11th Comment, Attachment 5).]

Importantly, the FDA did not require or specifically rely on randomized clinical trials in reaching its reclassification decision. Rather, FDA concluded that human clinical studies are not required for each new Topical Oxygen device clearance because the safety and effectiveness is well established in existing clinical literature. Furthermore, FDA may only reclassify a currently marketed device if evidence adequately demonstrating safety and effectiveness of the device is submitted for consideration. If the evidence on Topical Oxygen devices had not been sufficient to convince FDA of the devices’ effectives to treat chronic ulcers, more than ten years ago, FDA would not have had the authority to determine that the reclassification was warranted.

It is clear that Topical Oxygen is not HBO; this is even stated in the NCD. But, it is absolute opaque as to why the “Topical Application of Oxygen” is included in NCD 20.29. We fully support your proposed decision to remove Section C and “Topical Application of Oxygen” from NCD 20.29.

One other major difference between HBO and Topical Oxygen is the treatment setting. HBO requires the patient to travel to a facility with a hyperbaric chamber. On the other hand, Topical Oxygen can be used in the home setting eliminating transportation and contributing to off-loading (staying off your feet). This ultimately has a great impact on the patient’s quality of life. Imagine a patient who has long been battling a chronic wound that will not heal and who would be able to receive effective treatment in his or her home without risking additional infection on a trip, or multiple trips, to a health care facility. We believe that this is a truly beneficial and patient-centered treatment alternative, with little risk, and potential for significant improvement in outcomes and quality of life that should be made available to all Medicare beneficiaries.

We again thank you for your time and attention to this important information. We urge CMS to use this opportunity to evaluate the substantial body of new evidence since its last consideration of Topical Oxygen and align its analyses with FDA’s by establishing a NCD that provides coverage for Topical Oxygen. As we have discussed, we believe that Topical Oxygen is safe and effective for FDA-cleared indications; that there is sufficient clinical evidence to support Medicare coverage of Topical Oxygen as an effective wound treatment modality; and finally, that many patients would experience an improved quality of life by being able to receive successful wound treatment in their homes. We will make ourselves available to discuss any questions related to these comments.

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February 7, 2017

Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services
Mailstop S3-02-01
7500 Security Blvd
Baltimore MD 21244

Dear Ms. Syrek Jensen:

The Advanced Medical Technology Association (AdvaMed) is pleased to offer the following comments on the Centers for Medicare & Medicaid Services’ (CMS) Proposed Coverage Decision Memorandum for Screening for Hyperbaric Oxygen (HBO) Therapy (Section, Topical Oxygen).¹

AdvaMed’s member companies produce the life-saving and life-enhancing medical devices, diagnostic products and health information systems that are transforming health care through earlier disease detection, less invasive procedures and more effective treatments. AdvaMed members range from the largest to the smallest medical technology innovators and companies.

We support CMS’ proposal to remove the national non-coverage determination for topical oxygen therapy, based on changes in the evidence over time, and to give Medicare Administrative Contractors (MACs) the authority to determine coverage of this therapy for the treatment of chronic wounds. We further concur with CMS’ proposal to amend the NCD manual by removing the coverage exclusion for this therapy and creating a new section that will allow Medicare coverage to be determined by local contractors.

AdvaMed has long-supported the use of sound evidence to inform medical practice. We agree with CMS’ decision, upon review of the reconsideration request and examination of current evidence, that a national non-coverage determination for topical oxygen therapy is no longer necessary or appropriate.

As additional evidence is generated supporting the use of a technology or service, we believe that Medicare’s coverage policies should be nimble and able to reflect those changes

AdvaMed would also like to provide comments on the evidence discussion contained in Section VII of the draft coverage determination, in which CMS discusses the Agency’s preference for complete wound closure as the most objective and clinically meaningful endpoint in studies, as opposed to wound healing without complete closure. The evidence discussion centers around the challenges associated with obtaining valid, reliable data and comparing such data across studies, due in part to variations in study design.

We appreciate CMS’ recognition that not all wounds heal completely, or in a timely manner. We also appreciate CMS’ statements that “if wound closure is not to be obtained, the investigational treatment should allow the patient to accomplish a return to previous function and activities (with or without an accompanying change in wound healing trajectory).”

AdvaMed’s Wound Healing & Tissue Regeneration Sector produced a consensus document (attached) entitled “Guiding Principles for Clinical Research in Chronic Wound Healing,” which presented recommendations for evidence-based guidelines for safety, efficacy and effectiveness in chronic wound research. AdvaMed supports guiding principles for wound care policy that were promulgated by the World Union of Wound Healing Societies in 2010 (attached)². The consensus document emphasizes intermediate wound care outcomes (in addition to complete wound closure) that are important benchmarks for evaluating the effectiveness of wound care products and services. The document addresses a number of challenges in wound care, noting that a variety of different approaches or therapies may be required to achieve complete wound closure, and that wound healing is not always appropriately evaluated by measuring wound closure, as this may not be the immediate, intended goal.

Examples of alternate endpoints include:

• Control of exudate;
• Reduction of odor;
• Stimulation of tissue growth to decrease wound volume/surface area;
• Alleviation of pain with dressing change (or between dressing changes);
• Reduction of bacterial bioburden; and
• Protection of the periwound skin.

In its draft decision m emo, CMS acknowledges these alternative endpoints can be meaningful and valid. AdvaMed supports this assertion. We would highlight that research studies to examine the effectiveness of a particular therapy should include measures that are related to the purpose of that therapy (e.g. control of exudation, pain reduction) in order to best understand the intended effect, which may not, in fact, be wound closure.

We appreciate the opportunity to provide these comments on the proposed coverage memorandum. If you have questions regarding these comments or if you require additional information, please contact either DeChane Dorsey,Esq., Vice President, Payment and Health Care Delivery Policy, at (202) 434-7218 or ddorsey@advamed.org, or Chandra Branham, Esq., Vice President, Payment and Health Care Delivery Policy, at (202) 434-7219 or cbranham@advamed.org.

Sincerely,

Donald May
Executive Vice President
Payment and Health Care Delivery Policy

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As a wound care nurse im quite familiar with the HBO treatments and how oxygen therapy is of great help in tissue perfusion and wound healing. EO2 is the most similar device to having an HBO tx. Many patient don't qualify for HBO tx so EO2 is the other option.

I like the fact that Patient don't deprive from their ADLs while carrying this magnificent device with them while oxygen is being deliver to wound. I have seeing the results in one of our patient with a chronic DFU, after several different treatments EO2 change his life by healing his foot ulcer.

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We had the opportunity to use the TransCu O2® Oxygen Delivery System in several patients at the University of Miami. Specifically at the Wound Care Center and at the Dermatology Research Department. We did a case series in patients with lower leg ulcers of different etiologies (venous leg ulcers, arterial ulcers, diabetic foot ulcers, sickle cell disease ulcers, among others). And we obtained interesting results.

Particularly, there was a case of a 65 y/o male patient with history of diabetes mellitus type 2 and arterial Insuficiency, with a nonpainful ulcer on the right great toe of 9 months duration. On physical examination, a 0.8 x 0.4 x 0.5 cm (0.32 cm2) ulcer was present on the plantar aspect of the right hallux. The patient achieved complete closure after receiving CDO at a constant oxygen flow rate of 3 mL/hr, in addition to offloading as standard of care for 35 days.

For months, the patient received different treatment options, from debridement and offloading, to topical wound dressings, cellular and acellular matrices. Until we considered HBO as the next step. However, since the patient was claustrophobic and this is one important contraindication to this therapy, we could not treat him with HBO.

Thanks to the EO2 providers we were able to get a device for the patient, and get his ulcer healed completely.

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Dear CMS,

I work for the University of Rochester in Rochester, NY practicing both Dermatology since 2003, and wound and ostomy Care since 1999. Specifically, I am an ANCC Board Certified NP, Certified Ostomy Specialist (COCN), Dermatology Certified Nurse Practitioner (DCNP) and Wound, Ostomy, Continence specialist.

I was introduced to TransCu O2 approximately three months ago. I have a patient who had a pressure injury from a device used to contain her stool effluent. It was a chronic wound under her ileostomy wafer that had been open for over a year and with correction of the device, it did not resolve using advanced wound care products such as hydrofiber, alginate, collagen, silver nitrate, ionic silver, cadexomer iodine, bismuth non stick with petrolatum and so on. The constant wounds would cause leaking of her appliance, and daily changes for her ileostomy appliance which is normally changed twice weekly. She kept asking me for Hyperbaric Oxygen Treatments, and as you know already, she did not qualify for this treatment due to the strict guidelines for approval from Medicare. Then it occurred to me that I had been introduced to the TransCu O2 smart wound therapy at a conference I had attended. I called my local representative from Mission Concepts and soon was on my way to treating my first of three patients I have on this therapy. This ulcer essentially closed in approximately 7 weeks, and my patient’s quality of life is now improved. Her wafer is now staying 2 days instead of one, a step in the right direction.

My second case study involves a patient with ulcerative colitis and a venous leg ulcer with a co- commitment underlying pyoderma gangrenosum auto immune disease open for more than 6 years, with intermittent pseudomonas. It was nearly closed after two years of intense therapy with multilayered compression wraps, hydrofiber, alginate, collagen, silver nitrate, ionic silver, cadexomer iodine, bismuth non stick with petrolatum and many systemic treatments such as steroids, antibiotics, dapsone and doxy anti inflammatories and kenalog injections. It flared dramatically last year and we resumed prednisone, compression, and advanced wound care therapies but the progress has been arduous. She did not qualify for Hyperbaric Oxygen either. We then implemented TransCu O2 on this patient as our second case study- and her wound is making terrific progress 12 weeks in. The quality of the granulation tissue is better due angiogenesis, she is not in any pain, no more infections as the oxygen flow and moisture is controlled, and she is almost completely weaned off of her prednisone. Her wound dimensions thus far are reduced by about 40% or 17 cm2 smaller.

My third case involves a patient with crohn’s disease with a hypergranulating wound under her colostomy wafer for 2 years, again having used all of the previously mentioned treatments, and a biopsy consistent with pyoderma gangrenosum as well. She has been using the TransCu O2 for 3 weeks now, and her wound has decreased by more than 50%, it no longer is painful, no longer has hypergranulation or signs of pseudomonas, and all while she is receiving remicade infusions for her Crohn’s.

There are commonalities between these patients: All three are very compliant patients with an interest in healing. All three have auto immune conditions that negate against wound healing on immune suppression. Two of three are currently working and holding down jobs while they have these wounds. Two of three have wounds under their prosthetic bowel devices. All three of them have wounds located in an anaerobic environment, and they all had open wounds for greater than one year.

As a provider of chronic wound care I cannot over emphasize the difficulty of having limited access to some advanced wound care products and the newest “smart” wound care devices. In particular HBO and Negative pressure therapy are only approved for certain types of wounds and are difficult to get in the outpatient setting. Our health system has both of these delivery care systems, but very few of my patients are covered, or can withstand the daily treatment regimens of going to clinic for HBO. There exists a very large population of patients that need more than what the medical device marketplace provides. The TransCu O2 is safer than using steroids, antibiotics, anti inflammatories and reduces infection by providing an oxygen rich environment where bacteria cannot grow. I have not seen one side effect from using this that was detrimental to continuation of treatment. It has “wearable” shoulder strap and is easy to use even if patients are employed, and manages pain so that less workdays are missed. In comparison to missed work, drug treatment costs, other advanced wound therapies the TransCu O2 is cost effective and I know we are on the cusp of bringing an incredibly exciting product to a more widespread market for our patients in the US.

I haven’t been this excited about something like this in a very long time. I am sure you have seen the data on quicker closure rates and cost reduction in comparison to conservative therapy. PLEASE move to approve this therapy for all wounds without restriction of etiology, along with reasonable reimbursement costs to DME companies so that this scientifically powerful treatment can be available at a fair supplier/ consumer cost to improve access to our patients who need it. Make this a smart decision and help us help our patients to a healed state, reducing health care burden and overall costs to the taxpayers.

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Wound care has become a prominent field in medicine and surgery. With the steady rise in the ageing population healthcare in all settings is presented with unique opportunities to improve outcomes. For all stakeholders rising costs and reduced reimbursement has direct cause and effect. Chronic non-healing wounds have a prevalence of 2% in the United States, and cost an estimated $50 billion annually. The treatment of diabetes and its complications generated at least $116 billion in direct costs; at least 33% of these costs were linked to the treatment of foot ulcers. With these costs in mind, we have a unique opportunity to reduce costs and accelerate healing time with the application EO2 device.

In our vascular practice, we put the EO2 device on a variety of wounds. One patient had a non-healing diabetic foot wound which had been ongoing for more than 9 months. It healed with the application of the EO2 device in 4 weeks. Another patient had a non-healing venous stasis ulcer for over 14 months. The patient did not have diabetes, but had a wound that would not heal. Several applications of a skin substitute failed. The EO2 healed this wound in 5 weeks. EO2 should not be reserved for just the diabetic wounds, failed flap or burn which is the present criteria for HBO in wound healing centers. As we have seen in this office, it can be used on a variety of wounds.
EO2 has the potential to reduce the number of hours needed for home health care for the chronic wound. Looking over the orders written from our office over the past year, to home health agencies, wound care far exceeds any other reason. The estimated time for healing a chronic wound on average, has exceeded 4 months.

The EO2 should be an option for all wound care patients regardless of cause, if it’s a wound that has failed to heal for whatever reasons. The EO2 is quiet, small and unobtrusive. It will save patients lost time from work, speed healing and enhance other modalities presently used for wound care, in addition to saving millions of dollars in health care costs. The EO2 is truly going to be a game changer in wound care.

Please consider this device for all non-healing wounds.

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[PHI Redacted] has suffered with Pyoderma Gangrenosum in her inside lower calf/ankle since July 2010. The disease initially destroyed an area of tissue 10cm long, 8cm wide, and 1cm deep. A series of Remicaid infusions stopped the progression but the physical destruction of the tissue was extensive. The intense burning 24/7 pain she endured from 2010 through 2013 is indescribable. Between 2010 and 2014, various matrix collagen materials along with Hydrofera and similar pad coverings/wraps (daily) were tried. Multiple weekly dermatology wound care appts., tapering to weekly and monthly, along with in-home caregiver [PHI Redacted] daily compression wraps through 2014, got the wound down to 2cm x 2cm x 3mm deep, but not fully closed. The wound flared again in the Fall of 2015, and by June of 2016 was back to 8cm x 6cm x 6mm deep, raging and painful. Weekly dermatology appts. were reinstated with a course of antibiotics for infection, and oral+local injection corticosteroids. The compression wraps and wound scraping were only marginally effective in reversing the wound progression. In the Fall of 2016 the URMC dermatology care professional suggested the use of direct wound oxygen therapy using something called Transcu O2. After careful study, [PHI Redacted] agreed to support the 24/7 commitment to this approach. To summarize, she saw nearly a complete elimination of the constant Pyoderma burning pain by the end of the first week of treatment with the Transcu. The daily care with the treatment required cleaning with Vashe wash, apply anti-maceration cream and Cavilon, a simple Tubigrip or 3M Coban 2 Lite wrap to press the OxySpur pad over the wound area, and an outer Coban wrap. Less than 90 days into the treatment, her wound has been replaced by all new tissue covering an area 6cm x 3.5cm and it is at original normal level of the surrounding skin area. It is in the final stage of full "skin-over" healing. The texture and quality of this oxygen nurtured tissue is significantly better than the tissue that had not fully filled the area between 2010 and 2013. It looks better and is not easily re-injured like the tissue was in 2013. The use of the Transcu O2 has given [PHI Redacted] a feeling that there is finally "light at the end of the tunnel" after 6.5 years of a severely limited quality of life. Pyoderma and the resulting vascular wound ended her full time management career in 2010, and took away her quality of life, as the location of the wound impaired her mobility. If the Transcu were not available now, she would have little hope of ever having a quality of life again. It is a small unit she has been able to conceal and wear to job she is able to work a few hours a week. Pyoderma stole her quality of life. The Transcu is restoring it in a fraction of the time it took to get only partial healing over a 4 year period years ago using pre-Transcu methods. I hope the Transcu is accepted by insurance, as many more people could see the healing [PHI Redacted] is experiencing. Thank You for your time.

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