Autologous Blood-Derived Products for Chronic Non-Healing Wounds

Our facility has been using Autologel for over two years with phenominal success on very difficult cases. In over 100 patients we only had one that did not respond to treatment. Autologel has reduced our overall wound cost,decreased length of stay, decreased the need for very expensive grafing procedures, and allowed for easy and less costly discharges to home or other facilities by reducing the need for for things like negative pressure wound therapy (NPWT).

I would highly recomend the approval of Autologel especially for increased physiican use in outpatient settings. Our experience is that it should reduce the overall cost to Medicare and more importantly will improve outcomes.

For disclosure purposes, I have no financial interest in Cytomedix other then lowering cost of care for our patients and improving outcomes.

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I fully support Medicare in the decision to begin coverage of PRP for open wounds, even in the limited basis outlined. I have heard of the benefits of PRP for many years, and have had limited and successful exposure to a couple of the systems. Recently, I used AutoloGel on a post-surgical trans-met amputation site that I had to debride so that nearly the entire end of the amputation was visible. I would not have expected that large a wound to close for weeks, even with Apligraf. In 6 days it was completely granulated over and epithelializing with AutoloGel. My very large population of Medicare patients would definitely benefit from this powerful modality. I hope that data collection will allow my compromised patients to access PRP, rather than the elite patients that are normally part of RCT’s.

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I am the Director of the Multidisciplinary Wound Care Clinic at the Miami VA Medical Center and the MD in charge of the Wound Care Team on our Spinal Cord Unit. I am very excited that CMS is considering Autologel PRP for Coverage with Evidence. No one treatment is right for all patients' wounds-this modality has been successful in healing wounds that have failed many other advanced modalities. We were particularly impressed with its performance in the Spinal Cord population for tunneling wounds and decubitus ulcers. Below the level of injury, wounds are much more difficult to heal and we achieved complete, durable closure in 2/3 of the patients treated. I am concerned that treatment would be limited to those patients who qualify for a randomized controlled trial. This standard frequently produces results that are not applicable to the larger Medicare population. The patients who develop these wounds have multiple co-morbities: a prospective registry would allow treatment of a broader range of patients and still answer the questions about efficacy. Wound healing for Spinal Cord patients means the difference between bed confinement and regaining their life. I am reminded in particular of a patient with paraplegia who had been forced to choose between healing his sacral pressure ulcer and keeping his lawn service open. Autologel healed the wound during the off season: 3 prior years of other modalities had failed. It remains durably closed to this day. Coverage of Autologel will allow many other patients to benefit from this treatment

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This repost of our original comments for consideration of the AutoloGel process summarized the hopes and prayers of the Indian Health Service Wound Healing Program for Oklahoma and reinterates the need to have this process available for wounded patients. While our budget for the IHS was increased a small percentage; our overall budget for our patient population is very small and any opportunity to obtain reimbursement for an advanced therapy is greatly needed and appreciated.

Wounds represent a great expense to the Indian Health Service system in both costs and provider time. The impact on the patients and their families is far greater in terms of frustration, morbidity and potential for amputation. Over 62% of patients who receive their first amputation do not survive five years.

Non-healing wounds lead to amputation and facilitate exacerbation of co-morbid conditions. Since beginning to use the AutoloGel system in 2004, the Area has been able to facilitate healing of many recalcitrant wounds and prevent amputations, the use of PRP has been one of the platform therapies to accomplish this healing.

The Oklahoma City Area Indian Health Service now has a state-of-the-art direct care wound program available to all patients within the Oklahoma City Area IHS system. Utilizing a proven approach to treat both non-healing and acute wounds, the program offers an organized method of treating and healing wounds that includes conservative care and appropriate intervention with advanced therapies such as PRP, using the AutoloGel System.

There is general consensus that not only does having PRP give the patients and providers more options for treating and healing wounds it saves already stretched health care dollars by facilitating faster healing, fewer opportunities for infection (by healing faster), and higher level of patient satisfaction.

When evaluating the efficacy of the AutoloGel System, the Oklahoma City Area undertook a special evaluation of the product in the framework of an Educational Initiative. The goal of the initiative was to determine if providers within the Oklahoma City Area would be able to effectively treat patients as a part of the direct care program using advanced therapies appropriately.

At the conclusion of the Initiative which lasted one year, the benefits of the program and the AutoloGel System was evident. The program and the outcomes are described below as a part of a submitted Abstract to the Symposium on Advanced Wound Care and Medical Research Forum; April 30 – May 1, 2006; San Antonio, TX.

It is our heartfelt request that this product be considered for reimbursement and approval.

Thank you,

Patricia Stevenson, APRN, ACNS, CWS-BC
Wound Program Coordinator/Contractor
Indian Health Service – Oklahoma City Area

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Dear Doctor Jacques: I am writing in support of National Coverage Analysis CAG-00190R3 regarding the use of autologous blood-derived products in treatment of chronic non-healing wounds.

In 2008, I collaborated in the development and publication of an economic model that compared treatment outcomes using autologous platelet rich plasma to standard of care and to the use of other advanced wound healing products and therapies in treatment of chronic non-healing diabetic foot ulcers. (Adv Skin Wound Care. 2008;21:568-75.) Our research compared results reported in the published peer reviewed literature to outcomes reported by Driver and colleagues (2006). We found that use of PRP resulted in reduced time to healing, reduced infection and amputation and lower cost of care than alternative therapies.

Because differences among persons with diabetic foot ulcers and even among different ulcers on the same patient make it difficult to design and recruit patients for a prospective, well controlled clinical trial, a prospective registry that will enroll all PRP patients regardless of complications or comorbidities presents a valuable alternative in studying the range of treatment outcomes resulting from use of PRP for chronic, nonhealing diabetic foot ulcers in the "real world" care setting.

I agree that the evidence is sufficient to to conclude that the use of PRP is reasonable and necessary in treatment of chronic, non-healing diabetic wounds. I encourage CMS to finalize CAG-00190R3 to ensure that Medicare beneficiaries suffering with chronic non-healing diabetic foot ulcers will have appropriate access to treatment using PRP.

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Louis Jacques, MD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Mail Stop C1-09-06
7500 Security Boulevard
Baltimore, Maryland 21244-1850

Dear Dr. Jacques:

Thank you for the opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS) proposed decision memo for Autologous Blood-Derived Products for Chronic Non-Healing Wounds (CAG-00190R3). America’s Health Insurance Plans (AHIP) is the national association for the health insurance industry. Our members provide coverage to more than 200 million Americans, offering a broad range of health insurance products in the commercial market and demonstrating a strong commitment to participation in public programs.

General Comments

AHIP and our member plans support CMS’s efforts to ensure that Medicare beneficiaries receive access to safe and effective services that can improve health outcomes, as determined bycurrent and robust clinical evidence.

Based on the available evidence, our members support CMS’ proposed decision to require patients to enroll in a randomized clinical trial that meets the criteria outlined by the proposed decision memo. Support for well-designed studies would increase the fund of knowledge regarding this therapeutic approach and potentially add an important new treatment option for this challenging condition. 

Thank you for the opportunity to comment on this important issue.

Sincerely,

/s/
Carmella Bocchino
Executive Vice President
Clinical Affairs and Strategic Planning

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June 8, 2012

ELECTRONICALLY FILED

CAGinquiries@cms.hhs.gov

Re: Autologous Blood-Derived Products for Chronic Non-Healing Wounds (CAG- 00190R3).

Dear Sir/Madam:

On behalf of Organogenesis, I am pleased to submit the following comments on the proposed National Coverage Decision (NCD) for Autologous Blood-Derived Products for Chronic Non-Healing Wounds (CAG-00190R3). Organogenesis is a biotechnology company based in Canton, Massachusetts, that manufacturers and markets ApligrafR (Q4101), a unique human skin substitute for diabetics and others who suffer from chronic ulcers.

Recommendation:

The Centers for Medicare and Medicaid Services (CMS) should continue to not cover platelet rich plasma (PRP) and should not finalize its proposal to cover PRP under Coverage with Evidence Development (CED). If CMS declines to agree with our recommendation then we recommend that CMS establish additional trial design requirements to those in the proposed decision memo for the purpose of addressing a number of data validity issues, including the inherent variability in the quantity and quality of platelets and other bioactive substances contained in autologous PRP which can be due to, among other things, (1) the patient, (2) the type of equipment and (3) operator ability, in order to increase the chance that the results of any clinical trials performed under CED will provide CMS with valid clinical data.

Discussion

In its proposed decision to cover autologous PRP under CED, CMS states the following:

In the above quotation from the proposed decision memo, while CMS believes that PRP may have the potential to benefit Medicare beneficiaries, CMS also notes the many, seemingly fatal, flaws of virtually all the autologous PRP clinical trials that it reviewed. Specifically, CMS states that each clinical trial on autologous PRP "has a number of flaws that would question the validity of their findings." CMS also states that the meta-analyses of autologous PRP are subject to the same criticism because they are based on these flawed trials.

Therefore, we wonder, what threshold evidentiary requirements CMS has in place to determine whether to propose that an item or service be covered under CED. It appears to us that if CMS covers autologous PRP under CED then virtually any item or service would qualify for CED if such coverage is requested. We are concerned that a CMS "belief" that an item or service (e.g., autologous PRP) may benefit Medicare beneficiaries which is not supported by at least some level 1 or 2 evidence, will make it extremely difficult for CMS to make consistent determinations as to whether the item or service should be non-covered or covered under CED. Essentially, we believe that covering autologous PRP under CED will, require from a consistency point of view, coverage of virtually any item or service under CED if that item or service has been the subject of a few case series and/or poorly designed clinical trials - such as is the case with autologous PRP.

The reason this is so important is that coverage under CED means that Medicare will spend a significant amount of tax dollars on clinical trials (e.g., for autologous PRP) in order to collect data upon which it can determine that the item or service is medically necessary. We do not believe the government should undertake such coverage and spend taxpayer dollars on CED unless there is sufficient evidence to show that those dollars are being well spent. As stated in our recommendation above and discussed in more detail below, we do not believe that Medicare should cover autologous PRP under CED and that the manufacturers of equipment that produce PRP should be responsible for sponsoring and conducting such trials until there is sufficient level 1 and 2 evidence showing effectiveness of PRP in healing chronic wounds, to justify consideration of Medicare coverage under CED. One specific concern we have is that if autologous PRP is covered under CED, the message being sent to manufacturers is that if they sponsor and conduct a few poorly designed clinical trials on their product, they are likely to successfully obtain coverage under CED for that product.

Organogenesis strongly believes that the existing evidence does not support CED for PRP and that manufacturers of equipment that produces PRP should pay for the clinical trials necessary to show medical necessity.

We agree with all the concerns and trial flaws noted by CMS. We also have additional concerns which we discuss below. Although we strongly believe that CMS should continue non-coverage of PRP, we recognize that CMS may disagree with our recommendation. Therefore, in case CMS finalizes its proposal to cover PRP under CED, we have also included recommendations to strengthen the CED requirements in the proposed NCD because they are not rigorous enough to ensure that clinical trials result in valid data that will assist CMS in making a coverage decision.

For the following reasons, we do not believe that the data supporting autologous PRP rises to the level to justify spending Medicare dollars to determine whether autologous PRP is medically necessary for the treatment of chronic wounds.

First, there are other therapies such as Apligraf and Dermagraft which have been shown to be safe and effective for the treatment of diabetic foot ulcers and venous stasis ulcers, which are covered by all Medicare Administrative Contractors (MACs) and which can be used on most patients who would be eligible for PRP. Apligraf and Dermagraft have received pre-market approval (PMA) from the FDA for the treatment of chronic wounds - in the case of Apligraf, for diabetic foot ulcers and venous stasis ulcers. To obtain FDA approval, Organogenesis performed two large well designed clinical trials which demonstrated that Apligraf was superior to the existing standard of care in treating chronic wounds. These prospective, randomized, multicenter trials excluded ulcers that were responsive to standard care during the screening period and employed the strict efficacy endpoint of complete wound closure defined as 100% epithlialization without drainage. Long-term follow-up was conducted on patients to assess safety and ulcer recurrence, and Cox proportional hazards regression analysis was performed on key variables known to impact healing to assess the individual and combined effects of these factors on time to wound closure.

Apligraf and Dermagraft are the only two medical devices we are aware of that are approved for "treatment" of chronic wounds - as opposed to "management" of chronic wounds which is the indication for all 510(k) cleared wound care products. In addition, Apligraf and Dermagraft are well studied and approved products that are available to physicians for the treatment of diabetic foot ulcers and venous stasis ulcers in the same group of patients for whom autologous PRP might be considered. Therefore, an unmet medical need does not exist. In our view, as a threshold, CMS should not consider any type of national coverage, including CED, for any wound care product unless there is an unmet medical need and the medical necessity of the product is supported by evidence at least as robust as that which exists for Apligraf and Dermagraft which, as stated above, are approved for the treatment of diabetic foot ulcers and venous stasis ulcers and are covered by Medicare.

Second, there are inherent issues about patient-to-patient variability in the quality and quantity of autologous PRP which will make it extremely difficult to obtain valid clinical data that can be extrapolated to patients not in the clinical trials. These issues are set forth below:

• It is unclear whether CMS is proposing to study the FDA cleared equipment or the platelet related products that the equipment produces. The FDA has cleared a number of devices for preparing platelet rich plasma products. The Table below depicts some of these devices, the platelet concentrate they produce, time of processing, type of product and their FDA cleared indications.

Technology	Increase in Platelet Concentration	Time to Process	Final Product	FDA-Cleared Indications for Use
Cytomedix AutoloGel	1 x (Physiologic)	10 minutes	Active PRP GEL	The AutoGel System is intended to be used at the point of care for the safe and rapid preparation of PRP gel from a small sample of a patient's own blood. Under the supervision of a healthcare professional, the PRP gel produced by the AutoloGel™ System is suitable for exuding wounds, such as leg ulcers, pressure ulcers, and diabetic ulcers and for the management of mechanically or surgically-debrided wounds.
Harvest Smart-PReP 2 APC +	4.6 x to 7.6 x	16 minutes	Platelet Concentrate	The SmartPReP is designed to be used for the safe and rapid preparation of autologous PRP from a small sample of blood at the patient's point of care. The PRP can be mixed with autograft or allograft bone grafting material prior to application to an orthopedic surgical site as deemed necessary by the clinical use requirements
Sorin Angel	3.0 x to 4.3 x	25 minutes	Platelet Concentrate	Intended to be used at the patient's point of care for the safe and rapid preparation of platelet poor plasma and PRP from a sample of whole blood. The plasma and concentrated platelets produced can be used for diagnostic tests. The PRP from the COBE® Angel Whole Blood Separation System can also be mixed with autograft and/or allograft bone prior to application to an orthopedic site as deemed necessary by the clinical use requirements.
ArterioCyte-Medtronic Magellan	3.6 to 5.1 x	33 mintues	Platelet Concentrate	The Magellan Autologous Platelet Separator System is designed to be used in the clinical laboratory or intraoperatively at the point of care for the safe and rapid preparation of platelet poor plasma and PRP from a sample of a mixture of blood and bone marrow. The plasma and concentrated platelets produced can be used for diagnostic tests. Additionally, the PRP can be mixed with autograft and/or allograft bone prior to application to an orthopedic site.
Biomet GPS II	2.3 x to 8 x	27 minutes	Platelet Concentrate	For the safe and rapid preparation of autologous PRP from a small sample of blood at the patient's point of care. The PRP can be mixed with autograft and allograft bone prior to application to an orthopedic surgical site as deemed necessary by clinical use requirements
De Puy Symphony II	4 x to 6 x	16 minutes	Platelet Concentrate	Designed to be used for the safe and rapid preparation of autologous PRP from a small sample of blood at the patient's point of care. The PRP can be mixed with autograft or allograft bone grafting material prior to application to an orthopedic surgical site as deemed necessary by the clinical use requirements.

As can easily be seen, not all products produce the same final product and the indications for use are different for each piece of equipment. Therefore, if CMS finalizes its proposal, it will need to be very clear exactly what it wants to study and to make an a prior determination as to whether data obtained using one type of equipment will be applicable to other equipment that may not be studied at all as part of the CED process.
• Each of these products prepares autologous PRP products differently and none was required to submit clinical data to the FDA demonstrating what the product contains (e.g., bioactive substances). The FDA clearances are for preparing autologous PRP and do not include any requirements for the quality of the preparation.
• Any preparation of autologous PRP is highly operator dependent. In other words, the quality and quantity of platelets and other bioactive substances contained in, autologous PRP will vary based on the experience, training and ability of the clinical staff preparing the autologous PRP. Therefore, the quantity and concentration of platelets and other bioactive substances is extremely operator dependent and will likely vary patient by patient.
• The quantity and quality of platelets and other bioactive substances, in autologous PRP is completely dependent on the morbidities and disease burden of each patient. For example, the quality and quantity of the platelets and other bioactive substances in PRP will be entirely different in an 80 year old patient taking immunosuppressive medications as opposed to a 65 year old diabetic patient on Insulin. This means that no two preparations of PRP will ever be the same and individual clinical effects will vary due to this inherent heterogeneity.

Any trial designed to study the safety and effectiveness of PRP in Medicare patients will need to address these issues. It does not appear to us that these issues have been raised to CMS by Cytomedix or by other commenters, nor were they raised by CMS in its proposed decision memo. Further, to our knowledge, these confounding factors have never been addressed in any publication or clinical trial performed on PRP and until they are worked out we do not believe that data from any trial, including those with a "randomized controlled" design will provide valid data that can be used by CMS in making a coverage determination for PRP.

Third, we are also very concerned that CMS appears to require that only one of three specified outcomes, which it identifies as being "clinically significant" need to be addressed. These are: a) complete wound healing, b) ability to return to previous function and resumption of normal activities or c) reduction of wound size or healing trajectory which results in (b) above.

We believe CMS should follow the requirements established by the FDA for the evidence required to obtain an indication for wound healing (i.e PMA or BLA). Clearly defined endpoints (i.e. complete wound healing) and greater clarity on what constitutes 'clinical significance' should be established to ensure the evidence generated meets appropriately stringent thresholds to warrant consideration for CMS coverage.

If CMS declines to agree with our recommendation to continue to non-cover autologous PRP then we recommend that CMS include additional clinical trial design criteria and clearly defined efficacy endpoints that will address the issues we raised about variability in the quantity and quality of platelets and other bioactive substances in autologous PRP and the overall clinical significance of the data generated.

We appreciate the opportunity to submit these comments. We would be pleased to answer any questions CMS may have. Please contact Antonio S Montecalvo, Director, Customer Support Services at 401-447-8951.

Sincerely,

/s/
Gary S. Gillheeney, Sr.
Executive Vice President, Chief Operating Officer, & Chief Financial Officer

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I am Cytomedix's former attorney (2001-2007) and remain a significant shareholder of the company. I applaud CMS on the courage and vision shown in its proposed decision memo. As CMS knows all too well, the chronic wound market is vast and growing, yet no chronic wound therapy has produced anything close to the desired healing rates that Cytomedix's submissions suggest are possible using Autologel.

In reviewing the comments recently filed, I was struck by the comments of Organogenesis, a long-time recipient of CMS's beneficence, in challenging CMS's proposed support of an alternative solution for the treatment of chronic wounds. Particularly striking was Organogenesis's statement that consideration of an autologous PRP therapy is unnecessary when products like Apligraf and Dermagraft are "safe and effective." Such a claim, in my view, debases the lay meaning I attach to the word "effective" because widely available studies using Apligraf, for example, show only slightly over 50% complete healing efficiency in venous and diabetic foot ulcers, respectively. These tepid results, while "statistically significant," in fact are no better from a patient's (or CMS's) perspective than a mere flip of a coin. (See, http://biomed.brown.edu/Courses/BI108/BI108_2001_Groups/Tissue_Engineered_Skin/effectiveness.htm#DFU_Results). CMS and its patient beneficiaries deserve better than 1:1 odds, and so it makes eminent sense until near 100% efficiencies are achieved for CMS to encourage development of promising alternative therapies for the treatment of debilitating chronic wounds.

I, therefore, strongly disagree with Organogenesis's position that non-coverage of autologous PRP therapies should continue. I suspect, however, that the motive of Organogenesis's CFO in strenuously objecting to the proposed decision memo is driven in significant measure by the direct threat to his spreadsheet projections of future sales, profits, and shareholder returns if the healing results from the proposed CED using autologous PRP therapies prove more robust than what is being achieved through use of Apligraf and Dermagraft.

Conversely, because Cytomedix's paramount goal since the day of its founding in 1998 has been the complete and cost-effective healing of chronic wounds in order to improve patient quality of life (and even survival in extreme cases), Cytomedix has long advocated consideration and application of a host of alternative therapies, and to that end has initiated and participated in several studies that have demonstrated the superior results that might be achieved by combining Autologel with such alternative therapies (like NWPT). Of course, with an open mind, such studies can also be developed with Apligraf and Dermagraft using the CED regimen and perhaps greatly improve the efficiencies of those synthetic therapies.

Even more to the point, the suggestion that there is no need for a product like Autologel when products like Apligraf and Dermagraft are readily available and reimbursed by CMS is disproven by at least one known occurrence of a patient's nonhealing chronic wound trajectory using Apligraf being subsequently converted to a healing trajectory using Autologel. Further, and more broadly, for Organogenesis to object to reimbursement of autologous PRP therapies because of an impossibility of standardization is a reductio ad absurdum argument that, if taken to its logical extreme, would advocate against some of the most promising autologous therapies under development (including autologous stem cell therapies).

Still, the decision memo of 2008, the proposed decision memo of 2012, and common sense tells us that the autologous PRP genie must be carefully let out of the bottle. I have long believed that any CMS coverage, even under the auspices of a CED program, should be preceded by FDA approval not only of the device itself, but of a device approved by the FDA as suitable for use in the treatment of chronic wounds. This further qualification of devices and therapies eligible for CED development has the significant benefit to CMS of lessening the burden on it of having to determine whether any particular autologous PRP device is or is not suitable for use in the treatment of chronic wounds. It also provides a clear line of demarcation that takes the guesswork out of the process and provides certainty to companies desiring to have their autologous PRP devices approved for possible reimbursement in the chronic wound arena.

Given the diabetic epidemic facing this country, it is fair to say that most families in this country have experienced first-hand the debilitating effects both direct and indirect of non-healing chronic wounds. Mine has. Your proposed decision memo shows that CMS is not content with existing therapies, which we know will never achieve 100% wound healing efficiency and which define "efficiency" as not much better than 1:1 odds. Cytomedix's results with Autologel suggest that the goal of 100% healing efficiency is more attainable than ever believed possible. As such, I hope that CMS stays the course and issues a final decision memo that encourages companies like Cytomedix to further develop evidence under the CED regimen that will enable CMS to determine once-and-for-all whether autologous PRP therapies using devices approved by the FDA as suitable for use in the treatment of chronic wounds moves us one giant step forward in the battle against chronic wounds.

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To:   Coverage and Analysis Group, Center for Medicare and Medicaid Services

From:    Martin P. Rosendale, Chief Executive Officer; James M Hinson, Jr., MD, FCCP; Carelyn P. Fylling, RN, MSN, CWS, CLNC; Cytomedix, Inc

Re:    Public Comment Regarding Proposed Decision Memo for Autologous Blood-Derived Products for the Treatment of Chronic Non-Healing Wounds (CAG -00190R3)

Date:    June 8, 2012

Acknowledgement

Cytomedix references the proposed decision issued on May 9, 2012 by the Coverage and Analysis Group (CAG) of the Center for Medicare and Medicaid Services (CMS) and appreciates the review of our submission for Reconsideration, the public comments, your review of the literature, and our productive discussions during our meetings. Cytomedix will work with CMS to define and complete a mutually agreeable Coverage with Evidence Development (CED) Study.

The CAG emphasized several points in the analysis of our prior submission. Particularly, in its decision for CED, CMS noted that while it found no conclusive evidence to support Medicare coverage for platelet rich plasma (PRP) such as the PRP formulated by Cytomedix’s proprietary device, (AutoloGel™) for chronic, non-healing wounds, there was also no conclusive evidence that PRP lacked a benefit. Thus, because of the significant burden of chronic non-healing wounds on the Medicare beneficiary population, their treating practitioners and their caregivers, CMS believes that it is appropriate to use CED to support the generation of more evidence to clarify the impact of PRP on the health outcomes of Medicare beneficiaries with chronic, non- healing wounds. CAG requested that this evidence be obtained using approved clinical studies in a research setting where there are added patient safeguards, monitoring, and clinical expertise.

CMS emphasized that the safety of PRP was not in question, as the medical literature has not shown that adverse event rates are higher or more severe in the PRP treated group when compared to a control group. CMS also requested the proposed evidence demonstrate “meaningful clinical benefit for the treatment of chronic wounds”, which could “potentially lead to improved patient function, and decreased patient dependence on other aspects of the health care system.” Believing that “evidence as yet is insufficient to support these outcomes”, CMS has requested “additional data gathered in the context of clinical care” to “further clarify the impact of these items and services on the health of Medicare beneficiaries”, and has asked for “patient-centered health benefits” in proposing that PRP used to treat chronic non-healing diabetic, venous and/or pressure wounds be covered under Coverage with Evidence Development (CED) under §1862(a)(1)(E) of the Act.”

Reemphasizing this point, CMS noted “chronic non-healing diabetic, venous and/or pressure wounds are an important cause of disability and burden for beneficiaries and society. More rigorous study of PRP therapy may yet produce evidence of improved health benefit for patients with chronic non-healing diabetic, venous and/or pressure wounds.” This comment will address CMS’s concerns and explain the process through which the type and quality of data contemplated by the CED process can be achieved in an efficient manner.

CMS Requests in the Proposed Decision

Cytomedix agrees with CMS that difficulties have plagued the development of an informative PRP evidence base and appreciates that CMS is providing an opportunity to address the limitations of previous studies. In so doing, CAG made a series of requests, importantly the following:

Studies of Efficacy: Randomized Clinical Trials

Cytomedix recognizes that in evidence-based medicine the RCT constitutes the highest level of evidence for individual studies. A therapeutic RCT is most useful to demonstrate efficacy of a given treatment, defined as the ability of the treatment undergoing testing to provide benefit to the patient in addition to or compared to the standard of care (SOC) or another treatment under controlled conditions, or to provide evidence of equivalency using non-inferiority testing. The magnitude of the difference between the SOC and treatment arms can be expressed as the effect size, which is the standardized mean difference when outcomes are continuous variables or the odds or relative risk ratio when outcomes are dichotomous.

The advantages of the well-conducted, well-designed, and adequately powered RCT are that many kinds of bias can be minimized (although not always entirely eliminated). These include the baseline characteristics of the two groups, population choice bias, selection bias, ascertainment bias, regulation bias, wrong design bias, and a host of other concerns (Jadad and Enkin, 2008). The reduction of bias always comes with a cost, usually that of restricting the entry populations. The inclusion and exclusion criteria that are designed to reduce the biases also lead to a significant lack of generalizability to clinical practice (Carter et al, 2009), are undermined by standard of care heterogeneity in multicenter trials, unrealistic margins for equivalence in non-inferiority trials, doubt about the results when loss to follow up is high in longer trials, especially with large differentials between groups, and inadequate statistical power for the primary outcome.

Challenges of Randomized Clinical Trials in Wound Care that affect CED

RCTs in wound care contain a number of elements that reduce the generalizability of the results. Attempts to constrain populations to reasonably sized evaluable groups using inclusion and exclusion criteria preclude the examination of effects of the studied treatment on more difficult wounds, in co-morbid populations or in unstable subjects. Carter et al (2009) documented that more than 50% of the affected populations were not eligible for routinely designed RCTs in wound care. These trials also may exclude a large number of the Medicare beneficiaries because of age, co-morbidities, and other restrictions. Examples of exclusion criteria that limit the generalizability to the usual Medicare wound care population include: wounds too large, too severe a wound grade, peripheral arterial disease, infection, osteomyelitis, cellulitis, corticosteroid treatment, hyperglycemia, immunosuppressive drugs, alcohol/drug abuse, liver impairment, renal impairment, bleeding disorders, cancer, renal dialysis, anticoagulants, connective tissue disease, neuropathy, antiplatelet drugs, vasoactive drugs, gastrointestinal disease, respiratory disease, severe cardiac disease, and diabetes. Because the Medicare beneficiary often has one or more of these exclusions, an RCT would diminish the utility of the results coming from such a trial.

RCTs in wound care tend to be of relatively short duration (typically 8-16 weeks) because of the difficulties of retaining subjects in longer RCTs, which impacts the ability to use long-term outcome and safety measures. This short duration can also create analytical issues when proportion of wounds healed is the primary outcome measure, as the inclusion and exclusion are chosen to define wounds that can heal in that shorter time, in order to achieve a manageable wound healing differential that is sufficiently large to provide statistical relevance for inferential testing. When length of any study is constrained, the use of time to healing is a more useful primary outcome as it compares the cumulative effect of improved wound healing in one arm versus another over any given period of time. Most importantly, short-duration RCTs cannot answer many practical issues concerned with overall effectiveness of a product or service in wound care, such as recurrence of an ulcer over one year, or hospitalization rates due to complications from a difficult-to-heal ulcer.

Cytomedix believes that while an adequate and well-controlled randomized trial may be appropriate for the purpose of establishing the initial efficacy of a product or service, the context of the CED request emphasized above has a different and distinct focus. As a result, an RCT is likely to be ineffective in establishing effectiveness for the product that can be generalized and applied through the range of target wounds in the CMS beneficiary populations. Thus, for a variety of technical reasons we also believe that an RCT is less desirable than other methods for establishment of the requests proffered by CMS.

Studies of Effectiveness: Observational Trials

Notwithstanding the broad acceptance of RCTs, there are genuine weaknesses inherent in this type of study design when compared with observational studies. While RCTs involve study groups that are very similar before treatment, they tend to involve a limited number of participants, often underrepresent key patient groups, and may require a protocol that does not reflect typical care patterns outside of the clinical trial setting. In contrast, an observational study can involve large numbers of typical patients in routine care settings and can focus on specific vulnerable populations (Avorn J, 2007).

Many analyses have demonstrated the disparities between the results of clinical trials and results in actual clinical practice (Wenneberg, 1998, Konstsam, 2000). Reports from the Institute of Medicine and the Congressional Budget Office in 2007 cited the importance of patient registries in developing comparative effectiveness evidence. (IOM and CBO, 2007) The Federal Coordinating Council for Comparative Effectiveness Research (CER) in its Report to the President and the Congress (June 30, 2009) defined CER as, “the conduct and synthesis of research comparing benefits and harms of different interventions and strategies to prevent, diagnose, treat and monitor health conditions in ‘real world’ settings.” The report specifically identifies patient registries as a core component of CER data infrastructure (CBO, 2007).

Advantages of Observational Trials in Wound Care

The significant issue faced in any systematic gathering of evidence in patients with chronic non-healing wounds, which is more problematic in an RCT design, is inclusion of the broad populations with the three different types of wounds (diabetic foot ulcers [DFUs], venous leg ulcers [VLUs], and pressure ulcers [PUs]) into one trial, as the characteristics of the wounds and treatment are very different. For example, diabetic foot ulcers tend to be smaller and deeper and at higher risk for complications (infection, progression of infection, gangrene, and amputation) compared to venous ulcers. The majority of PUs exist in patients at long-term care facilities (LTCs) and long term acute care facilities (LTACs) and so outpatient wound care clinics see less of this type of wound; and the visit frequency of PUs is much lower compared to DFUs, with much routine care of the wound done by home health agencies, especially for non-ambulatory patients. Finally, in real world wound care practice, advanced therapeutics for PUs, and to some extent VLUs, tend to be given later rather than sooner compared to DFUs due to the potential threat of amputation if the wound does not improve.

Observational trial designs appear to better fit the needs for CED: “The purpose of Coverage with Evidence Development (CED) is to generate data on the utilization and impact of the item or service evaluated in the National Coverage Determination (NCD) so that Medicare can a) document the appropriateness of use of that item or claim of service in Medicare beneficiaries under current coverage; b) consider future changes in coverage for the item or service; c) generate clinical information that will improve the evidence base on which providers base their recommendations to Medicare beneficiaries regarding the item or service. (Center for Medicare and Medicaid Services, 2006) All of this data can be accessed through a high quality registry that is reflecting the impact on Medicare beneficiaries.

Observational trial designs (e.g., cohort or any comparative group design) using a registry can provide complementary results to those obtained by RCTs: “Observational studies can be a useful and important complementary analytic complement to clinical trials.”(Agency for Healthcare Research and Quality (AHRQ). Accessed May 24, 2012). Well-conducted, well-designed, observational studies that adjust for important confounding factors can in fact provide better answers to these questions than a poorly designed or poorly conducted RCT at much lower cost and less utilization of resources (Concato et al, 2000). A CMS MEDCAC meeting acknowledged that there is benefit to analysis of “real world” data if information from large numbers can be collected in a uniform fashion. (CMS, MEDCAC Meeting, March 29, 2005)

Observational Trials in a Registry Setting

An effective medical registry is a systematic collection of a clearly defined set of health and demographic data for patients with specific health characteristics, held in a central database for a predefined purpose (Arts et al, 2002). Using these precepts, registries have been designed and used as effective methods of gathering observational data in settings in which RCT are impractical. Some of the commonly used purposes for creating registries are to describe the natural history of disease; to determine clinical effectiveness or cost effectiveness of health care products and services; to measure or monitor safety and harm; and/or to measure quality of care (Gliklich and Dreyer, 2010). Product registries include patients who have been exposed to biopharmaceutical products or medical devices while health services registries consist of patients who have had a common procedure, clinical encounter, or hospitalization, and disease or condition registries are defined by patients having the same diagnosis, such as cystic fibrosis or heart failure (Gliklich and Dreyer, 2010).

A registry can be used for an observational study to evaluate effectiveness. The Agency for Healthcare Research and Quality (AHRQ) defines a registry as “. . ..an organized system that uses observational study methods to collect uniform data (clinical and other) to evaluate specified outcomes for a population defined by a particular disease, condition, or exposure, and that serves one or more predetermined scientific, clinical, or policy purposes.” (Gliklich and Dreyer, 2010) The strong external validity of registries is achieved by the fact that they include “typical patients,” unlike RCTs (Concato et al, 2000). Registry data can provide a good description of the course of a disease and impact of interventions in actual practice and may be more relevant to decision-making than the data derived from clinical trials. (Benson, et al, 2000) “Even though registries have more opportunities to introduce bias (systematic error), well designed observational studies can approximate the effects of interventions as well as RCTs on the same topic, and in particular, in the evaluation of health care effectiveness.” (Black, 2011) The GRADE working group states: “Randomized controlled trials are not always feasible and in some instances, observational studies may provide better evidence . . . the results of RCTs may not always be applicable if the participants are highly selected relative to the population of interest.” (The GRADE Working Group, 2004).

Finally, the use of a well-designed registry is consistent with CMS’s own CED policy. When CMS first published guidance on CED in 2006, it stated that “[t]he purpose of Coverage with Evidence Development (CED) is to generate data on the utilization and impact of the item or service evaluated in the National Coverage Determination (NCD) so that Medicare can a) document the appropriateness of use of that item or claim of service in Medicare beneficiaries under current coverage; b) consider future changes in coverage for the item or service; c) generate clinical information that will improve the evidence base on which providers base their recommendations to Medicare beneficiaries regarding the item or service. (Center for Medicare and Medicaid Services, 2006) All of this data can be obtained and accessed through a high quality registry t