View Public Comments for Autologous Blood-Derived Products for Chronic Non-Healing Wounds (CAG-00190R3)

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

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.

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:

CMS has requested study of the three categorized wound types; diabetic, venous, and pressure ulcers. Wound care experts and the US Food and Drug Administration (FDA) clearly agree that there are biologically distinct ulcer types that have differing etiologies and behaviors. (FDA Guidance for Industry, Chronic Cutaneous Ulcer and Burn Wounds-Developing Products for Treatment. June 2006) These different ulcer types cannot be appropriately apportioned in an epidemiological sense and must be studied independently by separate trials. CMS also noted, and Cytomedix agrees, that due to multiple factors in the treatment populations, it is difficult to generalize the efficacy demonstrated in studies on therapy from one type of ulcer to another type. Standard of care differs by wound type. This includes techniques to promote wound healing, debridement or removal of necrotic tissue, wound cleansing and dressings that promote a moist wound environment. The use of systemic treatments including antibiotics and optimizing nutritional status also is highly variable.

CMS noted the need to allow and control for “ulcer specific therapies”. There are conventional therapeutic modalities that may apply to certain subgroups of patients depending on their type of wound such as diabetic, venous, and pressure ulcers. No single wound dressing is sufficient for all types of wounds and few are ideally suited for the treatment of a single wound through all phases of healing (Lait & Smith 1998).

CMS noted that there are at least three possible outcome measures that can be used as primary or secondary endpoints for analysis; each can be understood as a benefit for CMS beneficiaries; complete wound healing; the ability to return to previous function and resumption of normal activities; and reduction of wound size or healing trajectory that results in the patient’s ability to return to previous function and resumption of normal activities.

CMS also requested a Randomized Clinical Trial (RCT) and noted the contents and requirements of such a trial to fulfill the CED request.

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.

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.

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).

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)

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 that reflects the real world impact on the quality of care received by Medicare beneficiaries.

An extensive, validated registry in wound care already exists and can be adapted to a CED decision. The U.S. Wound Registry was created in 2005 as a non-profit organization. At the basis of this registry is an Electronic Health Record (EHR) certified for stage I of meaningful use designed to handle the entire documentation requirements specific to wound care. Clinical and administrative data are maintained on servers hosted by the vendor and accessed through a secure portal using remote desktop protocols. The U.S. Wound Registry contains the de-identified electronic health records of patients since 2000. Currently there are 124 active facilities in the United States, with new wound centers coming online each month. Users agree to participate in the “U.S. Wound Registry,” and this agreement allows the company to access and analyze facility data in a “de-identified” fashion in accordance with HIPAA privacy requirements and under control of an Institutional Review Board. Currently there are more than 500,000 visits evaluating 78,000 wounds in more than 30,000 patients.

This proprietary database is designed to provide accurate documentation of clinical encounters with patients to ensure that billing of CMS and other payers is accurate and appropriately coded. This includes detailed clinical information to the level that would be required to support documentation, including specifics on demographics, concomitant medications, prior history, wound history, wound photographs and measurements, specific details of treatments (including advanced treatments, and the acuity of the patient at each visit. Elements of Quality of Life (QOL) scoring systems are either in place or can be placed (Fife et al, 2007). The integrity of the data is high as a result of rigorous quality checking. Patients are automatically tracked through their visits to any wound care clinic within the system, and thus if they were part of a trial much longer term outcomes could be obtained. The data contained in this registry form the most comprehensive dataset in the United States. Most importantly, as a broad geographic cross-section of wound centers, the data comprise reliable examples of “real world practice” that can be extrapolated to larger populations.

The U.S. Registry provides several advantages as the mechanism by which data could be collected for a prospective observational trial. And, data obtained from a trial in which this registry is used can be easily compared with existing data as they are in exactly the same format.

Cytomedix understands that an RCT or an observational design could be formed to satisfactorily answer the points raised by CMS in regard to PRP (AutoloGel). However, we believe that the observational design provides the best overall measure of effectiveness for the targeted beneficiary population, and specifically addresses issues of patient centered health benefits, generalizability, cost effectiveness, patient function and use of other aspects of the health care system. Cytomedix proposes that a prospective, observational cohort study using the U.S. Wound Registry is the most complete methodology available to satisfy the Coverage with Evidence Development Study. The exclusion criteria would be very limited, allowing wound patients normally excluded from RCT’s to be included in the study and thus increasing the generalizability of the trial results to real world wound care practice. The setting would be the outpatient wound care clinics that contribute to the U.S. Wound Registry augmented if necessary by other clinics and settings in which data can be incorporated into the registry. Two cohorts would be followed: those wounds treated with standard of care and those treated with standard of care and, in addition, AutoloGel is included in the treatment program. Outcome data for diabetic, venous, and pressure ulcers would be analyzed separately, rather than as a total group to accommodate for the ulcer specific therapies. Wounds could be followed for an extended period so recurrence could be analyzed. Thus prospective observational cohort registry design can meet all the requirements stipulated for a quality RCT as delineated in the proposed decision.

Cytomedix appreciates the opportunity to participate in CED as a means to provide access for Medicare beneficiaries to be treated with PRP while CMS continues to collect evidence to support the effectiveness of the product. Cytomedix believes a properly designed registry based prospective observational study would be optimal to meet the CMS requests to be met and allows “additional data gathered in the context of clinical care”.

Cytomedix is committed to work with CMS to reach agreement on the appropriate CED study.

References

Agency for Healthcare Research and Quality. Lessons from outcomes and effectiveness research. Available at: http://www.ahrq.gov/clinic/out2res/outcom3.htm. Accessed May 24, 2012.

Arts DG, de Keizer NF, Scheffer JG. Defining and improving data quality in medical registries: A literature review, case study, and generic framework. J Am Med Inform Assoc 2002;9:600-11.

Avorn J. In defense of pharmacoepidemiology – embracing the yin and yang of drug research. NEJM. 2007:357:2219-2221.

Benson, et al, A comparison of observational studies and randomized, controlled trials, N Engl J Med 2000;342:1878-86.

Black N. Why we need observational studies to evaluate the effectiveness of health care. BMJ May 11;212 (7040):1215-8

Carter MJ, Fife CE, Walker D, Thomson B. Estimating the applicability of wound care randomized controlled trials to general wound-care populations by estimating the percentage of individuals excluded from a typical wound-care population in such trials. Adv Skin Wound Care. 2009;22:316-24.

Centers for Medicare & Medicaid Services. Guidance for the Public, Industry, and CMS Staff: National Coverage Determinations with Data Collection as a Condition of Coverage: Coverage with Evidence Development. July 12, 2006.

Centers for Medicare & Medicaid Services, MEDCAC Meeting on Chronic Wound Care, March 29, 2005 Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342:1887-92.

Congressional Budget Office (CBO). Research on Comparative Effectiveness of Medical Treatments: Issues and Options for an Expanded Federal role 2007. Accessed 2012: athttp://www.cbo.gov/ftpdocs/88xx/doc8891/12-18-ComparativeEffectiveness.pdf.

Fife CE, Walker D, Farrow W, Otto G. Wound center facility billing: A retrospective analysis of time, wound size, and acuity scoring for determining facility level of service. Ostomy Wound Manage. 2007;53:34-44.

Food and Drug Administration (FDA). Guidance for Industry: Chronic Cutaneous Ulcer and Burn Wounds-Developing Products for Treatment. June 2006. [internet] Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071324.pdf. Accessed June 1, 2012.

Gliklich RE, Dreyer NA, eds. Registries for Evaluating Patient Outcomes: A User’s Guide. 2nd ed. (Prepared by Outcome DEcIDE Center [Outcome Sciences, Inc. d/b/a Outcome] under Contract No. HHSA29020050035I TO3.) AHRQ Publication No.10-EHC049. Rockville, MD: Agency for Healthcare Research and Quality. September 2010.

IOM and Congressional Budget Office. Learning what works best: the Nation’s need for evidence on comparative effectiveness in health care. Washington DC: National Academy Press; 2007.pp 1-80.

Jadad AR, Enkin MW. Randomized controlled trials: Questions, answers, and musings. New York: Wiley; 2008, 29-47.

Konstam. Progress in heart failure management? Lessons from the real world. Circulation 2000, 102:1076.

Lait M, Smith L. Wound Management: a Literature Review. J Clin Nurs. 1998;7:11-17

The GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004;(328):1-8.

Wenneberg. Variation in carotid endarterectomy mortality in the Medicare population. JAMA 1998;279; 1278-81.