text:
The page could not be loaded. The CMS.gov Web site currently does not fully support browsers with
Instructions for enabling "JavaScript" can be found here.
Please note that if you choose to continue without enabling "JavaScript" certain functionalities on this website may not be available.
CMS covers extracorporeal photopheresis (ECP) for the treatment of bronchiolitis obliterans syndrome (BOS) following lung allograft transplantation only when ECP is provided under a clinical research study that meets the following conditions.
The clinical research study meets the requirements specified below to assess the effect of ECP for
the treatment of BOS following lung allograft transplantation. The clinical study must address one or more aspects of the following question:
This decision does not modify existing requirements for any other covered or non-covered indication for ECP (Section 110.4 Medicare National Coverage Determinations Manual).
The required clinical study must adhere to the following standards of scientific integrity and relevance to the Medicare population:
Consistent with section 1142 of the Social Security Act, AHRQ supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions.
Any clinical study undertaken pursuant to this NCD must be approved no later than April 30, 2014, two (2) years from the effective date of this NCD. If there are no approved clinical studies on or before April 30, 2014, this NCD for ECP treatment for patients who have received lung allografts and then developed progressive BOS refractory to immunosuppressive drug treatment will expire, and coverage will revert to the policy in effect prior to April 30, 2012. Any clinical study approved by April 30, 2014, will adhere to the timeframe designated in the approved clinical study protocol.
To: Administrative File: CAG-00324R2
Extracorporeal Photopheresis (ECP)
From: Louis Jacques, MD
Director, Coverage and Analysis Group
Tamara Syrek Jensen, JD
Deputy Director, Coverage and Analysis Group
James Rollins, MD, PhD
Division Director
Kimberly Long
Jeffrey Roche, MD, MPH
Medical Officer
Rosemarie Hakim, PhD
Subject: Final Decision Memorandum for CAG-00324R Extracorporeal Photopheresis (ECP)
Date: April 30, 2012
The clinical research study meets the requirements specified below to assess the effect of ECP for the treatment of BOS following lung allograft transplantation. The clinical study must address one or more aspects of the following question:
A. Extracorporeal photopheresis (ECP)
ECP is a medical procedure in which a patient's white blood cells are exposed first to the drug 8-methoxypsoralen (8-MOP) and then to ultraviolet A (UVA) light. The procedure starts with the removal of the patient's blood, which is centrifuged to isolate the white blood cells. The drug is typically added to the white blood cells after they have been removed from the patient (referred to as ex vivo administration) but the drug can alternatively be administered to the patient before the white blood cells are withdrawn. After UVA light exposure, the treated white blood cells are re-infused into the patient.
ECP is usually performed on two consecutive days at four-week intervals with clinical evaluation at six months to determine response. The duration of treatment varies significantly depending on the medical condition being treated, and the patient's response to the treatments.
ECP is frequently administered via the UVAR® XTS™ system, an FDA-approved automated apheresis and processing system. This system collects a patient's blood, isolates the white blood cells, adds 8-MOP and irradiates the treated white blood cells with UVA. Other systems and protocols have been used to administer ECP. In this decision memorandum as in previous ones, CMS is evaluating ECP as a procedure, and not a specific system for administering ECP.
The exact mechanism of action of ECP on the immune system is still unclear. It is thought that when activated, 8-MOP molecules bind with the DNA of the white blood cells, which kills the cells. The dead white blood cells, once reinfused into the patient, stimulate multiple different cells and proteins of the patient's immune system in a series of cascading reactions. This activation of the immune system then impacts the illness being treated. The precise manner in which chronic rejection of a lung allograft is affected by ECP is unknown.
B. Bronchiolitis Obliterans Syndrome (BOS) Following Lung Allograft Transplantation
BOS was described in 1984 in a small series of transplant recipients who developed progressive decline in lung function of non-infectious cause, beginning several months to a few years after heart-lung transplantation (Burke 1984). BOS refers to progressive decline in respiratory function. Its relation to chronic rejection and long-term failure survival of lung allografts stimulated a number of efforts to improve the immunosuppressive regimen for transplant patients in the 1990's. However, BOS is estimated to be present in more than 50% of lung allograft recipients at five years after transplantation, and remains a major obstacle to long-term lung transplant survival (Belperio 2009).
Clinically, BOS has an insidious onset with progressive exertional dyspnea, often accompanied by cough. Sometimes a bronchial infection seems to trigger its onset, with acute dyspnea, wheezing and the development of obstruction. Later in the course of the disease, superinfections and bacterial or fungal colonization are common. At that time, CT scan of the thorax often reveals bronchiectasis and other signs of chronic infection. Once established, untreated BOS may develop progressively and lead to severe obstruction with respiratory insufficiency and death resulting from an infectious exacerbation. Sometimes, episodes of progressive loss of lung function alternate with stable intervals. (Verleden 2005)
The histologic diagnosis of obliterative bronchiolitis (OB), a manifestation of chronic lung allograft rejection, depends on recognizing a pattern of progressive damage to the small airways. The sequence of pathologic changes in OB includes development of lymphocytic bronchiolitis; epithelial damage and ulceration; proliferation of fibroblasts and intraluminal granulation tissue; and ultimately fibrosis and scarring of small, non-cartilaginous bronchioles (Belperio 2009). Advanced disease can culminate in total obstruction and fibrotic obliteration of bronchioles. The patchy nature of OB, particularly in its early stages, has frustrated monitoring efforts after transplantation due to the relative insensitivity of serial biopsies to detect OB (Verleden 2005).
Because a reliable sign of BOS was unavailable from histopathologic examination of serial biopsies for OB, a consensus definition emerged (Belperio 2009) in which the diagnosis of BOS was defined by a sustained ( greater than 3 weeks) decline in expiratory flow rates, provided that alternative causes of pulmonary dysfunction have been excluded. International efforts (published first in 1993 and then revised in 2002) by professional societies such as ISHLT defined BOS clinically, in terms of forced expiratory volume in one second (FEV1), reflecting the persistent airflow obstruction seen in chronic allograft rejection (Estenne 2002). The 2002 ISHLT definition of BOS severity is shown in the following table. Note that, within each BOS severity category below, subtypes 'a' and 'b' exist, based on either no pathological evidene of OB or no pathological material for evaluation ('a') or pathological evidence of OB ('b').
Table: ISHLT 2002 Definition of BOS Severity
> 90%
BOS 0-p
81% to 90%
66% to 80%
51% to 65%
50% or less
Although BOS is rare within the first year after lung transplantation, the cumulative incidence of BOS ranges from 43 to 80% within five years of transplantation. Data from the ISHLT registry, representing more than 10,000 transplants followed from April 1994 through June 2006, showed that 25% had developed BOS by 2.5 years, and 50% by 5.6 years.
Survival after development of BOS varies by rapidity of decline of pulmonary function: in one study, those with more rapid decline survived a median of 29 months, while those with slower decline survived a median of 58 months (Belperio 2009). Worsening BOS grade (from 1 to 2 or from 2 to 3) is associated with higher mortality (Burton 2007).
Other studies have reviewed the role of inflammation and repair in the development of BOS in lung allograft recipients. The complex balance of factors including host immune reaction to foreign tissue; airway infection; ischemia; other host factors including gastroesophageal reflux; and potentially a localized graft-versus-host reaction by surviving donor lymphocytes interacting with recipient antigens has been summarized (Belperio 2009).
Because a specific cause of BOS is not yet known, various approaches have been proposed for its prevention or control (other than ECP, the topic of this NCD reconsideration). These include improved immunosuppression following transplantation; better histocompatibility matching of recipients to donor lungs; use of broad-spectrum antibiotics, such as azithromycin to reduce BOS risk; more effective anti-lymphocyte therapies and combination regimens; and improved allograft screening for infectious potential. (For example, Vos 2011)
In April 1998, CMS issued a national coverage determination (NCD) for ECP providing coverage by Medicare only when used in the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL) that has not responded to other therapy.
In December 2006, CMS issued a reconsideration of its 1998 NCD that determined that ECP is reasonable and necessary for patients with acute cardiac allograft rejection whose disease is refractory to standard immunosuppressive drug treatment; and patients with chronic graft versus host disease whose disease is refractory to standard immunosuppressive drug treatment. CMS also determined that ECP is not reasonable and necessary for the treatment of bullous pemphigoid and pemphigus vulgaris.
All other indications for ECP remain non-covered.
A. Current Request
CMS received a formal written request for reconsideration to add coverage for ECP treatment for patients who have received lung allografts and then developed progressive BOS refractory to immunosuppressive drug treatment. The request was submitted by Doctors RR Hachem and GJ Despotis, both of the Washington University in Saint Louis School of Medicine, and KE Berman of Health Research Associates (referred to as 'the NCD requesters').
B. Benefit Category
Medicare is a defined benefit program. An item or service must fall within a benefit category as a prerequisite to Medicare coverage §1812 (Scope of Part A); §1832 (Scope of Part B) and §1861(s) (Definition of Medical and Other Health Services) of the Act. ECP is considered to be within the following benefit category: 1861(s) (1) (physician services).
August 4, 2011
CMS accepts the formal request for reconsideration to add coverage for ECP treatment for patients who have received lung allografts and then developed progressive bronchiolitis obliterans syndrome (BOS) refractory to immunosuppressive drug treatment. A tracking sheet was posted on the web site and the initial 30 day public comment period commenced.
September 3, 2011
The initial 30 day public comment period ended. 22 timely comments were received.
February 2, 2012
Proposed decision posted
March 3, 2012
The second 30 day public comment period ended. 3 timely comments were received.
April 30, 2012
Final decision posted
In April 1987, the FDA approved (docket number 87M-0136) the application of Therakos, Inc. (Johnson and Johnson) for pre-market approval of the UVAR Photopheresis System. (Source: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm?id=16433)
In August 1999, the FDA approved the Therakos UVAR XTS system (PMA #P860003/S31). While this is an upgrade to the original device, the fundamental technology, function and intended use has not changed. (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm?id=8758)
In 1999, the FDA approved UVADEX® (methoxsalen) Sterile Solution, which is indicated for extracorporeal administration with the UVAR Photopheresis System in the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL) that is unresponsive to other forms of treatment. (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm?id=18471)
In March 2009, the FDA approved the Therakos CELLEX system (PMA #P860003/S48). While this is an upgrade to the original device, the fundamental technology, function and intended use has not changed. (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?start_search=1&applicant=&tradename=&productcode=LNR&pmanumber=p&advisorycommittee=&docketnumber=&supplementtype=&expeditedreview=&ivdproducts=off&decisiondatefrom=1/1/2009&decisiondateto=1/1/2010¬icedatefrom=¬icedateto=&so)
When making national coverage determinations, CMS generally evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary.
A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A.
Public commenters sometimes cite the published clinical evidence and provide CMS with useful information. Public comments that provide information based on unpublished evidence, such as the results of individual practitioners or patients, are less rigorous and, therefore, less useful for making a coverage determination. CMS uses the initial comment period to inform its proposed decision. CMS responds in detail to the public comments that were received in response to the proposed decision when it issues the final decision memorandum.
A. Introduction
This section provides a summary of the evidence that CMS considered during the review. No randomized controlled clinical trials were found that investigated the use of ECP in lung allograft recipients with BOS refractory to immunosuppressive drug therapy. The evidence reviewed for this decision memorandum, therefore, consists of results from uncontrolled clinical trials and from case studies published as full length literature articles. We note for the sake of clarification of terms that certain sections of this document refer to an existing international classification of the severity of BOS, the 2002 International Society for Heart and Lung Transplantation (ISHLT) definition of BOS (please see table, p. 5). In one area, we refer to an earlier (1993) version of this classification used by the Villanueva 2000 study (please see p. 12 below), one clinical study germane to this decision.
B. Discussion of Evidence Reviewed
1. Question and Outcomes
The goal of ECP therapy is to eliminate the immunological attack on the lungs, especially on the bronchioles. In the absence of more direct measures, such as serial biopsies of the bronchioles, the primary outcome measured in clinical studies and case studies reviewed was progression of BOS, measured as the change in rate of decline in FEV1.
CMS prefers evidence about health outcomes actually experienced by the patient, such as survival after transplant. Another patient-centered health outcome is quality of life. Additionally, a decrease in disease activity due to ECP, even if it is less than a total resolution of disease activity, may reduce the patient's need for immunosuppressive drug doses and thereby lessen the risk of infection.
2. External Technology Assessments
CMS did not request an external technology assessment (TA) on this issue.
3. Internal technology assessment
The reviewed evidence was gathered from articles submitted by the NCD requesters and from a literature search of the PubMed database by CMS staff.
The NCD requesters provided the full text of 47 articles they considered relevant to the requested reconsideration. Of the 47 submitted articles, 16/47 were review articles or professional society consensus statements, and one of 47 was a letter to the editor. Of the remaining 30/47 articles, 25 were clinical studies on topics unrelated to the specific research question for this NCD reconsideration. Of the remaining five of 47 articles, three were clinical studies with fewer than ten human lung allograft recipients with BOS refractory to immunosuppressive drug therapy for which ECP was used as treatment. Two articles (Morrell 2010 and Benden 2008) are summarized below. In addition, the requesters submitted a detailed public comment (see below under Section VII, 'Public Comments').
Literature search methods
In August 2011, CMS staff used the search terms "bronchiolitis obliterans syndrome" and "extracorporeal photopheresis" to find relevant articles.
CMS also reviewed all information submitted by the NCD requesters. The information they provided consisted of the 47 published articles of various types (noted above); and, received separately as a public comment, a summary and interpretation of a recent clinical study (Morrell 2010) for which two of the requesters were co-authors (Drs. Despotis and Hachem).
CMS also reviewed any references submitted with any public comments. Of eleven references from public comments:
In its own literature search, CMS included clinical studies of ECP in human subjects with BOS not responding to immunosuppressive therapy, in which at least ten individuals participated, and in which sufficient data was provided to assess study design, execution, and findings. CMS did not identify any articles in addition to those provided by the NCD requesters or by public commenters. In addition, CMS staff found that the published medical literature on ECP for BOS did not include any systematic reviews or meta-analyses.
Retrospective Case Series
Benden C, Speich R, Hofbauer GF, et al. ECP after lung transplantation: a ten year single-center experience. Transplantation 2008; 86(11): 1625-7.
In this report, results of a retrospective case series from one transplant center are based on twelve lung transplant patients undergoing ECP for BOS refractory to aggressive immunosuppressant therapy. [CMS notes that this article also included results of ECP therapy for twelve other patients, none of whom developed BOS, who received ECP for recurrent acute rejection of the lung allograft. Results of ECP therapy for these twelve other patients are not summarized for this analysis.] Insufficient information was provided in the report to establish the ages, genders, types of transplants received (unilateral or bilateral lung), or underlying diagnoses leading to transplantation, of the twelve patients undergoing ECP for BOS. All twelve patients with ECP for BOS completed twelve two-day cycles of ECP. At the start of ECP therapy, five of these twelve patients had BOS 1; two of the twelve had BOS 2; and the remaining five had BOS 3. The change in rate of decline in FEV1 was the primary outcome measure; graft survival post-ECP was the secondary outcome measure. The authors reported that the mean rates of decline in FEV1 were 112 ml/month before ECP and 12 mL/month after ECP (n=12, P=0.011, 95% confidence interval (CI) for change in rate of decline: 28 – 171 mL/month). The authors also reported that there was no significant change after ECP in absolute values of FEV1. Among patients dying during the 10 year study period, the cause of death was BOS. No ECP-related adverse events were reported, among any study patients. The authors concluded that ECP reduces the rate of decline of lung function in lung transplant recipients with BOS and is well-tolerated. The authors mentioned that during the study, all patients were treated with a cyclosporine-A based immunosuppressant regimen.
Morrell MR, Despotis GJ, Lublin DM, et al. The efficacy of photopheresis for BOS after lung transplantation. J Heart Lung Transplant 2010 Apr; 29 (4): 424-31.
In this retrospective study, the authors analyzed the efficacy and safety of ECP for BOS at one institution. Between January 2000 and January 2007, 60 lung allograft recipients were treated with ECP for BOS. The participants included 32 men and 28 women, with median age (and range) of 58 (21-72) years. Primary diagnosis before transplantation included COPD (43%), CF (18%), idiopathic pulmonary fibrosis (15%), alpha-1-antitrypsin (A1AT) deficiency (13%), primary pulmonary hypertension (5%), and other (5%). Following transplantation, patients had been maintained on a triple drug immunosuppression regimen, with acute rejection episodes treated with steroids and documented based on followup bronchoscopies. BOS was diagnosed according to ISHLT standards. A 24-session ECP protocol was initiated when a progressive decline in a patient's lung function was refractory to cytolytic therapy with antithymocyte globulin, optimization of the drug immunosuppression regimen, and use of azithromycin. The outcome used was rate of decline (in milliliters (mL) per month) of FEV1 before and after ECP. Of the study group of 60 patients, four were
excluded from further analysis due to death from respiratory failure before completing the entire ECP treatment protocol. For the other 56 patients studied, the mean rate of change in FEV1 during the 6 months before ECP initiation was -116.0 mL/month. During the 6 months period after ECP initiation, the mean rate of change in FEV1 was -28.9 mL/month. The mean difference in the rate of change in FEV1 from before to after ECP was 87.1 mL/month (P < 0.0001), 95% CI 57.3 – 116.9 mL/month). The authors evaluated the potential for length-time bias by excluding five patients (of 56) with BOS 1, but found that the mean difference in the rate of decline of FEV1 in 51 other patients (with BOS 2 and BOS 3) remained significant. In 14/56 patients, lung function improved, i.e., in these fourteen patients, FEV1 at 6 months after ECP increased by an average of 121 mL. Analysis of the response of the entire study group (n=51) during the extended period of twelve months after ECP demonstrated improvement of the mean difference in rate of change of FEV1 during the twelve months after ECP. The authors also investigated complications during treatment with ECP in all 60 patients. Eight patients were hospitalized for catheter-related sepsis. One of these eight patients died. No other complications were reported. The authors concluded that the differences from before ECP to both 6- and 12-month periods after ECP in rate of change of FEV1 seen in lung transplant recipients with BOS was significant, but they commented that limitations included the retrospective design of the study, the absence of a external control group, and the possibly confounding effect that ECP was used in conjunction with other immunosuppressive modalities that varied by individual patient. The authors suggested that further research would be appropriate.
Villanueva J, Bhorade SM, Robinson JA, et al. Extracorporeal Photopheresis for the treatment of lung allograft rejection. Annals of Transplantation 2000; 5(3): 44-7.
In this study of the use of ECP for the treatment of BOS, the authors retrospectively identified 14 patients which included three patients for clinical staging of BOS category 'a' and eleven patients who had biopsy proven OB. (CMS Note: this study used the 1993 ISHLT BOS severity category definitions (Cooper 1993).) Of these 14 patients, seven were female, and seven were male. The patients' mean age was 46 years. Seven of the 14 patients underwent bilateral lung transplantation; six underwent single lung transplantation, and one underwent heart lung transplantation. Primary diagnoses before transplantation included six patients with emphysema, five with cystic fibrosis, two with idiopathic pulmonary fibrosis, and one for pulmonary hypertension. All of the patients received standard immunosuppression with a three-drug regimen initially consisting of cyclosporine, azathioprine, and prednisone. Patients underwent ECP every two weeks for two months, and every month for two months, for a total of 6 treatments. FEV1 measurements were taken before and after ECP. Acute rejection episodes were treated with intravenous methylprednisolone, and some patients also received, antithymocyte globulin, total lymph node irradiation, and/or methotrexate for refractory rejection. The authors reported that at the time of diagnosis three patients were classified as BOS 0b; five as BOS 1, three as BOS 2, and three as BOS 3. In these 14 patients, time from transplantation to BOS development ranged from 7-51 months, with an average of 24 months. Eight of 14 patients were alive at the conclusion of the study. Mean (+/- SD) survival duration for all patients, after ECP therapy was 43 +/- 12 months, with mean survival of patients with BOS 2 or BOS 3 being 14 +/- 10 months. In six of 14 patients who died during the study period causes of death included BOS in four patients with BOS 2 or BOS 3, and lung cancer in two patients, one with BOS 1, and one with BOS 3. Among these six patients, deaths occurred from 6 – 34 months after ECP, with an average of 13 months after ECP. The authors noted no significant adverse events due to ECP treatment. The authors acknowledged that the small size and retrospective design of this study, the lack of randomized assignment of the treated group, and the absence of controls limited its generalizability. The authors concluded that ECP appears to be a promising therapy, especially for patients with less severe types of BOS.
Additional retrospective case reports or small cases series:
CMS was also informed of four additional publications describing small case series (n < 10) as summarized in the following table. These articles would not have been reviewed by CMS as sources of evidence given the inclusion criteria indicated above.
Cited as:
Number of Participants
Meloni 2007
Outcome studied: effect on CD4+ CD25+ Treg cells after ECP.
O'Hagan 1999
Brief clinical report
Salerno 1999
Outcome studied: subjective improvement.
Slovis 1995
Brief case series (letter to the editor). Insufficient data for review.
A Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) meeting was not convened on this issue.
5. Evidence-based guidelines
The American Society for Apheresis (ASFA) provided an evidence-based summary of ECP for treatment of BOS developing in lung allograft recipients. CMS did not find any other evidence-based guidelines relevant to this final decision.
Szczepiorkowski ZM, Winters JL, Bandarenko N, et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice—Evidence-Based Approach from the Apheresis Applications Committee of the American Society for Apheresis. Journal of Clinical Apheresis 25:83–177 (2010)
An evidence-based professional guideline from ASFA (Szczepiorkowski 2010) examined a variety of apheresis procedures, including ECP treatment for BOS developing in lung allograft recipients. ASFA considered BOS in lung allograft recipients to be a category II indication, that is, "(a) Disorder(s) for which apheresis is accepted as second-line therapy, either as a standalone treatment or in conjunction with other modes of treatment." On p. 126 of that article, a summary page with information about ECP for lung allograft rejection included the following.
"… At first, ECP was used in the context of refractory BOS (Stages 2-3) in which beneficial effect was demonstrated by initial stabilization or improvement in FEV1. Since then, the literature suggested that ECP may be an effective therapeutic modality for stabilization of lung function in patients with persistent acute rejection and early BOS (Stages 0-p -1), thus preventing further loss of pulmonary function. As ECP is not likely to reverse fibroblast proliferation in the transplanted lung, earlier initiation of ECP may arrest BOS progression thereby inducing improvement in the patient's clinical status and FEV1. Two recent largest studies to date (60 and 24 patients) showed that ECP significantly reduced the rate of decline in lung function in transplant recipients with BOS in all stages as measured by FEV1. … Importantly, ECP is well tolerated and is not associated with an increased risk of infection, a common complication of immunosuppressant drugs." (Szczepiorkowski 2010, p. 126)
These authors gave ECP for BOS a category II assignment (Disorders for which apheresis is accepted as second-line therapy, either as a standalone treatment or in conjunction with other modes of treatment.) They assessed the type of evidence for ECP for BOS as Type II-3, which they define as "Obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments could also be regarded as this type of evidence." Their recommendation for ECP for BOS was Grade 1C, defined as "Strong recommendation, low-quality or very low-quality evidence" supported by observational studies or case series. They noted that, for Grade 1C recommendations, the recommendation could change if higher-quality evidence becomes available.
6. Professional Society Position Statements
Two professional societies expressed positions via submitted public comment.
The American Association of Blood Banks (AABB) stated that there currently is no other proven therapy other than ECP for lung allograft patients with BOS for whom standard immunosuppressive drug treatment has not been effective.
The American Society for Apheresis (ASFA) stated that ECP is a reasonable and clinically appropriate second line therapy to addressing lung allograft rejection. They acknowledge that most of the published data is limited to observational studies and to gather randomized clinical trial evidence on specific treatments of rare disorders is extremely difficult. (Please also see above summary of ASFA evidence-based assessment of ECP for BOS (Szczepiorkowski 2010).)
7. Expert Opinion
We did not receive any expert opinions during the comment periods.
8. Public Comments
Initial Comment Period: August 4, 2011 – September 3, 2011
CMS received 22 timely public comments during the first public comment period. All of the comments supported the request to add coverage for ECP treatment for patients who have received lung allografts and then developed progressive BOS refractory to immunosuppressive drug treatment. Of these public comments received, thirteen/22 were from physicians, eight of whom specialize in lung transplantation, five/22 were from professors of medicine, two/22 were from professional societies, one/22 was from an individual who did not identify an associated organization or profession and one/22 was from the NCD requesters.
Of the 22 public comments, eleven contained one or more references, including in one case, references within a PowerPoint presentation sent with a comment. A review of the 11 unique published references showed that:
One public comment, submitted by the NCD requesters in their public comment on this reconsideration, provided a re-analysis of the Morrell 2010 article (for which two of the requesters were co-authors) focusing on the study's 25 Medicare patients, to determine whether Medicare beneficiaries specifically benefitted from ECP therapy. The re-analysis they provided is excerpted from their public comment below.
"Analysis of Medicare Sub-Cohort Treated With ECP Between 1/1/2000 – 12/31/2007
"In our previously published study,1 regression slope values were calculated to develop a linear relationship between measured FEV1 values vs. time; these slope values reflect mean rates of change in FEV1 over time for all patients (n = 56) included in our analysis. Pursuant to interest expressed by CMS staff, we extended our analyses to examine the mean monthly rates of change in the Medicare (n = 25) and non-Medicare (n = 31) patient sub-cohorts. These rates of change were calculated for (1) the six-month period prior to initiation of ECP, (2) the six-month period following initiation of ECP, and (3) the 12-month period following initiation of ECP. Comparisons of mean monthly rates of decline in FEV1 prior to ECP versus six-month and 12-month post-ECP appear in Tables 1 and 2 below.
"As presented in Table 1 below, the mean rate of decline in FEV1 during the 6-month period before the initiation of ECP in the Medicare sub-cohort was -98.7 mL/month. The mean decrement in FEV1 during this 6-month period was 594 mL. During the 6-month period after the initiation of ECP, the mean rate of decline decreased to -31.9 mL/month. The mean decline in FEV1 during the 6 months after ECP initiation was 192 mL. The mean difference in the rate of decline of FEV1 was 66.8 mL/month (95% confidence interval [CI], 22.0 – 111.4 mL/month; p < 0.005).
"Table 1. Mean monthly rates of decline in FEV1, pre-ECP and 6 months post-ECP
6 months prior to ECP (mL)
6 months post-ECP (mL)
Mean difference (mL) (95% CI)
Medicare (n =2 5)
- 98.7
- 31.9
66.8 (22.2 - 111.4)
Non-Medicare (n = 31)
- 129.9
- 26.4
< 0.0001
103.4 (62.1 - 144.8)
All Patients (n = 56)
- 28.9
87.1 (57.3 - 116.9)
"The analysis was extended to twelve months after the initiation of ECP to evaluate the durability of the response; these findings are presented in Table 2 below. In the Medicare sub-cohort, the mean rate of decline over the twelve months following initiation of ECP was -24.3 mL/month, and the mean decrement in FEV1 during this 12-month period was 144 mL. The mean difference in the rate of decline between this 12-month period and the period before ECP was 74.4 mL (95% CI, 30.9 – 117.9 mL/month; p = 0.002).
"Table 2. Mean monthly rates of decline in FEV1, pre-ECP and twelve months post-ECP
12 months post-ECP (mL)
Medicare (n=25)
74.4 (30.9 - 117.9)
Non-Medicare (n=31)
110.8 (73.0 - 148.7)
All Patients (n=56)
94.6 (66.5 - 122.6)
The NCD requesters also noted in their public comment that in a search of the national registry of clinical trials (clinicaltrials.gov), they identified two trials involving treatment of BOS in lung transplantation recipients. Finally, they noted that changes in pulmonary function after ECP treatment, as measured by changes in rate of FEV1 decline, was the sole primary outcome measure in these two trials.
They also noted that "We could not identify any controlled or single assignment clinical trials, evaluating any intervention to treat established BOS in lung transplantation patients that specified mortality as a primary outcome measure in the medical literature or in the ClinicalTrials.gov database."
Second Comment Period: February 2, 2012 – March 3, 2012
CMS received three timely comments during the proposed decision comment period. Two of the three comments support the request to grant coverage with evidence development for ECP treatment for patients who have received lung allografts and then developed progressive BOS refractory to immunosuppressive drug treatment. The third comment appears neutral. Of these public comments received, one was from a lung transplant physician who is also one of the NCD requesters, and the other two were from professional associations: AHIP and AdvaMed. No new evidence was provided through the comments received. The comments and CMS' responses are summarized below:
Comments in support of the proposed decision:
AHIP agrees with the proposed decision but noted that CMS should include a detailed process for disclosing that coverage is limited to beneficiaries enrolled in a clinical trial and a protocol for ensuring full understanding and consent of the beneficiary.
CMS appreciates the supportive comment. Any approved clinical study must adhere to the standards of scientific integrity and relevance to the Medicare population; specifically elements (f), "the research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46," and (g), "all aspects of the research study are conducted according to appropriate standards of scientific integrity." These standards are clearly described in the decision summary of the final decision.
AdvaMed did not express a specific view on the proposed decision but expressed concerns about CED and pointed out that it recently submitted comments on the CED guidance in general. AdvaMed suggested that CMS collaborate with stakeholders to clearly identify the data collection objectives, consider the minimum data necessary to achieve those objectives, and collaborate with stakeholders to clearly identify scientifically supported study endpoints and the duration of data collection in advance.
CMS appreciates the comment. We will be mindful of these comments if a protocol is submitted within the two (2) year timeframe.
The comment received by a lung transplant physician who is also one of the requesters agrees with the proposed decision but points out that improvement in lung function would be an unlikely and unrealistic endpoint but rather stabilizing or arresting the decline in lung function might be a more accurate endpoint.
CMS appreciates the support for the proposed decision, and agrees with the commenter that stabilizing or arresting further decline in lung function would be an appropriate endpoint. We have modified the final decision language to include 'decrease in the rate of decline of FEV1' as an endpoint.
Full text public comments without personal health information can be viewed at http://www.cms.gov/medicare-coverage-database/details/nca-view-public-comments.aspx?NCAId=255&ExpandComments=n&ver=3&NcaName=Extracorporeal+Photopheresis+(ECP)&DocID=CAG-00324R2&bc=gAAAAAgAIAAA& .
National coverage determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally by Medicare (§1862(l) of the Act).
In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B, and must not be otherwise excluded from coverage. Moreover, section 1862(a)(1) of the Social Security Act in part states that, with limited exceptions, no payment may be made under part A or part B for any expenses incurred for items or services:
Section 1142 of the Social Security Act describes the authority of the AHRQ. Under section 1142, research may be conducted and supported on the outcomes, effectiveness, and appropriateness of health care services and procedures to identify the manner in which diseases, disorders, and other health conditions can be prevented, diagnosed, treated, and managed clinically
Section 1862(a)(1)(E) allows Medicare to cover under coverage with evidence development (CED) certain items or services where additional data gathered in the context of clinical care would further clarify the impact of these items and services on the health of Medicare beneficiaries. For your convenience, the 2006 CED guidance document is available at www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/ced.pdf.
In analyzing the evidence, CMS focused on evidence that speaks to whether or not ECP provides patient-centered health benefits (such as improved survival, less severe BOS, or improved QOL) when used as a second- or third-line treatment of Medicare patients with chronic lung allograft rejection BOS refractory to the usual immunosuppressive therapy regimen.
We note first that the only available evidence is based on conclusions from several retrospective case series. Their limitations as sources of evidence have been acknowledged by their authors. In one article (Benden 2008), the authors commented that, because their study was not a randomized controlled trial (RCT), "unintentional bias may have impacted patient outcome". The decision to commence ECP was at the treating clinician's discretion, leading to the potential for confounding due to variation in treatment. These authors accordingly note that "(d)uring the study period, all recipients were treated with a cyclosporine A-based immunosuppressant regime; however, changes occurred with regards to induction therapy and antiproliferative agents." Finally, the authors acknowledge the small size (n = 12) of the group of recipients with BOS treated with ECP. In several ways, the features (and limitations) of the Benden 2008 study are closely comparable to those of the two other studies reviewed below.
In a second article (Morrell 2010), the authors recognized that "(t)his study has some inherent limitations because of the retrospective design. Our study lacked an external control population for comparison. However, individual patients acted as their own controls to assess a spirometric response to ECP, as recommended in the most recent ISHLT update on BOS. The decision to initiate ECP was made on clinical grounds; thus, all eligible patients may not have been treated with ECP. … It is possible that the reduction in the rate of decline after ECP is related to the natural history of BOS itself, rather than the ECP treatment." The authors suggested that a study of FEV1 with a control group of untreated lung allograft recipients with BOS would be both difficult and unethical. The authors commented that the study group experienced a more rapid onset of BOS compared with previously reported data (Trulock 2007), yet the median survival from BOS onset in the study group was "similar to that reported in previous studies" published in the late 1990s. These authors suggested that "(f)urther randomized controlled trials comparing ECP with other immunomodulatory therapies such as cytolytic therapy are necessary to better understand the role and effect of ECP in the management of BOS." Finally, the authors excluded four patients from analysis who died before ECP therapy was complete, but, without further explanation, did not include these patients in their discussion of adverse events during ECP.
The authors of the third retrospective series reviewed for this NCD reconsideration (Villanueva 2000) commented that "(t)his study … was limited by its retrospective design and the small number of patients … It is known that the decline of FEV1 and the survival of patients BOS is variable. Therefore it is possible that the observed effects may be due to chance and not to ECP." They also commented on several other limitations: including lack of randomization and variation in immunosuppressive therapy for individual patients. The authors suggested that further randomized prospective studies should be performed to evaluate the role of ECP in the treatment of BOS. In addition, this article did not include the physiological data (i.e., changes in FEV1 over time) as studied in the Benden 2008 and Morrell 2010 series. This article is more of a descriptive study looking at survival based on BOS classification, using the 1993 ISHLT definitions. For these reasons, this article is not methodologically comparable to the Benden 2008 and Morrell 2010 articles and its findings (other than demographics and adverse events reported) are not further discussed in this analysis.
In summary, the three articles describing outcomes of ECP in patients with BOS after receiving lung allografts may be subject to biases and confounding for several reasons (e.g., selection bias), including those mentioned by their authors. We note in particular variations in individual therapy noted in these articles both prior to and after the onset of BOS. These articles do not provide data separating the effects of these varying therapies from that of ECP are not provided. However, for this national coverage analysis, they contain the only direct evidence available from clinical trials, as confirmed by CMS' internal evidence assessment.
To answer the question above, an ideal clinical study would include a standardized treatment regimen (e.g., indicating in advance a standardized approach to ECP patient selection, frequency, intensity, and duration) and physiological (outcome) assessment methods. Such a study could potentially use a pre-test / post-test design, with each patient serving as their own control. Such designs may help minimize bias and promote uniform data collection and analysis. Lacking the option of an RCT design, other designs which would have been preferred for their greater resistance to potential sources of bias include, for example, prospective clinical trials (including registries) focused on outcomes that indicate benefit relevant to patients. However, such potentially more persuasive sources of evidence were not available.
CMS notes that other published studies have assessed alternative modalities to avoid BOS progression, e.g., the use of azithromycin to prevent BOS in patients with evidence of acute inflammatory cells (neutrophils) in the bronchioalveolar lavage (Vos 2011), or more aggressive treatment of gastroesophageal reflux to protect bronchial epithelium from damage that may provoke BOS in patients not responsive to azithromycin (Mertens 2011). Because the Morrell 2010 article mentions the use of azithromycin to control BOS, the potential for an interaction between the treatment effects due to azithromycin and those due to ECP exists, and may need to be considered in designing future studies.
Although a number of patients studied were ineligible for Medicare on the grounds of age alone (i.e., they were not 65 years of age or older) an unpublished survey of seven of eight transplant centers by the NCD reconsideration requesters indicated that Medicare beneficiaries account for about 50% of lung transplantation caseload. After transplantation, patients younger than 65 years of age may qualify due to permanent disability status. The median ages of BOS onset in two of the three retrospective case series reviewed are given in the following table (data was not available on the subgroup of twelve patients with BOS treated with ECP in the Benden 2008 study).
Median Age at BOS Onset
Morrell 2010
58 years
Villanueva 2000
48 years
The data that ECP therapy leads to stabilization or improvement in FEV1 decline in lung allograft recipients with BOS are summarized below. (As noted above, the Villanueva 2000 article did not provide quantitative information on FEV1 decline, using instead BOS severity in its published comparisons.) We note that, in the data about the Medicare cohort tabulated below, mean FEV1 did not improve, but declined at a slower rate. However, the authors of the Morrell 2010 article indicate that a subgroup of 14/56 patients did experience some improvement of FEV1 (mean improvement: 121 mL) following ECP therapy.
Cited Study:
Mean FEV1 change before ECP therapy
Mean FEV1 change after ECP therapy
Study group size and p value
Benden 2008**
- 112 mL/month
- 12 mL/month
N=12; p = 0.011
- All patients*
- 116.0 mL/month
- 28.9 mL/month
N=56; p < 0.0001
- - Medicare cohort*
- 98.7 mL/month
- 31.9 mL/month
n=25; p = 0.005
- - Non-Medicare*
- 129.9 mL/month
-26.4 mL/month
n=31; p < 0.0001
* - comparison in Morrell 2010 is between the mean rate of decline in the six months before ECP treatment and the mean rate of decline in the six months following ECP treatment.
** - comparison in Benden 2008 is between the average FEV1 'gradient' (per month) between the best post-operative (baseline) FEV1 and the FEV1 preceding ECP treatment; the post-ECP average gradient was based on serial FEV1 measurement following completion of twelve cycles of ECP through the last available FEV1 prior to death or the conclusion of the study period, whichever came first.
In summary, based on less preferable retrospective studies as the only available sources of evidence, CMS concludes that the currently available evidence is insufficient to convincingly demonstrate that ECP treatment improves patient-centered health outcomes for Medicare beneficiaries who have developed BOS following lung transplantation. Additional evidence of improvement of patient-centered healthcare outcomes (potentially including studies of improved quality of life in lung allograft recipients due to ECP treatment) would be more persuasive in this circumstance. Thus we concluded that ECP for Medicare beneficiaries who have developed BOS following lung transplantation is not
reasonable and necessary under 1862(a)(1)(A) of the Act.
We believe, based on our review of the available evidence, that CED is an appropriate coverage alternative for ECP for this indication. As explained in the 2006 CED guidance document, cited above, CED facilitates development of additional evidence from approved clinical studies in order to clarify the impact of an item or service on the health outcomes of Medicare beneficiaries. CED enables this additional development of evidence within a research setting where there are added safety, patient protections, monitoring and clinical expertise.
CMS has previously emphasized three key conditions governing the appropriateness of a CED coverage determination. The first key condition is that the basic safety of the proposed item or service must be assured. In the case of ECP for this indication, its basic safety has been confirmed by findings from these studies. Adverse events during ECP were noted in ten of 56 patients in the Morrell study. These ten adverse events included eight bacterial line infections, one of which was associated with sepsis and death; one thrombosis distal to the catheter tip, which responded to thrombolytic therapy; and one episode of transient hypotension during ECP, which was treated successfully with a saline fluid bolus. No adverse events were recorded in any of the twelve patients with BOS treated with ECP in the Benden 2008 study. Two of 14 patients in the Villanueva 2000 study suffered line related sepsis that cleared after catheter removal and the use of antibiotic therapy.
This evidence for basic safety of ECP therapy for this indication is summarized in the following table:
Benden 2008
1.78% (sepsis, death)
14% (non-fatal sepsis)
In addition, CMS has indicated that for Medicare beneficiaries who have undergone lung transplantation, ECP is reasonable and necessary for patients with acute cardiac allograft rejection refractory to standard immunosuppressive drug treatment. We believe that this decision speaks to the basic safety of ECP treatment of Medicare allograft recipients. We note also the existing FDA approval for the components of ECP therapy (as indicated above in Section V).
A second key condition for CED is the potential benefit of the item or service to Medicare beneficiaries. For this part of the analysis, the re-analysis of the Morrell 2010 data by the NCD requesters becomes of importance.
In their reanalysis, the NCD requesters compared the monthly rate of decline of FEV1 before and after ECP in both Medicare and non-Medicare patients. They found that this decline was significantly lower following ECP therapy in both groups; that is, there was evidence of a significant change in the rate of decline of FEV1 in the Medicare subgroup:
- Medicare
- Non-Medicare
CMS notes that the need for evidence that a slowing of the rate of decline in FEV1 has the potential for positive impact on patient quality of life. However, rate of FEV1 decline has been associated with mortality among patients with non-transplant related lung conditions including COPD (for example, Ketelaars 1996). CMS believes that a lower rate of FEV1 decline has not yet been associated with improvement in any other measurable health outcome and encourages further research into this question.
The third key condition for CED is difficulty in conducting adequately powered clinical studies. CMS is aware that clinical studies of ECP for this indication may be more difficult to perform due to the limited number of Medicare beneficiaries who would not only be clinically eligible but also would prospectively agree to participate in such studies. An indication of the difficulty of such trials is the relative lack of current research efforts listed on http://www.clinicaltrials.gov for the search terms 'ECP' and 'bronchiolitis obliterans'. One such study, entitled "Extracorporeal Photopheresis in Patients With Bronchiolitis Obliterans Syndrome (BOS) After Lung Transplantation" (clinicaltrials.gov identifier: NCT00502554), was described as 'Terminated' as of October 27, 2011, with the explanation, "insufficient patient recruitment and ECP capacity."
We also note the public comment of ASFA, which mentioned the difficulty of conducting such trials. However, CMS believes that a clinical trial including qualifying patients from multiple transplant centers could overcome this difficulty. We also recognize that other study designs (other than randomized controlled trials) may be appropriate to address the research questions above.
CMS has determined that based on the available evidence, ECP for this indication fulfills the criteria for CED coverage.
Health Disparities
A review of articles discussed above in this decision memorandum reveals no analysis of ECP clinical outcome by racial or ethnic categories. Any inference about relative benefits of ECP for control of BOS among lung transplantation recipients in specific racial or ethnic groups would be, at best, speculative. CMS also notes the absence of evidence about benefits or harms related to other population classifiers that have been associated historically with healthcare access or outcome disparities, such as gender, sexual orientation, religion, and age, and encourages additional studies in which such associations might be studied.
However, there is some information about disparity in overall survival among lung transplant recipients. In a large retrospective cohort study, based on 16,875 adults who received primary lung transplants from 1987 to 2009 according to the Uniform Network for Organ Sharing (UNOS) database, Liu et al., 2011 examined the risk of death after lung transplant for nonwhites compared with that for whites using time-to-event analysis. The percentage of nonwhite transplant recipients increased from 8.8% (before 1996) to 15.0% (2005-2009). In the modern transplant era (2001-2009), survival improved for all patients. However, a greater improvement among nonwhites has eliminated the disparities in survival between the races (5-year survival, 52.5% vs. 51.6%). The authors concluded that, in contrast to the period 1987-2000, there was no significant difference in lung transplant survival between whites and nonwhites in the period 2001-2009. The authors commented that advances in surgical technique or immunosuppressant therapy might account for this change. However, this study did not collect data on incidence of BOS; causes of death among study subjects; or exposure to ECP therapy for the various racial and ethnic subgroups.
This lack of evidence about racial and ethnic factors and the response to ECP treatment represents in our view an evidence gap which we encourage trial designers to consider when proposing clinical trial designs for ECP under this NCD. While recognizing that this consideration may complicate the design of appropriate clinical studies, we will nevertheless prefer clinical study proposals in which data on racial and ethnic factors are specifically collected and analyzed.
Duration of CED coverage for ECP for this indication
CMS considers the results of all CED clinical studies critical in the evolution of medical technology and in the evaluation of the benefit of items and services covered under CED. Because of this, CMS does not consider an NCD that requires CED as a condition of payment to be a permanent policy. In the past, CMS has not put time limitations on NCDs that require enrollment in clinical studies for coverage. This has led to a number of circumstances that could have been avoided by establishing time limits, including having a standing NCD without any CED clinical studies being conducted and allowing payment for services provided in studies that have never produced evidence. In order to avoid these circumstances for this CED NCD, CMS proposes setting the specific time limits described below.
This CED decision will have a two stage expiration process. In the first stage, we will require that all clinical studies under which there is CED coverage for ECP for BOS must be approved within two years of the date on which this final NCD is issued. If there are no approved clinical studies on that date, this NCD will expire and coverage of ECP for BOS will revert to the coverage policy in effect prior to the issuance of this NCD. We base this time period on CMS' experience with earlier CED decisions in which approvals for CED clinical trials have been completed within several months after the NCD date.
If there is at least one approved clinical study, we will proceed to the second stage. For each approved study of ECP for BOS, we will establish a specific time period during which ECP will be covered under this NCD. We will allow enough time, based on the study protocol, for the expected number of patients to be enrolled and for the treatment to be administered to the last patient in the study. After that, coverage for ECP for BOS for the particular clinical study will no longer be available. The time period will be based on the following factors:
This NCD will expire with the expiration of the latest allowed time frame for a clinical study approved for CED under this NCD.
CMS has determined that the evidence is insufficient to conclude that, in Medicare beneficiaries with BOS developing after lung allograft transplantation refractory to standard immunosuppressive therapy, ECP will improve patient centered health outcomes. However, based on its previously published criteria for considering CED, CMS concludes that evidence of basic safety, potential for patient-centered health outcome improvement, and demonstrated difficulty of conducting appropriate clinical trials are sufficient in combination to persuade CMS to propose this form of coverage for ECP therapy for BOS after lung allograft transplantation.
As noted above, an ideal clinical study would include a standardized treatment regimen (e.g., indicating in advance a standardized approach to ECP patient selection, frequency, intensity, and duration) and physiological (outcome) assessment methods. Such a study could potentially use a pre-test / post-test design, with each patient serving as their own control. Such designs may help minimize bias and promote uniform data collection and analysis. Lacking the option of an RCT design, other designs which would have been preferred for their greater resistance to potential sources of bias include, for example, prospective clinical trials (including registries) focused on outcomes that indicate benefit relevant to patients.
Any clinical study undertaken pursuant to this NCD must be approved no later than April 30, 2014, two (2) years from the effective date of this NCD. If there are no approved clinical studies on or before April 30, 2014, this NCD for extracorporeal photopheresis treatment for patients who have received lung allografts and then developed progressive BOS refractory to immunosuppressive drug treatment will expire, and coverage will revert to the policy in effect prior to April 30, 2012. Any clinical study approved by April 30, 2014, will adhere to the timeframe designated in the approved clinical study protocol.
CMS also notes that no evidence from this final decision memorandum supports any modification of existing coverage status of ECP used for other indications (e.g., for cutaneous T-cell lymphoma).
The Centers for Medicare & Medicaid Services (CMS) has determined that the available evidence is insufficient to conclude that ECP improves beneficiary health outcomes as second-line therapy for Medicare beneficiaries who are recipients of lung allografts and who have developed BOS refractory to standard immunosuppressive therapy. We therefore determine that coverage for ECP for this indication is not reasonable and necessary under§ 1862 (a) (1) (A) of the Social Security Act (hereinafter 'the Act').
However, we believe that ECP may, upon development of additional evidence, prove to represent a substantial benefit to Medicare beneficiaries who are recipients of lung transplants and who have developed BOS refractory to standard immunosuppressive therapy. CMS review of clinical trials confirms not only the basic safety of ECP therapy but also the difficulty of conducting clinical trials. Therefore, CMS has determined that ECP for this indication be approved under Coverage with Evidence Development (CED).
Accordingly, CMS covers ECP for this indication only when ECP is provided under a clinical research study that meets the following conditions.
We note for the sake of clarification of terms that certain sections of this document refer to an existing international classification of the severity of BOS, the 2002 International Society for Heart and Lung Transplantation (ISHLT) definition of BOS (please see table, p. 5). In one area, we refer to an earlier (1993) version of this classification used by the Villanueva 2000 study (please see p. 12 below), one clinical study germane to this decision.
This decision would not modify existing requirements for any other covered or non-covered indication for ECP (Section 110.4 Medicare National Coverage Determinations Manual).
General Methodological Principles of Study Design
(Section VI of the Decision Memorandum)
When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of an illness or injury or to improve the functioning of a malformed body member. The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients.
We divide the assessment of clinical evidence into three stages: 1) the quality of the individual studies; 2) the generalizability of findings from individual studies to the Medicare population; and 3) overarching conclusions that can be drawn from the body of the evidence on the direction and magnitude of the intervention's potential risks and benefits.
The methodological principles described below represent a broad discussion of the issues we consider when reviewing clinical evidence. However, it should be noted that each coverage determination has its unique methodological aspects.
Assessing Individual Studies
Methodologists have developed criteria to determine weaknesses and strengths of clinical research. Strength of evidence generally refers to: 1) the scientific validity underlying study findings regarding causal relationships between health care interventions and health outcomes; and 2) the reduction of bias. In general, some of the methodological attributes associated with stronger evidence include those listed below:
Regardless of whether the design of a study is a randomized controlled trial, a non-randomized controlled trial, a cohort study or a case-control study, the primary criterion for methodological strength or quality is the extent to which differences between intervention and control groups can be attributed to the intervention studied. This is known as internal validity. Various types of bias can undermine internal validity. These include:
In principle, rankings of research design have been based on the ability of each study design category to minimize these biases. A randomized controlled trial minimizes systematic bias (in theory) by selecting a sample of participants from a particular population and allocating them randomly to the intervention and control groups. Thus, in general, randomized controlled studies have been typically assigned the greatest strength, followed by non-randomized clinical trials and controlled observational studies. The design, conduct and analysis of trials are important factors as well. For example, a well designed and conducted observational study with a large sample size may provide stronger evidence than a poorly designed and conducted randomized controlled trial with a small sample size. The following is a representative list of study designs (some of which have alternative names) ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias:
When there are merely associations but not causal relationships between a study's variables and outcomes, it is important not to draw causal inferences. Confounding refers to independent variables that systematically vary with the causal variable. This distorts measurement of the outcome of interest because its effect size is mixed with the effects of other extraneous factors. For observational, and in some cases randomized controlled trials, the method in which confounding factors are handled (either through stratification or appropriate statistical modeling) are of particular concern. For example, in order to interpret and generalize conclusions to our population of Medicare patients, it may be necessary for studies to match or stratify their intervention and control groups by patient age or co-morbidities.
Methodological strength is, therefore, a multidimensional concept that relates to the design, implementation and analysis of a clinical study. In addition, thorough documentation of the conduct of the research, particularly study selection criteria, rate of attrition and process for data collection, is essential for CMS to adequately assess and consider the evidence.
Generalizability of Clinical Evidence to the Medicare Population
The applicability of the results of a study to other populations, settings, treatment regimens and outcomes assessed is known as external validity. Even well-designed and well-conducted trials may not supply the evidence needed if the results of a study are not applicable to the Medicare population. Evidence that provides accurate information about a population or setting not well represented in the Medicare program would be considered but would suffer from limited generalizability.
The extent to which the results of a trial are applicable to other circumstances is often a matter of judgment that depends on specific study characteristics, primarily the patient population studied (age, sex, severity of disease and presence of co-morbidities) and the care setting (primary to tertiary level of care, as well as the experience and specialization of the care provider). Additional relevant variables are treatment regimens (dosage, timing and route of administration), co-interventions or concomitant therapies, and type of outcome and length of follow-up.
The level of care and the experience of the providers in the study are other crucial elements in assessing a study's external validity. Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings. For example, an investigator's lengthy and detailed explanations of the potential benefits of the intervention and/or the use of new equipment provided to the academic center by the study sponsor may raise doubts about the applicability of study findings to community practice.
Given the evidence available in the research literature, some degree of generalization about an intervention's potential benefits and harms is invariably required in making coverage determinations for the Medicare population. Conditions that assist us in making reasonable generalizations are biologic plausibility, similarities between the populations studied and Medicare patients (age, sex, ethnicity and clinical presentation) and similarities of the intervention studied to those that would be routinely available in community practice.
A study's selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations. One of the goals of our determination process is to assess health outcomes. We are interested in the results of changed patient management not just altered management. These outcomes include resultant risks and benefits such as increased or decreased morbidity and mortality. In order to make this determination, it is often necessary to evaluate whether the strength of the evidence is adequate to draw conclusions about the direction and magnitude of each individual outcome relevant to the intervention under study. In addition, it is important that an intervention's benefits are clinically significant and durable, rather than marginal or short-lived. Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.
If key health outcomes have not been studied or the direction of clinical effect is inconclusive, we may also evaluate the strength and adequacy of indirect evidence linking intermediate or surrogate outcomes to our outcomes of interest.
Assessing the Relative Magnitude of Risks and Benefits
Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits. Health outcomes are one of several considerations in determining whether an item or service is reasonable and necessary. For most determinations, CMS evaluates whether reported benefits translate into improved health outcomes. CMS places greater emphasis on health outcomes actually experienced by patients, such as quality of life, functional status, duration of disability, morbidity and mortality, and less emphasis on outcomes that patients do not directly experience, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses. The direction, magnitude and consistency of the risks and benefits across studies are also important considerations. Based on the analysis of the strength of the evidence, CMS assesses the relative magnitude of an intervention or technology's benefits and risk of harm to Medicare beneficiaries.
Coverage with Evidence Development (CED): CED allows coverage of certain items or services where additional data gathered in the context of clinical care would further clarify the impact of these items and services on the health of Medicare beneficiaries. Medicare coverage may be extended to patients enrolled in a clinical research study. In this case, the research is conducted under section 1862(a) (1) (E) of the Social Security Act, which authorizes Medicare coverage for certain studies supported by AHRQ. CED allows us to provide coverage for an item or service because it is provided within a research setting where there are added safety, patient protections, monitoring, and clinical expertise.
CED projects provide the necessary new evidence to influence clinical practice and help Medicare beneficiaries and providers make more informed diagnostic and therapeutic decisions. CMS may use the evidence in a National Coverage Determination (NCD) reconsideration to determine if a change in Medicare coverage is appropriate under section 1862(a)(1)(A).
Please complete the sections below entitled "Required Information" and "NCD/CED Coverage Requirements," and return to CMS for review (see email and mailing addresses below). Electronic submissions are preferable.
After preliminary review of the application (and any attached documentation) CMS will electronically notify the principal investigator (or the designated contact person) that we have received the application with all required information. Alternatively, we will request further information about an application with incomplete items.
The information provided in the sections on the following pages pertains to clinical research studies which intend to qualify for CED as specified in the NCD on extracorporeal photopheresis (ECP) for the treatment of bronchiolitis obliterans syndrome (BOS) following lung allograft transplantation, CAG-00324R2, issued in final form on April 30, 2012 by CMS, and available at http://www.cms.gov/medicare-coverage-database/details/nca-details.aspx?NCAId=255.
If the information provided fulfills these NCD requirements as judged by CMS, then extracorporeal photopheresis (ECP) for the treatment of bronchiolitis obliterans syndrome (BOS) following lung allograft transplantation required by the study may be reimbursable for study participants who are Medicare beneficiaries, pursuant to §1862(a)(1)(E) of the Social Security Act. If CMS approves the study, we will provide billing instructions for Medicare reimbursement of the extracorporeal photopheresis (ECP) for the treatment of bronchiolitis obliterans syndrome (BOS) following lung allograft transplantation under CED.
Within 90 days of receipt of a completed application, we will send the results of CMS' review of the application. There are three possible outcomes of the review process: accept, revise, and reject. If we request a revision, the applicant must submit the revision within 30 days of notification. CMS will review the revised application and notify the applicant of our final decision within 30 days of receipt of the revised application.
CMS will review and evaluate the protocol to ensure that the proposed study protocol meets the following requirements.
The protocol should describe the criteria for Medicare beneficiaries to be included and excluded from the study.
The protocol should define each outcome to be studied and explain method(s) and timing(s) of outcome assessment(s). The description should include expected length of follow up for participants. The study sample size and duration should allow for reliable estimate(s) of all outcome endpoints.
At minimum, the outcomes to be studied must include the following for the study to be eligible for coverage:
Note: Please include a specific reference to the page or pages in your application with your response to the following.
Submit the "Required Information," "NCD/CED Coverage Requirements," and study protocol to: Kimberly Long; email@example.com
Incidence of lung transplants in the Medicare population [PDF, 32KB]
Antonelli-Incalzi R, Imperiale C, Bellia V, Catalano F, Scichilone N, Pistelli R, et al. Do GOLD
stages of COPD severity really correspond to differences in health status? The European Respiratory Journal. 2003;22:444-449.
Barr ML, Meiser BM, Eisen HJ, Roberts RF, Livi U, Dall'Amico R, et al. Photopheresis for the
prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. New England Journal of Medicine. 1998; 339(24): 1744-51.
Belkin RA, Henig NR, Singer LG, Chaparro C, Rubenstein RC, Xie SX, et al. Risk factors for death of
patients with cystic fibrosis awaiting lung transplantation. American Journal of Respiratory and Critical Care Medicine. 2006;173:659-666.
Belperio JA, Lake K, Tazelaar H, Keane MP, Strieter RM, Lynch JP 3rd. Bronchiolitis
obliterans syndrome complicating lung or heart-lung transplantation. Seminars in Respiratory and Critical Care Medicine. 2003;24(5): 499-530.
Belperio JA, Weigt SS, Fishbein MC, Lynch JP 3rd. Chronic lung allograft rejection. The Proceedings of the American Thoracic Society. 2009;6:108-121.
Benden C, Speich R, Hofbauer GF, Irani S, Eich-Wanger C, Russi EW, et al. Extracorporeal photopheresis after lung transplantation: a 10-year single-center experience. Transplantation. 2008; 86(11):1625-7.
Bladon J, Taylor PC. Extracorporeal photopheresis: a focus on apoptosis and cytokines. Journal of Dermatological Science. 2006;43:85-94.
Boehler A, Kesten S, Weder W, Speich R. Bronchiolitis obliterans after lung transplantation. Chest.
Burke CM, Theodore J, Dawkins KD, Yousem SA, Blank N, Billingham ME, et al. Post-transplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation.
Chest 1984 Dec; 86(6): 824-9.
Burton CM, Carlsen J, Mortensen J, Andersen CB, Milman N, Iversen M. Long-term survival after lung transplantation depends on development and severity of bronchiolitis obliterans syndrome. The Journal of Heart and Lung Transplantation. 2007;26:681-686.
Cooper JD, Billingham M, Egan T, Hertz MI, Higenbottam T, Lynch J, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation. Journal of Heart and Lung Transplantation. 1993;12:713.
Couriel DR, Hosing C, Saliba R, Shpall EJ, Anderlini P, Rhodes B, et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood. 2006;107:3074-3080.
Date H, Lynch JP, Sundaresan S, Patterson A, Trulock EP. The impact of cytolytic therapy on bronchiolitis obliterans syndrome. The Journal of Heart and Lung Transplantation. 1998;17:869-875.
Dirksen A, Dijkman JH, Madsen F, Stoel B, Hutchison DCS, Uirik CS, et al. A Randomized Clinical Trial of a1-Antitrypsin Augmentation Therapy. American Journal of Respiratory and Critical Care
Medicine. 1999;160:1468-1472.
Dirksen A, Holstein-Rathlou N, Madsen F, Skovgaard LT, Ulrik CS, Heckscher T, Kok-Jensen A. Long-range correlations of serial FEV measurements in emphysematous patients and normal subjects. Journal of Applied Physiology. 1998;85(1):259-265.
Edelson RL. Light-activated drugs. Scientific American. 1988; 68-75.
Estenne M, Hertz MI. Bronchiolitis obliterans after human lung transplantation. American Journal of
Respiratory and Critical Care Medicine. 2002;166:440-444.
Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz M, et al. Bronchiolitis obliterans syndrome 2001: an update of a diagnostic criteria. The Journal of Heart and Lung Transplantation. 2002;21:297-310.
Fletcher C, Peto R. The natural history of chronic airflow obstruction. British Medical
Journal. 1977;1:1645-1648.
Girgis RE, Tu I, Berry GJ, Reichenspurner H, Valentine VG, Conte JV, et al. Risk factors for the
development of obliterative bronchiolitis after lung transplantation. The Journal of Heart and Lung Transplantation. 1996;15:1200-1208.
Gottlieb J, Szangolies J, Koehnlein T, Golpon H, Simon A, Welte T. Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation. Transplantation. 2008;85(1):36-41.
Hadjiliadis D, Steele MP, Govert JA, Davis RD, Palmer SM. Outcome of lung transplant patients admitted to the medical ICU. Chest. 2004;125:1040-1045.
Hansen EF, Phanareth K, Laursen LC, Kok-Jensen A, Dirksen A. Reversible and irreversible airflow obstruction as predictor of overall mortality in asthma and chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine. 1999;159:1267-1271.
Hayes D Jr. A review of bronchiolitis obliterans syndrome and therapeutic strategies. Journal of
Cardiothoracic Surgery. 2011;6:92.
Heshmati F. Mechanisms of action of extracorporeal photochemotherapy. Transfusion and Apheresis Science. 2003;29:61-70.
Kerem E, Reisman J, Corey M, Canny GJ, Levison H. Prediction of mortality in patients with cystic fibrosis. The New England Journal of Medicine. 1992;326:1187-1191.
Ketelaars CAJ, Schlösser MAG, Mostert R, Huyer Abu-Saad H, Halftens RJG, Wouters EFM. Determinants of health-related quality of life in patients with chronic obstructive pulmonary disease. Thorax. 1996;51:39-43.
Khavari P. Cytotoxic cellular mediators of the immune response to neoplasia: a review. The Yale Journal of Biology and Medicine. 1987;60:409-419.
Lamioni A, Parisi F, Isacchi G, Giorda E, Di Cesare S, Landolfo A, et al. The immunological
effects of extracorporeal photopheresis unraveled: induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo. Transplantation. 2005; 79(7): 846-50.
Liu V, Weill D, Bhattacharya J. Racial disparities in survival after lung transplantation. Archives of Surgery. 2011; 146(3):286-293.
Maeda A. Extracorporeal photochemotherapy. Journal of Dermatological Science. 2009;54:150-156.
Maeda A, Schwarz A, Bullinger A, Morita A, Peritt D, Schwarz T. Experimental extracorporeal photopheresis inhibits the sensitization and effector phases of contact hypersensitivity via two mechanisms: generation of IL-10 and induction of regulatory T cells. Journal of Immunology. 2008; 181(9): 5956-62.
Meloni F, Cascina a, Miserere S, Perotti C, Vitulo P, Fietta AM. Peripheral CD4, CD25 TREG cell
counts and the response to extracorporeal photopheresis in lung transplant recipients. Transplantation Proceedings. 2007;39:213-217.
Mertens V, Blondeau K, Van Oudenhove L, et al. Bile acids aspiration reduces survival in lung transplant recipients with BOS despite azithromycin. Am J Transplant. 2011 Feb; 11(2): 329-35.
Milla CE, Warwick WJ. Risk of death in cystic fibrosis patients with severly compromised lung function. Chest. 1998;113:1230-34.
Morrell MR,Despotis GJ,Lublin DM,Patterson GA,Trulock EP,Hachem RR. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. The Journal of Heart and Lung Transplantation. 2010; 29(4):424-431.
Nicod LP. Mechanisms of airway obliteration after lung transplantation. Proceedings of the American Thoracic Society. 2006;3(5):444-9.
O'Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine. 2001;164:770-777.
O'Hagan AR, Stillwell PC, Arroliga A, Koo A. Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation. Chest. 1999; 115: 1459-1462.
Paradis I, Yousem S, Griffith B. Airway obstruction and bronchiolitis obliterans after lung transplantation. Clinics in Chest Medicine. 1993;14(4);751-763.
Parrish JA, Fitzpatrick TB, Tanenbaum L, Pathak MA. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. The New England Journal of Medicine.
Pauwels RA, Buist AS, Calverley PMA, Jenkins CR, Hurd SS (on behalf of the GOLD scientific committee). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine. 2001;163:1256-1276.
Perez MI, Edelson RL, John L, Laroche L, Berger CL. Inhibition of antiskin allograft immunity induced by infusions with photoinactivated effector T lymphocytes (PET Cells). The Yale Journal of Biology and Medicine. 1989;62:595-609.
Ryan G, Knuiman MW, Divitini MI, James A, Musk AW, Bartholomew HC. Decline in lung function and mortality: the Busselton health study. The Journal of Epidemiology and Community Health.
Salerno CT, Park SJ, Kreykes NS, Kulick DM, Savik K, Hertz MI, Bolman RM 3rd. The Journal of Thoracic and Cardiovascular Surgery: Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis. The Journal of Thoracic and Cardiovascular Surgery. 1999; 117(6): 1063-9.
Sin DD, Wu L, Paul Man SF. The relationship between reduced lung function and cardiovascular mortality. Chest. 2005; 127: 1952-59.
Sircar K, Hnizdo E, Petsonk E, Attfield M. Decline in lung function and mortality: implications for medical monitoring. Occupational and Environmental Medicine. 2007; 64: 461-466.
Slovis BS, Loyd JE, King LE Jr. Photopheresis for chronic rejection of lung allografts. The New England
Journal of Medicine. 1995; 332(14): 962.
Ståhl E, Lindberg A, Jansson S, Rönmark E, Svensson K, Andersson F, et al. Health-related quality of life is related to COPD disease severity. Health and Quality of Life Outcomes. 2005; 3: 56.
Szczepiorkowski ZM,Winters JL,Bandarenko N,Kim HC,Linenberger ML,Marques MB,et al. Guidelines on the use of therapeutic apheresis in clinical practice evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher. 2010; 25(3): 83-177.
Tockman MS, Pearson JD, Fleg JL, Metter EJ, Kao SY, Rampal KG, et al. Rapid decline in FEV1; a new risk factor for coronary heart disease mortality. American Journal of Respiratory and Critical Care Medicine.
1995; 151: 390-398.
Trulock EP, Christie JD, Edwards LB, Boucek MM, Aurora P, Taylor DO, et al. Registry of the ISHLT: 24th official adult lung and heart-lung transplantation report 2007. J Heart Lung Transplant 2007; 26: 782-95.
Verleden GM, DuPont LJ, Van Raemdonck DE. Is it bronchiolitis obliterans syndrome or is it chronic rejection: a reappraisal? Eur Respir J 2005; 25: 221-4.
Villanueva J, Bhorade SM, Robinson JA, Husain AN, Garrity ER Jr. Extracorporeal photopheresis for the treatment of lung allograft rejection. Annals of Transplantation. 2000; 5(3): 44-47.
Vos R, Vanaudenaerde BM, Verleden SE, De Vleeschauwer SI, Willems-Widyastuti A, Van Raemdonck DE, et al. A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.
Eur Respir J. 2011 Jan; 37(1): 164-72. Epub 2010 Jun 18.
Wise RA. The value of forced expiratory volume in 1 second decline in the assessment of chronic obstructive pulmonary disease progression. The American Journal of Medicine. 2006; 119(10A): S4-S11.
Xia CQ, Campbell KA, Clare-Salzler MJ. Extracorporeal photopheresis-induced immune tolerance: a focus on modulation of antigen-presenting cells and induction of regulatory T cells by apoptotic cells. Current Opinion in Organ Transplantation. 2009;14(4):338-343.
Yoo EK, Rook AH, Elenitsas R, Gasparro FP, Vowels BR. Apoptosis induction by ultraviolet light A and photochemotherapy in cutaneous T-cell lymphoma: relevance to mechanism of therapeutic action. The Journal of Investigative Dermatology. 1996;107:235-242.
Young RP, Hopkins R, Eaton TE. Forced expiratory volume in one second: not just a lung function test
but a marker of premature death from all causes. The European Respiratory Journal. 2007;30:616-622.


text:
brianbeecroft necesitaba un nuevo diseño de página web y lanzó un concurso de diseño en 99designs.
Un ganador ha sido elegido entre 81 diseños de 15 diseñadores freelance.
We are a leading photography training company based in the UK, but with a worldwide client base (http://www.digitalmasterclass.co.uk). We offer online courses and a range of photography workshops which are nationally accredited .
We are expanding and feel we need to move forward with a new more professional modern looking website.
Our users are typically professional adults looking to either improve their photographic skills for their hobby or intend a career change with the intent to become a professional photographer.
We require a design for our website http://www.digitalmasterclass.co.uk.
Currently we don't have a logo, but we would envisage using DMC for this. A logo design isn't a main requirement of the brief but we would look sympathetically towards the inclusion of one within the design.
We would like the design to be creative, simple but professional; not complicated, but with a limited colour pallet in keeping with the photography genre.
We will require the full psd file for both pages and the logo in a suitable format (if supplied) for the project to be complete.
We require a design for the home page and one sample course page.
The homepage should reflect our ethos as a company and easily directs would-be students to our range of courses: see our current home page.
The course page needs to be simple, clean, professional looking, and easy to navigate such as this example http://www.aspect2i.co.uk/beginner-…-ID39.html.
Java scripting should be kept to a minimum to aid SEO.

subset: commoncrawl


text:
Freight-hauling heavy trucks consume a significant portion of any country's annual fuel needs. With rising fuel prices, truck manufacturers are under ongoing pressure to improve fuel economy.
At the same time, trucks contribute a large portion of vehicular pollutant emissions. With significant public concern over greenhouse gas and other pollutant emissions, truck manufacturers are being pressured to drastically reduce tailpipe emissions. In 2010, the U.S. Environmental Protection Agency (EPA) enacted highly stringent emissions standards for trucks, and the European Union will implement tightened standards (Euro-6) at the beginning of 2014.
The bus sector is growing as well, primarily due to rising public transportation needs in emerging economies — such as China, India and other developing countries — and renewed interest in public transportation in developed nations, such as the United States. Like truck manufacturers, bus manufacturers face pressures to reduce tailpipe emissions and fuel consumption.
To address these issues, truck and bus makers as well as suppliers are busy developing technologies such as selective catalytic reduction (SCR) and diesel particular filters (DPF). At the same time, they are working continually to optimize diesel engines to reduce emissions and fuel consumption. Organizations are researching completely new technologies,such as opposed piston engines, that show great - promise. Rounding out the list are hybrid–electric powertrains and fuel cells, particularly in the bus segment: Driven by green initiatives, many cities are incorporating environmentally friendly electric buses into their municipal fleets.
Whether the application is SCR, opposed piston engines, hybrid–electric powertrains, fuel cells or optimized aerodynamics, ANSYS is ready with powerful and validated tools to solve technically advanced leading-edge engineering problems.


text:
ECHL Game Night: 12-27-12
Florida Everblades 1 vs. Orlando Solar Bears 2
F Alex Hutchings, FLA: 0-0-0, -2, 3 SOG, 0 PIM
Season totals: 24 GP, 9-11-20, E, 17 PIM
D Charles Landry, FLA: 0-0-0, E, 0 SOG, 0 PIM
Season totals: 25 GP, 1-5-6, +2, 21 PIM
F Maxime Langelier-Parent, FLA: Did not play
Season totals: 1 GP, 1-0-1, -1, 0 PIM
(Syracuse Crunch contract)
D Daniel Milan, FLA: Did not play
Season totals: 13 GP, 1-0-1, -2, 12 PIM
G Pat Nagle, FLA: Did not play
Season totals: 12 GP, 5-5-1, 0 SO, 3.47 GAA, 315 S / 355 SA (.887 SV%)
After falling behind 2-0 to Orlando during a three-minute span in the second period, Florida scored a short-handed goal approaching the midpoint of the final frame but could not complete the comeback. Aaron Bogosian scored the lone goal for the Everblades. The power play units of both clubs struggled mightily, combining to go 0-for-9 and each allowing a goal against. John Muse got the start over Pat Nagle and stopped thirty of thirty-two shots taken by the Solar Bears. Dan Milan and Maxime Langelier-Parent, still recovering from an injury sustained early in the season, were inactive. Florida (14-11-6, 34 PTS) and Orlando (13-15-4, 28 PTS) finish their five-game, home-and-home series Saturday night.
Official Recap | Box Score
|All times are GMT -5. The time now is 08:16 AM.
Powered by vBulletin® Version 3.7.2
Copyright ©2000 - 2019, Jelsoft Enterprises Ltd.
Copyright © 2005-2008, BoltProspects.com. All Rights Reserved.


text:
GREEN-minded investors are being sought to fund solar panels at the Malvern Cube community centre.
The Malvern Community Energy Co-operative is planning to install the panels on the roof of the centre in Albert Road North, to provide it with cheap energy and sell the surplus to the electricity grid.
The co-op opened a share offer earlier this year, looking to find £40,000 to finance the project.
Now, with about £20,000 already in place, the Co-op is reminding would-be investors that the share offer closes on Friday, May 9.
County and district councillor John Raine, who chairs Malvern Hills District Council's recently-established policy group on energy efficiency, said that according to a 2006 report, the district had one of the largest carbon footprint s in
the country
He said: "Although this partly reflects our largely rural and relatively affluent population, by investing in solar power, you can help us address this unwelcome distinction,
"I applaud the initiative of the co-op. Investment in this exemplar of community-based co-operative enterprise will not only reduce the cost of electricity for Cube users, but will also help to make the district a leader, rather than a laggard in the low-carbon future to which we all aspire."
Robin Coates of the co-op said: "Subscription to the share offer is off to a good start, with around half the necessary capital committed. The offer closes on May 9, and with the publication of the IPCC report, others might be inspired to contribute and feel they are doing something positive."
More information is available from malverncommunityenergy.org/shareoffer.


text:
THE Online Trend Should Have EVERY Australian Parent Worried
Teenagers who are as young as 14 are using adult-only dating apps like Tinder and posting pictures of themselves in their school uniforms.
Founder of ySafe Solutions said the underage use of Tinder was 'rife' when speaking to Perth Now.
She said many of the students were even using photos of themselves in their school uniforms and mostly attended single-sex private schools.
Ms Foster believes that teens are using it to 'raise their social status' among their peers at school.
'But the more and more students that do that, the more that are jumping on board, it becomes sort of a normalised thing to do,' she told Perth Now.
Tinder users must be above the age of 18 to sign up but school-aged teens are lying about it to set up accounts.
Tinder was 'no more immune from people who lie about their age than any other social media platform', a spokesperson said.
Just last week, a man was prosecuted after he was found to be hunting for teenage girls on tinder after he was exposed by a group of Melbourne University students who set up fake profiles pretending to be a 15-year-old girl.
BONUS: The TV Meltdown That Could See A Favourite Leave


text:
Posted on Jul 24, 2015
How to Help Maintain Independence and In Home Help
For those who love to live life freely, getting older can start to feel very limiting. As we age, mobility can become difficult without some sort of assistance and there are medications that can make driving unsafe. Our senior generation has worked hard throughout their lives and deserve to live how they wish; and usually remaining at home is the popular choice.
With medication reminders, mobility assistance and companionship, in home help from a caring and compassionate caregiver might be the route to go for your loved one. Your senior loved one can maintain independence and live in the comforts and familiarity of their own home for as long as possible with some assistance. For some families, proximity to a loved one may make providing assistance difficult. This is where in home help from Senior Helpers of Clearwater comes in to give your family peace of mind.
Many seniors currently live active lifestyles and wish to remain a part of their social circles and participate in local events. Some medications and dementia related diseases may make driving unsafe. A trusted caregiver from Senior Helpers can provide the transportation to and from local events, appointments, and shopping as desired by a senior loved one. Transportation helps to maintain independence because a senior loved one is still a part of their community without worry about returning home safely.
Another way to provide some independence for an elderly loved one is to look into having items delivered directly to their home. Some grocery stores have begun offering delivery services. There are also many online stores that provide subscription delivery for household items such as paper towels, toilet paper, dry goods and other useful daily items. Having items delivered can reduce the need to go grocery shopping as often. This saves time that can be better spent visiting with family and friends.
Household chores are another part of life that can fall by the wayside as we get older. Just a little bit of assistance with daily tasks such as light housekeeping, laundry, and putting away dishes can greatly lighten the load of a senior loved one. Look around your loved one's home for trip hazards and put away loose items on the floor that might create a fall. Independent living at home can be very successful with injury prevention. Thinking ahead of ways to make living at home a success can greatly improve your loved one's wellbeing, both physically and emotionally.
If you would like to learn more about caring and consistent in home elderly care, along with the many benefits of professional senior care or dementia and Alzheimer's care, call Senior Helpers of Clearwater to speak to a senior care specialist today 727-210-1414! The compassionate senior care specialists at Senior Helpers can also guide you through the process of receiving the Veterans Administration Aid and Attendance Benefit if your elderly loved one is a veteran. In home senior care allows your loved one to stay in the comforts of their own home for as long as possible while receiving the level of care they need. Senior Helpers of Clearwater provides a wide range of services including Alzheimer's and dementia care, personal assistance, companionship, and so much more to all areas of Largo, Seminole, and St. Petersburg.