Stem Cell Transplantation (Multiple Myeloma, Myelofibrosis, and Sickle Cell Disease)

We appreciate the thorough analysis of the published evidence in support of hematopoietic stem cell transplantation( HCT) for sickle cell disease. We also express our appreciation of the recognition by CMS of the serious medical consequences of sickle cell disease and the willingness of CMS to support HCT for sickle cell disease. We recognize that the evidence of the efficacy of HCT for sickle cell disease is based on clinical trials that have enrolled relatively small numbers of patients and which have not included control arms of patients who did not receive HCT. In fact, with the view to address this very gap in the field we are now opening STRIDE-2/BMT CTN 1503, the first comparative trial of HCT to standard of care in adults with sickle cell disease. This study is funded by the NHLBI and BMT CTN will serve as the data coordinating center. This study will biologically assign approximately 60 patients with available HLA matched donors to the HCT arm and approximately 140 subjects without HLA matched donors to the control arm. Such as study design allows us to avoid selection bias in assignment of patients to the two arms. We propose to establish long term follow up and track survival and outcome of patients enrolled in the control arm of the STRIDE study.

Criticism of the lack of control arm in clinical trials of HCT for sickle cell disease must however, take into account the logistical problems of conducting such clinical trials. it is relatively straightforward to conduct comparative trials of HCT and standard of care in malignant diseases such as leukemia/lymphoma or myeloma, since there is a high rate of mortality in the short term, differential rates of survival can be determined in a 2-3 year follow up period. In contrast in non-malignant disease such as sickle cell disease, premature mortality rates, while increased may occur over several years. Thus, comparative trials of`HCT and standard of care in sickle cell disease may have to last 10-15 years to demonstrate a difference in survival in the transplanted arm. This is clearly outside the realm of possibility of most clinical trials of HCT for sickle cell disease. Thus, while the draft decision to only support HCT for Sickle cell in the context of a comparative clinical trial is well intentioned and supported by solid theoretical principles,it is likely to have the effect of denying access to HCT for the vast majority of patients with sickle cell disease and will in effect block any further progress in the field. We urge CMS to consider support of HCT for sickle cell disease with a CIBMTR registry based continued evidence development. Registry based studies further supported by long term outcomes described in studies such as the STRIDe comparative trial described above are likely to produce more evidence supporting the role of HCT for sickle cell disease.

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Dear Commissioner,

[PHI Redacted] patient with post Essential Thrombocythemia-myelofibrosis and an active participant on MPN-NET, an online, mutual help group for all patients with Philadelphia negative myeloproliferative neoplasms, including primary myelofibrosis. The proposed change to require transplant candidates who seek Medicare coverage for the procedure to be enrolled in a clinical trial with contemporaneous controls is designed to advance medical science, but will not because the preconditions are unobtainable by precisely those high risk patients who are the candidates for stem cell transplantation. Instead, additional patients will go without the transplant procedures which are their only hope of life extension.

Rather than require contemporaneous controls I respectfully request that you adopt the more flexible rules pioneered by Dr. Anthony Fauci for AIDS patients who had the same life expectancy as high risk myelofibrosis patients to allow progress without contemporaneous sacrifice of life and hope. Medscape.com recently reported that " After the realization that an inflexible system was leading patients to make impossible choices, Dr Fauci, with the help of activists in New York and San Francisco, proposed the "parallel track." In that system, researchers adhered to a strict protocol, according to the rules, but in parallel provided access to a drug on an experimental basis to patients with informed consent."

Similar flexibility should be permitted in order to allow humane Medicare coverage of primary myelofibrosis patients who need stem cell transplants.

I thank you in advance for considering all the options to advance science and the interests of the individual patents whom we ask to contribute to that advancement.

Sincerely,

Antje Hjerpe
MPN Education Foundation MPN-NET

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Dear Commissioner,

[PHI Redacted] patient with polycythemia vera and an active participant on MPN-NET, an online, mutual help group for all patients with Philadelphia negative myeloproliferative neoplasms, including primary myelofibrosis. The proposed change to require transplant candidates who seek Medicare coverage for the procedure to be enrolled in a clinical trial with contemporaneous controls is designed to advance medical science, but will not because the preconditions are unobtainable by precisely those high risk patients who are the candidates for stem cell transplantation. Instead, additional patients will go without the transplant procedures which are their only hope of life extension.

Rather than require contemporaneous controls I respectfully request that you adopt the more flexible rules pioneered by Dr. Anthony Fauci for AIDS patients who had the same life expectancy as high risk myelofibrosis patients to allow progress without contemporaneous sacrifice of life and hope. Medscape.com recently reported that " After the realization that an inflexible system was leading patients to make impossible choices, Dr Fauci, with the help of activists in New York and San Francisco, proposed the "parallel track." In that system, researchers adhered to a strict protocol, according to the rules, but in parallel provided access to a drug on an experimental basis to patients with informed consent."

Similar flexibility should be permitted in order to allow humane Medicare coverage of primary myelofibrosis patients who need stem cell transplants.

I thank you in advance for considering all the options to advance science and the interests of the individual patents whom we ask to contribute to that advancement.

Sincerely,

David Alexander

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November 28, 2015

To Whom It May Concern:

This letter is in response to the recent CMS proposal regarding changes in coverage for allogeneic transplantation for the treatment of multiple myeloma, myelofibrosis, and sickle cell disease. CMS has proposed to cover items and services necessary for research under §1862(a)(1)(E) using the Coverage with Evidence Development (CED) paradigm. The Blood and Marrow Transplant Program at the James Cancer Hospital and Richard J Solove Research Institute at The Ohio State University advocates that CMS remove the requirement for non-HCT controls in such research trials.

While we recognize that randomized, controlled trials are the gold standard of cancer research, given that these are rare diseases including this requirement would create an undue burden in terms of time for patient accrual and outcomes assessments.

Significant advances both in disease treatments afforded by new therapeutic and also in peritransplantation supportive care introduced during the time it would take to accrue to such studies could make the findings irrelevant with respect to current standard of care. As an illustration, Jaccard et al. performed a study comparing autologous transplantation to oral melphalan in the treatment of AL amyloidosis. The multicenter study, which accrued 50 patients to each arm over 5 years, took approximately two additional years to publish the findings. Of note, early treatment-related mortality (EM) was 24% for transplanted patients.[i] Based on the Jaccard et al study, D’Souza et al. postulated that better risk stratification in patients with cardiac AL afforded by cardiac biomarkers, which became available after completion of the Jaccard study, along with improved peri-transplant supportive care would lead to a much lower EM rate and an improvement in outcomes in this patient population. In a retrospective study, D’Souza et al found EM rates progressively fell between 1995 and 2012 with a corresponding increase in overall survival warranting continued research into this treatment modality. [ii]

We urge CMS to replace the proposed requirement for concurrent non-HCT controls with an assessment method imilar to what the FDA uses to assess outcomes for rare diseases. This method allows for alternative requirements for the type and quantity of data required for approval of drugs for indications in rare diseases. [iii] Given the scarcity of patients with rare diseases who are eligible for any given study, it is critical to consider efficient study designs and methods that enable the conduct of clinical trials with small numbers of patients. Such methods include various cross-over designs, or the use of historical controls and enrichment strategies, where appropriate. [iv] As an example of the willingness of the FDA to accept comparison with historical controls, eculizumab received FDA approval for the treatment of atypical hemolytic uremic syndrome (aHUS) based upon four prospective and one retrospective single arm trials. [v]

In addition, researchers in blood and marrow transplantation have recently reviewed the data regarding allogeneic transplantation in these rare diseases. This assessment was recently published by Majhail et al., who performed a review of allogeneic HCT for multiple myeloma (sensitive relapse, refractory, and plasma cell leukemia), sickle cell disease, and myelofibrosis (primary, low risk; primary, intermediate/high risk; and secondary) in adults. In these diseases, performance of allogeneic transplantation was listed as a level C recommendation (Standard of Care, Clinical Evidence Available). This category includes indications for which large clinical trials and observational studies are not available. However, HCT has been shown to be an effective therapy with acceptable risk of morbidity and mortality in sufficiently large single- or multicenter cohort studies. The authors likened level C recommendation to the level of evidence and consensus comparable with NCCN category 2A recommendation (“Based upon lower-level evidence, there is uniform consensus that the intervention is appropriate”). [vi]

The James Cancer Hospital is an academic tertiary cancer center and therefore receives many referrals for the treatment of the most complex and rare diseases. Our institution strives to provide optimal care for these patients including curative options. In the cases of myeloma, myelofibrosis, and sickle cell disease, outside of allogeneic transplantation there is currently no curative therapy. Furthermore, non-transplant outcomes in all of these diseases are well established, raising concerns regarding the ethics of mandating non-HCT control arms.

Sincerely,

Leslie Andritsos, MD
Associate Professor of Internal Medicine, Division of Hematology
Director of Clinical Operations, Division of Hematology, Department of Internal Medicine
The Ohio State Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute

Steve Devine, MD
Associate Professor of Internal Medicine, Division of Hematology
Director of the Bone Marrow Transplant Program, Division of Hematology, Department of Internal Medicine
The Ohio State Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute

[i] Jaccard A, Moreau P, Leblond V et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med 2007; 357:1083-1093.

[ii] D’Souza A, Dispenzieri A, Wirk B et al. Improved outcomes after autologous hematopoietic cell transplantation for light chain amyloidosis: a Center for International blood and Marrow Transplant Research study. J Clin Oncol 2015; 33:3741-3749.

[iii] Rare Disease and Clinical Trials. Anne Pariser, M.D. Office of Translational Sciences. Center for Drug Evaluation and Research. FDA. 11/4/2014. http://www.fda.gov/downloads/drugs/newsevents/ucm440797.pdf

[iv] Report: Complex Issues in Developing Drugs and Biological Products for Rare Diseases and Accelerating the Development of Therapies for Pediatric Rare Diseases Including Strategic Plan: Accelerating the Development of Therapies for Pediatric Rare Diseases. U.S. Department of Health and Human Services, Food and Drug Administration . As required by the Food and Drug Administration Safety and Innovation Act, Section 510 and Prescription Drug User Fee Act Performance Goals Section IX.E.4. July 2014. http://www.fda.gov/downloads/regulatoryinformation/legislation/significantamendmentstothefdcact/fdasia/ucm404104.pdf

[v] Soliris® (eculizumab) package insert. Alexion pharmaceuticals, Inc.4/2014. http://soliris.net/sites/default/files/assets/soliris_pi.pdf

[vi] Majhail SN, Farnia SH, Carpenter PA et al. Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation Biol Blood Marrow Transplant xxx (2015) 1e7

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I would like to express my strongest support for extending Medicare coverage to patients with Myelofibrosis. As a transplant physician at the University of Michigan, it is a heartwrenching to have patients with life-threatening illnesses which are potentially curable with stem cell transplants but are not within reach for patients based on their insurance. Capturing the outcome data from these transplants is essential in advancing the field and the experience CMS has gained in supporting a trial design for transplant in Myelodysplastic Syndrome (MDS) is an excellent example as what is possible without a concurrent non-HCT control, which is extremely problematic in this rare disease.

Thank you for considering this important issue.

Steven C. Goldstein, MD
Associate Clinical Director, Adult Blood and Marrow Transplant Program
University of Michigan Comprehensive Cancer Center

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CMS Draft Decision Memo Regarding Reimbursement for Hematopoietic Stem Cell Transplantation in Myeloma Medicare Beneficiaries

On October 29, the Centers for Medicare and Medicaid Services (CMS) issued a proposed decision memo regarding Medicare coverage for allogeneic hematopoietic cell transplant (HCT) for three indication – Multiple Myeloma, Primary Myelofibrosis and Sickle Cell disease. While welcome the proposed decision to consider allogeneic HCT in myeloma, we wish share our comments and concerns regarding the decision for allogenic transplant coverage in this disease.  

• Multiple Myeloma, a blood cancer, with a higher incidence in African Americans is currently treated with a variety of drugs, autologous (cells from one’s own body) hematopoietic (blood) stem cell transplantation (HCT) and, in some cases with very high risk features, with allogeneic (cells from another person) HCT. Medicare currently does NOT cover any allogeneic HCTs for Myeloma. Allogeneic HCT i

Background re: Myeloma and allogeneic HCT:

• Myeloma is a rare disease with a median age of onset of approximately 69 years
• It is a debilitating disease with traditionally a high transplant related mortality after allogeneic HCT recipients.
• Allogeneic HCT may represent the only curative therapy. However the feasibility of allogeneic HCT is only for a minority whose fitness levels and lack of co morbidities makes HCT safe while their disease risk is high based on modern risk stratification tools (karyotyping, FISH, Gene expression).

Allogeneic HCT works in these diseases by replacing abnormal blood cells with normal blood cells.  It has not been commonly used because the procedure itself carries a risk of toxicity and the chance of early death.  However, recent advances have made HCT a much safer procedure and there are patients with Myeloma, PMF and SCD whose prognosis with standard therapy is so poor that HCT is a preferred option.

Coverage with Evidence Development

Medicare has proposed Coverage with Evidence Development (CED), which means that Medicare beneficiaries have coverage for transplant if they participate in an approved clinical study.  This is the same mechanism currently in place for Medicare’s coverage of another blood disorder,  Myelodysplastic Syndromes (MDS).  While coverage within a study does create additional tracking and reporting burdens, this mechanism has worked successfully for MDS and has allowed over 1400 patients with MDS to receive HCT.  It has been facilitated by using the Center for International Blood and Marrow Transplant Research (CIBMTR), a federally funded research group that collects clinical data on all of the allogeneic HCTs being done in the United States. The CIBMTR is a research affiliation between the Medical College of Wisconsin in Milwaukee and the National Marrow Donor Program in Minneapolis. Data provided to CIBMR for Medicare beneficiaries receiving HCT for MDS has been analyzed and reported to CMS on a routine basis since the program was started in December 2010.  Implementation of this program more than tripled the number of HCTs for MDS annually in the United States, by removing the financial barrier to treatment.

While we greatly appreciate CMS’s intent to provide a pathway to coverage for Myeloma, PMF and SCD through clinical studies, the proposed study requirements for are different than those required in the MDS study and will be extremely difficult to satisfy by the transplant community.

At the current time, we feel that the study structures being proposed are prohibitive due to a lack of understanding on the part of CMS staff and do not stem from a deliberate intention to block access to HCT.

Issue of Concern: Concurrent non-HCT Controls

The primary issue of concern with the proposed decision is with CMS’s requirement for concurrent non-HCT controls.  Concurrent non-HCT controls are problematic for the following reasons:

• Requiring concurrent non-HCT controls which will severely hinder our ability to accrue patients. Concurrent controls are highly problematic for these indications, due to their rarity and severity.  Most patients will be seeking any and all curative options for their illness, making it unlikely for them to consent to participation in a non-HCT control group. Additionally, there is no established infrastructure to collect data on nontransplant outcomes of these diseases that is analogous to the collection of transplant outcomes done by the CIBMTR and building one, even if possible, would be expensive and take a long time. Individual studies that include concurrent controls would also be expensive, take a long time to implement and would likely be available at a minority of transplant centers, thereby limiting access.
• CMS is interested in long-term survival and quality-of-life outcomes. The timeline to accumulate sufficient numbers of patients into these studies and to evaluate the long-term endpoints of interest to CMS will be very lengthy – at least 5-10 years, if not 20 years.  We support Medicare’s interest in understanding the late consequences of the procedure by developing long-term follow-up data on a sufficient number of transplant recipients.  However, due to this extended timeframe, we need to ensure that patients have wide access to these studies and that the studies are not structured in a way that limits participation to a small group of patients or centers.  Broad access to these trials is essential due to ethical considerations in being able to offer the only current potentially curative therapy available to patients with a known poor prognosis. 
• The non-HCT outcomes of these illnesses are well-known. These are indications that prove fatal within short timeframes or, in the case of SCD, cause significant morbidity and pain.  We understand CMS’s need to demonstrate effectiveness of a therapy in their particular beneficiary groups (age 65+ or those who are disabled), but further documentation of well-established and severe or fatal clinical outcomes is unnecessary.
• These indications are rare diseases that do not fit CMS’s usual model for clinical study designs. The vast majority of the coverage decisions CMS makes are related to drugs and devices, many of which are utilized in clinical indications with substantially higher incidence and prevalence rates than those affecting transplant patients.  CMS should be encouraged to consider alternate frameworks for rare diseases and low-volume procedures of curative intent, similar to the Breakthrough and Accelerated Approval Processes utilized by the U.S. Food and Drug Administration for orphan conditions. 

Our Proposed Alternative

We are asking stakeholder to petition CMS to remove the requirement for concurrent non-HCT controls and to accept a variety of study designs, including cohort studies through the CIBMTR, that will advance our understanding of the role of allogeneic transplantation in these diseases and optimize transplantation outcomes. Such an approach will avoid disparity in access to curative therapy and speed the progress of research that will benefit our patients.

Parameswaran Hari MD (Medical College of Wisconsin

On behalf of the Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup.

Amrita Krishnan MD – City of Hope

Siddharth Ganguly MD – University of Kansas

Luciano Costa MD – University of Alabama

David H Vesole MD, PhD – Georgetown University

Edward Stadtmauer MD – University of Pennsylvania

Taiga Nishihora MD - H. Lee Moffitt Cancer Center & Research Institute

Koen Van Besien MD – Cornell University

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To Whom it may concern:

This letter is in regards to the recent announcement for the proposal coverage of allogeneic transplantation for multiple myeloma, myelofibrosis, and sickle cell disease. We appreciate that CMS is offering trying to cover items and services necessary for research under §1862(a)(1)(E) for allogeneic HSCT for certain Medicare beneficiaries with multiple myeloma, myelofibrosis, and sickle cell disease  using the Coverage with Evidence Development (CED) paradigm.to provide coverage for Medicare beneficiaries with sickle cell disease, myelofibrosis, and mulitple myeloma  I am a Clinical Pharmacist Specialist with The. Bone Marrow Transplant program at the James Cancer Hospital and Richard J Solove Research Institute at The Ohio State University and I advocates  that CMS remove the requirement of non-HCT controls in such research trials.

As all three are rare diseases, accrual to non-HCT controlled trials would be difficult. The time to accrue and assess outcomes would likely be in the range of 10 - 20 years. Significant advancements not only in disease treatment afforded by new therapeutic agents but also peritransplantation supportive care improvements introduced over the time it takes to complete such studies could make the findings irrelevant with respect to current standard of care. As an illustration, Jaccard et al performed a study comparing autologous transplant with oral melphalan in the treatment of AL amyloidosis. The multicenter study which accrued 50 patients to each arm over 5 years took an approximate additional two years to publish the findings. Of note early treatment-related mortality (EM) was 24% for transplant patients.ⁱ Based on the Jaccard et al study, D'Souza et al postulated that better detection and risk stratification in patients with cardiac AL afforded by cardiac biomarkers available after completion of the Jaccard study along with improved peritransplantation supportive care would lead to a much lower EM rate and an improvement in autologous transplantation outcomes in this patient population. In a retrospective study, D'Souza et al found EM rates progressively fell between 1995 and 2012 with a corresponding increase in overall survival warranting continued research into this treatment venue.

We encourage CMS to replace concurrent non-HCT controls in these clinical trials with an assessment method similar to what the FDA uses to assess outcomes for rare diseases. Statute allows for flexibility and exercise of scientific judgment in kinds and quantity of data required for a particular drug for an indication.ⁱⁱⁱ With a scarcity of patients who have rare diseases available for any given study, it is critical to consider efficient designs and methods enabling the conduct of studies with small numbers of patients. Such methods include various cross-over designs, use of historical control studies and enrichment strategies, where appropriate.^iv As an example of the FDA willingness to accept comparison with historical controls, eculizumab received FDA approval for the treatment of atypical hemolytic uremic syndrome (aHUS) based upon four prospective and one retrospective single arm trials.^v

In place of concurrent non-HCT controlled trials, consider accepting assessment methods described in Majhail et al recently published review of HCT indications as an alternative method to decide coverage. Allogeneic HCT for multiple myeloma (sensitive relapse, refractory, plasma cell leukemia), sickle cell disease and myelofibrosis (primary, low risk; primary, intermediate/high risk; secondary) in adults are listed as a recommendation level C (Standard of Care, Clinical Evidence Available). This category includes indications for which large clinical trials and observational studies are not available. However, HCT has been shown to be an effective therapy with acceptable risk of morbidity and mortality in sufficiently large single- or multicenter cohort studies. The authors likened level C recommendation to the level of evidence and consensus comparable with NCCN category 2A recommendation ("Based upon lower-level evidence, there is uniform consensus that the intervention is appropriate").^vi

The James is an academic tertiary cancer center; and therefore receives many referrals for the most complex and rare diseases. Our institution strives to provide optimal care for these patients and majority are seeking curative options, making it unlikely for them to consent to participate in a non-HCT control-based study. Those patients determined ineligible for transplantation are likely poor controls and would not provide an appropriate comparative analysis. Especially in the case of myelofibrosis, the remaining eligible patients who elect not to pursue transplant will likely be an extremely small subset within an already limited population. Myelofibrosis is a rare disease that consists of high morbidity and mortality; an allogeneic transplant is the only potential option for a cure. Non-HCT outcomes of multiple myeloma and sickle cell disease are well established; fatal for myeloma while high morbidity and pain associated with sickle cell disease. We understand the need for controlled evidence for effectiveness of therapy in this population (age > 65 or those disabled), but further documentation of well-established and severe or fatal outcomes are unnecessary.

Sincerely,

Julianna Roddy, PharmD, BCOP

Clinical Pharmacist Specialist, Bone Marrow Transplant/Hematology
Arthur G. James Cancer Hospital and Richard J. Solove Research 
The Ohio State University
Department of Pharmacy
460 West 10th, Room C150
Columbus, Ohio, 43210

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While I am strongly in favor of covering HCST for Multiple Myeloma; (2) Sickle Cell Disease; and (3) Myelofibrosis, O believe it is unethical to link such coverage to participation in clinical trials. This amounts to coercion of patients to participate in research. Furthermore, the requirement for a so-called control group which is denied life-saving therapy is also unethical. Existing epidemiological data on untreated outcomes already exists for these patients, as does data on HCST risks.

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[PHI Redacted] diagnosed with polycythemia vera ten years ago. [PHI Redacted] diagnosed with moderate myelofibrosis, secondary to PV, and recent blood work seems to indicate that the myelofibrosis may be progressing. I appreciate that CMS is trying to provide coverage for Medicare beneficiaries with myelofibrosis, however requiring concurrent controls in these clinical studies might limit access to this important and potentially lifesaving therapy. I urge CMS to reconsider this requirement for concurrent controls to ensure that stem cell transplants are an option for all MPN patients including those with PV such as [PHI Redacted].

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[PHI Redacted] was diagnosed with polycythemia vera ten years ago. Two years ago she was diagnosed with moderate myelofibrosis, secondary to PV, and recent blood work seems to indicate that the myelofibrosis may be progressing. I appreciate that CMS is trying to provide coverage for Medicare beneficiaries with myelofibrosis, however requiring concurrent controls in these clinical studies might limit her access to this important and potentially lifesaving therapy. I urge CMS to reconsider this requirement for concurrent controls to ensure that stem cell transplants are an option for ALL MPN patients including those with PV such as [PHI Redacted].

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These comments are offered in support of my friend who was diagnosed more than two years ago as having myelofibrosis. They are also motivated by public interest considerations.

On January 23, 2015, Be the Match and other organizations formally requested that the Centers for Medicare and Medicaid Services (CMS) reconsider its National Coverage Determination(NCD) in section 110.8.1 of the Medicare National Coverage Determination Manual for allogenic hematopoietc stem cell transplantation for a number of indications including essential thrombocytopenia (ET), polycythemia vera (PV), and myelofibrosis (MF).

These groups asked that CMS expand the scope of coverage to Medicare/Medicaid beneficiaries for stem cell transplantation for these indications, to further medical research and because such coverage is provided by private commercial health insurance carriers to persons who are not old enough to qualify for Medicare. Moreover, the guidelines of various professional organizations call for stem cell transplantation when these conditions are not responding to medications.

In response, CMS released a proposed decision memo (CAG-00444R), and it said it would consider comments submitted by November 28, 2015 in a final decision memorandum as required by section 1862(l)(3) of the Social Security Act.

Although CMS found that there currently is insufficient evidence demonstrating (1) improved health outcomes for ET, PV and MF patients undergoing stem cell transplantation, and (2) that this procedure is reasonable and necessary for the treatment of MF, the agency did note that professional organization guidelines for clinical management of MF provide for stem cell transplants in appropriate cases.

CMS also pointed out, for example, that the British Committee for Standards in Haematology, in its evidence based guideline for management of primary and secondary MF, noted the lack of ”randomized controlled trials” in this respect. On the other hand, the British Committee also stated that “[s]ince the initial report of successful HSCT in myelofibrosis (Dokal et al, 1989), multiple publications have confirmed the potentially curative effect of HSCT with stable engraftment and reversal of bone marrow fibrosis [Devine et al., 2002; other study citations omitted].”

CMS also acknowledged that there were limited treatment options for patients who have high risk MF or highly symptomatic disease despite maximal conventional therapy. But, in these circumstances, the only curative option currently available is stem cell transplantation, although there are clinical trials underway to assess the safety and efficacy of a potentially curative medication, imetelstat (Geron/Jannsen). Thus, in MF patients who have progressed and who no longer respond to medications, stem cell transplantation is a reasonable and very necessary procedure providing for improved health outcomes.

Even so, based on its assessment of the medical literature, CMS said it would expand coverage for stem cell transplantation for MF patients in clinical trials, but only if such trials provide for matched concurrent non-transplant controls. However, none of the studies CMS cites in the medical literature had concurrent non-transplant matched controls, nor did these studies propose such trials in the future, nor did any of the professional organizations, whose guidelines were reviewed by CMS, recommend trials with concurrent non-transplant matched controls.

However, The European Society for Blood and Marrow Transplantation (EBMT) and the European School of Haematology (ESH) state that allogenic stem cell transplantation is the “standard of care” for HLA-identical sibling donors and matched unrelated donors. These groups further state that transplants from unmatched donors should be carried out only at accredited and experienced centers on institutional review board approved protocols - i.e., in clinical trials. But, Medicare patients would not even qualify for such trials because all study participants would undergo stem cell transplantation.

Also, the British Committee recommended that transplant eligible patients, defined as persons who are deemed fit enough to undergo the procedure and having an HLA matched sibling or unrelated donor of intermediate risk, especially those who are transfusion dependent, should be considered for myeloablative allogenic stem cell transplantation. The Committee further recommended that “every effort should be made to enroll patients in prospective clinical studies” to assess myeloablative versus reduced intensity conditioning regimens for older (Medicare-age) patients. Again, under the proposed CMS standard, older MF patients would not have Medicare coverage to permit their enrollment in these prospective studies.

Nor would patients in the prospective studies reported by Kroger (2009) and Rondelli (2014) - cited by CMS in the “analysis” section of its proposed decision memo - have qualified for Medicare coverage.

Accordingly, the proposed CMS coverage standard would not allow Medicare-age, older MF patients to participate in various well-recommended clinical trials. This unnecessary age restriction on participation in such trials is to the detriment of current patients, future patients, and to the public at large.

The proposed standard limiting coverage to only clinical studies with concurrent non-transplant matched controls seems to give inadequate consideration to the nature of PV, ET which can progress to MF; and that both primary MF, post-PV MF, and post-ET MF can progress to acute myelogenous leukemia (AML). When these MF patients no longer respond to conventional treatment, the only other currently available treatment with curative outcomes is stem cell transplantation.

On the other hand, patients whose MF has not progressed and who are still responding to medications would not likely choose to undergo stem cell transplantation sooner than necessary - unless forced to do so given certain insurance considerations (see below).

Thus, there is no reasonable probability of even enrolling adequate numbers of non-transplant patients in a clinical trial of stem cell transplantation. So, too, NIH ethical considerations of “fair subject selection” in the recruitment of patients would also limit enrollment of non-transplant participants.

Absent enrollment in prospective studies such as contemplated by the British Committee, EBMT and ESH, and as reported by Kroger (2009) and Rondelli (2014), the condition of Medicare-age patients, whose disease had progressed, and who were no longer responding to medications would deteriorate.

Further, because the proposed CMS standard bears no relation to, or track, the coverage provided by private health care carriers, patients who are approaching the age of Medicare eligibility could well have to choose whether to undergo stem cell transplantation sooner than they otherwise would, simply because of the availability of their current health insurance and the non-availability of coverage once they reach the age of Medicare eligibility.

So, too, final adoption of the proposed CMS standard for Medicare coverage will cause further emotional stress in these patients, their families and friends, thereby making an already difficult situation needlessly even more difficult.

Accordingly, it is respectfully requested that CMS carefully reconsider its proposed decision memo and adopt a more enlightened, non-discriminatory standard - one which would not eliminate any reasonable opportunity for Medicare-age beneficiaries with PV, ET, MF to have access to the only known current treatment that can result in curative outcomes. The difficulty in enrolling concurrent non-transplant controls in transplant clinical trials, and important ethical considerations, explain why none of the studies (both prospective and retrospective) cited by CMS in its analysis, and none of the professional groups whose guidelines CMS likewise noted, have suggested any trials with concurrent non-transplant matched controls.

The bottom line is that the proposed CMS standard of requiring concurrent non-transplant matched controls fails to realistically meet its stated goal of expanding coverage to older Americans with MF, especially MF patients with identical HLA-matched sibling donors.

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I am commenting on proposed rule CAG-00444R, which would allow for blood stem cell transplants for myelofibrosis patients to be covered by Medicare only under trial-like conditions, where half would receive a life-saving transplant and the other half would not.

This proposal does not go far enough, as research and practice for this disease have proven one thing – a transplant is the lone way to cure MF. There is no drug therapy that can treat it.

In a recent interview in "Oncology," a leading expert in this disease, Dr. Ronald Hoffman of Mt. Sinai Hospital in New York, said, “Stem cell transplantation is the only curative treatment. All the other agents we’ve discussed are really palliative and do not seem to lead to cure."

There need not be further delay in enacting policy that allows for Medicare coverage for physician-recommended blood stem cell transplant – without stipulations – for MF patients. Denying this coverage chooses death over life, despair over hope.

I understand the financial cost involved in this life-saving procedure. However, MF is a rare condition, with only 18,000 in the U.S. afflicted. According to the Leukemia & Lymphoma Society, only about five percent of those are appropriate for transplant consideration. And of that five percent, only a fraction are Medicare recipients. The cost to CMS then of covering a full transplant – considering the benefit to those impacted, their families and the community – would be minuscule.

According to the proposed decision memo, for such a trial to be effective there needs to be a sample size of greater than 100. But it may take years to find the necessary number of qualified individuals who are otherwise healthy (another stipulation in the proposal).

Looking at the studies cited in the memo, the number of otherwise healthy patients over 65 was so small that, in each case, it took years to reach the proposed number. Yet given how quickly this disease comes on, we may not have that time.

I have a dear friend with MF, and he’s in that five percent whose doctors consider a candidate for transplant – and he’s recently of Medicare age. For now his condition is stable, and may it stay so for a year or so. But should the need for transplant come to pass, can you imagine informing this compassionate, productive father, husband and friend that he is not able to have this life-saving treatment because Medicare won’t cover it? Neither can I.

For him and for many others, blood stem cell transplant for individuals with MF should be a covered procedure, with no stipulations beyond the patient’s physicians believing that it will save a life.

Thank you for your consideration and desire to make Medicare more effective and compassionate.

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Comments from the American Society of Hematology are below. A signed letter with the same comments will be submitted as well.

November 27, 2015

Tamara Syrek-Jensen
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Office of Clinical Standards and Quality
Coverage and Analysis Group
7500 Security Boulevard, Mail Stop C1-09-06
Baltimore, Maryland 21244-1850

Dear Ms. Syrek-Jensen:

The American Society of Hematology (ASH) is pleased to offer comments on the proposed national coverage determination on stem cell transplantation. ASH represents more than 15,000 clinicians and scientists worldwide committed to the study and treatment of blood and blood-related diseases. These diseases encompass malignant hematologic disorders such as leukemia, lymphoma, and multiple myeloma and non-malignant conditions such as sickle cell anemia, thalassemia, aplastic anemia, venous thromboembolism, hemophilia, and iron deficiency anemia. In addition, hematologists have been pioneers in the fields of stem cell biology, regenerative medicine, bone marrow transplantation, transfusion medicine, gene therapy, and the development of many drugs for the prevention and treatment of heart attacks and strokes. The Society is also committed to improving the nation’s health through public health initiatives. ASH membership is comprised of basic scientists, physician scientists, PhD researchers, as well as physicians working in diverse settings, including universities, hospitals and private practices. The diseases in question within this coverage determination are typically treated by hematologists and nearly every physician who provides stem cell transplant is a hematologist.

ASH was very supportive of the initial request for the changes in coverage made by the National Marrow Donor Program (NMDP) and the American Society of Blood and Marrow Transplant (ASBMT) earlier this year; ASH conveyed this message via online comments submitted on May 30, 2015. The Society is very appreciative of the positive response to the request for changes in coverage.

As requested, CMS has proposed to change coverage policy so that sickle cell disease and myelofibrosis are covered if patients meet certain conditions. Previously, these conditions were not mentioned in the national coverage determination so coverage determinations were made by local contractors. NMDP and ASBMT also requested that multiple myeloma be removed from the list of non-covered indications for stem cell transplant, but CMS went one step further and has proposed to include it on a list of covered conditions.

ASH supports the proposed coverage changes that will allow patients with sickle cell disease, myelofibrosis, and multiple myeloma the opportunity to receive allogeneic stem cell transplant if appropriate. ASH is also supportive of the proposal for coverage with evidence development (CED), which will help to contribute to the evidence for these services which have not been studied as rigorously as some other services due to the relative rarity of the disease and the acuity of the patients. Fortunately, all patients receiving stem cell transplants are tracked through the Center for International Blood and Marrow Transplant Registry (CIBMTR), so a new data collection method does not need to be developed.

While ASH supports the majority of the elements of the proposed coverage determination, the Society is concerned about the proposal that studies developed to collect evidence include prospective concurrent control patients who do not receive allogeneic transplant. CED is a framework that has been working successfully for myelodysplastic syndrome (MDS) since 2010. While there are additional data and reporting requirements associated with this coverage structure, over 1400 patients that previously had no access to stem cell transplantation as a therapy for their condition have received a transplant. The study requirements proposed for myelofibrosis, multiple myeloma and sickle cell disease are very different than the model that has been used successfully for MDS.

ASH believes that the requirement for concurrent non-transplant control groups may limit access to the service despite the coverage expansion. Several methodologic factors hinder the ability to develop a concurrent non-transplant control group appropriate for comparison to a transplant cohort, particularly for sickle cell disease and myelofibrosis. Sickle cell disease and primary myelofibrosis are very rare diseases. Their incidence and prevalence in the US is lower than MDS. They are uncommon diseases that are uncommonly transplanted. Comparative clinical studies typically limit accrual to a highly selected cohort of patients at a limited number of transplant centers. This could have the unintentional negative consequence of restricting access to transplant for patients with these diseases, rather than improving it. More importantly, it will yield small numbers of patients and insufficient power to address meaningful clinical questions about prognostic factors for patients, policy makers and physicians.

ASH recommends that CMS remove the requirement for concurrent enrollment of patients in a non-transplant arm from the coverage determination and instead gather comparative data from other sources. ASH is pleased that CMS is moving forward with expanding coverage for this important service while continuing to gather evidence. If you have any questions, please contact Brian Whitman, Senior Manager of Policy and Practice at bwhitman@hematology.org.

Sincerely,

David A. Williams, MD
President

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Comments regarding proposed decision on Medicare coverage for HCT for Multiple Myeloma, Sickle Cell Disease and Myelofibrosis-

These are rare disease! Please consider alternate frameworks similar to the Breakthrough and Accelerated Approval Processes utilized by the FDA for orphan conditions.

Remove the requirement for concurrent non-HCT controls. Patients will be seeking any and all curative options for their illness, making it unlikely for them to consent to participation in a non-HCT control group.

We already know what happens in non-HCT treatments. Further documentation of well-established and severe or fatal clinical outcomes are unnecessary.

Sincerely,
Laura Bernhard

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[PHI Redacted] diagnosed in 2011 with Myelofibrosis and to many doctors before that bone marrow test that confirmed [PHI Redacted] The problem is many insurances and also medicare dosen't seem to know much about it or cover the treatment for it. [PHI Redacted] should be given a chance to live the same as everyone else and insurance should be covering the cost as do other cancers. This is cancer of the bone marrow and the blood. Please HELP!!!!

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In Multiple Myeloma , there are recent concensus guidelines published for salvage allogeneic TX ( S Giralt et al Biol of Blood and BM Transpl, vol21, page 2039, v 21, 2015). Overall allogeneic TX is reasonable to consider in patient with early relapse after primary therapy ie 24 months after primary therapy including auto TX and/or high-risk cytogenetics, plasma cell leukemia etc). Preference though is to enroll on clinical trial . I agree that prspective randomzied trials are needed in these patients to compare allogeneic TX to other therapy. Also of note many studies are also loooking at adding maintenance therapy after allog TX and would be reasonable to compare auto to allog with both arms getting same maintenance therapy post TX. Seems maybe reasonable to encorporate these recommendations into guidelines.

The only ablative regimen commparison of auto and allog up front was the aborted SWOG study ( Barlogie B et al JCO 2006, 24, 929) the allog arm was closed early due to high trm but did suggest long term survivors in allogeneic TX arm 39%. So, does raise the question again if done in prospective trials of doing auto with maintenance therapy vs ablative allogeneic TX in current era would lead to better outcomes.

Mini allogeneic TX alone do not show in current data any benefit when stand alone and would be clear to not include.

I believe the data with auto tx alone vs auto /mini allog TX for newly diaignozed patients is more controversial. Bruno B et al (NEJM 2007, 356, 1100) found improved DFS and S in auto tx followed by non myeloablative allogeniec TX . But IFM 99-03 trial (Graban F et al BLood 2006, v107, 3474) and CTN trial 0102 ( Krishnan A et al Lancet Oncol 2011, V12, 1195) did not show any PFS or S advanatge.

In general, a numer of papers have shown that high risk cytogenetics do not get that much advantage from an auto TX with shorter time before relapse and Kroger's group has shown that allogeneic TX can overcome some of that bad risk issue.

I believe the key is to clearly defining the group offering allogeneic TX to so will get best chance to determine groups best likely to benefit and would recommend aligning also with recent concensus paper.

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Patients with myelofibrosis, multiple myeloma and sickle cell disease are currently unable to undergo allogeneic stem cell transplant if Medicare is their only coverage. These patients come to the same clinics and interact with other patients who are able to have transplant covered by third party payers such as BlueCross Blue Shield, Aetna, Cigna and United HealthCare. Allogeneic stem cell transplant is the only curative therapy for these patients. Being on the administrative side and having to explain why we can’t offer transplant due to insurance coverage is very difficult, especially when patients have met someone with the same disease whose transplant is covered by insurance. It seems Medicare patients are being discriminated against and not offered the same standard of care treatment.

All three of these diagnosis are chronic diseases and patients may already be on Social Security disability. Medicare becomes effective after receiving Social Security disability benefits for two years, so many patients are under age 65. These are patients who have a potential curative treatment with allogeneic transplant but are denied this potential life-saving opportunity. Please reconsider and allow Medicare patients to have an allogeneic stem cell transplant for myelofibrosis, multiple myeloma and sickle cell disease without all of the clinical trial restrictions. Allogeneic transplant is the standard of care in most transplant centers.

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I am sure much of what is being sent has to do with the need to keep all treatment options available. For MM I will make a slightly different argument. We can debate whether PBSCT gives better outcomes. Certainly, it has never been shown to be inferior to alternatives, it is associated with less in the way of long-term toxicities and is the only modality that offers the opportunity to be a decade long treatment-free survivor.

My argument is more practical. At the current time it is, by far, the least expensive alternative. It would behoove CMS to push as many patients as possible to an approach with potentially superior outcomes, lower toxicity and if performed without unproven post-transplant maintenance, the lowest costs.

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To whom it may concern:

I am director of the BMT program at Loyola University Medical Center for 30 years and have published ~150 articles on BMT and hematologic malignancies including on allogeneic transplantation for myelofibrosis.

While I am supportive of each of these three indications, I am concerned given the selection process for transplant we have instituted for myelofibrosis (transfusion dependency; weight loss of > 10% due to disease; pain due to aplenomegaly; systemic symptoms that impact quality of life; and no one with significant hepatic involvement) that are associated with a survival of < 2 years without transplant that the 40-50% chance of a long term remission with transplant will be denied to patients participating in a trial with a no transplant arm. I would suggest a trial design similar to that you have instituted for MDS would work well here and still permit us to transplant all eligible patients with this life saving therapy.

Thank you for your consideration

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I am the Division Director of Hematologic Malignancies and Cellular Therapeutics, and the Medical Director of the Blood and Marrow Transplant at the University of Kansas Cancer Center. I am extremely grateful that CMS is allowing coverage for multiple myeloma, sickle cell disease and myelofibrosis patients. Clinical outcomes data indicates allogeneic stem cell transplant for these indications is an optimal treatment strategy. I am confident this decision on behalf of CMS will help save lives and improve the overall quality of life for patients who are currently unable to receive this therapeutic option due to Medicare’s current coverage guidelines.

However, I strongly urge CMS to consider removing the requirement for the non-SCT control group. Allogeneic stem cell transplantation is currently the only curative approach for these high-risk, aggressive disease types and I believe this trial would essentially be curative therapy versus non-curative therapy which seems unethical. For example, in the setting of high-risk myelofibrosis, there is strong evidence to suggest a role of transplantation in appropriately selected patients. I would find it unethical to suggest no transplantation if otherwise the patient is a good candidate and has a donor. Moreover, in my history conducting clinical trials it is highly unlikely that these terminally ill patients will consent to be on randomized trial with only one arm having a known curative approach. These controls will prevent many critically ill patients from benefiting from a potentially curative, life-saving therapy. Again, I am grateful for recent changes in coverage, but I strongly believe having this as a randomized trial could be discouraging to patients, families, and all health care providers. I hope you will consider removing this arm so all patients may have the ability to have CMS coverage for a potentially life-saving stem cell transplant.

Lastly, I would like to reference the laudable efforts of the CIBMTR who have played a vital role in improving the outcomes of stem cell transplantation. Through CMS efforts, the CIBMTR has illustrated the importance of high quality data on transplant recipients in subgroups of interest, which has been demonstrated in the current CED study of transplantation for Myelodysplastic Syndromes (MDS), which the CIBMTR has collected data for more than 1,200 transplant recipients older than 65 years from more than 100 centers over the last five years, starting just a few months after CMS’s MDS decision memo. I strongly urge CMS to not limit the design of trials which will merit reimbursement for transplantation of multiple myeloma, SCD and myelofibrosis, but instead accept a variety of trial designs, including cohort studies through the CIBMTR, that will advance our understanding of the role of allogeneic transplantation in these diseases and optimize transplantation outcomes.

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November 24, 2015

Tamara Syrek-Jensen
Acting Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Office of Clinical Standards and Quality
Coverage and Analysis Group
7500 Security Boulevard, Mail Stop C1-09-06
Baltimore, Maryland  21244-1850

E-mail: CAGinquiries@cms.hhs.gov

RE:  National Coverage Analysis (NCA) for Stem Cell Transplantation (Multiple Myeloma, Myelofibrosis, and Sickle Cell Disease) (CAG-00444R)

Dear Ms. Syrek-Jensen:

We are writing on behalf of the American Society for Blood and Marrow Transplantation (ASBMT) and the American Society of Clinical Oncology (ASCO) to provide comments on the proposed National Coverage Analysis for Stem Cell Transplantation for Multiple Myeloma, Myelofibrosis, and Sickle Cell Disease (CAG-00444R).

Since 1993, the American Society for Blood and Marrow Transplantation has been the national professional association that promotes education, research and clinical affairs that advance the field of cellular therapy and blood and marrow transplantation.

ASCO represents nearly 40,000 physicians and health care professionals involved in cancer clinical care and research from all oncology disciplines and subspecialties.

One of the major issues identified by our memberships and a focus of activity of the ASBMT and ASCO is access to the life saving potential of allogeneic hematopoietic cell transplant (allo HCT).  This led the ASBMT to partner with the NMDP/Be The Match and formally request CMS consider coverage of allo HCT for specific relevant diagnoses in January 2015.  Recently, the CMS issued a proposed decision memo in response to this request.  While ASBMT and ASCO members appreciate the efforts of the CMS in considering coverage of allo HCT for myelofibrosis, multiple myeloma, and sickle cell disease, we must highlight our concern regarding the potential implications of the decision memo as currently written.

Myelofibrosis and multiple myeloma are hematologic malignancies that increase with age and the median age of onset for both is the later 60s.  Over half of the patients with these diagnoses are in their “Medicare years”.

As allo HCT is the only curative therapy for these patients, decreasing barriers to obtaining a transplant is a critical concern of our memberships.  Similarly, although sickle cell disease is an inherited hemoglobinopathy and the vast majority of patients suitable for allo HCT are younger than 65, many are Medicare/Medicaid beneficiaries due to disease-related disability.

While the proposal that coverage for allo HCT for myelofibrosis, multiple myeloma and sickle cell disease be within a Coverage with Evidence Development (CED) program matches the pathway that led to CMS coverage of allo HCT for MDS, there are significant differences in the details that will result in decreased and unequal access to allo HCT across the country.  Specifically the requirement that the studies developed to collect evidence include prospective concurrent non-HCT controls rather than available databases that may not be completely concurrent essentially shuts the door on allo HCT for many patients.

There are a number of methodological issues including the rarity of the diseases that would require prolonged accrual to reach statistical validity, the longer-time horizon likely needed to see the curative benefit vs. the short-term morbidity and mortality of allo HCT and the expanding donor options that decrease those who could be biologically assigned to a non-transplant treatment/observation arm based on donor availability are a few.  In addition the practical reality, illustrated by the prior experience with MDS, where the majority of allo HCT centers were able to participate in the observational study through the Center for International Blood and Marrow Transplant but only about a quarter were able to open the prospective comparative trial through the Blood and Marrow Transplant Clinical Trials Group, would further slow the accrual of any trial and provide uneven access to Medicare patients based solely on geography. A less burdensome, observational database model more akin to the current MDS CED observational study would mitigate against these untoward results of the draft proposed study requirements.

Another potential concern that can be raised by CMS is that a too liberal decision memo and study requirements will result in inappropriate application and overuse of allo HCT in these illnesses.  As practicing transplant physicians who understand the resource intense nature of such transplants and the capacity limitations at transplant programs, rational decision making on whom and when and how to transplant is subject of day to day discussions amongst team members.  Coverage will not result in misapplication and overuse.  In Canada, a single payer model that has transplant outcomes equivalent to those in the United States, the decision to transplant is left to the medical team.  Unrestricted freedom to transplant patients whom physicians deem appropriate has not resulted in overuse of allo HCT for these diagnoses.  They remain uncommon indications for transplant in the age over 65 population (personal communication, CB from Canadian BMT Registry).  In addition, as a result of The Stem Cell Therapeutic and Research Act, all allo HCT in the United States are registered and have ongoing follow up data reported.  Centers are compared based on complexity adjusted patient outcomes and those underperforming suffer the consequences of being removed from payer networks and decreased referrals.  There are no incentives to over transplant this population and the necessary data can be acquired by means that do not necessitate the burdensome and discriminatory aspects of prospective clinical trials with concurrent non-HCT controls.

As professional societies that represent physicians caring for patients with these conditions, the ASBMT and ASCO have within their mission statements a commitment to ensure optimal access and the most appropriate application of therapies including HCT to patients across the country.  As written, the CMS decision memo regarding the application of allo HCT in patients with myelofibrosis, multiple myeloma and sickle cell disease in the Medicare population unintentionally but potentially seriously limits access to curative therapy and evidence building.  It is for these reasons that we encourage CMS reconsider the requirements laid out in the Decision Memo, particularly as relates to the design of studies within the CED approach.

We thank you for your efforts and consideration.

Sincerely,

Effie Petersdorf, MD    
President, ASBMT

Julie M. Vose, MD, MBA, FASCO
ASCO President

Christopher Bredeson MD MSc FRCPC 
President Elect, ASBMT

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CMS Draft Decision Memo Regarding Reimbursement for Hematopoietic Stem Cell Transplantation in Myeloma for Medicare Beneficiaries

On October 29, the Centers for Medicare and Medicaid Services (CMS) issued a proposed decision memo regarding Medicare coverage for allogeneic hematopoietic cell transplant (HCT) for three indications – Multiple Myeloma (MM), Primary Myelofibrosis and Sickle Cell disease. While welcomeing the proposed decision to consider allogeneic HCT in myeloma, we wish to share our comments and concerns regarding the wording of the decision that could limit for allogenic transplant coverage in this disease.

Background re: Myeloma and allogeneic HCT:

In summary, allogeneic HCT has not been commonly used because the procedure itself carries a risk of toxicity and the chance of early death especially in older / frail persons. Recent advances have made HCT a much safer procedure and there are patients with MM in the Medicare eligible group whose prognosis with standard therapy is so poor that alloHCT would be a preferred option, if accessible.

Coverage with Evidence Development

Medicare has proposed Coverage with Evidence Development (CED), which means that Medicare beneficiaries have coverage for transplant if they participate in an approved clinical study. This is the same mechanism currently in place for Medicare’s coverage of another blood disorder, Myelodysplastic Syndromes (MDS). This mechanism has worked successfully for MDS and has allowed over 1400 patients with MDS to receive HCT. It has been facilitated by using the Center for International Blood and Marrow Transplant Research (CIBMTR), a federally funded research group that collects clinical data on all of the allogeneic HCTs being done in the United States. Data provided to CIBMR for Medicare beneficiaries receiving HCT for MDS has been analyzed and reported to CMS on a routine basis since the program was started in December 2010. Implementation of this program more than tripled the number of HCTs for MDS annually in the United States, by removing the financial barrier to treatment.

While we greatly appreciate CMS’s intent to provide a pathway to coverage for Myeloma through clinical studies, the proposed study requirements for CED are different than those required in the MDS study and will be extremely difficult to satisfy by the transplant community. We feel that the study structures being proposed are prohibitive due to a lack of understanding of the disease process and eligibility for allogeneic transplantation in Myeloma.
Major Issue of Concern: Concurrent non-HCT Controls for allo-HCT recipients in MM

The primary issue of concern with the proposed decision is with CMS’s requirement for concurrent non-HCT controls. Concurrent non-HCT controls are problematic for the following reasons:

Our Proposed Alternative

We are petitioning CMS to remove the requirement for concurrent non-HCT controls and to accept diverse study designs, including studies through the CIBMTR, that will advance our understanding of the role of allogeneic transplantation and optimize transplantation outcomes in specific patient groups identified by clinical and molecular methods. Such an approach will avoid disparity in access to curative therapy and speed the process of understanding the role of allogeneic HCT in this patient population.

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As a transplant physician who has spent the last 15 years of my career trying to increase utilization of BMT as a curative therapy for children and young adults with sickle cell disease, I am very concerned about the CMS proposed ruling that allogeneic HSCT for sickle cell disease (SCD) will be covered by Medicare only for certain beneficiaries with sickle cell disease who participate in a prospective clinical study with concurrent non-transplanted controls. The CMS review of published data on outcomes of matched sibling donor transplants for SCD failed to look at a 59 patient multicenter, PROSPECTIVE, NHLBI funded trial of matched sibling donor BMT for children with severe SCD conducted by Dr. Mark Walters and colleagues from 1991-2000. This trial clearly showed very good outcomes and a functional cure of SCD in severely affected children with SCD with transplant related mortality similar to that seen in children (all phenotypes) with SCD during childhood as part of the natural history of the disease. Several other single center and multicenter retrospective analyses have confirmed these findings. My concerns are two-fold:

1) There is general consensus amongst the pediatric hematology and BMT physician community that HLA matched sibling donor BMT should be considered as STANDARD OF CARE for children with severe SCD (i.e those meeting the Walters study inclusion criteria) who have unaffected matched sibling donors. The CMS proposed rule will lump this cohort of transplant eligible SCD patients into a CED requirement and create an additional barrier for patients seeking a curative therapy for this progressively organ damaging and prematurely lethal disease.

2) While I agree that transplants for SCD using alternative donors (matched unrelated donors, haploidentical related donors, etc) should be performed in the context of a clinical trial, the proposed decision that allogeneic HSCT for sickle cell disease (SCD) will be covered by Medicare only for certain beneficiaries with sickle cell disease who participate in a prospective clinical study with concurrent non-transplanted controls poses additional barriers to advancing this field of study. There are several studies that have historically shown low participation rates of African-Americans in clinical trials. The requirement of a concurrent non-transplant cohort in a CED trial will only add to this problem.

I implore the CMS to reconsider this proposed decision for SCD patients to exclude patients with severe disease manifestations and matched sibling donors seeking transplantation as a curative therapy from having to enroll onto CED trials and to reconsider the recommendation that such CED trials include non-transplanted controls. Thank you.

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Sanofi US is submitting these comments in support of CAG-00444R proposed decision memorandum to expand the Medicare National Coverage policy regarding hematopoietic stem cell transplantation (HSCT). As a healthcare company backed by world class research and development, Sanofi is developing innovative therapies to help Medicare beneficiaries lead longer, healthier, and more productive lives. Our company is pursuing leading patient solutions in major therapeutic areas including oncology, diabetes, cardiovascular disease, central nervous system, internal medicine, and vaccines. Our mission is to discover, develop and make available to physicians and their patients innovative, effective, well-tolerated, and high quality treatments that fulfill vital health care needs. While we strongly support the Coverage Analysis Group’s proposal to make allogeneic HSCT available to Medicare patients as a treatment for sickle cell disease, primary myelofibrosis (PMF) and multiple myeloma (MM), we wish to raise some concerns regarding the operational conditions to be imposed for this revised policy.

We appreciate CMS’ willingness to make the coverage with evidence development (CED) protocol available for this purpose. Our main concerns, however, are that the Proposed Decision Memo is overly prescriptive in permissible trial design and includes a requirement for a non-HCT arm to serve as a control group for the purposes of comparison to the transplant group. Patients that have been seeking Medicare coverage for HCT treatment for sickle cell disease and PMF diagnoses for some time are seeking a curative treatment and those with multiple myeloma are seeking more effective therapy that can delay the progression of their disease with fewer disease symptoms and an improved quality of life. Assigning some of these patients to a concurrent non-HCT comparison group is both unrealistic as a practical matter and unacceptable as a compassionate matter. Most patients undertake the attendant risks of HCT in exchange for the possibility of cure or significant improvement in overall survival. Patients who have long-awaited coverage for this procedure are unlikely to agree to randomization with the chance of being assigned to a non-transplant control arm. These diseases are rare and serious, ultimately fatal, conditions. Developing sufficient numbers to satisfy this requirement would be exceedingly difficult. We believe there are sufficient data in the CIBMTR’s outcomes registry and other observational data which can provide valid comparators. This data can supply sufficient evidence that CMS needs to make necessary inferences and judgments regarding future coverage decisions. We urge the CMS CAG to remove the requirement for a non-HCT comparator arm and permit greater flexibility in designing CED trials for allogeneic HCT for sickle cell, PMF and multiple myeloma.

In addition to our concerns noted above, in light of the CAG’s proposal to revise and update Medicare coverage policy for HCT, Sanofi would also like to raise an additional concern regarding the current national coverage policy for HCT. For some time, there have been new clinical developments and needs concerning autologous HCT for multiple myeloma. These developments include recognition of a broader, clinically-suitable age range for HCT candidates, autologous HCT at relapse and the use of “tandem transplant” procedure in appropriate patients. Although at this time, the CAG is proposing the limited set of revisions set out in the Proposed Decision Memo CAG-00444R to its current HSCT coverage policy, we encourage the CAG and CMS to continue to be receptive to additional modifications to Medicare coverage of autologous and allogeneic HCT that will keep pace with recent developments in HCT practice. Thank you for your consideration.

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Dear CMS;

Thank you for this opportunity to comment on the proposed guidelines for establishing guidelines regarding payment for allogeneic stem cell transplantation in patients with Myelofibrosis, Sickle Cell Anemia and Multiple Myeloma. While I understand and agree with the need to collect non-transplant control data to support the value of this approach in these conditions, I am concerned that what you have proposed will not be an acceptable option for many of these patients. There is, for example, significant evidence that MF is a disease for which there are no curative or even particularly effective therapeutic alternatives to allogeneic transplant. As a result, and in light of the current availability of multiple effective sources of donor stem cells, it would be difficult to justify not transplanting a patient with this disease assuming he or she were in adequate physicial conditon and without major co-morbidities. In both sickle cell disease and multiple myeloma, there are alternative treatments, but the majority of patients referred for consideration of allogeneic stem cell transplant are likely to have failed multiple prior therapies and to have progressive and possibly life-threatening conditions for which standard non-transplant therapies have either been tried and proven unsuccessful or are very unlikely to be effective. For sickle cell disease this likely means repetitive painful and debilitating sickle crises or strokes requiring frequent red cell exchange transfusions or, in the case of multiple myeloma, patients with progressive or extremely high risk disease that has likely already failed an autologous transplamnt and other novel treatments.

An alternative to this is to attempt to access registrational databases such as those managed by the Center for International Bone Marrow Transplant or the Medicare SEER database. Another alternative are databases being established by groups such as the UNC Lineberger Comprehensive Cancer Center and UNC School of Public Health which compile claims data comprised of records from Medicare, Medicaid and BCBS of NC.

While none of these options are as appealing as a prospective controlled trial, I feel it is likely impossible to undertake such a study in these populations at this time, and that your proposal represents an unacceptable requirement for moving forward with the current CMS plan.

Thank you for allowing me the opportunity to comment on your proposal and please feel free to contact me if you think it would be helpful.

Regards,

Thomas C. Shea, MD
Professor of Medicine
Director, UNC Bone Marrow and Stem Cell Transplant Program
Associate Director for Clinical Outreach, UNC Lineberger Comprehensive Cancer Center
UNC Chapel Hill
Past Chair, Center for International Bone Marrow Transplant Research

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National Marrow Donor Program, Be The Match
500 N. 5th Street
Minneapolis, MN 55401

Tamara Syrek-Jensen
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Office of Clinical Standards and Quality
Coverage and Analysis Group
7500 Security Boulevard, Mail Stop C1-09-06
Baltimore, Maryland 21244-1850

November 23, 2015

The National Marrow Donor Program (NMDP) is the world’s leading nonprofit organization focused on saving lives through blood, marrow and cord blood hematopoietic cell transplantation (HCT). The NMDP operates the Be The Match® registry, the largest and most diverse donor registry in the world, through a competed contract overseen by the Health Resources and Services Administration (HRSA) Division of Transplantation. In addition to operating the registry, the NMDP holds the HRSA contract for the Office of Patient Advocacy/Single Point of Access and is responsible for assisting patients facing barriers to transplant. Through this congressionally-established office, the NMDP helps patients navigate the complexities of the health care system, with a primary focus on insurance and financial barriers that prevent patients from receiving a transplant.

The limitations of Medicare coverage for HCT is the single greatest insurance barrier faced by the patients we serve. Because of the age-related onset of most hematologic malignancies, many of the individuals seeking transplantation are Medicare beneficiaries. As operators of the HRSA OPA/SPA contract, and as an organization whose mission is to deliver cures for blood cancers, we continue to actively pursue significant improvements to access to HCT on behalf of our Medicare beneficiary stakeholders. We very much appreciate CMS’s partnership in finding a way to provide these patients with the treatment options they are seeking.

We understand and appreciate that CMS is trying to provide a pathway to coverage for allogeneic HCT for myelofibrosis, multiple myeloma and sickle cell disease through its proposal for the use of Coverage with Evidence Development (CED). CED is a framework that has been working successfully for myelodysplastic syndrome (MDS) since 2010. While there are additional data and reporting requirements associated with this coverage structure, over 1400 patients that previously had no access to HCT as a therapy for their condition have received a transplant. However, the study requirements proposed for myelofibrosis, multiple myeloma and sickle cell disease are very different than the model that has been used successfully for MDS.

The proposed requirement for concurrent non-HCT controls, without also having a parallel observational study arm, will greatly limit the access that most beneficiaries will have to HCT, despite CMS’s positive intentions. The American College of Surgeons Commission on Cancer has accredited over 1500 cancer hospitals in the United States . However, HCT is a highly-specialized medical field; allogeneic transplantation is performed in approximately 130 adult transplant programs in the United States, most within major academic medical centers . Of these 130 allogenic transplant centers, 105 are actively participating in the observational study for MDS, while only 34 centers are able to allocate enough research resources to participate in the comparative clinical trial. To clarify – the MDS comparative clinical trial is open in approximately one-quarter (25%) of the allogenic transplant centers in the country and approximately 2% of the Commission of Cancer Accredited facilities in the United States.

Application of the study design as proposed by CMS will result in unequal access to care for its beneficiaries based on where they reside. We expect that the number of centers that would be able open studies that satisfy the current proposed requirements in the current National Coverage Analysis to be even fewer than those participating in the MDS comparative trial, due to decreased numbers of affected patients in any particular geographic area in conjunction with the increased comparative data requirements. As Medicare does not provide travel and lodging relocation benefits to beneficiaries, many will be unable to seek treatment due to the lack of a participating hospital in their area. Due to the access issues described, we strongly object to CMS’s proposed requirement for concurrent non-HCT controls and ask CMS to remove this requirement from the final coverage decision.

We understand the need for CMS to have data on low volume conditions, particularly those that will be new or expanded services to the beneficiary population. However, CMS’s concern that clinically established outcomes will differ in the beneficiary population due to age, and its proposed corresponding study requirements to demonstrate this relationship, is likely unsupported. As part of the MDS CED CIBMTR study, interim analyses are reported to CMS on a regular basis. These analyses have all demonstrated that there are no statistically significant differences in outcomes between patients age 55-64 and patients age 65 and older . Due to the age-associated development of hematologic malignancies, the affected population naturally clusters around the age of transition to Medicare. The median age of diagnosis for multiple myeloma is 69 and for myelofibrosis, the median age of diagnosis is 67 years . Commercial insurance carriers routinely provide coverage for transplantation for these disease indications and this coverage does not have age requirements associated with it. As these payers provide coverage for members up to their 65th birthday, the Medicare population of transplant recipients are not substantially older than those who receive transplant coverage under commercial policies.

Medicare’s coverage of HCT for expanded indications will not drive inappropriate use of transplant in beneficiaries that are clinically inappropriate. Transplant is a clinically intensive procedure and the physicians that provide this care treat it accordingly; it is not provided as a ‘last-chance’ effort for all patients that fail other therapies. The Stem Cell Therapeutic and Research Act (reauthorized in 2010) requires that all providers submit data on each allogeneic transplant that they provide, including long-term follow-up data. Each center receives an aggregate score based on the overall survival data for all patients treated by the center – there are no exclusions for particular patient categories or age ranges. This score is utilized by commercial payers to assess transplant program performance and, subsequently, appropriateness for inclusion in their provider networks. This system inherently motivates physicians to apply evidence-based clinical patient eligibility criteria to those seeking care.

We understand that CMS needs to carefully consider the coverage policies it applies to the beneficiary population and we recognize that CMS is attempting to expand coverage in a way that will positively impact beneficiaries affected by these illnesses. We are willing to fulfill the administrative requirements of CED, but ask that CMS understand the needs of its beneficiary population and the unequal access conditions it will create for beneficiaries by applying the currently proposed study requirements. We are eager to assist in efforts to improve access for our patient stakeholders. Please contact Stephanie Farnia (612-884-8640, sfarnia@ndmp.org) with any additional questions on this issue.

Sincerely,

Jeffrey Chell, M.D.
Chief Executive Officer
National Marrow Donor Program, Be The Match

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November 23, 2015

CMS Coverage Analysis Group
Baltimore, MD

RE: CAG-00444R Proposed Decision for SCT

As the Project Director of the Stem Cell Therapeutic Outcomes Database (SCTOD), and Principal Investigator of the approved observational study of hematopoietic cell transplantation (HCT) in patients over age 65 with Myelodysplastic Syndrome (MDS) under CED (Protocol #: CAG-0415N), I would like to provide some perspective on the national coverage determination described in the proposed decision memo CAG-00444R.

The transplant community is very appreciative of CMS’ efforts to provide a framework for coverage, and therefore access, to allogeneic HCT for Medicare patients with sickle cell disease, primary myelofibrosis (PMF) and multiple myeloma (MM). We believe the CED mechanism coupled with the CIBMTR Outcomes Registry can provide the infrastructure to develop medical evidence to guide policy for these diseases using an appropriate study design. As Project Director of the SCTOD, we look forward to collaborating with the transplant community and CMS to accomplish this.

However, there are substantial limitations in the requirements outlined in the proposed decision memo that will preclude our ability to effectively develop a scientifically valid study that qualifies under CED.

Most important among these limitations is the proposed requirement for a concurrent non-HCT control arm. Several methodologic factors hinder our ability to develop a concurrent non-HCT control group appropriate for comparison to a transplant cohort, particularly for sickle cell disease and PMF. These diseases are rare, particularly when considering the severity of illness that makes a patient ‘eligible’ for consideration of transplantation. Long study accrual times will therefore be necessary to generate sufficient study power to address issues of appropriateness and effectiveness. Alternative treatments for these diseases have lower morbidity and mortality than allogeneic HCT in the short term, but they are not curative and provide less long-term relief from symptom burden. Comparative studies designed with anything less than long-term (5-10 years) follow-up may inherently bias outcomes against the HCT cohort, especially given small numbers of study participants. Biologic assignment to a comparison group based on donor availability is less feasible as alternative donor sources become more prevalent and safe for use in allogeneic HCT. Since the severe outcomes for these diseases are already well-known, patients eligible to receive HCT wish to pursue curative options, and are unlikely to accept random assignment to a non-HCT control group. Similarly, patients ineligible for HCT based on other medical conditions are not an appropriate control group for valid comparative analysis. For these reasons, studies with concurrent non-HCT control groups are not practical.

Our collective experience with MDS has shown CMS’ decision to provide coverage for allogeneic HCT under the CED mechanism substantially expanded access to this treatment over the last 5 years. In fact, following approval of our study, annual access to HCT for patients over age 65 has expanded nearly 4 fold compared to 2010. Since HCT remains the only curative treatment for MDS, this represents a significant health benefit for about 300 patients over age 65 each year. Without coverage through Medicare as modified in 2010, approximately 225 of these patients are likely to have been excluded from allogeneic HCT annually.

Transplants under CED have been performed in 105 centers, with a median of 1.4 transplants per center per year. The range was wide and 44 centers performed 1 or fewer transplants in this population per year; another 28 centers transplanted only 2 such transplants a year. Few, if any, of these centers with low volumes would have been motivated to open a trial that required concurrent controls. In fact, no center is in a position to open trials that will accrue very few patients. For context, only 34 US transplant centers have opened the comparative clinical trial in MDS being conducted by the Blood and Marrow Transplant Clinical Trials Network despite an effort to enroll as many as possible. The success of the current CED study was the ability to fold the data collection and analysis into the existing CIBMTR Outcomes Registry which studies all transplant recipients.

Sickle cell disease and, particularly, PMF are very rare diseases. Their incidence and prevalence in the US is lower than MDS. They are uncommon diseases that are uncommonly transplanted. Based upon our experience from the MDS observational study, large numbers of patients were required to answer important prognostic questions based on the patient, disease and center-based factors outlined in the MDS coverage decision memo than initially projected. Comparative clinical studies typically limit accrual to a highly selected cohort of patients at a limited number of HCT centers. This could have the unintentional negative consequence of restricting access to HCT for patients with these diseases, rather than improving it. More importantly, it will yield small numbers of patients and insufficient power to address meaningful clinical questions about prognostic factors for patients, policy makers and physicians.

Finally, with regard to multiple myeloma, restricting controls to patients receiving non-transplant therapy ignores the fact that autologous transplantation is a standard of care treatment for multiple myeloma that is already covered by CMS. It also eliminates the possibility of comparisons to a readily available concurrent control group already being included in the CIBMTR’s Outcomes Registry.

Based on these limitations inherent in the approach outlined in the draft decision memo, I strongly suggest that CMS remove the requirement for concurrent non-HCT controls from the final decision memo in favor of alternative observational designs supported in the CED for MDS, especially for sickle cell disease and PMF, and to allow data on autologous transplant recipients being collected by CIBMTR to be used as a valid control for studying allotransplants for multiple myeloma. Cohort studies using data collected through the CIBMTR provide the opportunity to acquire data for all recipients of allogeneic HCT and address scientific questions of prognosis to optimize transplantation outcomes for these diseases. CIBMTR also has the methodologic expertise and experience to effectively use these data for comparison with non-concurrent disease-specific control cohorts as they are identified.

Sincerely,

J. Douglas Rizzo, MD MS
Senior Scientific Director, CIBMTR
Project Director, Stem Cell Therapeutic Outcomes Database
Professor, Department of Medicine
Medical College of Wisconsin
9200 W Wisconsin Avenue, Suite C5500
Milwaukee, WI 53226

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I appreciate the efforts by CMS to expand coverage and access to allogeneic stem cell transplant for patients with myeloma, myelofibrosis and sickle cell disease.

I am a stem cell transplant physician at the University of Kansas Cancer Center. I have specialized in the care of patients with hematologic malignancies and bone marrow disorders for over 10 years. It is critically important that patients with these diseases be offered stem cell transplantation, as it is the only curative treatment for their disease. However, a requirement for concurrent non-transplant controls will only serve to slow our progress in making transplant safer and more effective for these patients. It would be unethical for me to allow a patient with a potentially curative therapy to be randomized to a non-transplant arm. I encourage CMS to consider removing this requirement as it will not only hinder the field of stem cell transplantation, but will limit patient access to this curative therapy.

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November 25, 2015

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Blvd., Mail Stop S3-02-01
Baltimore, MD 21244-1850

Re: Proposed Decision Memo for Stem Cell Transplantation (Multiple Myeloma, Myelofibrosis, and Sickle Cell Disease (CAG-00444R)

Dear Ms. Jensen:

On behalf of the thousands of individual and institutional members involved in cellular therapies that we represent, AABB would like to provide comments and feedback regarding the Centers for Medicare and Medicaid Services’ (CMS) recent proposed decision to modify the existing National Coverage Determination to expand coverage for allogeneic hematopoietic stem cell transplantation (HSCT) for multiple myeloma, myelofibrosis and sickle cell disease (SCD).

AABB applauds CMS’ effort to open an important door for coverage for our nation's Medicare population. However, we are very concerned that the proposal, as written, would severely hinder patient access to potentially life-saving transplants by setting overly stringent and burdensome requirements for covered eligible trials. The proposed decision states that the coverage for HSCT would be allowed for these indications only through an approved study including a concurrent control group and focusing primarily on survival.

Allogeneic HSCT is currently the only potentially curative therapeutic option available for these diseases and, as such, it may be very difficult to enroll concurrent non-transplant controls. Patients seeking a curative option may be unwilling to be randomized to the control arm or be followed as a member of a non-transplant cohort. Moreover, studies of HSCT focusing primarily on survival in the short term (2-3 years) may have difficulty demonstrating a survival benefit for allogeneic HSCT, especially in patients with diseases like SCD, which is a chronic disease characterized by progressive organ damage, a very poor quality of life and shortened lifespan. SCD patients receiving transplants may demonstrate inferior short-term survival but then experience superior survival results in the long-term and enjoy a better quality of life.

It should also be noted that matched sibling donor transplantation in children with severe SCD results in >90% disease-free survival and can be considered a standard-of-care therapeutic option for these patients. If third party payers and state Medicaid programs follow the CMS guidelines, the proposed CMS decision will create a barrier to transplant access for this patient population.

AABB strongly urges CMS to amend its proposed requirements for study parameters, including removing the unnecessary use of concurrent controls. More reasonable study parameters should be put in place to allow for both greater patient access to life-saving transplants and valuable evaluation of this therapy.

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My family and I strongly support expansion of coverage fpr these conditions. I have a friend who has successfully undergone transplant with fantastic results but related the issues of research design and how it could have badly affected his ability to receive the treatment he needed.

Furthermore, any policy changes should apply to all who might need transplant without regard to age and CMS should provide coverage for transplant when the doctor believes it is the best treatment option.

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To the attention of: CMS Coverage Analysis Group

We, the undersigned, are writing in response to the proposed CMS rule on transplant coverage for patients with the rare form of blood cancer called Primary Myelofibrosis. Each of us is a hematologist specializing in the care of these patients and together we have a large collective experience on the management of this rare, heterogeneous and largely lethal condition.

We applaud the efforts CMS is making to codify the application of allogeneic stem-cell transplantation in this unique patient population. Allogeneic transplantation is a critical part of the care trajectory for a subset of patients with this disease. We are anxious to collaborate in a way that gathers critical data on the outcomes of such transplants as well as ensures that there is no inappropriate limitation imposed on patients who, under the current climate, would be eligible to proceed with the procedure. The approach utilized for transplant for Myelodysplastic Syndromes Coverage with Evidence Development (CED) could serve as a model for achieving this balance.

In particular, we are concerned with regard to the proposed wording of the rule requiring any transplant study to include concurrent non-transplant controls. Our concerns center on the following:

• In this rare and aggressive condition, most patients considering HCT are seeking any and all curative options for their illness. HCT is the only curative therapy for myelofibrosis, making it unlikely for them to consent to participation in a non-HCT control group.
• Patients who are ineligible for stem-cell transplantation because of co-morbidities or other illness-related complications are inherently poor controls and, thus, will not provide CMS with the comparative analysis that they seek.
• Eligible patients who opt against transplantation are likely to be a relatively small subset – thus undermining the comparative nature of the trial.
• Most consensus-based clinical guidelines currently recommend transplantation for fit individuals with higher-risk disease or markers indicating more aggressive disease behavior. These guidelines do not use age alone to drive transplant decision-making. They do provide a useful framework for identifying suitable older patients for inclusion in observational studies of HCT that can be powered to understand the outcome of HCT in this age group and to address identification of prognostic factors for outcome.

We would urge CMS to remove the requirement for concurrent non-HCT controls and work with the transplant and hematologic malignancy community to craft a feasible alternative design for a national transplant study in this devastating disease – much like the CED study currently in place for Myelodysplastic Syndromes. We thank you for your attention.

Sincerely,

Laura C. Michaelis, MD
Associate Professor of Medicine
Department of Medicine, Division of Hematology/Oncology
Medical College of Wisconsin, Froedtert Hospital

Camille N. Abboud, MD
Professor of Medicine
Division of Oncology
Bone Marrow Transplantation & Leukemia
Washington University in St Louis Medical School

Ehab L. Atallah, MD
Associate Professor,
Department of Medicine, Division of Hematology/Oncology
Medical College of Wisconsin/Froedtert hospital

Koen van Besien, MD
Director, Stem Cell Transplant Program
Professor of Medicine
Joan and Sanford I Weill Department of Medicine
Weill Cornell Medical College

Jorge Eduardo Cortes, MD
Deputy Department Chair
Department of Leukemia, Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center

Naval G. Daver, MD
Assistant Professor
Department of Leukemia, Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center

Aaron Gerds, MD
Associate Staff
Department of Hematology and Oncology
Cleveland Clinic

Parameswaran Hari, MD, MRCP, MS
Armand Quick – William Stapp Professor of Hematology
Section Head, Hematological Malignancies
Director, Adult Blood and Marrow Transplant Program
Medical College of Wisconsin/Froedtert Hospital

Tsiporah B. Hsore, MD
Associate Directory of Bone Marrow and Stem Cell Transplantation Program
Division of Hematology/Oncology
Weill Cornell Medical School

Elias Jabbour, MD
Associate Professor
Department of Leukemia, Division of Cancer Medicine
University of Texas MD Anderson Cancer Center

Navneet Majhail, MD, MS
Director, Cleveland Clinic Blood & Marrow Transplant Program
Staff Physician, Department of Hematology and Oncology
Taussig Cancer Institute
Professor of Medicine, Cleveland Clinic Lerner College of Medicine.

John O. Mascarenhas, MD
Associate Professor of Medicine
Hematology and Medical Oncology
Mount Sinai School of Medicine
Mouth Sinai Hospital

Ruben A. Mesa, MD
Professor of Medicine
Chair, Division of Hematology & Medical Oncology
Mayo Clinic, Arizona

Stephen T. Oh, MD, PhD
Assistant Professor, Department of Medicine
Division of Hematology
Washington University School of Medicine, St. Louis

Jeanne M. Palmer, MD
Assistant Professor of Medicine
Division of Hematology & Medical Oncology
Mayo Clinic. Arizona

Marcelo Pasquini, MD
Associate Professor of Medicine in the Division of Hematology and Oncology
Department of Medicine, Division of Hematology/Oncology
Medical College of Wisconsin, Froedtert Hospital

Miguel-Angel Perales, MD
Deputy Chief, Adult Bone Marrow Transplantation Service
Director, Adult Stem Cell Transplantation Fellowship
Memorial Sloan Kettering Cancer Center?

Daniel A. Pollyea, MD, MS
Assistant Professor
Clinical Director of Leukemia Services
Division of Hematology, Hematologic Malignancies and Stem Cell Transplantation
University of Colorado Cancer Center
University of Colorado School of Medicine

Uday R. Popat, MD
Professor, Department of Stem Cell Transplantation, Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center

Damiano Rondelli, MD
Michael Reese Professor of Hematology
Chief, Division of Hematology/Oncology
Director, Blood & Marrow Transplant
Associate Director for Clinical Research, UI Cancer Center
University of Illinois Hospital & Health Sciences System

Michael R. Savona, MD
Associate Professor of Medicine
Director, Hematology Early Therapeutics Program
Vanderbilt –Ingram Cancer Center
Vanderbilt University Medical Center

Jerry L. Spivak, MD
Professor of Medicine and Oncology
Director, the Johns Hopkins Center for the Chronic Myeloproliferative Disorders
Hematology Division
Johns Hopkins University School of Medicine

Brady Lee Stein, MD
Assistant Professor
Department of Medicine, Hematology Oncology Division
Feinberg School of Medicine
Northwestern Memorial Hospital

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This letter is written in support of CMS changing its coverage policy in relationship to payment for bone marrow transplant for patients with myelofibrosis. Myelofibrosis is one of many chronic myeloid disorders. CMS has determined that bone marrow transplantation is appropriate in some of the chronic myeloid disorders but not in myelofibrosis. Since these are “overlapping” disorders, with one disorder many times progressing to another, the artificial distinctions that have been used to determine payment should NOT be used to withhold payment for a possibly life-saving therapy.

We request that CMS reevaluate their denial of payments for bone marrow transplantation for patients with some chronic myeloid disorders while paying pay for it for others. Each patient with a chronic myeloid disorder should be offered the benefit of a bone marrow transplant based on the recommendation of the specialist physicians caring for that patient. These physicians know the patient best and will only recommend this therapy when it is absolutely necessary for that individual.

We believe that CMS should change its policy and pay for bone marrow transplants for all patients whose doctors believe it would be a life-saving procedure when the patient has any of the chronic myeloid disorders, and we request that you make this change.

Respectfully,

Richard and Shirley Perkins

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In 2008 [PHI Redacted] was diagnosed with Primary Myelofibrosis. According to her hematologist she was in a low risk category and had a relatively good prognosis. However the first thing her hematologist did was to determine if her either of her two brothers was a suitable match for a stem cell transplant.

It is quite well recognized among the MPN expert community how PMF can progress to the point where, based on diagnostic markers an emergent situation exists, for which a stem cell transplant is the only viable option to save a patient's life.

While research into effective drug therapies for PMF shows promise with some new drugs in the final stages of clinical trials, none of the new drugs are expected to effect what could be thought of as a "cure" but would constitute only a "holding action" against the disease.

So far only the stem cell transplant has demonstrated the ability to cure PMF.

Therefore in the absence of any truly curative alternatives to the stem cell transplant, I would encourage CMS not to deny this life saving treatment to any patients via a concurrent therapy approach but instead continue with the observational study approach of stem cell transplant with aim of improving the outcomes of the procedure.

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The Sarah Cannon Blood Cancer Network (SCBCN) is very appreciative that CMS is trying to provide a pathway to coverage for hematopoietic cell transplantation (HCT) for Sickle Cell Disease, Myelofibrosis and Multiple Myeloma.

The experience of the eight programs in the SCBCN is reflected in the more than 11,000 patients who have received HCT in our centers and the almost 1,000 patients, including over 200 Medicare beneficiaries, we will transplant this year (www.SarahCannon.com).

We believe this proposed decision is important to assure access for Medicare beneficiaries to potentially lifesaving therapy for these diseases. While it is essential to remember that HCT is standard of care, we support the proposed use of Coverage with Evidence Determination (CED) such that Medicare beneficiaries have coverage for transplant if they participate in an approved clinical trial. This mechanism does create additional tracking and reporting burdens, but it has proved very successful for patients with Myelodysplastic syndrome with more than 1400 patients receiving treatment.

We appreciate the intent to provide a pathway to coverage for these three diseases through clinical studies, but the proposed study requirements for Sickle Cell Disease, Multiple Myeloma and Myelofibrosis are different than those required in the myelodysplastic study and will be extremely difficult to satisfy by the transplant community. The primary concern with the proposal is the requirement for concurrent non-HCT controls for these uncommon and life-threatening diseases. As there are no other potentially curative treatment options, it is unlikely patients will consent to participate in a non-HCT control group. Biologic assignment trials in allogeneic HCT are less feasible and less relevant as alternative donor sources are increasingly accepted by the transplant community. Patients who have other factors that render them ineligible for the procedure are likely to be poor controls and will not provide CMS with the comparative analysis that they seek. In the case of Myelofibrosis, those remaining patients that are HCT-eligible but do not elect to pursue transplant will likely be a very small subset within an already limited population.

Our concern is that any proposed coverage mechanism assures that Medicare Beneficiaries have access to HCT as a potentially lifesaving therapy. The experience with Myelodysplastic Syndrome is instructional. The impact of being able to enroll patients in the Center for International Bone Marrow Transplant Research (CIBMTR) observational study has greatly facilitated access to treatment for Medicare beneficiaries and all of our centers participate and submit data on those patients. For a number of reasons, however, only one of our eight centers is participating in the BMT-CTN 1102. Among these are that patients are often initially seen and followed by physicians who refer to our centers so that we do not directly follow them and cannot commit resources for the needed data management. Another is the obvious difficulty in enrolling patients with known poor prognosis in a non-HCT treatment when they are seeking HCT with alternative donor sources as a potentially curative option. BMT-CTN 1102 is open in only 39 centers and presently accounts for only 15% of HCT performed for Medicare beneficiaries. As with Myelodysplastic Syndrome, the diseases under consideration warrant trial designs that assure access for patients and that will advance our understanding of the role of HCT. It is possible we may need to limit these studies to observational trials because of small numbers, the difficulty in finding suitable controls, and the need to provide access to patients.

We understand that these indications are rare diseases that do not fit CMS’s usual model for clinical study designs. We would like for CMS to consider alternate frameworks for rare diseases and low-volume procedures of curative intent, similar to the Breakthrough and Accelerated Approval Processes utilized by the U.S. Food and Drug Administration for orphan conditions. We support the need to understand late consequences of HCT, but in the current proposal, the timeline to accumulate sufficient numbers of patients into these studies and to evaluate the long-term endpoints of interest to CMS will be very lengthy, perhaps decades. Due to this extended timeframe, we need to ensure that patients have wide access to these studies and that the studies are not structured in a way that limits participation to a small group of patients or centers. Broad access to these trials is essential due to ethical considerations in being able to offer the only current potentially curative therapy available to patients with a known poor prognosis.

The non-HCT outcomes of these illnesses are well-known. These are indications that prove fatal within short timeframes or, in the case of Sickle Cell Disease, cause significant morbidity and pain. We understand CMS’s need to demonstrate effectiveness of a therapy in their particular beneficiary groups, but further documentation of well-established and severe or fatal clinical outcomes are unnecessary.

We are asking that CMS remove the requirement for concurrent non-HCT controls and consider other options such as observational study designs, utilizing linkages between the CIBMTR registry and other databases and using identified non-concurrent cohort data sets developed in other trials. We believe this is important to design meaningful studies that will provide the information we all want about HCT in these populations while preserving access to HCT. We want to work with CMS to assure access to Medicare beneficiaries because it is standard of care and we are honored to serve this important population.

Thank you for your consideration,

C. Fred LeMaistre MD
Senior Vice President
Physician in Chief, Hematology
Sarah Cannon

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Dear Ms. Gilbreath ,

As an experienced medical oncologist and Chief Medical Officer of Signal Genetics, I understand the therapeutic challenge for newly diagnosed patients with multiple myeloma with "high risk" features. Their poor outcome with standard treatment modalities including high dose melphalan and tandem HSCT is discouraging, but has prompted a great deal of clinical investigation into a more accurate definition of "high risk" and advanced therapies (including allotransplantaion) with greater promise.

To better understand the clinical utility of allotransplantation in Medicare recipients, CMS has developed a CED Proposed Decision Memo for Stem Cell Transplantation (Multiple Myeloma, Myelofibrosis, and Sickle Cell Disease) (CAG-0444R) in which they request proposals by qualified groups to perform a prospective randomized study comparing Allo SCT or not for newly diagnosed patients at high risk for early relapse and death.

With gene expression profiling becoming one of the accepted standards for defining high risk along with FISH, it seems appropriate to include MyPRSR as one of the metrics required to qualify a patient as high risk. This assay is commercially available at a CLIA, CAP and New York State approved reference laboratory in Little Rock, AR in an extensively validated, highly accurate high throughput assay using robust microarray technology.

I am writing to you and attaching my document on "Improving Patient Outcomes in Multiple Myeloma with Gene Expression Profiling" to obtain your support for including MyPRS as part of the CED study of allotransplantation for high risk Medicare patients. Please don't hesistate to contact me for any additional information.

Respectfully,

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I appreciate that CMS is trying to provide coverage for Medicare beneficiaries with sickle cell disease.
I am the Clinical Director, Division of Blood and Marrow Transplantation and Cellular Therapies at a top 10 Children’s Hospital. I am a clinician researcher and have over 20 years’ experience as transplant physician. We treat children, teenagers and adults with sickle cell disease and want to be able to offer transplantation as a treatment option for their disease.

I encourage CMS to consider removing the requirement for concurrent controls in these clinical studies because it will limit Medicare beneficiary's ability to access this important therapy. For a large number of patients with sickle cell disease, transplant therapy would be transformative, leading to a significant improvement in quality of life and likely prolongation of lifespan. While some areas of transplant therapy should be in the realm of well-designed research trials, there is sufficient existing data on success and safety of transplants in sickle cell disease and this treatment should be broadly available to patients who are eligible, not only inside but outside of clinical trials.

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[PHI Redacted] Saving one life saves an entire world.

It is necessary to consider that allogenic stem cell transplants do have favorable outcomes. In many cases, to deny someone access to the transplant is the same as condemming them to death from their disease.
I would encourage CMS to provide access to all patients when this is the only treatment option, and when their doctor recommends it.
It is not reasonable that research design should result in patients not getting the care they need.

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As a physician with knowledge of the potential benefits for stem cell therapy for many diseases, and as the father of a young man with MPN (Polycythemia Vera), I am concerned about the restrictive nature of the changes you are contemplating.

It would be a grave injustice and likely a tragic waste of valuable lives if the restrictions are maintained as stated.

Participation in all stem cell transplantation clinical studies should be open to all MPN patients. Please be fair to all of us!

Sincerely,

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Dear Center for Medicaid and Medicare Services,

Thank you for the opportunity to comment on the demonstration project that CMS is sponsoring to provide allogeneic bone marrow transplantation coverage for Medicare beneficiaries with sickle cell anemia, myelofibrosis and multiple myeloma. I am a bone marrow transplant physician at Christiana Care Health System and Director of the Blood and Marrow Transplant Program.

Strong data exists as to the benefit of early transplantation in young sickle cell anemia patients. This can be a life altering, lifesaving medical treatment and should be made available to young people with severe sickle cell anemia.

Similarly in adults advanced myelofibrosis is a difficult to treat and noncurable disease with a well-defined natural history. The only curable treatment available today is allogeneic stem cell transplantation. The benefit of this has been proven in younger patients and this benefit should extend to older Medicare age patients as well.

Allogeneic bone marrow transplantation for multiple myeloma is a tantalizing, curable intent therapy, for this grave and as yet incurable hematologic malignancy. While early studies suggest high toxicity including mortality, those that to survive off and go onto long-term disease control. We need to offer this valuable therapy to patients who have limited other choices for treatment.

Finally requiring concurrent controls for these trials is not a requirement in my mind as we well no the natural history of these diseases. Comparison to historical controls should be adequate to determine a benefit and overall survival and disease-free survival.

Thank you for the opportunity to comment on these issues.

Sincerely,

Frank Beardell M.D.
Delaware Clinical and Laboratory Physicians, PA
Helen F Graham Cancer Center
Medical Director, Blood and Marrow Transplant Program
Christiana Care Health System
Wilmington, Delaware

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Allotransplantation for myeloma, myelofibrosis and sickle cell disease is already a proven curative treatment and is routinely covered by most commercial insurance plans. For every transplant indication in patients <65 years old, data now supports efficacy in fit older patients.

Because this is understood by well-informed patients, any requirement for randomization places patients in an untenable position of having to risk not receiving a treatment for their disease recommended by a consensus of expert transplant physicians.

In patients with myelodysplastic syndrome, CMS has already established the (well-founded) precedent of using contemporaneous non-randomized controls to confirm the observations cited above. This precedent should be followed for these newer indications.

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I appreciate that CMS is trying to provide coverage for Medicare beneficiaries with Myelofibrosis and other related blood disorders.

I encourage CMS to consider removing the requirement for concurrent controls in these clinical studies because it will limit a Medicare beneficiary's ability to access this important therapy.

[PHI Redacted] had a bone marrow disorder that affected her blood. [PHI Redacted] Also as an African American, sickle cell disease targets people of my race and any treatment like stem cell transplantation that may help people with this disorder is always a good thing

I want to ensure that stem cell transplants are an option for ALL MPN patients.

Thanks for the opportunity to comment

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I appreciate that CMS is trying to provide coverage for Medicare beneficiaries with Sickle Cell, Myelofibrosis, and Multiple Myeloma.

I am a physician at City of Hope National Medical Center. We treat patients with these diseases and want to be able to offer transplantation as a treatment option for their disease.

I encourage CMS to consider removing the requirement for concurrent controls in these clinical studies because it will limit Medicare beneficiary's ability to access this important therapy – which is the only known curative approach for the diseases above. While there are other treatment options available, limiting the access to the curative modality will adversely impact the patients' overall prognosis and well being.

Sincerely,

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On behalf of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), we want to thank CMS for reconsidering expansion of the national coverage determination for allogeneic transplantation to include multiple myeloma, sickle cell disease (SCD) and primary myelofibrosis (PMF). This thoughtful reconsideration is warranted given the improvements in transplant-related mortality, especially in older adults, afforded by new strategies for pretransplant conditioning and prevention of graft-versus-host disease (GVHD), and given the curative potential of allogeneic transplantation.

We understand and support CMS’s desire to fund these transplants in the context of studies designed to assess their benefit in the population it serves. As a National Institutes of Health-funded multicenter clinical trials group focused on blood and marrow transplantation, we are committed to designing, implementing and completing clinical studies focused on improving outcomes of transplant recipients and on elucidating the role of transplantation in life-threatening blood disorders, both cancer and non-cancer.

Financial barriers are an important problem for patients considering enrollment on BMT CTN trials. Lack of CMS coverage for allogeneic and sequential autologous transplantation in multiple myeloma prevented many older patients from enrolling on two large BMT CTN trials evaluating the role of allotransplantation and post-transplant consolidation in myeloma. This precluded assessing data in a large sample of the Medicare-eligible population (only 97 patients on those two studies, which enrolled a total of 1468 patients, were over the age of 65 years, although the median age of newly diagnosed myeloma patients is 69). We would welcome a change in policy that would ensure that Medicare patients have the same opportunity as others to participate in these national studies.

That said, we are concerned that some of the language in the draft decision memo will either not alleviate or, in fact, may increase the barriers to clinical trial participation faced by Medicare beneficiaries. The requirements that eligible studies include a concurrent control group and that the focus be primarily on survival are the most problematic, for several reasons.

1. High risk multiple myeloma (the situation where allogeneic transplantation is performed), SCD, and PMF are rare diseases, making it difficult, sometimes impossible, to enroll sufficient numbers of patients to clinical trials, even to single arm trials. It took the BMT CTN six years to enroll 30 patients to a single arm Phase II trial of allogeneic transplantation for children with severe SCD, despite the participation of multiple centers. Requiring concurrent controls will make it substantially more difficult as discussed in #2.

2. The decision to undergo HCT is a complex process for patients with diseases that can be palliated but not cured with non-transplant therapy. It requires accepting the risk of an earlier death from transplant-related mortality in exchange for a chance at cure. Once physicians and patients accept the idea of a curative therapy, despite its risks, they often are unwilling to accept non-curative treatment (standard of care) when a suitable donor is available. With the broad array of acceptable donor sources currently available, most patients will have such a donor.

3. It is not possible to have one trial design for Medicare beneficiaries and another for non-Medicare beneficiaries in rare diseases such as these. Given the limited patient populations, trial designs that maximize timely accrual must be selected – this means that single arm trials will often be preferred, thereby preventing access to Medicare beneficiaries. The BMT CTN recently launched a Phase II trial of allogeneic transplantation for high risk myeloma that evaluates novel conditioning and posttransplant and maintenance therapies to improve disease control, the major obstacle to treatment success in this disease group. We would like to extend this trial to Medicare beneficiaries but they would not be eligible under the current language. Similarly, we will soon launch a Phase II trial of haploidentical transplantation in young adults with severe SCD that tests a regimen with a very good safety profile in other settings; Medicare beneficiaries would not be eligible. Both of these trials have been peer-reviewed by the medical and scientific community and judged to be ethical, safe and important. Medicare beneficiaries should have access to these trials.

4. Fortunately, the natural histories of high risk myeloma, SCD and PMF are well known, as are risk factors for mortality with nontransplant therapy, making it possible to assess the results of transplantation in relation to standard of care. Each of the trials noted above specifically discusses what level of success would warrant considering the therapy a “success” given what we know about these natural histories. Two examples of data collections that would be useful, even if not concurrent, for the purpose of benchmarking “success” include data being collected in a large (target n=660), NCI-funded multicenter trial of early versus late autotransplant in myeloma (Principal Investigator, Paul Richardson, Dana Farber Cancer Institute) and in longitudinal cohort studies of SCD (Steinberg MH, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5 year follow-up. Am J Hematol 85 (6): 403-408, 2010.)

5. The nature of transplantation as a therapy is that most of the risk of death from the procedure occurs early, followed by a survival plateau. This contrasts with nontransplant therapies for these diseases where mortality from treatment may be low but the risk of death from the disease is continuous. Evaluations that focus on early and intermediate survival outcomes will often fail to appreciate the long-term value of transplantation.

6. With regard to multiple myeloma, failure to allow autologous transplantation as a potential comparator therapy ignores a commonly used and accepted therapy for which CMS already provides reimbursement and a situation where concurrent experience would be available through the Center for International Blood and Marrow Transplantation’s (CIBMTR) outcomes registry.

7. Finally, restricting coverage to patients enrolled in trials with concurrent controls prevents use of the CIBMTR outcomes registry for evidence development, a powerful tool for amassing a critical mass of data with which to evaluate the outcomes of transplantation in rare diseases. Even if we were able to open trials with concurrent controls in each of these situations in the BMT CTN, only a minority of potentially eligible patients would have access to a participating center, thereby perpetuating disparity in access and losing valuable information that would further our understanding of this therapy. The power of the CIBMTR in providing high quality data on transplant recipients in subgroups of interest has been demonstrated in the current CIBMTR CED study of transplantation for Myelodysplastic Syndromes (MDS), which has collected data for more than 1200 transplant recipients older than 65 years from more than 100 centers over the last five years, starting just a few months after CMS’s MDS decision memo. This contrasts with BMT CTN 1102, a biologic assignment trial that took two years to develop and activate and which compares HLA-matched transplantation with nontransplant care. This study has collected data on only 70 patients older than 65 years over the past two years, accounting for less than 15% of the MDS transplants done in Medicare-eligible patients during this period, despite activation in 35 transplant centers. Additionally, this trial is encountering difficulties in enrollment because patients with known poor prognosis are seeking transplantation with other donor sources.

In summary, we strongly urge CMS to not limit the design of trials that will merit reimbursement for transplantation of multiple myeloma, SCD and PMD but instead, as was the case for MDS, to accept a variety of trial designs, including cohort studies through the CIBMTR, that will advance our understanding of the role of allogeneic transplantation in these diseases and optimize transplantation outcomes. Such an approach will avoid disparity in access to curative therapy and speed the progress of research that will benefit our patients.

- Mary M. Horowitz, Frederick R. Appelbaum, Steven Devine, Richard J. Jones, Adam Mendizabal, Dennis L. Confer, on behalf of the Blood and Marrow Transplant Clinical Trials Network

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I appreciate that CMS is trying to provide coverage for Medicare beneficiaries with Sickle Cell disease, Myelofibrosis, and Multiple Myeloma.

I am a Salil Goorha, MD at Batist Cancer Center in Memphis, TN. We treat patients with these diseases and want to be able to offer transplantation as a treatment option for their disease.
I encourage CMS to consider removing the requirement for concurrent controls in these clinical studies because it will limit Medicare beneficiary's ability to access this important therapy.
If concurrent controls are mandated in these clinical studies, some patients will not be allowed to undergo the stem cell transplant procedure. Very few patients will want to enroll into a clinical study in which they will not be allowed to undergo the stem cell transplant procedure, because this treatment is the standard of care for these diseases. Because most patients will want to enroll in these studies, we will not be able to understand the role of stem cell transplant in the treatment of these disease.
I would urge any person considering implementing these proposals to put themselves in the position of a patient with one of these diseases. Would you enroll yourself in a study where there is a strong possibility that you would not get the standard of care treatment?

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Thank you for considering Coverage with Evidence Development (CED) for allogeneic stem cell transplantation and for providing this opportunity for public comment.

CED can be a powerful and valuable tool for collecting effectiveness data and informing future clinical and coverage decisions. I applaud CMS for proposing CED to provide Medicare Beneficiaries access to potentially effective, and possibly life-saving, therapies.

Stem cell transplantation is a rapidly growing and evolving field. Stem cells can be derived from multiple sources, such as bone marrow, cord blood, and peripheral blood. There may also be differences in technique, cell concentration or formulation. It will be beneficial, and possibly critical, for CMS to accept numerous CED protocols, and to be prepared to differentiate between protocols when the final published data is analyzed.

Many of the public comments posted to date from experts in the field have pointed out the challenges associated with concurrent controls. Concurrent or prospective controls are the gold standard for efficacy studies in tightly defined, even exclusive, patient cohorts. In real-world effectiveness studies, concurrent controls can present challenges, and even prevent access, for patients selected to be in the control group. I encourage CMS to be less prescriptive in the final NCD memo regarding the study design. Provide guidance, and reserve the right to approve or deny protocols, but allow sponsors the ability to present alternatives that could be more effective and may provide more inclusive access.

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November 18, 2015

Re: CAG-00444R Proposed Decision for SCT

Dear CMS,

The Stanford Blood & Marrow Transplant Program has performed over 5,800 transplants since being founded in 1987. In fiscal year 2015 we performed 359 transplants, of which almost 10% were for patients with Medicare as their primary coverage. As a part of the NCI-designated Stanford Cancer Institute, our program seeks to advance the science of hematopoietic cell transplantation while providing high quality care for our patients.

It was with great interest that we read the Center for Medicare Services "Proposed Decision Memo for Stem Cell Transplantation," which addresses coverage of allogeneic hematopoietic cell transplantation for patients with multiple myeloma, myelofibrosis and Sickle Cell Disease. In 2010, CMS approved a CIBMTR HCT study for Medicare patients with M DS, which allowed coverage of this treatment for Medicare patients who participate in the trial. The Coverage with Evidence Development (CED) for allogeneic HCT for MDS has allowed over 1,400 Medicare patients to undergo this potentially lifesaving treatment, an accrual number that will provide important information regarding efficacy in this patient population.

Unfortunately, the newly proposed CED differs significantly from the successful model of the MDS CED. The requirement of concurrent, non-HCT controls causes great concern, and would severely hamper access to care and the ability to accrue sufficient numbers of patients to these studies.

While we are very encouraged by the CMS proposed decision to allow coverage for allogeneic hematopoietic cell transplantation for multiple myeloma, myelofibrosis and sickle cell disease under a CED, we ask that you remove the requirement for non-HCT control arms and instead follow the successful model of the MDS CED.

Sincerely,

Robert S. Negrin, M.D.
Professor of Medicine
Chief, Division of Blood and Marrow Transplantation

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To the good folks who make decisions re our Medicare coverage. Myelofibrosis is a terrible disease that impacts, for the most part, the elderly. In many instances, the elderly are more so than others, unable to help themselves. There are a very few organizations that are now doing extensive research with the hope of finding a cure, as there is non now and hopefully, at some point, prevention.

I would hope and encourage CMS to consider removing the requirement for concurrent controls in the clinical studies as by not doing so will limit Medicare beneficiaries ability to access this very important therapy.

We very much appreciate the efforts CMS is making in its attempts to provide coverage for Medicare patients with this terrible disease. Thank you.

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Thank you for considering including SCT for Myelofibrosis. THis bveneifit is critical to many patients. However, I would like to comment that the requirement to remove the requirement for concurrent controls in these clinical studies. During thecourse of the disease, a patient may suddenly have a significant turn of the disease into actual leukemia. When this condition occurs, there is very little time for the patient and the prognosis is very poor without an SCT. The timing of the SCT is critical to saving the life of the patient. Taking the time to find a study in which they could enroll could easily exceed the benefit of the SCT. This would additionally put undo stress on to the patient and caregivers. As well as potential travel costs to the study center, which may be very far from the patient home. Also, it would be recommended to cover SCT for all Myeloproliferative Neoplasms, which include PV, ET, MF and CML. [PHI Redacted]

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[PHI Redacted] I appreciate that CMS is trying to provide coverage for Medicare beneficiaries with MF. [PHI Redacted] I am concerned that the requirement for concurrent controls in these medical studies will end up limiting the access to this important treatment for Medicare patients [PHI Redacted] As you may or may not know, MF is usually not diagnosed until around the age of 60, so it hits older patients disproportionately. This makes it even more important that Medicare beneficiaries have every opportunity to access stem cell treatments, currently the only potential cure available for this disease which inexorably leads to leukemia and death. [PHI Redacted] died from MF in 1977, before stem cell treatments were available. [PHI Redacted] I beg you not to limit access to stem cell treatments in anyway. Thank you.

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Thank you for listening,
Francey

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[PHI Redacted] I fully support expanded coverage, but urge the Agency to find a reasonable way to conduct the research. It is not fair for some patients to be told that they cannot access a life-saving transplant while other patients can access them simply to evaluate the efficacy of the transplant, when there is clear evidence in younger groups of people of its success and we know the outcome of not obtaining a transplant.

I'm asking you to provide access to all beneficiaries for whom a life-saving transplant is the only treatment option, when their doctor believes it is the most appropriate treatment option.

Research design should not result in patients not getting the care they need.

Thank you for your time and consideration.

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Dear CMS,

I am writing to comment on the recently announced Proposed Decision Memo for Stem Cell Transplantation (Multiple Myeloma, Myelofibrosis, and Sickle Cell Disease). As a hematologist with more than 25 years of transplant experience who trained at the NIH, I welcome your goal of better characterizing the risk and benefits associated with allogeneic transplantation for these three diseases. Based on quite extensive literature and my experience, I believe there is good evidence that this type of transplant provides the only potential cure for myelofibrosis and sickle cell disease - but that outcomes could and should be better characterized between transplant and other therapies. I am concerned that under the proposed guidelines any patients to receive CMS support for transplant will need to be in a randomized trial. Does this mean that every site or several sites will need to establish such trials? This would seem to require vastly more resources than should be required to answer your proposed questions. As an alternative, I would propose CMS working with the transplant community to establish a multi-center trial that will be able to address the questions with sufficient power to provide conclusive answers, while allowing other centers, not specifically in the trial, to continue to transplant patients based on their best judgment and the current published data until the definitive results are received.

I would also like to raise the issue that the proposed questions may not be the most appropriate. For example, there is no question that, by definition, patients who undergo transplant will have a higher frequency of GVHD and other transplant related adverse events. More important indicators of whether transplant provides better quality of care might be QOL, performance status, subsequent hospitalizations, etc. as compared for transplanted and non-transplanted patients.

Thank you very much for the opportunity to comment. Please let me know if I can provide further input.

Sincerely,

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I would like to first commend CMS for looking to extend the coverage for MM, MPS and sickle cell. Each of these has substantial data that suggests benefit in appropriate patients. Frequently however this potentially curative option is limited due to lack of coverage. At our center we see a significant amount of MF who are transplanted. For patients with MM, we like most centers typically perform an autologous transplant however for younger patients or those who may have already failed an autologous transplant this is an important potential therapy. We don't see much SCD but there has been a huge shift in the utility and it again remains the only curative therapy for this disease.

Although this is an important first step the use of concurrent controls in my view might be extremely difficult and will delay our ability to determine outcomes. The difficulty is that the patient numbers are very small and make such studies very difficult to complete.
In MF this is the only known curative therapy for those with aggressive disease who are more likely to be transplanted. I can't think of a good ethical control that would now be acceptable given our current ability to find donors for virtually all patients.
In SCD most patients will be identified early when the toxicities are lower and again there is no good control available.
Finally for MM the patient numbers are much higher, however the number who we would consider for allogeneic transplant are very low. Once again given that they have often already failed conventional therapy including autologous transplant it will be difficult to find an appropriate control.
I currently have a younger patient who has progressed with virtually all therapy to date. He is someone who we are considering allogeneic transplant at the present time.

In addition although the majority of private insurers currently cover MF. the decision by CMS would set the table for the remainder as well as for SCD and MM.

It would be reasonable (and should be mandatory) that all such patients have their results collected by the CIBMTR so that the results can be reviewed by CMS as has been done for MDS. We and the majority of the transplant community, already report virtually all our patients to the CIBMTR (unless a patient does not provide consent). A requirement however would allow clear documentation of the results to the medical community.
Again I appreciate your consideration and urge you to quickly include NHL in this group.

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Stem Cell Transplant is the only potentially curative therapy for Myelofibrosis. SCT has proven effective at extending patient life and even eradicating disease. In the case of Myelofibrosis, patients both over and under 65 have benefited significantly from transplants. For Medicare to deny transplant coverage for MF robs a significant cohort of patients of their only chance of survival. In addition, MF often progresses to Acute Myeloid Leukemia, a disease which carries an even worse prognosis. If MF patients on Medicare must wait until they progress to acute leukemia before receiving a transplant, their chances of survival become miniscule. It makes little sense to refuse transplant coverage to patients at a stage in their disease where a positive transplant outcome is far more likely.

Moreover, this lack of coverage makes no sense given the exorbitant price of the only FDA-approved drug therapy for MF, JAK inhibitors, which cost insurance companies thousands of dollars per month while only alleviating symptoms. If a Medicare patient to whom transplant is not available is treated with JAK inhibitors for multiple years (as is often the case), insurance will ultimately pay hundreds of thousands of dollars similar to the cost of a transplant for treatment that does not cure the disease. If transplant coverage were granted to MF patients, Medicare would be investing money in a cure rather than a band-aid.

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Concerning MYELOMA ONLY. I am very pleased that CMS is reviewing the NCD for allogeneic transplants for myeloma patients. I began this advocacy on behalf of [PHI Redacted] who is a myeloma patient. It is imperative for CMS officials to consider carefully the issues of concern submitted by transplant physicians, hematologists, the National Marrow Donor Program and other stakeholders regarding, in particular, the requirement for "concurrent non-HCT controls" which will severely hinder the ability to accrue patients. And, since the non-HCT outcomes are well-known, further documentation of well-established and severe or fatal clinical outcomes is unnecessary. Myeloma is a rare disease that does not fit the usual model for clinical study design, so an alternate framework for this rare disease is necessary.

I respectfully submit the above remarks as a member of the "lay" community in an effort to lend support to the professionals who are submitting specific clinical comments for consideration. Thank you.

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I understand that CMS is trying to provide coverage for Medicare beneficiaries with Sickle Cell, Myelofibrosis, and Multiple Myeloma. I am so pleased for this consideration.

I am a Nurse Practitioner at Hackensack University Medical Center in NJ. We treat patients with these diseases and want to be able to offer transplantation as a treatment option for their disease. The literature shows transplant is a reasonable option for these patients and can offer cure or long-term control.

I encourage CMS to consider removing the requirement for concurrent controls in these clinical studies because it will limit Medicare beneficiary's ability to access this important therapy. This therapy should be accessible for all patients with these conditions, not just patients with private insurance. Thank you

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November 12, 2015

Centers for Medicaid and Medicare Services
Department of Health and Human Services

To Whom It May Concern:

We applaud the Centers for Medicaid and Medicare Services (CMS) for addressing the need to provide Medicare coverage for transplants through approved clinical trials. However, we believe the concurrent non-HCT control requirements would actually impede a patient's ability to participate rather than improve their options for transplant, which is clearly the agency's intent. Finding patients who would be eligible to participate in the clinical trial, and have elected not to pursue a transplant would be unlikely.

On behalf of the myeloproliferative neoplasm (MPN) community, and the myelofibrosis (MF) patients and their families, we are deeply concerned about the concurrent non-transplant control requirement in the CMS proposed rule to allow Medicare coverage for MF patients participating in approved clinical trials for allogeneic cell transplants (HCT). This proposed rule also applies to Sickle Cell Disease and Multiple Myeloma.

For many MF patients, a transplant may be their only option for survival. In addition, patients who are not eligible for the transplant for other reasons, would be poor controls and would not provide the CMS with the comparative analysis required. Even more difficult would be the ability to evaluate long-term results given the narrow scope of participants the proposed rule would create. Furthermore, many patients cannot overcome the additional obstacles participation in a clinical trial can create. For example, extra financial encumbrances, geography - or travel to trial sites, work schedule conflicts, and fear of the unknown.

We strongly urge the CMS to remove the concurrent non-HCT control requirements as part of the proposed rule for Medicare coverage of HCT. Our patient community deserves options that are viable and accessible.

Please consider amending this rule. Quality care and access to all treatment options available should be obtainable without restrictions.

Respectfully,

Ann Brazeau
CEO and Founder
MPN Advocacy & Education Int'l

Barbara Van Husen
President
MPN Research Foundation

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As the Director of Pediatric BMT at center committed to working with patients affected by Sicle Cell Disease, I am deeply concerned about the proposal that before CMS will pay for a transplant in sickle cell disease, the health care providers would be required to have a control group that was developed at the same time.

Those of us who have worked with patients and families afflicted with this disease, have seen first hand the natural evolution of this disease without curative BMT. Many patients have been cured from this debiliating disease via BMT and will attest to the reasons they opted for BMT. They wanted a cure, and weighing the risks and benefits of BMT, they wanted a chance to live free of the disease and a chance to achieve normal life expectancy. As you know, the life expectancy of someone with this disease is still significantly compared to the life expectancy of the average American.

The proposed requirement would essentially create a two tiered system for individuals with sickle cell disease. One in which the patient could only get a transplant if the institution had set up a control group and would apply only to those receiving public health insurance. The second standard of care would be for patients with private insurance where the payers recognize the life threatening and debilitating nature of the disease.

In the group of patients with private insurance the health care provider would allow for the only curative therapy to be undertaken.

On behalf of over 300 children affected with sickle cell disease at my center, I strongly object to the CMS recommendation of requiring a concurrent control group for sickle cell disease bone marrow transplant trials. This is not the case for life threatening cancers or immune deficiencies or metabolci disorders, where transplant is the only viable option and should not be the case for sickle cell disease.

I strongly reject the CMS plan for the poorly thought out future policy that will further fragment health care for this high risk and vulnerable SCD population.

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I appreciate that CMS is trying to provide coverage for Medicare beneficiaries with [Sickle Cell, Myelofibrosis, and Multiple Myeloma].

I am a bone marrow transplant physician and clinical researcher at Tufts Medical Center in Boston. Our center treats patients with these diseases and want to be able to offer transplantation as a treatment option for their disease.
I encourage CMS to consider removing the requirement for concurrent controls in these clinical studies because it will limit Medicare beneficiary's ability to access this important therapy. This therapy is potentially curative.

Thank you very much.

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I appreciate that CMS is trying to provide coverage for Medicare beneficiaries with Sickle Cell disease, Myelofibrosis, and Multiple Myeloma. But I have some concerns about options that may be curtailed with the current wording of these documents.

I am concerned that the current recommendations will limit access to hematopoietic cell transplantation - a life-saving and potentially curative treatment for these conditions. I encourage CMS to consider removing the requirement for concurrent controls in these clinical studies because it will limit Medicare beneficiary's ability to access this important therapy. As an Infectious Diseases physician, I have seen many patients experience major benefits to such treatment - and data strongly supports these options.

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[PHI Redacted] with Primary Myelofibrosis. At this point in time, and for the foreseeable future, SCT is the ONLY cure. I applaud your consideration of Medicare coverage for this procedure. However, the requirement that Medicare will pay for an SCT only if the patient is part of a clinical trial will rule out the vast majority of potential candidates for this life saving procedure. Rural patients in particular can rarely participate in clinical trials because of the expense and logistical obstacles. I am not aware of any ongoing or proposed clinical trials for SCT vs non SCT patients.. and indeed given that HCT is the only cure, such a trial would be ethically dubious.

Of course, the public (via Medicare) should only pay for procedures that have been proven to have a good chance for success. To that end, I would suggest that there have been many SCTs performed for patients with Myelofibrosis over the past. An rigorous epidemiological study of past cases would determine the efficacy of the procedure. It would be more timely and just as likely to yield useful results.

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I am requesting that CMS include consideration of Health Care Service Corporation (HCSC) medical policy coverage positions in its review of public comments on proposed coverage of the three relatively rare conditions referenced above.

HCSC, a Mutual Legal Reserve Company, has 15+ million members in 5 Blue Cross Blue Shield (BCBS) plans (TX, IL, OK, NM, MT) that are Independent Licensees of the Blue Cross and Blue Shield Association.

HCSC has conditional coverage of allogeneic transplant for all three conditions in the following pertinent medical policies:

All HCSC medical policies are available on the internet. They can be accessed on the Blue Cross Blue Shield of Texas (BCBSTX) website: bcbstx.com/provider

I would also like to add support for comments from the Center for International Blood and Marrow Transplant Research (CIBMTR), in particular study design issues related to requirements for non-HCT controls.

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Myleofibrosis stem cell transplant should be allowed without major restrictions if patients QOL is significantly affected and they're unable to work due to disease symptoms. Why would you want patients to suffer with symptoms and poor QOL especially of they're diagnosed much younger than the standard 60? Why make them feel like a constant burden to society because they are no longer able to work? Besides medical statistic data in your decision making process where's the human data? Do you think patients rest easy knowing theyre totally dependent on society at a significantly lowered pay? At a time when medical costs increase substantially, social security disability pay is low, you want to hit patients with "oh btw the only cure for you we won't cover". How about you include patients in your decision making process. Did anyone calculate the long term cost to the social security disability and Medicare system for someone originally diagnosed at 40? I suspect that cost far outweighs partial contribution to SCT. In addition, your restriction of it being tied to a clinical trial, managing a clinical trial is not cheap was the increased cost considered? Why not make exceptions if patients have an existing policy that covers some that Medicare allow supplemental coverage? You could easily require the facility to provide all statistical data instead of making patients find a clinical trial. There's so much more that you can do for patients, payients would rather not need the SCT . Not only do Patients have to battle symptoms everyday, They also have to battle for coverage of potential treatments and cures. Thanks for listening.

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Dear CMS:

As a CEO of Sickle Cell Disease Association of Tennessee [PHI Redacted], I am deeply concerned about the proposed edict that before CMS would pay for a transplant in sickle cell disease, the investigators would be required to have a control group that was developed at the same time. We have multiple individuals in our community based organization that have received a bone marrow transplant and have provided counseling and services before and after a transplant. The proposed requirement would essentially create a two tiered system for individuals with sickle cell disease. One in which the patient could only get a transplant if the institution had set up a control group and would apply only to those receiving public health insurance. The second standard of care be for patients with private insurance where the payers recognize the life threatening and debilitating nature of the disease, particularly for the adults, and would allow for the only curative therapy to be undertaken.

On behalf of over 1500 individuals affected with sickle cell disease living in the state of Tennessee, we strongly object to the CMS recommendation of requiring a concurrent control group for sickle cell disease bone marrow transplant trials. This is not the case for life threatening cancers where transplant is the only viable option and should not be the case for sickle cell disease. Respectfully, Trevor Thompson

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To whom it may concern:

I think it is very commendable that the CMS staff have taken significant time and effort to address the lack of coverage for Sickle Cell Disease and curative bone marrow transplantation. Allowing coverage to participate in a trial with transplant and control patients is quite attractive and in theory should answer questions about the benefit adults with sickle cell disease undergoing transplantation get compared to those who do not. Setting up such studies are very challenging, especially in sickle cell disease and takes a lot effort and time investment from investigators to ensure enrollment in treatment and controls arms (patients tend to not want to participate if they do not have a transplant donor option). This has lead to investigators then testing more innovative transplant approaches that may have even better outcomes than previously published without a control arm. In the case of the NIH's own trials, quite exciting results were published in the New England Journal of Medicine in 2009 (Hsieh et al, NEJM 2009) and Journal of the American Medical Association (Hsieh et al, JAMA 2014) with an 87% cure rate in adults with sickle cell disease and no control arm. Such a trial would not be able to be done nowadays outside of the NIH (insurance coverage not an issue for NIH participants), and a restriction of needing a control arm for non-NIH run studies means progress will be extremely slow and the majority of patients will be left without a transplant option thus meeting the expected early mortality.

As one multicenter trial of sickle cell disease with a control arm is already underway (STRIDE), and we will have the information as how transplant compares to non-transplant as well as modern data on a control group that other transplant trials can compare to, I encourage CMS to allow insurance coverage for participants in all transplant trials for sickle cell disease even those without a control arm. This will allow the field to continue to move forward, since newer and possibly better approaches to transplant can be tested simultaneously. This model has certainly been done for other diseases and sickle cell disease care stands to substantially benefit.

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The proposal to limit CMS-approved coverage for stem cell transplantation in sickle cell disease to participants in prospective clinical trials that include concurrent non-transplant controls will effectively constrain access to this curative therapy. There is comprehensive and compelling evidence of a clinical benefit of transplantation in recipients of all ages who have severe disease manifestations. A sickle cell disease clinical trial comparing transplant and non-transplant concurrent controls has never been performed, and the only such trial ever proposed and supported by NIH funding has not yet commenced. Despite this limitation, there have been a number of reports over the past 20 years showing that successful transplantation halts sickle related complications, and in children, confers a survival probability that does not appear different from survival in children who receive standard supportive care. Restricting access to a curative therapy in a disorder for which supportive care has not extended lifespan cannot be supported. I believe that CMS-approved coverage should be extended to all persons with sickle cell disease who have severe symptoms, and that central registries in combination with prospective clinical trials with or without concurrent non-transplant controls should be monitored for trends in utilization, outcomes, and refinement in the definition of the optimal application of this treatment, which together might be used to guide CMS coverage in the future.

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The Centers for Medicare and Medicaid Services (CMS) has proposed Medicare coverage for allogeneic hematopoietic cell transplant (HCT) for patients with three indications: (Multiple Myeloma, Sickle Cell Disease and Myelofibrosis), provided they participate in an approved clinical trial, similar to current HCT coverage for patients with MDS. However, as proposed, concurrent non-HCT controls are problematic for the following reasons:

Requiring concurrent non-HCT controls which will severely hinder the ability to accrue patients. Concurrent controls are highly problematic for these indications, due to their rarity and severity. Most patients will be seeking any and all curative options for their illness, making it unlikely for them to consent to participation in a non-HCT control group. Biologic assignment trials in allogeneic HCT are less feasible and less relevant as alternative donor sources are increasingly accepted by the transplant community. Patients who have other factors that render them ineligible for the procedure are likely to be poor controls and will not provide CMS with the comparative analysis that they seek.

The non-HCT outcomes of these illnesses are well-known. These are indications that prove fatal within short timeframes or, in the case of SCD, cause significant morbidity and pain; further documentation of well-established and severe or fatal clinical outcomes are unnecessary.

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Please reconsider the requirement of concurrent non-HCT controls when conducting these trials. There is much evidence already which supports the notion that survival of these diseases is not conducive without a transplant (ie: a new immune system) because their current immune system has failed. In the case of SCD, the patient is doomed to live a life full of pain, complications, limitations and numerous set-backs that impact personal growth and development, economic flourish, education, advacement and ultimately that person's potential contribution to the work force. They need transplants, too, to live to their full potential. In addition, there is some ethical debate about asking if a patient would be willing to forego transplant and instead be treated as a control for research, when enough evidence already exists to say that transplant is the only curative option. Others who are not candidates for transplant will have confounding variables that will make them poor controls. Please reconsider. Graciously: Brennan M. Parmelee, MSN, RN, CPN, CNE

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Although I do appreciate Medicare's requirements regarding the study process for the above three disease catagories, I would just like to remind the study investigators that "one size does not fit all." Having a diagnosis of any cancer is devastating, however Multiple Myeloma, Myelofibrosis & Sickle Cell Disease are exceptionally dreadful in that the current "standards of care" are only temporary fixes and we need to find something else that may very well offer these patients hope for cure or at least longer disease free survival. Especially for children with sickle cell. I would also like to remind you that it is not possible to have non-HCT controls for these three diseases because it would not be ehtical or in the best care of the patient to do that.

[PHI Redacted] But when someone is diagnosed with a fatal disease it is our duty to be able to offer them the best care possible and the only way to do that is through research. So I implore you to please work with the NMDP to find a reasonable way to help this group of patients and please also remember when devising your study plan that "one size does not fit all" - thank you.

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I am delighted that CMS is providing coverage for these 3 important diseases, I am concerned about the requirement for concomitant controls. In my view it is almost impossible to obtain valid control populations since few patients will be willing to be randomized. This is made particularly acute by a change in transplant practice in the last few years. Previously we can do a donor/no donor analysis which allowed us to use patients without histocompatible donors as suitable controls. While this approach had limitations and opportunities for bias it did allow a reasonable estimate of the relative benefit of transplantation. The new immunizations or the use of cord blood transplantation and haploidentical transplantation. This means that there are essentially no patients For whom there are no donors rated thus to identify a no donor cohort would require analysis of patients who are too old or too sick For transplantation thus providing a very poor control population. It is highly unlikely that patients with a known fatal disease with a known curative alternative will consent to be randomized. I think it is highly likely that we can obtain similar data using non-concurrent cohort populations or other observational study designs. While these alternatives have limitations with proper statistical analysis I think they can provide adequate information regarding nontransplant therapy.

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At Johns Hopkins, we only perform allogeneic blood or marrow transplantation (alloBMT) for myeloma, myelofibrosis, and sickle cell anemia on prospective clinical trials aimed at improving outcomes. We have worked closely with our local CMS carrier concerning our alloBMT clinical trials in sickle cell anemia and myelofibrosis, diseases on which CMS has been “silent” regarding coverage for alloBMT. Based on these interactions, the local carrier has chosen to cover alloBMT trials in these diseases. We periodically update our local carrier on the progress of these trials, which have established new standards of care relating to BMT in hematologic malignancies and sickle cell anemia. These interactions have facilitated important published scientific advances, such as demonstrating that all sickle cell anemia patients now have access to safe and effective alternative donor BMT that can cure the majority of patients. These trials have also found that this life-altering procedure can be performed at a life-time cost under $200,000, far less than the non-transplant costs of sickle cell anemia.

I fully support and encourage a proposal that such transplants only be covered on CMS-approved prospective clinical trials aimed at improving outcomes. However, I also believe requiring concurrent non-transplant controls will actually have the unexpected consequence of slowing progress toward improving such outcomes. Concurrent non-transplant controls essentially would be comparing “apples and oranges”: i.e., since alloBMT is currently the only curative approach for these diseases, the comparison would be curative therapy against non-curative therapy. Accordingly, how would a result showing an 80% cure rate but an associated 10% mortality be compared against a non-transplant approach associated with a 100% five- year survival but with persistent life-threatening symptoms? Further, the real questions regarding alloBMT for these diseases - whether it can be done safely and cost effectively – cannot be answered with comparisons against non-curative approaches. Finally, patients rarely join studies comparing curative and non-curative therapies, because the comparisons are contrived as just discussed. Thus, not only will progress toward cures be slowed, but patients interested in curative therapy will also be denied access. Shouldn’t informed patients have the ability to make a decision about the relative risks and benefits of a potentially curative approach with some toxicity versus a non-curative approach with life-threatening complications, especially when the curative therapy is likely less expensive in the long run? Clinical trials will be critical toward informing these decisions, but not if they can’t be successfully carried out as a result of a requirement for concurrent non-transplant controls.

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I have read your decision regarding myelofibrosis transplants.
I do not follow your logic. If myelofibrosis morphs into AML,it is. covered. At that point the patient is very sick and chances of a good outcome are low.
I am thankful that you pay about $240,000a year for Jakafi and Thalomid. tHese drugs arenot a cure and it is money not well spent. Why not spend a $500,000fora transplant thAt would give [PHI Redacted] His life back? iF docs feel this is viable, how can you play GOD?
[PHI Redacted] pLease find a way to HELP

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