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View Public Comments for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers (CAG-00451N)

Commenter:
Amoroso, Michael
Title:
Senior Vice President and Head of Worldwide Commer
Organization:
Kite Pharma
Date:
03/17/2019
Comment:

SUBMITTED ELECTRONICALLY

March 15, 2019

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services (CMS)
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell therapy for Cancers (CAG-0045IN)

Dear Ms. Syrek Jensen:

Kite Pharma (Kite), a Gilead Company, appreciates the opportunity to submit comments to the Centers for Medicare & Medicaid Services (CMS) in response to the proposed national coverage determination (NCD) for chimeric antigen receptor (CAR) T-cell therapy for cancer. Kite is engaged in the development of innovative cancer immunotherapies, in particular, CAR and T-cell receptor engineered cell therapies. Kite manufactures YESCARTA® (axicabtagene ciloleucel), the first Food and Drug Administration (FDA) approved CAR T-cell therapy for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (transformed follicular lymphoma, or TFL). YESCARTA is currently also being evaluated as a first line therapy for high risk B-cell lymphoma in Kite clinical study ZUMA-12.

We recognize the considerable time and attention CMS has applied to understanding CAR T-cell therapy and hearing from stakeholders. We greatly appreciate your careful consideration of this unique treatment and offer the recommendations below to help improve CMS’ draft NCD which proposes to cover CAR T-cell therapy for cancer within the context of Coverage with Evidence Development (CED). We note that while our comments comprise recommendations intended to refine the proposals to implement CED for CAR T, we continue to believe that CED is not necessary for CAR T labeled indications that have been approved by the FDA. As we described in our comments submitted in June 2018 during the first comment period for the CAR T national coverage analysis (NCA), we believe that the existing and growing body of evidence (24-month follow-up and real world experience data for YESCARTA, presented below) strongly supports that CAR T-cell therapy is reasonable and necessary for Medicare beneficiaries.

That said, if CMS chooses to establish requirements under CED for coverage of CAR T, we suggest that it include recent peer-reviewed articles and abstracts that have been accepted through a peer-review process in its evidence base for the NCD. In addition, we offer the following recommendations to ensure that Medicare beneficiaries have access to this breakthrough therapy. As discussed in more detail below, we recommend that CMS should:

  • Remove the CED coverage limit that restricts treatment to patients who have relapsed or refractory cancer to allow coverage for all patients with cancer who receive CAR T therapy for any FDA approved indications or indications recommended by the National Comprehensive Cancer Network (NCCN) with a Category 1 or 2 irrespective of line of therapy.
  • Clarify that the determination of whether a patient is experiencing comorbidities that would preclude benefit of CAR T should be made by the patient’s treating hematologist/oncologist for both the registry under Section 3(a) and any clinical study under 3(b).
  • Clarify how CMS expects the registry and clinical study design and data collection to answer the four CED questions and that investigators have broad discretion as to selecting the control group against which the CED data is collected.
  • Approve qualifying registry and clinical studies on the date of release of the final NCD or provide a mechanism to ensure there are no lapses in coverage between the date that the NCD is finalized and a qualifying registry and clinical studies are approved.
  • Clarify whether accreditation of a treatment provider by the Foundation for the Accreditation of Cellular Therapy (FACT) or other nationally recognized organization(s) is sufficient for meeting the facility requirements for coverage.

A. Evidence Supporting Current Use of CAR T Therapy is Strong and Growing

In its review of the current evidence base for CAR T, CMS found that “CAR T-cell therapy is a promising type of cancer immunotherapy” but identified what it considers to be significant gaps in the evidence, particularly related to the number of Medicare beneficiaries who have received CAR T therapy and the length of follow-up. We maintain that existing clinical studies demonstrate substantial improvement of health outcomes in Medicare beneficiaries treated with YESCARTA. ZUMA-1, the pivotal clinical study of YESCARTA, provides compelling evidence that YESCARTA offers a particularly substantial improvement in health outcomes for the Medicare-aged population with relapsed or refractory B-cell lymphomas.

The primary efficacy data for YESCARTA in the ZUMA-1 trial demonstrated a similar objective response rate (ORR) for patients in Phase 2 (N = 101) aged ≥ 65 years and those aged < 65 years (92% vs. 79%). The 12-month update of ZUMA-1 demonstrated similar outcomes for these age groups among all patients in the ZUMA-1 trial (Phase 1 and 2; N = 108). Results were as follows for patients aged 65 ≥ and those aged < 65 years: ORR, 89% vs. 80%; complete response (CR) rate, 70% vs. 54%; ongoing response rate, 48% vs. 40%, and 12-month overall survival (OS), 67% vs. 57%. Safety was also comparable for patients = 65 years and those < 65 years in the 12-month update: older patients had a lower incidence of serious adverse events (AEs) (37% vs. 62%) and Grade 3 or higher infections (19% vs. 31%). A higher incidence of Grade 3 or higher neurologic events (NEs) (44% vs. 28%) was driven by events that would be expected to occur more frequently in the ≥ 65 years age group (delirium, agitation, and disturbance in attention). These data demonstrate that subjects in ZUMA-1 who would be eligible for Medicare based on their age had robust durable responses to YESCARTA that were similar to those seen in overall ZUMA-1 population.

Further, we now are able to present additional evidence via the recently published 24-month follow-up data from ZUMA-1 (see Table 1).

Table 1. Comparison of ZUMA-1 12-Month and 24-Month Follow Up

  12 month
(n = 101)
24 month
(n = 101)
  ORR CR ORR CR
Best Objective Response, % 83 58 83 58
Ongoing Response, %a 42403937

These overall data, which provide follow-up for a median of 27.1 months, showed a median OS had not been reached. In addition, 93% of patients with ongoing response at 12 months remained in response at 24 months.

A subanalysis of 33 patients with high risk features of double-expressor or high-grade B-cell lymphoma (DE/HGBCL) showed a 91% ORR and a 70% CR rate, with 48% of patients in ongoing CR. Median duration of response (DOR) for complete responders has not been reached. Safety was also consistent between the 12- and 24-month follow up analyses; no new cases of cytokine release syndrome (CRS), NEs, or Grade 5 AEs and no cases of replication-competent retrovirus or YESCARTA–related secondary cancers were reported. At the 24-month follow-up, four patients had serious AEs unrelated to YESCARTA (mental status change, myelodysplastic syndromes, and/or infections). A copy of the Lancet publication is included with these comments and we ask that CMS include these study results and study results discussed further in this letter in the evidence review for the final NCD.

A subanalysis of the ZUMA-1 24-month analysis compared patients ≥ 65 years of age and < 65 years of age. These data have been submitted for presentation at the 2019 American Society of Oncology (ASCO) Annual Meeting. The results show efficacy and safety results consistent with those observed in the 12-month analysis, thus extending and confirming the benefit of YESCARTA in the population of patients aged ≥ 65 years. Data from this analysis will be available via the ASCO website in mid-April and we plan to share it with CMS when it is made publically available.

Notably, additional independent analyses of 72 patients treated with YESCARTA at MD Anderson Cancer Center confirm the results observed in ZUMA-1. The 72 patients comprised 20 patients ≥ 65 years and 52 patients < 65 years. Thirty-one patients (43%) received YESCARTA in the context of a clinical study and 41 patients (57%) received YESCARTA in the “real world” setting. Among 67 patients evaluable for efficacy, ORR and CR for those ≥ 65 years and < 65 years were not significantly different at day 30 (ORR, 94% vs 78%; CR, 71% vs 50%). With a median follow-up of 4.19 months, the estimated median OS was 15.4 months for both groups. Safety was comparable between the two age groups with respect to incidence and severity of CRS and CAR-related encephalopathy syndrome, tocilizumab usage, length of hospital stay, and intensive care unit admission rates and DOR.

Real world experience was also examined in a retrospective analysis of data from 274 patients treated with YESCARTA across 17 academic centers in the US. The real world dataset shows a numerically higher proportion of patients 65 years and older compared with ZUMA-1 (33% vs. 25%), a higher median age compared to ZUMA-1 (60 vs. 58 years of age), and a broader range of ages treated compared to ZUMA-1 (21 – 83 vs. 23 – 76 years of age).

The real world analysis examined outcomes in patients with a median follow up of 3.9 months, compared to patients analyzed in the ZUMA-1 12-month update with a median follow up of 15.4 months (see Table 2). . Efficacy and safety for patients treated in the real world and ZUMA-1, respectively, were similar, as follows: OR (81% vs. 82%), CR (57% vs. 58%), Grade 3 or higher CRS (7% vs. 13%) and Grade 3 or higher neurologic toxicity (33% vs. 31%).

Table 2. Efficacy of YESCARTA in a Real-World Study Compared to ZUMA-1 12-Month Follow Up

  Real World YESCARTA Evaluable Real World YESCARTA ZUMA-1
N=108
Median follow up, months 3.9 15.4
Best ORR at Day 90, N (%) 248a 201 (81) 89 (82)
Best CR at Day 90, N (%) 142 (57) 63 (58)

Safety was also comparable despite the fact that 43% of real world patients would have been excluded from ZUMA-1 based upon eligibility criteria (see Table 3). Among other exclusion criteria, 8% of patients treated in the real world had prior CD19 or CAR T cell therapy and 8% had a history of CNS lymphoma.

Safety and efficacy data for patients treated with YESCARTA in both clinical trials and the real world setting continue to be collected via long-term follow up. We recommend that CMS include the studies presented in this letter, which have been discussed in peer-reviewed articles and abstracts that have been accepted through a peer-review process, in its evidence base for the NCD.

B. Medicare Should Not Limit Coverage of CAR T to Relapsed or Refractory Cancer

CMS proposes that Medicare will cover CAR T-cell therapy for patients who:

  • Have relapsed or refractory cancer; and
  • Are currently experiencing any comorbidity that would otherwise preclude patient benefit.

In addition, CMS proposes that Medicare coverage will be limited to FDA-approved indications or to unapproved indications that are recommended by the NCCN with a Category 1 or 2 and only if certain provider requirements, including requirements for registry or clinical study participation, are met. CMS also proposes not to cover CAR T-cell therapy for patients who do not have relapsed or refractory cancer.

By limiting coverage to patients with relapsed or refractory cancer, CMS is peremptorily creating a barrier to future coverage for first line uses of CAR T-cell therapy that may be approved in the future. Because of this restriction physicians may be forced to select sub-optimal treatments for Medicare patients. In particular, proactively implementing a coverage restriction for FDA approved indications for CAR T therapies has the potential to create a situation where commercial, Medicaid, or otherwise ensured beneficiaries could have access to FDA approved therapies that are not available to Medicare beneficiaries.

CAR T is an entirely new therapy that is currently indicated for use in patients with refractory or relapsed cancer but is also being actively studied as a first line therapy for lymphoma patients. For example, Kite clinical study ZUMA-12 explores YESCARTA as first line therapy in high risk patients with historically poor prognosis due to gene rearrangements in the cancer cells that portend resistance to standard first-line chemoimmunotherapy. Specifically, the 2016 revision of the WHO classification for lymphomas included a new category, high grade B-cell lymphoma, which accounts for < 10% of DLBCL cases and is now considered distinct from DLBCL. , The median age at diagnosis is in the sixth to seventh decade of life.

High-grade B-cell lymphoma includes a subcategory characterized by gene rearrangements of MYC and BCL-2 and/or BCL-6 (i.e., double- or triple-hit lymphomas, depending on the number of rearrangements present). Double-hit and triple-hit lymphomas typically do not respond to rituximab-based chemoimmunotherapy and are more likely to involve the central nervous system (CNS). Published studies showed that 40% of patients with MYC translocations and 41% of patients with double-hit lymphoma were alive two years following first-line treatment. , Other high-risk patients eligible for treatment in ZUMA-12 are those with International Prognostic Index (IPI) score ≥ 3. Such scores were shown in previous studies to confer high risk independently from other factors (International Non-Hodgkin's Lymphoma Prognostic Factors Project 1993). , As described in a recent clinical trials planning meeting from the National Cancer Institute National Clinical Trials Network, patients with double- or triple-hit lymphoma have not been studied in prospective trials to date, and therefore, represent great unmet clinical need in DLBCL.

Patients with high-risk large B-cell lymphoma have an increased risk of relapse and death due to disease progression after first-line rituximab-based chemoimmunotherapy. ZUMA-12 is a Phase 2 multicenter, open-label study evaluating the safety and efficacy of YESCARTA as first-line therapy in adult subjects with high-risk large B cell lymphoma. Adult subjects in the ZUMA-12 study must have high-risk histologically confirmed large B-cell lymphoma. Approximately 40 subjects with high-risk large B-cell lymphoma, either high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 translocations (double-/triple-hit lymphomas) or high and high intermediate risk (IPI score ≥ 3) scores will be enrolled and treated with conditioning chemotherapy followed by a targeted dose of YESCARTA. The primary endpoint for the ZUMA-12 study is the CR rate and secondary endpoints include ORR, DOR, event-free survival (EFS), PFS, OS, AE incidence, and relapse with CNS disease. ZUMA-12 is a feasibility study of axicabtagene ciloleucel as first-line therapy which will lead to a registrational study.

If CMS finalizes the proposed non-coverage for all patients without relapsed or refractory cancer, Medicare beneficiaries without relapsed or refractory cancer would not be able to receive CAR T-cell therapy until CMS has received and completed a NCD reconsideration request. Such a revision to the NCD would take a minimum of nine months, and more likely would take over a year (e.g., to meet with CMS, prepare the request, and go through the NCA process). This would mean that Medicare patients without relapsed or refractory cancer would not have access to CAR T therapy for many months after FDA approval of an indication for patients treated in earlier lines of therapy. As a general matter, if CMS finalizes its proposal, it will need to reconsider the NCD for every new FDA approved indication outside of relapsed/refractory cancer, which means CMS could receive several NCD reconsideration requests in the next two to three years.

Kite recommends that CMS remove the coverage limitation that requires patients to have relapsed or refractory disease, particularly since other provisions of the NCD would limit coverage to only those indications which are approved by the FDA or recommended by NCCN. If CMS declines to completely remove this restriction, then we recommend that CMS allow Medicare Administrative Contractor (MAC) discretion to cover CAR T-cell therapy for non-relapsed/refractory indications. This approach would mitigate the potential for delays in patient access to CAR T-cell therapies approved for first line treatment in cancer by obviating the need for CMS to reconsider an existing NCD in order to establish coverage.

We have included as an attachment a red-lined version of the proposed NCD that shows our recommended refinements to this requirement.

C. Determination of Comorbidities That Would Prohibit CAR T Treatment Should Be Based on Discretion of the Treating Clinician

CMS proposes that Medicare coverage of CAR T will be limited to patients who are not currently experiencing “any comorbidity that would otherwise preclude patient benefit” and applies that requirement to all patients and covered uses, including those who are enrolled in a registry for FDA-approved indications under Section 3(a) of the NCD and those who are enrolled in a clinical study under Section 3(b) of the NCD for an indication recommended by NCCN. We are greatly concerned that CMS may be considering creating a list of comorbidities that would preclude coverage because the benefits and risks of CAR T therapy must be considered on an individual basis by the treating physician and the patient. Patients who are candidates for CAR T-cell therapy have complex medical conditions and have already received intense cancer treatments. The presence, severity, and combination of comorbidities that could affect whether an individual patient may or may not benefit from CAR T therapy must be considered on a patient-by-patient basis by the treating physician. By creating a list of comorbidities that would preclude coverage, CMS would also effectively be restricting coverage so that it is more restrictive than the FDA label.

The recent real-world data with YESCARTA described above underscore the importance of covering the medicine consistent with the label. 43% of leukapheresed patients in a real world study would have been excluded from the ZUMA-1 trial (see Table 3) based upon a range of criteria including thrombocytopenia, active DVT/PE, prior CD19 therapy, kidney disease, history of CNS lymphoma, congestive heart failure and prior allogeneic stem cell transplant. However, those clinical trial exclusions do not preclude patient responses in a real world setting. Notably, 47% of the patients in this real world data set achieved a CR at the three-month tumor assessment. These data suggest that determining candidacy for CAR T treatment is complex and should be determined by the treating physician on patient-by-patient basis.

Table 3. Characteristics Differentiating YESCARTA Patients in the Real-World from ZUMA-1

Criteria Excluded from ZUMA-1 N=124
N (%)
Platelets < 75 37 (13)
Active DVT/PE 27 (9)
Prior CD19 or CAR T cell therapy 24 (8)
GFR < 60 22 (8)
History of CNS lymphoma 22 (8)
Symptomatic pleural effusion 11 (4)
LVEF < 50% 10 (4)
Prior allogeneic SCT 7 (2)

The comorbidities that would prohibit treatment with CAR T per CMS include patients who were excluded from clinical trials for one or more of the following reasons: (1) the patient’s underlying disease may have made data interpretation difficult; and (2) unacceptable risk was perceived to be associated with the condition. Clinicians should be allowed to consider the benefit risk in patients with relapsed or refractory DLBCL and comorbidities, such as HBV and HCV, which could potentially be managed with antivirals, and should not be a priori excluded. Uncontrolled infection is a serious, but very treatable condition and does not necessarily preclude a patient from benefitting from CAR T-cell therapy. Autoimmune disorders remain a hypothetical risk; no evidence of exacerbation of pre-existing autoimmune disease or new onset autoimmune disease has been observed in clinical trials. Determining whether a specific condition would preclude patient benefit from CAR T therapy should be left to the discretion of the patient’s physician guided by the prescribing information in the FDA label.

As noted above, CAR T is an innovative new therapy and clinical understanding of its appropriate use is rapidly evolving. In fact, the real world data discussed in this letter shows that many patients who would not have met the inclusion criteria of ZUMA-1 do benefit from CAR T therapy. Therefore, locking in a specific list of conditions which would preclude Medicare coverage may inappropriately prevent some beneficiaries from receiving beneficial treatment. In summary, we ask that CMS allow individual clinicians to make this determination and not attempt to limit coverage based on specific comorbidities. Clinicians—specifically the hematologist or oncologist treating the patient’s cancer —are best positioned to determine whether the condition of that particular patient at the time of CAR T administration would preclude benefit from CAR T-cell therapy.

We have included as an attachment a red-lined version of the proposed NCD that shows our recommended refinements to this requirement.

D. CMS Should Clarify Expectations Related to Certain Registry/Study Design and Data Collection Elements

We believe that CMS’ intent is to confirm that real-world experience with CAR T-cell therapy is consistent with the results of clinical study data that was the basis for FDA approval and/or NCCN compendium updates and improves health outcomes of Medicare patients. We share CMS’ desire that data gathered under CED address any concerns that CMS may have about the use of CAR T outside of the controlled design of the pivot trials. If CMS finalizes the CED requirement for CAR T, we generally agree with the questions that CMS asks to be addressed and the specific data elements that are to be collected. However, there are several points that we ask CMS to clarify to ensure that the data gathered will be responsive to CMS’ questions regarding the use of CAR T and will ultimately support a NCD without CED requirements. Specifically we ask that CMS clarify the following points:

  • Researchers analyzing the data collected through the required registry/clinical have discretion to choose the appropriate cohort for comparison. We ask CMS to state that matched cohorts could but do not have to be part of the data collected by the registry or clinical study and that registry/study results can be compared to pivotal trial data or other published data.
  • Any expectations regarding how a study is to be appropriately powered (e.g., to show superiority, non-inferiority).
  • Collection of the proposed data elements is expected to be sufficient to answer the four CED questions.
  • How CMS expects to use PRO data in future coverage determinations. While these instruments will provide additional information regarding the patient experience, we are concerned that use of that data in CAR T coverage determinations may not be appropriate. Neither instrument is validated in a relapsed/refractory lymphoma population nor for use with CAR T therapies which are uniquely administered as a single infusion.
  • We believe that CMS’ intent in covering CAR T under CED is to increase the quantity of clinical evidence related to patient outcomes and experience and not to withhold coverage because one or more data points may be missing for an individual patient. We are particularly concerned that patients who are unable (due to site logistics, patient impairment, or other unforeseen technical issues) or unwilling to provide PRO data not be denied treatment. We understand that CMS has addressed similar issues with other CED registries through outreach to providers and registry leaders. If any issues with missing data develop for the CAR T registry, we ask that CMS commit to working with hospitals and the registry sponsor to improve data collection efforts while continuing to provide coverage for CAR T cell therapy.
  • We concur with CMS’ proposal not to require collection of PRO data for cases treated in the inpatient setting. PRO data is not currently being collected for CAR T patients in the existing registry with Center for International Blood and Marrow Transplant Research (CIBMTR) and we believe that any requirement to collect such data for CED coverage when care is provided would create inappropriate delays in approval of a qualifying registry and could create gaps where Medicare beneficiaries would not be able to receive CAR T therapy. Facilities wishing to collect PRO data could voluntarily choose to collect PRO data for a hospital inpatient.
  • Specify domains of interest for PRO data and how it is expected to help CMS understand changes in “symptom function health related quality of life”. For example, with symptoms, is the interest related to fatigue? With functioning, is the interest primarily around physical functioning? How will CMS isolate the effect of CAR T on PRO data from the effect of unrelated health conditions and comorbidities that may also affect the patient’s symptoms or function and change over time?
  • CMS has proposed that hospitals may use one of two PRO instruments (PROMIS or PRO-CTCAE) to report required data. We believe that the PROMIS instrument is the more appropriate of the two options and strongly encourage CMS to finalize the proposal that data collected through PROMIS will satisfy the PRO requirement.

We ask for these clarifications to ensure that the CED data collection requirement will gather meaningful evidence that will help answer the outstanding questions CMS has identified. Data collection and analysis requires devotion of significant effort and resources from providers, patients, and researchers. To the extent that CMS believes certain elements or requirements will be critical to future evidence reviews, we would prefer to know those expectations in advance. In order to assure that the proposed registry and clinical trial requirements are sufficient to answer the CED questions, we request that CMS clarify, among other things, the type of registry and clinical trial designs that will address the CED questions.

E. CMS Should Approve Qualifying Registry and/or Clinical Studies on the NCD Effective Date

In general, the CED requirements that CMS specifies in the proposed NCD are largely consistent with clinical studies already underway as part of FDA post-market requirements. Those requirements are primarily being met through a post marketing long-term follow up study, via a registry established by CIBMTR. We defer to CIBMTR about operational issues related to the registry and to the requirements for registry approval. That said, we urge CMS to approve a required registry on the same date as the final NCD is issued to eliminate the potential for gaps in coverage for Medicare beneficiaries. Should CMS not be able to approve a registry on the same date as the effective date of the NCD, we ask CMS to address how it intends to handle specific situations that may arise with CAR T patients. For example, we ask CMS to address coverage for a Medicare beneficiary who underwent apheresis prior to the release of the final NCD, but who will be infused with CAR T cell therapy after finalization of the NCD and before CMS has approved a registry. If there is a delay between the effective date of the NCD and the registry approval, we ask that CMS either 1) explicitly state that providers may choose to hold claims for CAR T-cell therapy until such time as an approved registry is available (subject to general claims processing submission requirements; or 2) explicitly state that claims submitted after registry approval but with date of service before approval of registry are covered.

F. CMS Should Adopt Provider Requirements Consistent with High Quality Care

As noted above, CAR T-cell therapy is an entirely new treatment option and we believe that it is appropriate that CMS establish certain requirements for providers who furnish this treatment to Medicare beneficiaries. However, those requirements should be consistent with provider experience for high quality clinical care while and avoiding placing unnecessary burden on CAR T providers. Currently, all of the authorized YESCARTA treatment sites are accredited by FACT. We recommend that CMS clarify that FACT or other national accreditation is sufficient for a site to qualify for coverage and that no additional attestation is necessary to confer coverage.

G. Summary

Kite greatly appreciates the opportunity to continue to engage with CMS on appropriate coverage of CAR T-cell therapy, including by offering comments on the proposed NCD. We offer the above recommendations to help ensure that Medicare beneficiaries have access to this breakthrough therapy and to ensure that, if CMS continues to believe additional evidence development is necessary to support coverage of CAR T, the evidence gathered will fully address the questions CMS has identified.

If you have any questions regarding the above comments, or if we can provide any additional information, please contact Jenna Waltersdorf at (650) 235-3215 or jenna.waltersdorf@gilead.com.

Sincerely,

\s\
Michael Amoroso
Senior Vice President and Head of Worldwide Commercial Cell Therapy
Kite Pharma

Redline of the Proposed NCD

A. The Centers for Medicare & Medicaid Services (CMS) proposes to cover autologous treatment with T-cells expressing at least one chimeric antigen receptor (CAR) through coverage with evidence development (CED) when prescribed by the treating oncologist, performed in a hospital, and all of the following requirements are met:

1. Patient has:
  1. Relapsed or refractory c Cancer; and
  2. not currently been experiencing any comorbidity that would otherwise preclude patient benefit, as determined by the patient’s treating hematologist/oncologist. This applies to Sections 3(a) and 3(b).
2. The hospital has:
  1. a Cellular Therapy Program consisting of an integrated medical team that includes a Clinical Program Director, a Quality Manager, and at least one physician experienced in cellular therapy, and demonstrates that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members;
  2. a designated care area that protects the patient from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment; and
  3. written guidelines when administering CAR T-cell therapy for patient communication, monitoring, and transfer to an intensive care unit.
3. The treatment meets the criteria in section a or b, below:
  1. Treatment is an FDA-approved biological, providing targeted therapy for a known antigen expressed in the patient’s cancer according to an FDA indication in a hospital. Repeat treatment when a patient receives more than one therapeutic dose of a specific CAR T-cell product using the same biological in the same patient is covered only when a new primary cancer diagnosis is made by the treating oncologist and the patient conditions are met. In addition, all of the following requirements must be met:
    1. If the patient is administered CAR T-cell therapy in the inpatient hospital setting, then the patient must be enrolled in, and the furnishing hospital is participating in, a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, follows the patient for at least two years, adheres to the standards of scientific integrity and relevance to the Medicare population as identified in section A.4 of this decision, and answers the three following CED questions:
      • How do patient outcomes compare to either the pivotal clinical trial(s) (i.e., the clinical trial(s) that served as the basis for FDA approval of the biological and/or for the FDA indication) of the biological or a cohort of controls receiving standard of care treatment?
      • How do the clinical characteristics of registry patients compare to the pivotal clinical trial(s)?
      • How do the clinical characteristics of registry patients affect the clinical endpoints relative to those in the pivotal clinical trial(s)?
    2. If the patient is administered CAR T-cell therapy in the outpatient hospital setting, then the patient must be enrolled in, and the furnishing hospital is participating in, a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, follows the patient for at least two years, adheres to the standards of scientific integrity and relevance to the Medicare population as identified in section A.4 of this decision, and answers the four following CED questions:
      • How do patient outcomes compare to either the pivotal clinical trial(s) (i.e., the clinical trial(s) that served as the basis for FDA approval of the biological and/or for the FDA indication) of the biological or a cohort of controls receiving standard of care treatment?
      • How do the clinical characteristics of registry patients compare to the pivotal clinical trial(s)?
      • How do the clinical characteristics of registry patients affect the clinical endpoints relative to those in the pivotal clinical trial(s)?
      • How does the patient report their symptom function health-related quality of life changes over the course of their treatment?
    3. The furnishing hospital shall address the CED questions on all registry patients by tracking the following clinical data elements at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the treatment is administered.
      • Age, gender and comorbidities;
      • specifics of cancer diagnosis (e.g., sub-classification, stage);
      • number(s) or line(s) of previous therapies, therapeutic agents previously administered;
      • days to disease progression;
      • days to recurrence;
      • overall survival; and
      • progression-free survival.
    4. To address a CED question on health-related quality of life, the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS®) or Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAETM) patient-reported outcome assessment must be used at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the treatment is administered.
  2. Treatment is an FDA-approved biological, indicated for use identified in the National Comprehensive Cancer Network Drugs & Biologics Compendium with Category 1 or 2 grade 2 or 1 on or after August 2017, and providing targeted therapy in a hospital for a known antigen expressed in the patient’s cancer. In addition, all of the following requirements must be met:
    1. Patients must be enrolled in a CMS-approved clinical study that consecutively enrolls patients and follows the patient for at least two years. The study shall adhere to the standards of scientific integrity and relevance to the Medicare population as identified in section A.4, and collect all data necessary, including health outcomes, and submit to CMS for approval a written executable analysis plan to address all of the following CED questions:
      • How do study patient outcomes compare to a cohort of controls receiving standard of care treatment?
      • How do the clinical characteristics of study patients compare to a cohort of controls receiving standard of care treatment?
      • How do the clinical characteristics of study patients affect the clinical endpoints relative to a cohort of controls receiving standard of care treatment?
      • How does the patient report their symptom function and health-related quality of life changes over the course of their treatment?
    2. The CED study shall address the CED questions on all study patients by tracking all the clinical data elements specified in A.3.a.iii-iv at baseline, at treatment, and at follow-up 3 months, 6 months, 12 months, and 24 months after the first treatment is administered.
Registries must be reviewed and approved by CMS. Potential registry sponsors must submit all registry documentation to CMS for approval including the written executable analysis plan and auditing plan. CMS will review the qualifications of candidate registries to ensure that the approved registry follows standard data collection practices and collects data necessary to evaluate the patient outcomes specified above. Registries and clinical trials approved under this NCD may have a superiority or non-inferiority design. The registry’s National Clinical Trial number must be recorded on the claim. 4. All CED studies must adhere to the following standards of scientific integrity and relevance to the Medicare population:
  1. The principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects.
  2. The rationale for the study is well supported by available scientific and medical evidence.
  3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
  4. The study design is methodologically appropriate and the anticipated number of enrolled subjects is sufficient to answer the research question(s) being asked in the National Coverage Determination.
  5. The study is sponsored by an organization or individual capable of completing it successfully.
  6. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and/or services, and the use and eventual disposition of the collected data.
  7. All aspects of the study are conducted according to appropriate standards of scientific integrity.
  8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
  9. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options.
  10. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries are also registered in the Agency for Healthcare Quality (AHRQ) Registry of Patient Registries (RoPR).
  11. The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint, even if the trial does not achieve its primary aim. The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessibly manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results).
  12. The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
  13. The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.

Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that meet the above-listed standards and address the above-listed research questions.

B. Noncoverage

CMS proposes to non-cover the use of T-cells expressing at least one CAR that is not an FDA-approved biological. We propose treatment using T-cells expressing at least one CAR when cancer patients do not have a cancer that meets any of the indications noted in A.1.a of this proposed decision would be covered at the discretion of the Part A/B Medicare Administrative Contractors non-covered. We propose treatment using T-cells expressing at least one CAR when not indicated in A.2.a or A.2.b of this proposed decision would be non-covered.

C. Other

This policy continues coverage for routine costs in clinical trials that use CAR T-cell therapy as an investigational agent that meet the requirements listed in NCD 310.1.

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