Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers

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 cancer; and
   2. not currently been experiencing any comorbidity that would otherwise preclude patient benefit.


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-CTCAE™) 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 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. 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 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.

See Appendix B for the proposed manual language.

CMS is seeking comments on our proposed decision. We will respond to public comments in a final decision memorandum, as required by §1862(l)(3) of the Social Security Act (the Act).

TO:		Administrative File:  CAG-00451N

FROM:	Tamara Syrek Jensen, JD
		Director, Coverage and Analysis Group

		Joseph Chin, MD, MS
		Deputy Director, Coverage and Analysis Group

		Lori M. Ashby, MA
		Director, Division of Policy and Evidence Review

		Daniel A. Caños, PhD
		Director, Evidence Development Division 

		Lori A. Paserchia, MD
		Lead Medical Officer

		Katherine B. Szarama, PhD
		Lead Analyst

SUBJECT:	Proposed National Coverage Determination for Chimeric Antigen Receptor (CAR) T-cell Therapy for Cancers

DATE:		February 15, 2019

I. Proposed Decision

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 cancer; and
   2. not currently been experiencing any comorbidity that would otherwise preclude patient benefit.


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-CTCAE™) 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 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. 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 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.

See Appendix B for the proposed manual language.

CMS is seeking comments on our proposed decision. We will respond to public comments in a final decision memorandum, as required by §1862(l)(3) of the Social Security Act (the Act).

II. Background

Throughout this document we use numerous acronyms, some of which are not defined as they are presented in direct quotations. Please find below a list of these acronyms and corresponding full terminology:

AATB - American Association of Tissue Banks
ACT - Adoptive Cell Therapy
AEs - adverse events
AIDS - Acquired immune deficiency syndrome
ALL - Acute Lymphoblastic Leukemia
AHRQ - Agency for Healthcare Research and Quality
ARC - American Red Cross
ASBMT - American Society for Blood and Marrow Transplantation
ASCT – Autologous stem cell transplantation
ASFA - American Society for Apheresis
AYA - adolescent and young adult
BCMA - B-cell maturation antigen
BLA - Biologics Licensing Application
BOMC - Mini-Cog, Blessed Orientation-Memory-Concentration
CAP - College of American Pathologists
CAR - Chimeric Antigen Receptor
CAR-T - Chimeric Antigen Receptor T-cells
CARG - Cancer and Aging Research Group score
CD-19 - Cluster of Differentiation 19
CED - Coverage with Evidence Development
CHOP - Children’s Hospital of Philadelphia
CIBMTR - Center for International Blood and Marrow Transplant Research
CMS - Centers for Medicare & Medicaid Services
CNS - central nervous system
CRASH - Chemotherapy Risk Assessment Scale for High-Age Patients
CR - complete response
CRi - complete response with incomplete hematologic/blood count recovery
CRS - cytokine release syndrome
DLBCL - diffuse large B-cell lymphoma
DLT - dose-limiting toxicity
DOR - duration of response
ECOG-PS - Eastern Cooperative Oncology Group Performance Status
ETASU - Elements To Assure Safe Use
FACT - Foundation for the Accreditation of Cellular Therapy
FDA - Food and Drug Administration
FL - Follicular Lymphoma
G8 - Geriatric-8
GA - geriatric assessment
GDS - Geriatric Depression Scale
HCT - allogeneic hematopoietic cell transplantation
HIV - human immunodeficiency virus
IADL - Instrumental activities of daily living
ICER - Institute for Clinical and Economic Review
ICU - Intensive Care Unit
ISCT - International Society for Cellular Therapy
MA - Medicare Advantage
MAC - Medicare Administrative Contractor
MEDCAC - Medicare Evidence Development and Coverage Advisory Committee
NCA - National Coverage Analysis
NCCN - National Comprehensive Cancer Network
NCD - National Coverage Determination
NCI – National Cancer Institute
NHL - Non-Hodgkin’s Lymphoma
NMDP - National Marrow Donor Program
NOS - not otherwise specified
ORR - overall response/remission rate
OS - overall survival
PFS - progression-free survival
Ph - Philadelphia
PMR - postmarketing requirements
PR - partial response
PRO - Patient-Reported Outcome
REMS - Risk Evaluation and Mitigation Strategies
R/R - relapsed/refractory
SBRA - Summary Basis for Regulatory Action
SEER - Surveillance, Epidemiology, and End Results Program
TA - technology assessment
US - United States
VES-13 - Vulnerable Elders Survey-13

Background on Cancer
What is cancer?
Cancer is a collection of related diseases of dividing cells that can start almost anywhere in or on the body, evade the immune system, and invade nearby tissues. Categories of cancer are typically organized by the location in the body and specific type of cell. These categories may include carcinoma, sarcoma, leukemia, lymphoma, multiple myeloma, melanoma, and brain and spinal cord tumors. There are also changes to these cells that are not considered cancer. These changes include hyperplasia—when a cell divides faster than normal—and dysplasia—a buildup of extra cells with abnormal shape and disorganization.

Lymphomas are cancers of lymphocytes (B cells or T cells) and consist of two main types. Hodgkin lymphoma arises usually from B cells and Non-Hodgkin lymphoma (NHL) can form from B cells or T cells. According to the American Cancer Society (2018), Hodgkin lymphoma is most common in early adulthood, with an average age of 39 at diagnosis, while NHL accounts for about four percent of all cancers in the U.S. with an estimate that about 74,680 adult and children (41,730 males and 32,950 females) will be diagnosed with NHL and about 19,910 people will die from NHL (11,510 males and 8,400 females) during 2018. The most common sub-type of NHL is diffuse large B cell lymphoma (DLBCL) representing 30-40% of all cases worldwide and has a number of different cell subtypes of origin to divide cases into germinal centre B cell like subtypes and activated B cell like subtypes (Li et al., 2018). Additionally, follicular lymphoma, which arises from B cells, affects people over 50 years old, and comprises nearly 20-30% of NHL. While NHL can occur at any age, the risk increases with age; more than half of patients are 65 or older at the time of diagnosis (American Cancer Society, 2018).

In its 2018 guideline, The National Comprehensive Cancer Network (NCCN) noted that the incidence of NHL increased significantly between 1970 and 1995 but has moderated since the mid-1990s. While the increase was attributed partly to the human immunodeficiency virus (HIV) epidemic and the development of AIDS-related NHL, much of the increase in incidence has been observed in patients in their sixth and seventh decades. As a result, patients with NHL may also have significant comorbidities.

Leukemias are cancers that arise from blood-lineages of the bone marrow. The type of leukemia depends of the type of cell and cell growth. Acute lymphoblastic leukemia (ALL) is also a cancer of B-cell origin that is associated with immature B-cells in the bone marrow, blood, and other organs. The NCCN (2018a) notes that "the age-adjusted incidence rate of ALL in the U.S. is 1.58 per 100,000 individuals per year" (National Cancer Institute (NCI), 2016a), with approximately 5,970 new cases and 1,440 deaths estimated in 2017 (Swerdlow et al., 2008). The median age at diagnosis for ALL is 15 years (NCI, 2016b) with 57.2% of patients diagnosed at younger than 20 years of age (NCI, 2016c). In contrast, 26.8% of cases are diagnosed at 45 years or older and only approximately 11% of patients are diagnosed at 65 years or older (NCI, 2016c). ALL represents 75% to 80% of acute leukemias among children, making it the most common form of childhood leukemia; by contrast, ALL represents approximately 20% of all leukemias among adults (Jabbour et al., 2005; Esparza et al., 2005). Chronic lymphoblastic leukemia (CLL) is a more slowly progressing type.

Multiple myeloma begins in a different type of cell, the plasma cell. According to the Surveillance, Epidemiology, and End Results (SEER) Program Cancer Statistics Review (Noone et al., 2018) there were an estimated 124,733 people living with myeloma in the US and the lifetime risk of developing this cancer at some point is approximately 0.8 percent. Additionally, the number of new cases per year is 6.7 per 100,000 with 3.3 deaths per 100,000. In general, plasma cell neoplasms are most common in people who are at middle age or older. Treatment can be based on the stage of cancer, which is the result of a determination of combination of factors including the amount of cancer in the body and biomarkers such as albumin in the blood.

What are the treatment options for cancer patients?
Cancer has many treatments available, with some seen as the standard of care and others only available in the context of a clinical trial. For some patients, participation in a clinical trial may be the best process to access a new potential treatment. Surgery may be performed to remove certain cancerous tumors. Radiation therapy can be delivered externally or internally to disrupt cell division and keep cells from growing. Drugs, such as chemotherapy, stop cancer cell growth and division depending on the type and stage of cancer being treated. Targeted therapy works to attack a subset of cells by leveraging specific cellular processes, such as protein synthesis and degradation. Immunotherapy is a type of cancer treatment that involves strengthening a patient’s own immune system. Different types of immunotherapy for cancer include biologicals such as monoclonal antibodies and cytokines, and drugs such as immune checkpoint inhibitors, and cancer vaccines. As one example, monoclonal antibodies identify and attach to substances on the cell surface to kill or keep cancer cells from spreading. Another method of rapidly-emerging immunotherapy is called adoptive cell transfer (ACT), which consists of the collection, alteration and then re-administration of a patient’s immune cells to attack the patient’s cancer. For example, in the case of stem cell transplantation, blood can be taken from the patient or a healthy donor, and these infused stem cells can restore the patient’s normal immune system. Each treatment has specific and sometimes distinct side effects and the population receiving a given treatment could be at risk for serious side effects or adverse events as a result.

Schuster et al. (2017), states that DLBCL "is successfully treated in about two thirds of patients with rituximab-based immunochemotherapy (Feugier et al., 2005; Pfreundschuh et al., 2006). When current frontline immunochemotherapy fails, high-dose chemotherapy with autologous stem-cell transplantation can lead to long-term disease-free survival (Gisselbrecht et al., 2010)." For patients with follicular lymphoma, there is "an excellent prognosis after receiving frontline rituximab-based therapies; however, in 20% of patients with follicular lymphoma, relapse occurs within 2 years after initial immunochemotherapy (Tan et al., 2013; Casulo et al., 2015). Among patients with relapsed follicular lymphoma that is refractory to rituximab and to alkylating-agent–based therapy, treatment with idelalisib or copanlisib, the only agents that have been approved by the Food and Drug Administration (FDA) for such patients, is associated with a median response duration of 10.8 and 12.2 months, respectively (Salles et al., 2017; Whippany et al., 2017)." (Schuster, 2017)

Crump et al. 2017 reported on the results of a large, international, multi-cohort, retrospective study of patient’s with NHL called SCHOLAR-1. The authors noted that "Published analyses of large-scale outcome data from patients with refractory DLBCL are limited" therefore the goal of the SCHOLAR-1 study was to evaluate the outcomes of currently available therapies for patients with refractory DLBCL in order to serve as a benchmark for future studies. The authors defined refractory DLBCL as "progressive disease (received ≥ 4 cycles of first-line therapy) or stable disease (received 2 cycles of later line therapy) as best response to chemotherapy or relapse ≤ 12 months after ASCT." Objective response rate, complete response rate and overall survival were estimated from the time of initiation of salvage therapy for refractory disease. The authors found "the objective response rate was 26% (complete response rate, 7%) to the next line of therapy, and the median overall survival was 6.3 months. Twenty percent of patients were alive at 2 years. Outcomes were consistently poor across patient subgroups and study cohorts."

Survival Rates from Cancer
Expected 5-year relative survival rates from 2008-2014 are derived from tables by socio-economic status, geography and race developed by the SEER program (Noone et al., 2018) and are available at https://seer.cancer.gov/csr/1975_2015/results_merged/topic_survival.pdf. The rates inclusive of both sexes and all races are reported here, while noticeable disparities are described in our analysis (see section VIII.). Survival rate in myeloma was 50.7%. Rates in lymphoma differed between Hodgkin (86.6%) and NHL (71.4%) as did rates in leukemia subsets between acute lymphocytic (68.1%) and chronic lymphocytic (84.2%).

According to the NCCN (2018a), the "The cure rates and survival outcomes for patients with ALL have improved dramatically over the past several decades, primarily among children (Ma et al., 2014). Improvements are largely owed to advances in the understanding of the molecular genetics and pathogenesis of the disease, the incorporation of risk-adapted therapy, the advent of new targeted agents, and the use of allogeneic hematopoietic cell transplantation (HCT). Data from the SEER database have shown a 5- year overall survival (OS) of 86% to 89% for children (Kenderian et al., 2013; Ma et al., 2014); however, AYA patients were reported to have a 5-year OS between 42% to 63% depending on the age range.

Adults have the poorest 5-year OS rate of 24.1% for patients between the ages of 40 and 59 and an even lower rate of 17.7% for patients between the ages of 60 and 69 (Pulte et al., 2014). Although the exact OS percentage can vary based on how the age range is defined for pediatric, AYA, and adult patients, the trend is nonetheless clear that OS decreases substantially with increased age. The exception is infants younger than age one, which is an age group that has not seen any improvement in survival over the last 30 years (Jabbour et al., 2005). The 5-year OS in this population is 55.8% (Ma et al., 2014). Cure rates for AYAs with ALL remain suboptimal compared with those for children, although substantial improvements have been seen with the recent adoption of pediatric treatment regimens (Stock et al., 2010). AYA patients represent a unique population, because they may receive treatment based on either a pediatric or an adult protocol, depending on local referral patterns and institutional practices." Schuster et al (2017) notes that "for most patients treated since the introduction of rituximab, the expected rate of 3-year event-free survival after autologous stem-cell transplantation is only approximately 20% (Gisselbrecht et al., 2010)." "These patients with early relapse have a poor prognosis, with a rate of 5-year overall survival of only 50% when they are treated with currently available therapies (Tan et al., 2013; Casulo et al., 2015)."

Background on Chimeric Antigen Receptor T-cell Therapy
A person’s immune system contains cells to help fight substances that are foreign to the body, such as bacterial and viral infections. These cells are called white blood cells, most of which are lymphocytes. The two main types of lymphocytes are B lymphocytes (B-cells) and T lymphocytes (T-cells). B-cells generate and release antibodies to fight infection, especially bacterial infections, while T-cells employ a number of other mechanisms to fight abnormal cells such as cancer. As previously described, one type of therapy that leverages the immune system—immunotherapy—is CAR T-cell therapy.

What is CAR T-cell therapy?
Chimeric Antigen Receptor T-cells (CAR T-cells) are T-cells that have been genetically altered in order to improve the ability of the T-cells to fight cancer. The genetic modification creates a new and special receptor on the surface of the T-cell. This special receptor is called a CAR and there are many CARs on the surface of the T-cell. CAR enhances the ability of the T-cell to recognize and attach to a specific protein, called an antigen, on the surface of a cancer cell. Currently there are two FDA-approved CAR T-cell products: tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™). These two CAR T-cell products have a CAR that recognizes a specific antigen on the surface of certain cells, called CD-19.

What are the toxicities associated with CAR T-cell therapy?
As with the administration of other types of cancer chemotherapy agents, administration of CAR T-cell therapy has associated toxicities. First, as a result of their normal duties, T-cells release cytokines in order to stimulate and direct an immune response. During administration of a CAR T-cell therapy, this significantly large number of T-cells present can lead to a massive release of cytokines, which leads to cytokine release syndrome (CRS)—a potentially life-threatening toxicity that produces a systemic inflammatory disorder mainly characterized by fever, rapid pulse (tachycardia) and low blood pressure (hypotension). The severity of CRS has been correlated with the patient’s cancer burden (Baruch et al. 2017) and has been managed with an FDA-approved drug called tocilizumab.

Another prominent toxicity associated with CAR T-cell therapy is neurotoxicity, which can include confusion or seizure-like activity. According to the NCI (2017d), "in nearly all patients the problem is short lived and reversible." Finally, a significant toxicity of some CAR T-cell therapy is B-cell aplasia, which is a mass die off of B-cells. Since a functional target of recently approved CAR T-cell products is also found on the surface of normal B-cells, this CAR T-cell therapy also destroys the normal B-cells, which leads to the decreased production of antibodies. To compensate, immunoglobulin therapy is administered in order to provide the patient with antibodies to fight off infections.

III. History of Medicare Coverage

CMS does not currently have an NCD on CAR T-cell therapy.

CMS received a complete, formal request for a national coverage determination from Efrem Castillo, MD, Medicare & Retirement Chief Medical Officer, UnitedHealthcare. The formal request letter can be viewed via the tracking sheet for this NCA on the CMS website at https://www.cms.gov/medicare-coverage-database/details/nca-tracking-sheet.aspx?NCAId=291.

CMS initiated this national coverage determination (NCD) to consider coverage under the Medicare Program for CAR T-cell therapy, a rapidly emerging adoptive cell transfer immunotherapy for select patients with relapsed or refractory cancers. Treatment protocols vary, but may be summarized in five steps:

1. lymphocyte harvesting from the patient with cancer;
2. creation of cancer-targeting lymphocytes in vitro using various immune modulators;
3. selection of lymphocytes with reactivity to cancer antigens using enzyme-linked immuno-assay;
4. depletion of the patient's remaining lymphocytes using immunosuppressive agents;
5. transfusion of the cancer-targeting lymphocytes back into the patient with cancer-this transfusion represents one treatment.

The scope of this review is limited to autologous transplant of T-cells expressing at least one CAR for treatment of patients with cancer.

Medicare is a defined benefit program. For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Social Security Act (the Act). CAR T-cell therapy falls under the benefit categories set forth in section §1861(b) "inpatient hospital services" and §1861(s)(2)(B) "hospital services". This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

IV. Timeline of Recent Activities

V. Food and Drug Administration (FDA) Status

The existing CAR T-cell therapies on the market were approved as biologics and, therefore, provisions of the Medicare statute for biologicals apply. To date, two CAR T-cell products have been approved by the FDA. The first CAR T-cell product, tisagenlecleucel, received FDA approval on August 30, 2017 for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. A second FDA indication for tisagenlecleucel was granted on May 1, 2018 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, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.

The second CAR T-cell product, axicabtagene ciloleucel received FDA approval on October 18, 2017 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL, not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma.

Additional information about the FDA approval of tisagenlecleucel, including the Risk Evaluation Mitigation Strategy (REMS) program, is found at https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm573706.htm.

Additional information about the FDA approval of axicabtagene ciloleucel, including the REMS program, is found at https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm581222.htm.

VI. General Methodological Principles

When making national coverage determinations, CMS generally evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary.

A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A.

Public comments sometimes cite published clinical evidence and give CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. Public comments that contain personal health information will not be made available to the public. CMS responds in detail to the public comments on a proposed national coverage determination when issuing the final national coverage determination.

VII. Evidence

This section provides a summary of the evidence we considered during our review. The evidence reviewed to date includes the published medical literature on pertinent clinical trials of autologous transplant of T-cells expressing at least one CAR for treatment of patients with cancer.

For this NCD, CMS searched for and determined whether the current evidence on CAR T-cell therapy is adequate to draw conclusions about health outcomes, as well as whether the body of evidence is generalizable to the Medicare population. This NCA summarizes the clinical evidence relating to the administration of the two FDA-approved CAR T-cell products, tisagenlecleucel and axicabtagene ciloleucel, in patients with FDA indications. The evidence CMS examines has as its focus health outcomes, i.e., the benefits and harms of a particular treatment. Independently assessed, validated instruments were most heavily weighted. Study endpoints should be clearly defined a priori to both improve the quality of clinical research and so as to allow comparison between clinical trials. In addition, we present evidence on non-FDA indications, as well as evidence of promising Phase I/II clinical trials developing additional CAR T-cell products earlier in the product lifecycle.

Key outcomes of interest to CMS in the treatment of cancer were long-term overall survival (OS, at least one year), progression-free survival (PFS), objective response rate (ORR) including complete response (CR) and partial response (PR), duration of response to specify days to disease progression and/or days to disease recurrence, peri-administration and long-term risk of AEs (especially any and all life-threatening AEs such as CRS), 30-day hospitalization rate, as well as health-related quality of life and function after the administration of CAR T-cell therapy in Medicare beneficiaries.

The development of an assessment in support of Medicare coverage decisions was based on the same general question for most all NCAs: "Is the evidence sufficient to conclude that the application of the item or service under study will improve health outcomes for Medicare patients?" For this NCD, the questions of interest were:

1. Is the evidence adequate to conclude that CAR T-cell therapy improves health outcomes for Medicare beneficiaries with relapsed or refractory large B-cell lymphoma?
2. Is the evidence adequate to conclude that CAR T-cell therapy improves health outcomes for Medicare beneficiaries with relapsed or refractory B-cell precursor acute lymphoblastic leukemia?
3. Is the evidence adequate to conclude that CAR T-cell therapy improves health outcomes for Medicare beneficiaries with other types of cancer?

CMS did not commission an external technology assessment (TA) on this topic. An English language TA was identified during our review and is summarized below.

On February 15, 2018, the Institute for Clinical and Economic Review (ICER), a self-proclaimed "independent non-profit research organization that evaluates medical evidence and convenes public deliberative bodies to help stakeholders interpret and apply evidence to improve patient outcomes and control costs," published a TA titled Chimeric Antigen Receptor T-Cell Therapy for B-Cell Cancers: Effectiveness and Value. As of this date, the TA is found at https://icer-review.org/material/car-t-final-report/.

In September, 2017, ICER performed a search of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials from September 25 – 27, 2017. ICER noted that they "sought out head-to-head studies for these interventions, but none were identified. Recognizing the current state of the evidence base for CAR T-cell therapy, we included single-arm trials and compared outcomes with historical control data." ICER also held discussions with patients and patient groups. The ICER analysis was reported by FDA indication.

Acute Lymphoblastic Leukemia
The ICER analysis included the results from three single-arm clinical trials for tisagenlecleucel for patients with relapsed or refractory ALL. Information for two of the trials (B2101J and B2205J), which were Phase I/II trials that had yet to be published in the clinical literature, was obtained from the Novartis FDA Advisory Committee Briefing Document (2017). Information for the remaining trial, the Phase II ELIANA trial, was obtained from Maude et al. (2017). The primary clinical endpoint selected was cure of the cancer, for which ICER noted there is "no accepted definition of a cure, as relapses can rarely occur more than 10 years after remission. A recent proposal is that children in remission four years after the completion of treatment could be considered cured (< 1% chance of relapse; Hunger and Mullighan, 2015; Pui et al., 2014). Thus, four-year event-free survival would be an ideal outcome."

ICER found the three clinical trials "to be of lower quality because they lack comparators. Furthermore, the studies are small and have short median follow-up, which adds to the uncertainty about long term outcomes with CAR-T therapy for pediatric B-cell ALL."

With regards to the primary clinical endpoint, four-year event-free survival, ICER noted that "none of the trials of CAR-T therapy have followed patients for that long. The reported overall remission rates for tisagenlecleucel in the three trials (from 69% to 95%) represents an optimistic presentation of the results that violates the intention to treat principle because they exclude patients who did not receive the therapy because of manufacturing failures, death prior to infusion, or adverse events (AEs). Table ES2 estimates the overall remission rates in the trials based on the number of patients enrolled in each trial (i.e., on an intention to treat basis)." Table ES2 is reproduced in its entirety.

Table ES2. Overall Remission Rates in Therapies for Relapsed or Refractory Childhood B-ALL

*Based on the number enrolled, not the number receiving the infusion with CAR-T cells

ICER also noted that while "this presentation suggests more modest benefits, the overall remission rates are higher with tisagenlecleucel than with the other therapies. Table ES3 below estimates the overall event-free survival in the trials based on the number of patients enrolled." Table ES3 is reproduced in its entirety.

Table ES3. Estimated Event-Free Survival at Six Months in Therapies for Relapsed or Refractory Childhood B-ALL

*Based on the number enrolled, not the number receiving the infusion with CAR-T cells or the number responding to treatment

With regards to toxicity, ICER stated that the "key AEs experienced by the first 68 patients who received an infusion of tisagenlecleucel in the ELIANA trial were reported in the package insert and are summarized in Table ES4 below." Table ES4 is reproduced in its entirety.

Table ES4. Key Adverse Events in the ELIANA trial (n=68)27

ICER noted that "Additional important grade three or higher adverse events include disseminated intravascular coagulation (9%), histiolymphocytic hemophagocytosis (7%), heart failure (7%), cardiac arrest (4%), seizures (3%), and intracranial hemorrhage (1%). There were 11 deaths: 7 from disease progression, 3 from infections, and one from intracranial hemorrhage. An additional important toxicity is hypogammaglobulinemia due to B-cell aplasia. B-cells are the target of tisagenlecleucel in order to keep the leukemia in remission. Patients without the immunoglobulins produced by B-cells are at risk for infections and are typically treated with monthly intravenous infusions of pooled immunoglobulins (IVIG). The Novartis briefing document for the FDA Advisory Committee states that "responding patients experienced continued B-cell aplasia indicating the long-term effect of tisagenlecleucel" and notes "B-cell aplasia ongoing for > 3 years (FDA Advisory Committee, 2017)." For those who require IVIG, the typical duration of use is unknown."

The authors summarized that for the ALL indication, the "ELIANA trial demonstrated CR rates for tisagenlecleucel that were substantially higher than those observed in recent trials of other drug therapies for heavily pre-treated pediatric patients with B-cell ALL. In addition, the disease-free survival and OS were also greater than those observed with other therapies, particularly in the earlier Phase I trials that have longer follow-up. There are important harms that occur commonly with tisagenlecleucel therapy (CRS, neurotoxicity, B-cell aplasia), but they are manageable and perceived by clinicians as arguably no worse than the serious AEs associated with chemotherapy in this patient population. Thus, the estimated net health benefit is substantial ("B+" rating)." The "B+" rating indicates "Moderate certainty of a small or substantial net health benefit, with high certainty of at least a small net health benefit."

B-Cell Lymphoma
For the FDA indication of B-cell lymphoma, ICER analyzed four clinical trials including a Phase I/II trial (Kochenderfer et al., 2017) and the Phase II ZUMA-1 trial (Neelapu et al., 2017) for axicabtagene ciloleucel as well as a Phase I/II trial (Schuster et al., 2017) and the Phase II JULIET trial (Schuster et al., 2017b—abstract only) for tisagenlecleucel. All four trials studied adults. All four were single-arm therefore ICER selected the SCHOLAR-1 study (Crump et al., 2017), which was an international, multi-cohort retrospective non-Hodgkin’s lymphoma research study that retrospectively evaluated outcomes in patients with refractory DLBCL, as a comparator for their analysis. In SCHOLAR-1, Crump et al., 2017, included patients with refractory DLBCL that was defined as "progressive disease or stable disease as best response at any point during chemotherapy (> 4 cycles of first-line or 2 cycles of later-line therapy) or relapsed at ≤ 12 months from autologous stem cell transplantation. SCHOLAR-1 pooled data from 2 phase 3 clinical trials (Lymphoma Academic Research Organization-CORAL and Canadian Cancer Trials Group LY.12) and two observational cohorts (MD Anderson Cancer Center and University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence)." ICER noted that the SCHOLAR-1 trial used the same inclusion and exclusion criteria as the ZUMA-1 trial to select a subset of patients with aggressive DLBCL. With regards to the primary clinical endpoint, ICER selected event-free survival two years after the completion of treatment as "a reasonable surrogate outcome" based on the work published by Maurer et al. (2014).

ICER noted that the "The ZUMA-1 and JULIET studies as well as the two single site studies were considered to be of lower quality because they lack comparators. Furthermore, the studies were small and of short median follow-up, which adds to the uncertainty about long term outcomes with CAR-T therapy for adult aggressive B-cell lymphoma." In addition, both "the ZUMA-1 and JULIET studies of CAR-T therapies for lymphoma followed patients for less than a median of two years, which limits conclusions about long term impact. Complete remission is a marker for long-term survival, but the majority of patients with B-cell lymphoma who have failed prior therapy usually relapse even after achieving subsequent remission."

Axicabtagene ciloleucel
For axicabtagene ciloleucel, results of the ICER analysis showed:

"Table ES6. Objective Response Rates Reported for Axicabtagene Ciloleucel for Relapsed or
Refractory Adult B-cell Lymphoma Compared with SCHOLAR-1

The complete remission rate for axicabtagene ciloleucel in ZUMA-1 (54%) shown in Table ES6 represents an optimistic presentation of the results that violates the intention to treat principle because it is based on patients who received the infusion of CAR T-cells and does not include the patients who enrolled in the trials but did not receive the therapy because of manufacturing failures, death prior to infusion, or AEs. Table ES7 below estimates the complete remission rate based on the number of patients enrolled in the trial." Table ES7 is reproduced in its entirety.

Table ES7. Estimated Complete Remission Rates for Axicabtagene Ciloleucel for Relapsed or
Refractory Adult B-cell Lymphoma Compared with SCHOLAR-1s

ICER noted that "Even with this change, the complete remission rate is much higher with axicabtagene ciloleucel than with the other therapies. In SCHOLAR-1, the median overall survival was 6.3 months and the Kaplan-Meier estimates for one and two-year survival rates were 28% and 20% respectively. At six months, the Kaplan-Meier estimates for overall survival were 80% in ZUMA-1 and 55% in SCHOLAR-1.

Neelapu and colleagues presented a propensity-score-matched analysis comparing the outcomes of ZUMA-1 to those of SCHOLAR-1 at American Society of Hematology (ASH) in December 2017 (Neelapu et al., 2017a). They reported that after matching, the ORR was 83% in ZUMA-1 and 33% in SCHOLAR-1 (treatment difference 49%, 95% CI 33% to 63%). Similarly, the estimated CR was 57% in ZUMA-1 and 12% in SCHOLAR-1 (treatment difference 46%, 95% CI 26% to 59%). The estimated HR for overall survival was 0.28 (95% CI 0.15 to 0.40) with 18-month OS estimated to be 47% in ZUMA-1 and 23% in SCHOLAR-1."

With regards to the toxicity of axicabtagene ciloleucel, ICER presented the following table:
"Table ES9. Key Adverse Events in the ZUMA-1 Trial (n=101)

Additional important grade 3 or higher adverse events include histiolymphocytic hemophagocytosis (1%), heart failure (6%), cardiac arrest (4%), seizures (4%) and pulmonary edema (9%). There were 44 deaths: 37 from disease progression, two from CRS, one from a pulmonary embolus, and four in patients with disease progression who were on subsequent therapies."

Tisagenlecleucel
The results of the ICER analysis of tisagenlecleucel for relapsed or refractory adult B-cell lymphoma showed:

"Table ES8. Objective Response Rates Reported for Tisagenlecleucel for Relapsed or Refractory
Adult B-Cell Lymphoma Compared with SCHOLAR-1

The complete remission rate for tisagenlecleucel in JULIET (40%) represents an optimistic presentation of the results that violates the intention to treat principle because it is based on patients who received the infusion of CAR-T cells and does not include the patients who enrolled in the trials but did not receive the therapy because of manufacturing failures, death prior to infusion, or AEs, nor does it include patients treated with tisagenlecleucel who had less than three months follow-up at the time of analysis. It was not possible to estimate a complete remission rate using an intent-to-treat analysis based on the data available from the public presentations. The reported CR and ORR in the JULIET trial (40% and 53% respectively) were slightly lower compared to the CR and ORR of the subset of patients with DLBCL in the ZUMA-1 trial (n=77) who were treated with axicabtagene ciloleucel (49% and 82%, respectively; Locke et al., 2017). However, the confidence intervals overlap extensively, and selection bias may also explain part of the differences. For example, the JULIET trial recruited patients from 10 different countries on 4 continents, while 21/22 sites for the ZUMA-1 trial were in the US (one in Israel). The complete remission rate (43%) among patients who received tisagenlecleucel was markedly higher than that observed in the SCHOLAR-1 trial (7%), which predominantly included adults with DLBCL (87% DLBCL). Given the paucity of the currently reported results for the ongoing JULIET trial, we were unable to project long-term outcomes for comparison with axicabtagene ciloleucel or the salvage regimens included in the SCHOLAR-1 study."

Below is a table showing the toxicity of tisagenlecleucel, as presented by ICER, as well as commentary by ICER:

"Table ES10. Key Adverse Events in the JULIET Trial (n=99)

There were no deaths or reported cases of cerebral edema.

Finally, there are theoretical concerns about mutagenesis from the insertion of the transgene into the patient’s T-cells for both CAR-T therapies. The risk is likely to be quite low, but is an important long-term concern for further study."

For the B-cell lymphoma indication, the authors summarize that the "ZUMA-1 trial demonstrated CR rates for axicabtagene ciloleucel that were substantially higher than those observed in recent trials of other drug therapies for heavily pre-treated adults with B-cell lymphoma as reported in the SCHOLAR-1 study. In addition, the disease-free survival and OS appear to be greater than those observed with other therapies, but follow-up in the ZUMA-1 trial is short (median 15.4 months). There are important harms that occur commonly with axicabtagene ciloleucel therapy (CRS, neurotoxicity, B-cell aplasia), but they are manageable and perceived by clinicians as arguably no worse than the serious AEs associated with chemotherapy in this patient population. Thus, the estimated net health benefit is substantial ("B+" rating).

There are no head to head trials of axicabtagene ciloleucel and tisagenlecleucel for patients with relapsed/refractory B-cell lymphomas. The ORR and CR with axicabtagene ciloleucel are somewhat higher than those for tisagenlecleucel, but could easily reflect differences in the patient populations or chance. Patients treated with axicabtagene ciloleucel appeared to have fewer grade 3/4 CRS events, but more grade 3/4 neurologic events. Again, this may represent real differences in the two CAR-T therapies because of differences in their co-stimulatory domains, selection bias, or chance. The lack of head-to-head randomized trials and the small number of patients studied render such judgements premature. Given the level of uncertainty, the evidence is insufficient to judge whether one of the CAR-T therapies is superior to the other ("I" rating)." The "I" rating equals a rating of "Insufficient" and indicates "Any situation in which the level of certainty in the evidence is low."

ICER Summary: CAR T-cell Therapy
In summary, for both tisagenlecleucel and axicabtagene ciloleucel and for both FDA indications, ICER noted a number of uncertainties with regards to the results of the above clinical trials including that "the studies of CAR-T therapies are all single-arm trials. Given the possibility of selection bias in these trials, it is impossible to compare outcomes from these trials to those of other trials without considerable uncertainty." In addition, "the trials themselves are small and have short follow-up. The sample sizes with outcomes in the trials are less than 100 participants, and the median follow-up in the trials is less than two years. Thus, estimates of outcomes from the trials have wide confidence intervals; as such, both the benefits and duration of and long-term relapse-free survival is unknown at this point.

A related uncertainty is the long-term harms of therapy. In the intermediate term, there is insufficient data to estimate how many patients will continue to have clinically important hypogammaglobulinemia from B-cell aplasia. There are also theoretical concerns about complications from the viral vectors used in the manufacturing process and of secondary malignancies related to mutations in the T-cells due to the manufacturing process. Finally, there may be unanticipated harms that arise as larger numbers of patients are followed for several years."

On June 20, 2018, CMS searched PubMed for clinical trials that focused on tisagenlecleucel or axicabtagene ciloleucel and were published in peer-reviewed journals. The literature search was limited by language (English), study population (human), article type (clinical trial) and timeframe (last ten years). Search terms included "chimeric antigen receptor," "CAR T," "T-cell," "CAR-T," "CART-19," "leukemia," and "lymphoma." Abstracts for the resultant citations were visually reviewed to find the clinical studies that focused on tisagenlecleucel or axicabtagene ciloleucel. From the PubMed search results, we found four relevant articles for lymphoma (Schuster et al., 2017; Neelapu et al., 2017; Kochenderfer et al., 2017; Locke et al., 2017) and two relevant articles for leukemia (Maude et al., 2014; Maude et al., 2018) that met our inclusion criteria.

We also searched the bibliography of each of the above articles, the citation list of clinical guidelines, professional society position statements and each public comment to find additional sources of clinical evidence for our review. We identified no new evidence from this search that met our criteria.

The full-text, peer-reviewed published literature articles that present the results of a clinical trial for tisagenlecleucel or axicabtagene ciloleucel are summarized below by FDA indication. Abstracts were excluded because they do not provide sufficient information about the clinical trial to support further review. Reviews, retrospective studies/case reports and commentaries were not included because they did not present the results of a data analysis (reviews), were of insufficient evidentiary weight compared to prospective clinical trials, or were subjective (commentaries). NCCN clinical guidelines and CMS approved compendia information were researched as part of this analysis. We include publicly accessible information, including the Summary Basis of Approval from the FDA website and professional society position statements as summarized in the Evidence Summary section that follows.

Tisagenlecleucel for Relapsed or Refractory ALL

Maude SL, Frey N, Shaw PA et al. Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. N Engl J Med 2014;371:1507-17.
The authors reported the two year outcomes of their Phase I/II clinical trial, which was a prospective, single arm, single center, open label, pilot study designed to assess the safety and feasibility of CART19 therapy (CTL019—the precursor to tisagenlecleucel; Novartis) in children and adults with chemotherapy-resistant or refractory CD19+ leukemia. Conditioning chemotherapy with etoposide/cyclophosphamide, fludarabine/cyclophosphamide, methotrexate/eytarabine, or cyclophosphamide/vincristine/adriamycin was administered one week prior to CTL019 infusion unless medically contraindicated. The administration of tocilizumab was standard for all occurrences of severe CRS. Severe CRS was defined as hypotension requiring two or more vasopressors or respiratory failure requiring mechanical ventilation. The administration of immunoglobulin was standard for all occurrences of B-cell aplasia. A CR was defined by morphologic assessment of the bone marrow as M1 (< five percent leukemic blasts) with no evidence of extramedullary disease.

A total of 30 patients with relapsed or refractory ALL were treated. Twenty-five were five to 22 years of age (pediatric cohort: median age at infusion was 11 years; 56% male); five were 26 to 60 years of age (adult cohort: median age at infusion was 47 years; 80% male).

Median follow-up was seven months (range, 1 – 24). At one month, 27 of 30 (90%) patients achieved a CR. Nineteen of 27 patients remained in remission with 15 patients receiving no further treatment and four patients withdrawing from the study to receive further treatment. Seven of 27 patients relapsed between six weeks and 8.5 months after infusion; three relapses were associated with loss of CTL019 T-cells. The remaining patient with a CR developed myelodysplastic syndrome and withdrew from the study. The six-month event-free survival rate was 67% (95% confidence interval [CI], 51 – 88). The six-month OS was 78% (95% CI, 65 – 95). The probability that a patient would have persistence of CTL019 at six months was 68% (95% CI, 50 – 92). The probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 – 94).

No deaths related to the administration of CTL019 were reported. CRS developed in all 30 patients, who were hospitalized for treatment of the CRS. Severe CRS developed in eight (27%) patients, which was treated in the intensive care unit with tocilizumab with full recovery. Thirteen patients developed neurologic adverse events ranging from delirium associated with high temperatures to global encephalopathy. All symptoms were reported to be self-limiting and fully resolved over two to three days without need for treatment or apparent long-term sequelae. B-cell aplasia occurred in all patients who experienced a response to CTL019 infusion and was reported to persist for up to one year.

The authors concluded that the "complete remission rate of 90% and sustained remissions of up to 2 years that were seen in this study are encouraging."

Maude SL, Laetsch TW, Buechner J et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med 2018;378:439-48.
Maude et al. reported the results of a single-arm, multi-center, global, open-label, Phase II clinical trial of single-dose tisagenlecleucel (formerly CTL019; Novartis) in patients with relapsed or refractory B-cell ALL. Patients had to be three years old or older at screening but no older than 21 years at diagnosis. There were 25 study sites in 11 countries (North America, Europe, Asia and Australia). The primary endpoint was ORR defined as the rate of a best overall response of either CR or CRi within three months. Responses were required to be maintained for at least 28 days. Secondary endpoints included the duration of remission, event-free survival (i.e., the time from infusion to the earliest of the following events: no response, relapse before response was maintained for at least 28 days, or relapse after having complete remission or complete remission with incomplete hematologic recovery), overall survival, cellular kinetics, and safety. An interim analysis was performed after 50 patients and the primary endpoint was met with an overall remission rate of 82% (95% CI, 69 – 91; p <0.001). This report presents results from an updated analysis of 75 patients who received tisagenlecleucel and had completed three months of follow-up or discontinued the study at an earlier point.

Ninety-two patients were enrolled and 75 patients received an infusion of tisagenlecleucel. Seventeen patients did not receive an infusion due to product-related issues (seven patients), death (seven patients) and AEs (three patients).

The median duration of follow-up after infusion was 13.1 months. Sixty-five (87%) of patients received bridging chemotherapy; 72 (96%) received lymphodepleting chemotherapy. For those who received an infusion, the median age was 11 years (range, 3 to 23). Forty three patients (57%) were male.

The ORR was 66% (95% CI, 56 to 76) in the intention-to-treat analysis (92 patients). For the 75 patients who received an infusion, 61 patients had a remission after at least 3 months of follow-up for an ORR of 81% (95% CI, 71 to 89). Forty-five of 75 patients (60%) had a CR and 16 (21%) had a CRi. All 61 patients had not reached a median DOR during the trial.

The OS for the 75 patients was 90% (95% CI, 81 to 95) 6 months after infusion and 76% (95% CI, 63 to 86) 12 months after infusion. The rate of relapse-free survival for patients who initially responded to the infusion was 80% (95% CI, 65 to 89) at six months and 59% (95% CI, 41 to 73) at 12 months. For those with an initial CR, 17 had a relapse before receiving additional anticancer therapy.

The median duration of persistence was 168 days (range, 20 to 617 days; 60 patients). No relationship between dose and expansion was observed.

The most common AEs of any grade included CRS (77%), fever (40%) and febrile neutropenia (36%). Sixty-six of 75 patients (88%) had a grade three or four AE; 55 of 75 patients (73%) had a grade three or four tisagenlecleucel-related AE.

Fifty-eight of 75 patients (77%) developed CRS with a median time to onset of three days (range, 1 to 22) and a median duration of eight days (range, 1 to 36). Thirty-five of 75 patients (47%) received care in the intensive care unit, with a median stay of seven days (range, 1 to 34). Twenty-eight patients (37%) received tocilizumab.

Neurologic events occurred in 30 of 75 patients (40%) within eight weeks after infusion. Ten (13%) were grade three neurologic events; no grade four events were reported. The most common neurotoxicity of any grade were encephalopathy (11%), confusion (9%), delirium (9%), tremor (8%), agitation (7%), and somnolence (7%). The frequency of severe neurologic events increased as the severity of CRS increased; grade three neurologic events occurred more frequently in patients with grade four CRS than among those with lesser grades of CRS (32% [6 of 19] vs. 7% [4 of 56], respectively; 95% CI for the difference, −1 to 50 percentage points). Seventy-five percent of grade three neurologic events resolved within 18 days of infusion. Four episodes of grade three neurologic events were unresolved in three patients—one patient at the time of discontinuation from the trial for no response; one patient at the time of death due to leukemia progression; one patient at the time of death due to encephalitis. Two of these episodes of grade three neurologic events were thought to be related to tisagenlecleucel (one each of encephalopathy and delirium).

Nineteen deaths were reported after infusion. Two patients died within 30 days (one patient with CRS and cerebral hemorrhage; one patient from progressive B-cell ALL). Seventeen patients died more than 30 days after infusion and were reported to be due to B-cell ALL relapse or progression (12 patients), viral–induced encephalitis in association with prolonged neutropenia and lymphopenia (1), systemic mycosis associated with neutropenia (1), after new therapies for B-cell ALL and unknown causes (1).

All patients who responded to the infusion developed B-cell aplasia and most (exact number not reported) were treated with immunoglobulin. The median time to B-cell recovery was not reached during the trial. The probability of maintenance of B-cell aplasia at 6 months after infusion was 83% (95% CI, 69 to 91).

The authors noted the results of this clinical trial show "high response rates" and remissions that are "durable, with a 6-month relapse-free survival rate of 80%" in patients with relapsed or refractory B-cell ALL.

Maude et al. noted that the "majority of neurologic events occurred concomitantly with CRS or shortly after its resolution" and were managed with supportive care.

The authors concluded that "tisagenlecleucel produced high remission rates and durable remissions without additional therapy in high-risk pediatric and young adult patients with relapsed or refractory B-cell ALL. The risks associated with tisagenlecleucel are substantial, leading to ICU-level care in some cases, but were mitigated in most patients with supportive measures and cytokine blockade."

Tisagenlecleucel for Relapsed or Refractory B-cell Lymphoma
Schuster SJ, Svoboda J, Chong EA et al. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med 2017;377:2545-54.

The authors conducted a prospective, single-arm, single-center, Phase I/II clinical trial of single-dose CTL019 (precursor to tisagenlecleucel; Novartis) in patients with relapsed or refractory DLBCL or refractory follicular lymphoma. Refractory disease for DLBCL was defined as disease for which the best response to chemotherapy was progressive or stable disease (stable disease was defined as < 12 months in duration after at least four cycles of first-line therapy or two cycles of second-line or later therapy) or relapse within 12 months or less after ASCT. Double-refractory follicular lymphoma was defined as progressive disease within six months after the last dose of rituximab and the last dose of an alkylating agent. Lymphodepleting chemotherapy was selected by the investigator based on each patient’s treatment history and clinical status. CTL019 was administered one to four days after lymphodepleting chemotherapy with cyclophosphamide, doxorubicin/etoposide/cyclophosphamide, bendamustine, radiation therapy/cyclophosphamide, or etoposide/cyclophosphamide. The primary endpoint was ORR at three months, which the authors did not define except to state that the response was evaluated by using the 1999 International Working Group response criteria as presented in Cheson 1999. Secondary endpoints were PFS, DOR and median survival time. The results of the analyses were not reported by age.

Thirty-eight patients were enrolled and 28 of these patients were infused with CTL019. Of the 10 enrolled patients who were not infused, four patients had rapid disease progression with clinical deterioration, five patients had an insufficient T-cell count for the manufacture of CTL019 cells and one patient withdrew consent. Of the 28 patients who were infused with CTL019, 14 (three women) had DLBCL and 14 (seven women) had follicular lymphoma. The median age was 58 years (range, 25 – 77) for patients with DLBCL and 59 years (range, 43 - 72) for patients with follicular lymphoma.

The median follow-up was 28.6 months. Three months after infusion with CTL019, 18 of the 28 patients had a response (64%; 95% CI, 44 to 81). By six months after infusion, 16 of 28 patients had a CR (57%; 95% CI, 37 to 76), including 6 of 14 patients with DLBCL (43%; 95% CI, 18 to 71) and 10 of 14 patients with follicular lymphoma (71%; 95% CI, 42 to 92). All patients with a CR at 6 months remained in remission for 7.7 to 37.9 months (median, 29.3 months).

Median PFS for patients with DLBCL was 3.2 months (95% CI, 0.9 to not reached); 43% of these patients were progression-free at the median follow-up of 28.6 months (95% CI, 18 to 66). For patients with follicular lymphoma, median PFS was not reached, and 70% (95% CI, 38 to 88) were progression-free at the median follow-up of 28.6 months.

For the median DOR, 86% of patients with DLBCL who had a response (95% CI, 33 to 98) and 89% of patients with refractory follicular lymphoma who had a response (95% CI, 43 to 98) had maintained the response by the median follow-up timepoint of 28.6 months.

Sixteen patients (57%) developed CRS; five of 16 had severe CRS. CRS resolved in all 16 patients with only one patient treated with tocilizumab. Eleven patients developed neurotoxicity ranging from mild cognitive disturbance to global encephalopathy. Three patients had grade three or higher encephalopathy. Neurotoxicity resolved fully within one week except for one patient with progressive neurologic deterioration and death.

The authors concluded that for patients with DLBCL or refractory follicular lymphoma and a poor prognosis, "our observed complete response rates of 43% for patients with diffuse large B-cell lymphoma and 71% for those with follicular lymphoma, with sustained remissions lasting up to 3 years after a single dose of CTL019 cells, support further development of this approach."

Axicabtagene ciloleucel for B-cell Lymphoma
Kochenderfer JN, Somerville RPT, Lu T et al. Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels. J Clin Oncol 2017;35:1803-1813.

Kochenderfer et al. conducted a prospective, single-arm, single-center, Phase I clinical trial of single-dose anti-CD 19 CAR-T-cells (precursor to axicabtagene ciloleucel; Kite Pharma) in patients with lymphoma. Lymphodepleting chemotherapy was administered prior to CAR T-cell therapy. The primary endpoint was ORR as defined by the revised International Working Group Table 2, Cheson 2007). Twenty-two patients were infused; 19 had DLBCL; two had follicular lymphoma and one had mantle cell lymphoma. All but five of the patients had refractory or relapsed disease. The age range was 26 to 67 years; six patients were 65 years old or older. Information about gender was not reported. The results of the analyses were not reported by age.

The ORR was 73%. Twelve of 22 (55%) achieved a CR with a median duration of 12.5 months without further chemotherapy. Four of 22 (18%) achieved a PR however no PRs were durable. The DOR range was seven to 24 months. The 12-month PFS for all patients was 63%. Fifty-five percent of patients developed severe neurologic toxicity. Rate of CRS was not reported. All acute toxicity was reported to resolve completely with one patient receiving steroids and two other patients receiving tocilizumab. The authors concluded that their "results should encourage further research aimed at developing CAR T-cell therapies with less toxicity and higher remission rates."

Locke FL, Neelapu SS, Bartlett NL et al. Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma. Molecular Therapy 2017;25:285-295.
Locke et al. reported the results of the Phase I portion of the Phase I/II ZUMA-1 clinical trial, which was a multicenter, single-arm, single-dose clinical trial of anti-CD 19 CAR T-cells (precursor to axicabtagene ciloleucel; now called KTE-C19; Kite Pharma) in patients with refractory DLBCL. Low-dose conditioning chemotherapy with cyclophosphamide and fludarabine was administered prior to KTE-C19 infusion. The primary endpoint was incidence of dose-limiting toxicity (DLT). Seven patients received an infusion of KTE-C19. The age range was 29 to 69 years; three patients were at least 65 years old. There were five men and two women.

ORR was 71% (5/7) within one month of the infusion; CR rate was 57% (n = 4/7). After at least 12 months of follow-up, three patients had an ongoing CR. One patient developed a DLT of grade four CRS and neurotoxicity. Grade three CRS and neurotoxicity developed in 14% (1/7) and 57% (4/7) patients, respectively. The authors concluded that this "regimen of KTE-C19 was safe for further study in phase 2 and induced durable remissions in patients with refractory DLBCL."

Neelapu SS, Locke FL, Bartlett NL et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med 2017b;377:2531-44.
Neelapu et al. reported the Phase II results of the ZUMA-1 clinical trial, which was a multi-center (22 in the U.S.; one in Israel), single-arm clinical trial of KTE-C19 (axicabtagene ciloleucel; Kite Pharma) in patients with refractory DLBCL. Low-dose conditioning chemotherapy with cyclophosphamide and fludarabine was administered prior to KTE-C19 infusion. Bridging chemotherapy was not permitted. Patients who experienced disease progression at least three months after an initial response were permitted to receive another infusion of KTE-C19. The primary endpoint for the primary analysis was ORR (combined rates of CR and PR) at six months as defined by the revised International Working Group Response Criteria for Malignant Lymphoma (Table 2, Cheson 2007). Secondary endpoints were DOR, PFS and OS. An analysis of data pooled from the Phase I and Phase II portions of the clinical trial was also reported as an updated analysis.

A total of 111 patients were enrolled; 24 of these patients were ≥ 65 years old; 68 patients (67%) were male. One hundred and one (91%) patients were infused with KTE-C19; it was not reported how many were ≥ 65 years old. Reasons for not receiving an infusion included: unsuccessful manufacture of the CAR T-cell product (one); AEs (four); death due to disease progression (one); nonmeasurable disease before conditioning chemotherapy (two); sepsis after conditioning chemotherapy but before KTE-C19 infusion (one); death due to multiple factors with laboratory abnormalities suggestive of tumor lysis syndrome, gastrointestinal bleeding and perforation, and disease progression after conditioning chemotherapy but before KTE-C19 infusion (one).

Primary Analysis
The primary analysis was performed on data with a median follow-up of 8.7 months. The median age was 58 years (range, 23 to 76). Seventy-seven patients had DLBCL and 24 had primary mediastinal B-cell lymphoma or transformed follicular lymphoma.

For the 101 patients who received an infusion, ORR was 82% (95% CI, 73 to 89); the CR rate was 54%. For the 24 patients who were at least 65 years old, the ORR was 92% (95% CI, 73 – 99%). The median time to response was one month (range, 0.8 to 6.0). The median DOR was 8.1 months (95% CI, 3.3 to yet to be reached). Response rates were consistent across age, disease stage, and use of tocilizumab or glucocorticoids. At the time of the primary analysis, 52 patients had disease progression, three patients had died from AEs during treatment, one patient started an alternative therapy before disease progression and 44 remained in remission (of whom 39 had a CR). Of the 52 patients who had disease progression after an initial response, nine were retreated with KTE-C19. Of these patients, five had a response (two CRs and three PRs).

Of the 101 patients who received an infusion, 95 (95%) developed a grade three or higher AE. The most common grade three or higher AEs were neutropenia (78%), anemia (43%), and thrombocytopenia (38%). AEs were not reported separately by age. CRS developed in 94 patients (93%); 37% were grade one and 44% were grade two. Thirteen percent were grade three or higher (9% grade 3; 3% grade 4; 1% grade 5). Fever, hypoxia, and hypotension were the most common symptoms of grade three or higher CRS. The median time from infusion to onset of CRS was 2 days (range, 1 to 12); the median time to resolution was eight days. Vasopressors were administered in 17% of the patients. All patients had full resolution of CRS except for one occurrence of grade five hemophagocytic lymphohistiocytosis.

Neurologic events developed in 65 patients (64%); 28% were grade three or higher. The most common grade three or higher neurologic events were encephalopathy (21%), confusion (9%), aphasia (7%), and somnolence (7%). The median onset of neurologic events occurred on day five (range, 1 to 17), with median resolution on day 17 after infusion. All neurologic events resolved except for four events that were present at the time of death (two deaths from progressive disease and two from AEs unrelated to the neurologic events). Forty-three percent of patients received tocilizumab and 27% received glucocorticoids for the management of CRS, the neurologic events, or both.

Updated Analysis

For the updated analysis of the pooled Phase I and Phase II data (108 patients), the median follow-up was 15.4 months with a minimum of 12 months. The ORR was 82% (95% CI, 73 –89%); (58% of this amount were CRs). For patients who did not have a CR by one month after infusion, 23 patients eventually had a CR as late as 15 months after infusion without additional therapies for cancer. Overall survival at 6 months was 78% (95% CI, 69 to 85), 59% (95% CI, 49 to 68) at 12 months and 52% (95% CI, 41 to 62) at 18 months. The median DOR was 11.1 months (95% CI, 3.9 to yet to be determined). The PFS at 6 months was 49% (95% CI, 39 to 58), 44% (95% CI, 34 to 53) at 12 months and 41% (95% CI, 31 to 50) at 15 months. Two patients who had a response underwent allogeneic stem-cell transplantation.

There were no new occurrences of CRS or neurologic toxicity to report compared to the primary analysis. There were 44 deaths (37 from disease progression; three from AEs including the two deaths already reported during the primary analysis plus another death from a pulmonary embolism that was judged not to be due to axicabtagene ciloleucel and four other deaths after disease progression and subsequent anti-cancer therapies that were judged not to be related to axicabtagene ciloleucel.

The authors stated that the 82% ORR and the 54% CR rate observed in their trial "compare favorably with the results of the recent SCHOLAR-1 study of existing therapies for this disease, which showed an objective response rate of 26% and a complete response rate of 7% (Crump et al., 2017). With a median follow-up of 15.4 months in our study, responses were ongoing in 42% of the patients, including in 40% who had a complete response, with the emergence of a plateau in the duration of the response curve at 6 months. Although most responses occurred in the first month, 23 patients had a complete response as late as 15 months. It would be reasonable to monitor patients who did not have a complete response at the first disease assessment and allow for an opportunity for an improved response, since consolidation with allogeneic stem-cell transplantation comes with a high rate of treatment-related death and would also ablate CAR T-cells."

Neelapu et al. found that the "incidence of the cytokine release syndrome and neurologic events of grade 3 or higher decreased over the course of the study, possibly because of increased experience at the study centers and a protocol amendment allowing for earlier administration of tocilizumab or glucocorticoids (Neelapu et al., 2017c)." The "use of tocilizumab or glucocorticoids did not appear to affect the overall response among the patients in our study." In conclusion, the authors stated that their "findings support the use of axi-cel as an effective therapeutic option in adult patients with relapsed or refractory large B-cell lymphoma after at least two prior systemic therapies."

FDA Regulatory History and Review for CAR T-cell Therapy
The following excerpts from FDA materials obtained via the FDA website are included to provide the regulatory background of the two CAR T-cell therapies that are currently FDA-approved.

Tisagenlecleucel for ALL
In its August 30, 2017 Summary Basis for Regulatory Action (SBRA), the FDA recommended regular approval of tisagenlecleucel for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. According to the FDA, "One clinical trial, CCTL019B2202 (B2202), conducted under a Special Protocol Assessment, provided the basis for the BLA submission for a regular approval for KYMRIAH.

The B2202 trial was adequate and well controlled and the review team concluded that the BLA contains substantial evidence to demonstrate effectiveness for the proposed indication. For the 63 patients in the efficacy analysis population, the CR rate was 63% (95% CI: 50%, 75%), and all patients in CR were MRD negative. With a median follow-up of 4.8 months, the median duration of CR was not reached.

The major risks of KYMRIAH include:

A Risk Evaluation and Mitigation Strategies (REMS) program is mandatory for tisagenlecleucel and axicabtagene ciloleucel due to the significant adverse effect profile of CAR T-cell therapy. The purpose of these REMS programs are to mitigate the risks of CRS and neurological toxicities by:

In summary, CAR T-cell therapy is known to have a significant risk for toxicity, which is reflected in the FDA requirements for a REMS program and a black box warning in the labeling for tisagenlecleucel and axicabtagene ciloleucel. Regarding the benefits of CAR T-cell therapy, the evidence from clinical studies for both tisagenlecleucel and axicabtagene ciloleucel is limited, especially for Medicare beneficiaries 65 years of age and older with a diagnosis of B-cell lymphoma, and weakened by the uncontrolled nature of the studies. The existence of gaps in the evidence due to these limitations are acknowledged in the FDA requirement for a 15-year post-marketing study, in the findings of an external technology assessment as well as in position statements and evidence-based clinical guidelines by professional organizations and the opinions provided by experts during the public comment period. Despite the gaps in evidence, significant toxicity, and the still to-be-determined net benefit-risk ratio for this new and rapidly-evolving field of cancer immunotherapy, CMS believes that CAR T-cell therapy shows promise in improving health outcomes in patients with cancer, and proposes to cover CAR T-cell therapy for an FDA-approved indication if other criteria are also met as discussed further in this analysis.

3. Is the evidence adequate to conclude that CAR T-cell therapy improves health outcomes for Medicare beneficiaries with other types of cancer?

We recognize there may be cases where patients could benefit from expanded clinical use of an FDA-approved biological, such as for example in the case of an Investigational New Drug (IND) application for expanded use, as well as from CAR T-cell products still in development. In addition, we identified over 50 cancer clinical trials currently recruiting patients who are 65 years old or older in the United States for applications of CAR T-cell therapy in cancers other than the currently FDA-indicated cancers (see Section VII.8 and Appendix C). We further see through recommendations by professional organizations such as the Society for Immunotherapy of Cancer that CAR T-cell therapy is an emerging immunotherapy. Therefore, we conclude the while current evidence does highlight specific evidentiary gaps, there is promise to potentially improving patient response to treatment and overall survival from many other cancers using CAR T-cell therapy.

If the answer to any of the questions above is positive, is the available evidence adequate to identify the characteristics of the patient, practitioner or facility that predict which beneficiaries are more likely to experience overall benefit or harm from CAR T-cell therapy?

We believe the current evidence base, which has significant gaps but demonstrates that CAR T-cell therapy is a promising type of cancer immunotherapy, supports coverage through the CED paradigm for further study in patients with cancer. Accordingly, we believe that patient, product, practitioner, and provider limitations are appropriate at this time in order to maximize the likelihood that Medicare beneficiaries experience a health benefit during and from treatment of their cancer with a CAR T-cell product. We discuss each of these conditions as follows:

Medicare Patient Population
Current FDA indications, and thus the current clinical evidence for CAR T-cell therapy, is limited to patients who have relapsed or refractory large B-cell lymphoma or relapsed or refractory B-cell precursor acute lymphoblastic leukemia. These patients have few treatment options, which influence their assessment and discussion of benefits and harms of options with their care provider. The evidence base for the B-cell lymphoma clinical studies is currently small especially for older adults where 33 patients who received axicabtagene ciloleucel and fewer than 28 patients who received tisagenlecleucel were 65 years old or older. Therefore there is very limited understanding of which Medicare beneficiaries are more likely to experience overall benefit or harm from CAR T-cell therapy. While the 25 year old and younger age range in the clinical studies for the acute lymphoblastic leukemia FDA indication is relevant to the disabled Medicare beneficiary population, the evidence base from these studies is currently small. Further study via CED will increase the size of the evidence base and improve the understanding of the effects and benefit-harm profile of tisagenlecleucel, axicabtagene ciloleucel as well as future CAR T-cell products and FDA indications. The current versions of NCCN evidence-based guidelines presented in the evidence section support the current FDA indications. Additionally, CMS proposes to cover additional uses of CAR T-cell therapy when supported by in the NCCN Drugs & Biologics Compendium with a grade of 2 or 1. We note that these guidelines are specific to treatment of cancer, publicly available, and include a review of the clinical evidence. In addition, the NCCN guidelines apply a standard grading system, with definitions for each category of evidence grade. Specifically, grades 2 and 1 include NCCN consensus that an intervention is appropriate.

Given that few clinical trials on CAR T-cell therapy have been performed and those data available have limited participation by Medicare beneficiaries, we performed an analysis of Medicare claims. We sought inpatient claims (see Appendix D) between October 2017 and November 2018 including both ICD-10-PCS procedure codes XW033C3 and XW043C3 and a drug charge greater than $300,000. We identified approximately 100 Medicare inpatient recipients. Of the 100 Medicare patients we identified in our claims analysis, 20 of the attributed inpatients did not survive. The 6 month overall survival for those with follow-up available in our claims analysis was approximately 64%. The average survival time of those that died was less than 100 days, and the average length of stay in the hospital for all inpatients was approximately 18 days. Analyses like these may support patients and their clinicians making more informed treatment decisions. Therefore, we seek additional analyses from commenters’ providing CAR T-cell therapy to broaden our current understanding of the patient experience especially those 65 and older.

Additionally, for the current FDA indications, patients have a poor prognosis. Consequently, patient quality of life is especially important and can impact patients’ decision-making. Therefore, valid and reliable measurement of health-related quality of life is important to inform patients in making critical treatment decisions with their physicians and caregivers. Assessing quality of life and functional status beyond one year following CAR T-cell therapy may therefore be important for a patient deciding whether the benefit from CAR T-cell administration aligns with their care plans and goals. CED will permit the collection of this type of information in the Medicare population. Therefore, we propose coverage for those with cancer who do have not comorbidities that would otherwise preclude patient benefit. We believe, based on limitations on FDA indications, contraindications, and the inclusion and exclusion criteria of published studies, that these limitations include examples such as primary central nervous system lymphoma, Burkitt lymphoma, HIV/AIDS, active Hepatitis B or C, active uncontrolled infection, any autoimmune disease currently requiring immune suppression, and active grade 2 to 4 graft-versus-host disease.

We recognize there may be circumstances when a patient receives more than one therapeutic dose of a specific CAR T-cell product. For this proposed decision, these circumstances are considered to be repeat treatments. To address these circumstances, we propose that repeat treatment using the same biological in the same patient more than once is covered only when a new primary cancer diagnosis is made by the treating oncologist and the patient conditions described in this proposed decision are met. We propose this because there is not sufficient specificity in the evidence available on the health outcomes experienced by patients receiving more than one therapeutic dose of a specific CAR T-cell product. We also note that the clinical review of the BLA for axicabtagene ciloleucel states that, "Of the 101 subjects who had CRS events, seven subjects received a second treatment . . . these subjects were considered as separate subjects. Four of these subjects had CRS Grade 4 and three had CRS Grade 2." Furthermore, no conclusions were provided regarding the safety of the second administration and efficacy analyses based on second treatment were not reported. Since more study is warranted to understand outstanding evidence gaps for these clinical scenarios, we propose that if treatment is an FDA-approved biological, indicated for use identified in the National Comprehensive Cancer Network Drugs & Biologics Compendium with 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, then it would be coverable in section (A)(2)(b) of this proposed decision, provided other coverage criteria are also met.

Practitioner and Provider Requirements
CAR T-cell therapy is associated with a significant risk of toxicity. Therefore, in order to establish appropriate beneficiary protections, we propose to cover CAR T-cell therapy in a hospital that meets certain requirements consistent with a nationally accredited Cellular Therapy Program. The following criteria are consistent with the performance of study sites where initial research on the safety of CAR T-cell therapy was performed (Maude et al., 2018; Kochenderfer et al., 2017; Neelapu et al., 2017b). Specifically, the hospital must have an integrated medical team that includes a Clinical Program Director, a Quality Manager, and at least one physician experienced in cellular therapy, and the hospital team must demonstrate that protocols, procedures, quality management, and clinical outcomes are consistent from regular interaction among all team members. Additionally, the hospital must have a designated care area that protects the patient receiving CAR T-cell therapy from transmission of infectious agents and allows for appropriate patient isolation as necessary for evaluation and treatment. Finally, the hospital must have written guidelines to apply when administering CAR T-cell therapy for patient communication, monitoring, and transfer to intensive care unit. Coverage is proposed for both the inpatient and outpatient hospital settings. Standards we would expect to find in a Cellular Therapy Program are included in the Foundation for the Accreditation of Cellular Therapy (FACT) Common Standards for Cellular Therapies (2015) and Standards for Immune Effector Cell Administration (2016) and describe quality management guidelines to incorporate performance data, as well as policies and procedures that address risk management of operations. These standards require a quality management program at the site of performance that establishes, maintains, monitors, and implements improvements in quality, process, and performance. The basis for FACT accreditation is documented compliance with the current edition of the applicable standards set. We believe adherence to criteria consistent with a nationally accredited Cellular Therapy Program promotes patient safety, and ensures best patient outcomes and optimal CAR T-cell therapy administration. We note that FACT accreditation, which considers these criteria, is also consistent with current practice by CAR T-cell manufacturers and participating hospitals involved with the administration of CAR T-cell therapy and care of patients. The data used for the FDA BLA approval were generated under safe study conditions. Therefore, to maintain the safety for beneficiaries to experience similar improvements in health outcomes overall, practitioner and provider criteria are listed in section I of this document.

Coverage with Evidence Development (CED)
As explained in the analysis, the majority of Medicare patients with relapsed or refractory leukemia or lymphoma are at risk of mortality due not only to their refractory or relapsed cancer but also to advanced age and/or the presence of concomitant illnesses. Therefore, we propose that patients receiving CAR T-cell therapy for a use listed as an FDA indication must be enrolled in a CED registry or study and the hospital with a nationally accredited cellular therapy program administering CAR T-cell therapy must be participating in a national, audited, prospective registry that meets the criteria identified by AHRQ (see Section I proposed decision). Coverage for off-label uses of FDA approved CAR T-cell products is discussed further in this section.

In order to ensure that data collected follows general methodological principles (see Appendix A), and is aligned with the goals in the 2014 CED Guidance Document, we propose that the registry should collect specific data elements and have a written executable analysis plan in place to address the following questions (to appropriately address some questions, Medicare claims or other outside data may be necessary):

• How do patient outcomes compare to either the initial pivotal clinical trial (i.e., the clinical trial(s) that served as the basis for FDA approval of the biological and the FDA indication for use) of the biological or a cohort of controls receiving standard of care treatment?


• How do the clinical characteristics of study patients affect the clinical endpoints relative to those in initial pivotal clinical trial(s) or a cohort of controls receiving standard of care treatment?


• How do the clinical characteristics of registry patients affect the clinical endpoints relative to those in the pivotal clinical trial(s) or a cohort of controls receiving standard of care treatment?


• How does the patient feel their health-related quality of life changes over the course of their treatment?

In order to compare clinical characteristics of study patients, the CED study must collect patient age, gender, and comorbidities. These subgroup analyses could address evidentiary gaps noted in our review of the existing evidence. Additionally, information on the specifics of cancer diagnosis (e.g., sub-classification, stage) as well as the previous regimen or line of therapy and therapeutic agents can address the questions raised by the studies that presented the number of previous therapies (Maude et al., 2018; Neelapu et al., 2017b). These studies did not analyze the impact of the types of previous lines of therapy administered to patients before receiving CAR T-cell therapy. Therefore, there are additional evidentiary questions raised by the extent to which the number or type of previous therapies administered to those in the Medicare population will affect outcomes after administration of CAR T-cell therapy. We also propose one CED question specific to outpatients, which we discuss in the subsection specific to outpatients further in this analysis.

In order to compare the clinical outcomes of study patients relative to existing evidence, the CED study must collect days to disease progression, days to recurrence, overall survival, and progression-free survival. Schuster et al. (2017), Kochenderfer et al. (2017), and Neelapu et al. (2017) have the duration of response and progression-free survival documented in evidence section. Questions remain as to the standard approach for utility of the duration of response and therefore analysis is proposed to include both the patient population with disease progression as well as those patients with disease recurrence. These aspects of the patient’s response can give further information to those patients as well as providers and caregivers on the best outcomes seen for the patients within similar subgroups. Furthermore, this new information on an expanded Medicare patient population could address identified evidentiary questions by this analysis. Evidence for overall survival is considered to be the gold standard for results in cancer clinical trials, however only three studies (Maude et al., 2014; Maude et al., 2018; Neelapu et al., 2017b) presented any information on overall survival and the limited sample size could not address overall survival for specific patient subpopulations. Therefore, additional evidence through the CED study, could address this limitation in analysis to better understand what patient subpopulations can expect from their treatment decisions.

Outpatient Setting: NCCN guidelines recommend specialized care for patients who receive CAR T-cell therapy. Additionally, patients who receive CAR T-cell therapy typically experience sometimes serious AEs within the first week after infusion. In addition to the needs of Medicare patients themselves, the ability of the patient’s caregivers and support network to recognize and handle related events may not be certain. Therefore, we are concerned about seriously ill patients with relapsed or refractory cancer who receive CAR T-cell therapy without a hospital inpatient admission to receive specialized care and monitor for serious AEs. To this end, consistent with NCCN guidelines, and the limited information regarding use of an FDA-approved product inconsistent with an FDA indication for use, we also propose that patients receiving CAR T-cell therapy for any other use and patients provided CAR T-cell therapy without hospital inpatient admission must address the CED question of how the patient feels their health-related quality of life changes over the course of their treatment and to this end collect patient’s health-related quality of life using an NIH patient-reported outcome assessment, including the PRO-CTCAE and PROMIS. This is consistent with the nine voting members on the panel who provided recommendations for these specific PRO assessments based on greater than intermediate confidence in the existing evidence, and believed that such assessments also support the desired characteristics requested by CMS. After receiving these recommendations, and considering the evidence, we believe that using such tools maximizes flexibility in study design to examine the most critical aspects of patient health-related quality of life.

Study Duration: When proposing the duration of CED study, we looked to the existing evidence for collection of clinical endpoints as well as the MEDCAC panel recommendations for specific study design characteristics, study duration, and suitable controls for applying PROs as an endpoint. The evidence for collection of clinical endpoints includes publications that performed assessment within the first three months (Maude et al., 2014; Maude et al., 2018; Schuster et al., 2017), as well as follow up assessment at 12 months (Maude et al., 2018, Kochenderfer et al., 2017; Locke et al., 2017) and 24 months or later (Maude et al., 2014; Schuster et al., 2017; Kochenderfer et al., 2017) to determine progression free survival and overall survival. In addition, the MEDCAC panel had more confidence in recommending fixed time-dependent frequency interval of PRO assessment (i.e. weekly, monthly, or yearly; average = 4.0) than variable event-dependent intervals (average = 2.1). The panel also had more confidence in recommending longer study durations to identify a meaningful durable treatment effect with a valid PRO (average = 4.1). Finally, the panel was most confident in evidence of PRO assessments that compared usual care versus protocol-driven intervention (average = 3.9) and when patients served as own controls (average = 3.8) than with use of historical controls (average = 2.0). After receiving these recommendations on PRO study duration, and considering the evidence for collection of clinical endpoints, we propose that assessments in CED studies must be performed at baseline and at follow-up 3 months, 6, months, 12 months, and 24 months after CAR T-cell therapy administration, to provide robust evidence collection consistent with existing published evidence and recommendations on PROs from independent experts.

A registry may also be considered for the evaluation of patient outcomes that we propose for off-label use of FDA-approved CAR T-cell therapy. In this case, the AHRQ has provided a guide (Gliklich et al., 2014) for researchers to apply to the analysis, interpretation, and reporting of registry data for the purposes of a controlled clinical study. Factors to be considered for this purpose are described in detail within the guide, but we emphasize here that results from a registry would be more meaningful and better interpretable when there is advanced consideration for the prospective patient population and explicit definition of exposures, endpoints, and outcomes. We believe this proposed decision takes into consideration the range of opportunities available to study the Medicare population and answer the specific CED questions for which evidence is not currently available and generalizable to the population we serve. To this end, we would expect that patients would be enrolled in a CMS-approved clinical study that consecutively enrolls patients and follows the patient for at least two years to answer specific CED questions and collect pre-specified data elements, which would be best-served considering the AHRQ guide when a registry is submitted for this purpose.

Considerations for Further Research
Based on our analysis, we recognize there may be cases where patients could benefit from Investigational New Drug (IND) applications for new CAR T-cell products still in development for FDA indicated cancers as well as CAR T-cell therapy in cancers other than the currently FDA indicated cancers. The end result of such research could improve health outcomes of Medicare beneficiaries.

CMS proposes to non-cover the use of T-cells expressing at least one CAR that is not an FDA-approved biological or when cancer patients do not have a cancer that meets any of the indications noted in A.1.a. of the proposed NCD. Additionally, we have listed in the proposed NCD that coverage will continue for routine care items and services furnished to patients who receive CAR T-cell therapy under a qualifying clinical trial. We believe it is important to note that 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.

Health Disparities

In order to provide data on health disparities in CAR T-cell therapy, we performed a search on terms "CAR T-cell therapy health disparities" in PubMed for any publication type. This search resulted in one publication (Shah et al., 2018). The authors present a summary of the current literature in hematopoietic cell transplant (HCT) and cellular therapy with a focus on program structure, system capacity, coordination of care, institutional standardization, and diversity and disparity of care, and quality of life. The authors recognize that the improved health outcomes include broad consideration for both the operations and infrastructure of the health care system that provide processes of care, as well as the symptom burden experienced by the patient. To this end, the authors questioned the geographical distribution of HCT centers, with variability in annual transplant volume, outcomes, and resources. To this end, the authors recommend standardization through FACT or the Joint Accreditation Committee ISCT-European Society for Blood and Marrow Transplant, and discussed the importance of metrics to document the effectiveness of interventions as a basis for further improvement. The authors also recommend additional focused interventions to counterbalance the effects of outcome disparities due to race, gender and socioeconomic status. While data have not been systematically collected on the administration of CAR T-cell therapy, disparities seen in HCT are considered in part due to a delay in referral to a transplant center, barriers to access, ability to work before transplant, and presence of support partner. While this data may be generalizable to other cancers, further research to identify the barriers that are unique to accessing and increasing the inclusion of a diverse population of patients in cancer clinical trials is warranted.

Summary
Based upon our review of the evidence, CMS proposes coverage for CAR T-cell therapy through the CED paradigm when patients, practitioners, and providers meet specific criteria in the context of a clinical study, to generate further evidence generalizable to the Medicare population. We recognize that this is a rapidly evolving field and that initial evidence appears promising but inconclusive at this time to definitely determine whether CAR T-cell therapy improves health outcomes in the Medicare population. Therefore, we are proposing that CAR T-cell therapy could only improve health outcomes for certain Medicare beneficiaries when furnished under conditions that maximize the conditions for successful treatment. These conditions include standard criteria for providers with sufficient expertise who perform the CAR T-cell administration to ensure the safety of Medicare beneficiaries in clinical studies under CED, and admit patients for therapy and subsequent clinical care in facilities that can successfully treat patients who may experience significant adverse effects. We believe that further evidence on patients’ health outcomes, in defined circumstances, under a national, prospective, audited registry, may lead to additional evidence that physicians, patients, and their caregivers can use to make informed treatment decisions.

For all other uses of CAR T-cell therapy, and uses when a patient is not admitted to the hospital, we believe that there is promising evidence on patient health-related quality of life. Therefore, we have proposed an additional CED question under these circumstances of clinical study. We believe that beneficiaries’ ability to attain improved health outcomes is maximized when this information is collected using a validated patient-reported outcome assessment, and data are analyzed, published, and incorporated into shared decision making. While we are mindful of ongoing research, we believe that this additional data collected in the context of a clinical CED study setting can further clarify the impact of CAR T-cell therapy on the Medicare patient population this proposed coverage determination is intended to serve. We also acknowledge that Medicare will continue coverage of routine care items and services under the clinical trial policy when a Medicare beneficiary receives an investigational CAR T-cell therapy. Based on the above evidence and conclusions, we believe the proposed Medicare coverage under the CED paradigm balances these evidentiary considerations and the interests of our beneficiaries.

IX. Conclusion

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 cancer; and
   2. not currently been experiencing any comorbidity that would otherwise preclude patient benefit.


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-CTCAE™) 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-approvedbiological, indicated for use identified in the National Comprehensive Cancer Network Drugs & Biologics Compendium with 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. 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 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.

See Appendix B for proposed NCD Manual language.

When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service is reasonable and necessary. The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients.

We divide the assessment of clinical evidence into three stages: 1) the quality of the individual studies; 2) the generalizability of findings from individual studies to the Medicare population; and 3) overarching conclusions that can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential risks and benefits.

The methodological principles described below represent a broad discussion of the issues we consider when reviewing clinical evidence. However, it should be noted that each coverage determination has its unique methodological aspects.

Assessing Individual Studies

Methodologists have developed criteria to determine weaknesses and strengths of clinical research. Strength of evidence generally refers to: 1) the scientific validity underlying study findings regarding causal relationships between health care interventions and health outcomes; and 2) the reduction of bias. In general, some of the methodological attributes associated with stronger evidence include those listed below:

• Use of randomization (allocation of patients to either intervention or control group) in order to minimize bias.
• Use of contemporaneous control groups (rather than historical controls) in order to ensure comparability between the intervention and control groups.
• Prospective (rather than retrospective) studies to ensure a more thorough and systematical assessment of factors related to outcomes.
• Larger sample sizes in studies to demonstrate both statistically significant as well as clinically significant outcomes that can be extrapolated to the Medicare population. Sample size should be large enough to make chance an nlikely explanation for what was found.
• Masking (blinding) to ensure patients and investigators do not know to that group patients were assigned (intervention or control). This is important especially in subjective outcomes, such as pain or quality of life, where enthusiasm and psychological factors may lead to an improved perceived outcome by either the patient or assessor.

Regardless of whether the design of a study is a randomized controlled trial, a non-randomized controlled trial, a cohort study or a case-control study, the primary criterion for methodological strength or quality is to the extent that differences between intervention and control groups can be attributed to the intervention studied. This is known as internal validity. Various types of bias can undermine internal validity. These include:

• Different characteristics between patients participating and those theoretically eligible for study but not participating (selection bias).
• Co-interventions or provision of care apart from the intervention under evaluation (performance bias).
• Differential assessment of outcome (detection bias).
• Occurrence and reporting of patients who do not complete the study (attrition bias).

In principle, rankings of research design have been based on the ability of each study design category to minimize these biases. A randomized controlled trial minimizes systematic bias (in theory) by selecting a sample of participants from a particular population and allocating them randomly to the intervention and control groups. Thus, in general, randomized controlled studies have been typically assigned the greatest strength, followed by non-randomized clinical trials and controlled observational studies. The design, conduct and analysis of trials are important factors as well. For example, a well-designed and conducted observational study with a large sample size may provide stronger evidence than a poorly designed and conducted randomized controlled trial with a small sample size. The following is a representative list of study designs (some of that have alternative names) ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias:

Randomized controlled trials
Non-randomized controlled trials
Prospective cohort studies
Retrospective case control studies
Cross-sectional studies
Surveillance studies (e. g. , using registries or surveys)
Consecutive case series
Single case reports

When there are merely associations but not causal relationships between a study’s variables and outcomes, it is important not to draw causal inferences. Confounding refers to independent variables that systematically vary with the causal variable. This distorts measurement of the outcome of interest because its effect size is mixed with the effects of other extraneous factors. For observational, and in some cases randomized controlled trials, the method in that confounding factors are handled (either through stratification or appropriate statistical modeling) are of particular concern. For example, in order to interpret and generalize conclusions to our population of Medicare patients, it may be necessary for studies to match or stratify their intervention and control groups by patient age or co-morbidities.

Methodological strength is, therefore, a multidimensional concept that relates to the design, implementation and analysis of a clinical study. In addition, thorough documentation of the conduct of the research, particularly study selection criteria, rate of attrition and process for data collection, is essential for CMS to adequately assess and consider the evidence.

Generalizability of Clinical Evidence to the Medicare Population

The applicability of the results of a study to other populations, settings, treatment regimens and outcomes assessed is known as external validity. Even well-designed and well-conducted trials may not supply the evidence needed if the results of a study are not applicable to the Medicare population. Evidence that provides accurate information about a population or setting not well represented in the Medicare program would be considered but would suffer from limited generalizability.

The extent to that the results of a trial are applicable to other circumstances is often a matter of judgment that depends on specific study characteristics, primarily the patient population studied (age, sex, severity of disease and presence of co-morbidities) and the care setting (primary to tertiary level of care, as well as the experience and specialization of the care provider). Additional relevant variables are treatment regimens (dosage, timing and route of administration), co-interventions or concomitant therapies, and type of outcome and length of follow-up.

The level of care and the experience of the providers in the study are other crucial elements in assessing a study’s external validity.  Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings.  For example, an investigator’s lengthy and detailed explanations of the potential benefits of the intervention and/or the use of new equipment provided to the academic center by the study sponsor may raise doubts about the applicability of study findings to community practice.

Given the evidence available in the research literature, some degree of generalization about an intervention’s potential benefits and harms is invariably required in making coverage determinations for the Medicare population.  Conditions that assist us in making reasonable generalizations are biologic plausibility, similarities between the populations studied and Medicare patients (age, sex, ethnicity and clinical presentation) and similarities of the intervention studied to those that would be routinely available in community practice.

A study’s selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations.  One of the goals of our determination process is to assess health outcomes.  These outcomes include resultant risks and benefits such as increased or decreased morbidity and mortality.  In order to make this determination, it is often necessary to evaluate whether the strength of the evidence is adequate to draw conclusions about the direction and magnitude of each individual outcome relevant to the intervention under study.  In addition, it is important that an intervention’s benefits are clinically significant and durable, rather than marginal or short-lived.  Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.

If key health outcomes have not been studied or the direction of clinical effect is inconclusive, we may also evaluate the strength and adequacy of indirect evidence linking intermediate or surrogate outcomes to our outcomes of interest.

Assessing the Relative Magnitude of Risks and Benefits

Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.  Health outcomes are one of several considerations in determining whether an item or service is reasonable and necessary.  CMS places greater emphasis on health outcomes actually experienced by patients, such as quality of life, functional status, duration of disability, morbidity and mortality, and less emphasis on outcomes that patients do not directly experience, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses.  The direction, magnitude, and consistency of the risks and benefits across studies are also important considerations.  Based on the analysis of the strength of the evidence, CMS assesses the relative magnitude of an intervention or technology’s benefits and risk of harm to Medicare beneficiaries.

Clinical trials of CAR T-cell products (CD19, CD20, CD22, CD123, BCMA, mesothelin, and EGFRvIII) currently recruiting patients with cancer aged 65 years or older in the United States.

Methods for claims analysis.

The Integrated Data Repository (IDR) is a high-volume data warehouse integrating Parts A, B, C, D, and DME claims, beneficiary and provider data sources, along with ancillary data such as contract information, risk scores, and many others. This retrospective claims analysis used administrative claims data from final action claims in the IDR to identify claims for CAR T-cell therapy administration and related services rendered from October 1, 2017, to November 9, 2018. To be considered within this analysis, claims with claim type code 60 and total charge amount greater than $300,000 associated with revenue center codes 025, 026, and 063 were considered. Average length of stay was calculated from all inpatient claims. Average time to death was calculated as the sum of days post-administration of CAR T-cell therapy for each patient who died divided by the total number of patients who died. Survival analysis is based on the method by Kaplan and Meier (1958). All results were approximated to the nearest ten. Technical assistance to researchers interested in the CMS Medicare and Medicaid data through the Chronic Conditions Data Warehouse (CCW) can be accessed through the Research Data Assistance Center (ResDAC). More information on accessing claims data is available at https://www.resdac.org/research-identifiable-files-rif-requests.

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