Radioimmunotherapy for Non-Hodgkin's Lymphoma

The Centers for Medicare & Medicaid Services (CMS) is seeking public comment on its proposed determination that there is insufficient evidence to change current policy on the off-label use of Zevalin® or BEXXAR® for the treatment of Non-Hodgkin’s Lymphoma.

This decision does not propose to modify the existing requirement for coverage of these and other anticancer diagnostic or therapeutic agents for FDA-approved indications.

This decision makes no change in coverage for any off-label uses of these agents in clinical trials. Contractors would continue to provide coverage for medically accepted uses of off-label indications when such uses are supported by evidence appearing in CMS-approved peer-reviewed medical literature.

We are requesting public comment on these proposed determinations pursuant to Section 731 of the Medicare Modernization Act.

To:		Administrative File CAG-00163N 
		Radioimmunotherapy for Non-Hodgkin's Lymphoma (CAG-00163N) 
 
From:	Steve E. Phurrough MD, MPA 
		Director, Coverage and Analysis Group 
 
		Louis B. Jacques, MD 
		Director, Division of Items and Devices 
 
		Francina Spencer 
		Analyst, Division of Items and Devices 
 
		Lori Paserchia MD 
		Medical Officer, Division of Medical and Surgical Services 
 
Subject:		Proposed Coverage Decision Memorandum for Radioimmunotherapy for Non-Hodgkin's Lymphoma (CAG-00163N)-V7 
 
Date:		May 4, 2005

I. Proposed Decision

The Centers for Medicare & Medicaid Services (CMS) is seeking public comment on its proposed determination that there is insufficient evidence to change current policy on the off-label use of Zevalin® or BEXXAR® for the treatment of Non-Hodgkin’s Lymphoma.

This decision does not propose to modify the existing requirement for coverage of these and other anticancer diagnostic or therapeutic agents for FDA-approved indications.

This decision makes no change in coverage for any off-label uses of these agents in clinical trials. Contractors would continue to provide coverage for medically accepted uses of off-label indications when such uses are supported by evidence appearing in CMS-approved peer-reviewed medical literature.

We are requesting public comment on these proposed determinations pursuant to Section 731 of the Medicare Modernization Act.

II. Clinical Background

Non-Hodgkin’s Lymphomas

Lymphomas are a group of malignant neoplasms that are characterized by the proliferation of cells native to the lymphoid tissues, which are most typically lymphocytes (including the B-cell and T-cell types). Within this broad category of neoplasms, which encompass a highly variable array of abnormal cellular morphologies, two major subsets have been defined: Hodgkin’s lymphoma and non-Hodgkin’s lymphomas (NHL). Hodgkin’s lymphoma has a distinctive cellular finding (i.e., the Reed-Sternberg cell). It almost always spreads by a characteristic pattern of contiguity from lymph node chain to lymph node chain, and unlike NHL, there is almost never a leukemic component in which malignant cells infiltrate the blood stream.

NHL is the fifth most common cause of cancer in the United States, with an estimated incidence of 63,600 cases in 2001 (FDA ODAC Briefing, 2001), and a steady increase in incidence since 1950 at a rate of approximately 4% per year. NHL is most commonly diagnosed in adults, often in the fifth to sixth decades.

Conventional chemotherapy, such as alkylating agents, can provide periods of remission for most patients, even though response rates decrease and the duration of remission becomes shorter with subsequent or additional chemotherapy. Although therapeutic variations are utilized, such as combination chemotherapy and high-dose chemotherapy with bone marrow transplantation (BMT), significant improvements in survival have not been realized. Not only do alkylating agents show decreasing response rates and durations of response with subsequent or additional administrations, but they are also associated with toxic side effects, including an increased risk of developing secondary leukemia.

Newer immunological-based approaches in NHL therapy have been developed to address the above shortfalls. B-lymphocytes have different types of signature proteins (or antigens) which coat the surface of the cells. These antigens can, in turn, be bound by proteins (monoclonal antibodies) in a highly selective manner such that the target of therapy is a homogeneous population of antigen-expressing malignant B-lymphocytes. In the case of follicular B-cell lymphomas, the target antigen of interest is CD20, which is expressed on virtually all lymphomas of this type. In November 1997, the FDA approved Rituximab (Rituxan®)¹ for the treatment of relapsed (i.e., those with recurrent signs and symptoms of disease after a period of remission) or refractory (i.e., those with failed conventional chemotherapy) low-grade or follicular CD20-positive B-cell NHL. Although Rituxan is characterized by a more favorable side-effect profile than conventional chemotherapy, some lymphomas may be resistant to Rituxan. Rituxan is administered weekly for 4 to 8 doses.

The first type of therapy for NHL using radioisotopes is a one-time therapeutic regimen utilizing Zevalin® (Ibritumomab tiuxetan radiolabeled with ⁹⁰Yttrium or ¹¹¹Indium) antibody together with Rituxan. The first step of this complex regimen utilizes ¹¹¹Indium-labeled Zevalin® to assess the biodistribution of a radioactively tagged anti-CD20 monoclonal antibody. This is followed seven to nine days later by a therapeutic step, which delivers a therapeutic dose of radiation (using ⁹⁰Yttrium attached to the same antibody) to the lymphocytes bearing the target (CD20 antigen).

Tositumomab and Iodine I 131 Tositumomab (BEXXAR®) is an anti-neoplastic radioimmunotherapeutic monoclonal antibody-based regimen composed of the monoclonal antibody, Tositumomab, and the radiolabeled monoclonal antibody, Iodine I 131 Tositumomab. The BEXXAR® therapeutic regimen is administered in two discrete steps: the dosimetric and therapeutic steps. Each step consists of a sequential infusion of Tositumomab followed by Iodine I 131 Tositumomab. The therapeutic step is administered 7-14 days after the dosimetric step.

III. History of Medicare Coverage Policies

An item or service is covered by Medicare Part A or Part B if it falls into one or more benefit categories, and is not otherwise excluded by statute from coverage. Medicare has provided reimbursement for anti-cancer therapy in a clinical setting when used in accordance with FDA-approved labeling.

We have concluded that the appropriate benefit categories in the Social Security Act for the above referenced items are diagnostic X-ray tests (§1861(s)(3)) and radioactive isotope therapy (§ 1861(s)(4)). In addition, appropriate benefit categories may be found under §1861(s)(2)(A), services and supplies furnished as incident to a physician's service, and under §1861(s)(2)(B), hospital services incident to physicians' services rendered to outpatients.

Presently, Medicare does not have a national coverage policy on the off-label use of Zevalin® or BEXXAR® in the management of indolent B-cell NHL.

IV. Timeline of Recent Activity

V. Food and Drug Administration (FDA) Status

Both CMS and the FDA review scientific evidence, and may review the same evidence, to make purchasing and regulatory decisions, respectively. However, CMS and its contractors make coverage determinations and the FDA makes premarket approval decisions under different statutory standards and different delegated authority.² Whereas the FDA must determine that a product is safe and effective as a condition of approval, CMS must determine that the product is reasonable and necessary as a condition of coverage under section 1862(a)(1)(A) of the Social Security Act. Under a premarket approval review, the FDA determines whether or not the product is safe and effective for its intended use that is stated in its proposed labeling. In assessing reasonable and necessary for a therapeutic, CMS determines, among other things, whether or not the product improves net health outcomes in the Medicare population that are at least equivalent to established alternatives. In the reasonable and necessary assessment, 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 FDA approved Zevalin® on February 19, 2002.

The BEXXAR® therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) was approved on June 27, 2003. (http://www.fda.gov/cder/foi/label/2003/tosicor062703LB.pdf, accessed January 27, 2005) On December 22, 2004, the FDA granted a supplementary approval (http://www.fda.gov/cder/foi/label/2004/125011_0024lbl.pdf, accessed January 27, 2005)

VI. General Methodological Principles of Study Design

When making national coverage determinations under 1862(a)(1)(A) of the Social Security Act, 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 for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve net health outcomes for patients. The General Methodological Principles of Study Design is located in Appendix B.

VII. Summary of Evidence

A. Introduction

Consistent findings across studies of net health outcomes associated with an intervention or diagnostic test as well as the magnitude of its risk and benefits are key to the coverage determination process.

The following question was addressed in order to evaluate whether or not the off-label use of these biologicals is reasonable and necessary under the Social Security Act:

Sources of Evidence

Documents available from the FDA were reviewed, including the Zevalin® and BEXXAR® labeling and the transcript from the September 11, 2001 Oncologic Drugs Advisory Committee, including the briefing document from the FDA staff presentation.

We reviewed the Idec briefing document from the September 11, 2001 Oncologic Drugs Advisory Committee, along with supplemental written material, which was requested by CMS to clarify pertinent methodological issues.

A package of clinical studies and letter of support regarding the NCD for Zevalin® was independently sent to CMS on August 7, 2002 by 11 cancer centers.

On September 4, 2003 GlaxoSmithKline submitted a summary of the off-label uses of BEXXAR® (rituximab-naïve, and previously-untreated patients with follicular NHL) and copies of the supporting clinical studies.

B. Discussion of Evidence Reviewed

1. External Technology Assessment

An external technology assessment was not performed in conjunction with the NCD review.

2. Internal Technology Assessment

A MEDLINE search was performed, using the PUBMED engine, with keywords “ibritumomab tiuxetan,” “radioimmunotherapy,” and “rituximab” and “low grade B-cell Non-Hodgkin’s lymphoma.” A second search was conducted using the PUBMED engine with keywords “bexxar NOT non Hodgkin’s Lymphoma” and “tositumomab NOT non Hodgkin’s lymphoma.” Only studies with primary data were included, in English and on human subjects, and case reports were excluded. Studies only conducted with respect to providing results on dosimetry and/or initial safety data (usually corresponding to Phase I/II trials) were not evaluated, although risks from therapy identified in these studies were considered.

Three studies for Zevalin® and one study for Bexxar® were considered in CMS's determination. The key elements from the four studies are presented in Appendix A.

3. MCAC

A Medicare Coverage Advisory Committee (MCAC) meeting was not convened for this review.

4. Evidence-Based guidelines

No evidence-based guidelines were found on the use of these agents for lymphoma.

5. Professional Society Position Statements

The American Society of Clinical Oncology urged that CMS cover FDA-approved uses of Zevalin®.

6. Public Comments

We received nine letters of support for Zevalin®³ regarding the management of indolent B-cell NHL. In addition, the Council on Radionuclides and Radiopharmaceuticals (CORAR) supported Medicare coverage of Zevalin® according to the FDA labeling, and there were similar letters of support from the American Society of Clinical Oncology and the Lymphoma Research Foundation. Although several articles were received as part of this correspondence, none of them provided additional relevant primary data than was already provided in the three clinical studies described above.

VIII. CMS Analysis

National coverage determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally under title XVIII of the Social Security Act. §1869(f)(1)(B). In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B, and must not be otherwise excluded from coverage. Moreover, with limited exceptions, the expenses incurred for items or services must be "reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member." §1862(a)(1)(A).

We believe that the evidence is insufficient to warrant a change from current Medicare coverage based on existing statute and regulation.

The proposal does not obviate the need for contractors to continue to review the medical literature and determine the conditions under which radioimmunotherapy used in anti-cancer diagnostic or treatment regimens for medically accepted indications is reasonable and necessary. Contractors will not infer from this NCD that any off-label uses of these agents should not be approved.

This policy also does not withdraw Medicare coverage for items and services that may be covered according to the existing national coverage policy for Routine Costs in a Clinical Trial (National Coverage Determination Manual, section 310.1).

IX. Proposed Decision

The Centers for Medicare & Medicaid Services (CMS) is seeking public comment on its proposed determination that there is insufficient evidence to change current policy on the off-label use of Zevalin® or BEXXAR® for the treatment of Non-Hodgkin’s Lymphoma.

This decision does not propose to modify the existing requirement for coverage of these and other anticancer diagnostic or therapeutic agents for FDA-approved indications.

This decision makes no change in coverage for any off-label uses of these agents in clinical trials. Contractors would continue to provide coverage for medically accepted uses of off-label indications when such uses are supported by evidence appearing in CMS-approved peer-reviewed medical literature.

We are requesting public comment on these proposed determinations pursuant to Section 731 of the Medicare Modernization Act.

Appendix A [PDF, 88KB]

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 net 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 unlikely explanation for what was found.
• Masking (blinding) to ensure patients and investigators do not know to which 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 the extent to which differences between intervention and control groups can be attributed to the intervention studied. This is known as internal validity. Various types of bias can undermine internal validity. These include:

• 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 which 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 which confounding factors are handled (either through stratification or appropriate statistical modeling) are of particular concern. For example, in order to interpret and generalize conclusions to our population of Medicare patients, it may be necessary for studies to match or stratify their intervention and control groups by patient age or co-morbidities.

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

Generalizability of Clinical Evidence to the Medicare Population

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

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

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

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

A study’s selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations. The goal of our determination process is to assess net 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.

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

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

¹ Hereinafter, Rituximab will be referred to as Rituxan unless otherwise specified.

² See Outpatient Prospective Payment System Final Rule. 67 Federal Register at 66755 (November 1, 2002).

³ Dana-Farber/Partners Cancer Care, Boston, Massachusetts
Fox Chase Cancer Center, Philadelphia, Pennsylvania
H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
Memorial Sloan-Kettering Cancer Center, New York, New York
Lombardi Cancer Center, Washington, D.C.
Mayo Clinic, Rochester, Minnesota
Neoplastic and Autoimmune Diseases Research Institute, Rancho Santa Fe, California
The Ohio State University, Columbus, Ohio

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