Positron Emission Tomography

The Centers for Medicare & Medicaid Services (CMS) proposes that local Medicare Administrative Contractors (MACs) may determine coverage within their respective jurisdictions for positron emission tomography (PET) using radiopharmaceuticals for their labeled indications for oncologic imaging that are approved by the U.S. Food and Drug Administration (FDA).

The effect of this decision, if finalized without change, would be to remove the national noncoverage for any of these identified uses of these radiopharmaceuticals that have not been more specifically determined nationally.  Thus this change would not apply to any use of PET using radiopharmaceuticals FDG (2-deoxy-2-[F-18] fluoro-D-Glucose (fluorodeoxyglucose)), NaF-18 (fluorine-18 labeled sodium fluoride), ammonia N-13, or rubidium Rb-82. This would not prevent CMS from determining national coverage for any of these uses in the future, and if such determinations are made, a future determination would supersede local contractor determinations under §1862(a)(1)(A) of the Social Security Act (the Act).

We are requesting public comments on this proposed decision pursuant to §1862(l) of the Act.  After consideration of these public comments and any additional evidence, we will issue a final determination responding to the public comments consistent with §1862(l)(3) of the Act.

To:		Administrative File: CAG-00065R2 
		Positron Emission Tomography 
 
From:	Louis Jacques, MD 
		Director, Coverage and Analysis Group 
 
		Tamara Syrek Jensen, JD 
		Deputy Director, Coverage and Analysis Group 
 
		James Rollins, MD, PhD 
		Division Director 
 
		Stuart Caplan, RN, MAS 
		Lead Analyst 
 
		Jeffrey Roche, MD, MPH 
		Medical Officer 
 
		Joseph Hutter, MD, MA 
		Medical Officer 
 
Subject:		Proposed Decision Memorandum for CAG-00065R2 Positron Emission Tomography (PET) 
 
Date:		December 13, 2012

I. Proposed Decision

The Centers for Medicare & Medicaid Services (CMS) proposes that local Medicare Administrative Contractors (MACs) may determine coverage within their respective jurisdictions for positron emission tomography (PET) using radiopharmaceuticals for their labeled indications for oncologic imaging that are approved by the U.S. Food and Drug Administration (FDA).

The effect of this decision, if finalized without change, would be to remove the national noncoverage for any of these identified uses of these radiopharmaceuticals that have not been more specifically determined nationally. Thus this change would not apply to any use of PET using radiopharmaceuticals FDG (2-deoxy-2-[F-18] fluoro-D-Glucose (fluorodeoxyglucose)), NaF-18 (fluorine-18 labeled sodium fluoride), ammonia N-13, or rubidium Rb-82. This would not prevent CMS from determining national coverage for any of these uses in the future, and if such determinations are made, a future determination would supersede local contractor determinations under §1862(a)(1)(A) of the Social Security Act (the Act).

We are requesting public comments on this proposed decision pursuant to §1862(l) of the Act. After consideration of these public comments and any additional evidence, we will issue a final determination responding to the public comments consistent with §1862(l)(3) of the Act.

II. Background

Throughout this memorandum, we use the term PET to refer to positron emission tomography or to a positron emission tomogram, depending on the context. FDG refers to 2-deoxy-2-[F-18] fluoro-D-Glucose (fluorodeoxyglucose). NaF-18 PET refers to PET imaging utilizing fluorine-18 labeled sodium fluoride as the radioactive tracer. NaF-18 is also known as F-18 sodium fluoride. Other radioisotopes that may be referred to below include rubidium-82 (rubidium Rb-82), nitrogen-13 (N-13), or carbon-11 (C-11).

We include integrated positron emission tomography/computerized tomography (PET/CT) and integrated positron emission tomography/magnetic resonance imaging (PET/MRI) in the term PET.

PET is a minimally invasive diagnostic imaging procedure used to evaluate normal tissue as well as diseased tissues in conditions such as cancer, ischemic heart disease and some neurologic disorders. Injected radioactive tracers (or radiopharmaceuticals) emit positrons when they decay. PET uses a positron camera (tomograph) to measure the decay of these tracers within human tissue. The relative differences among anatomic sites of rate of tracer decay provide biochemical information on the tissue being studied.

III. History of Medicare Coverage

Nationally, PET is generally noncovered except for specific covered uses of particular radioactive tracers (FDG, ammonia N-13, rubidium Rb-82 and NaF-18.) These covered uses are detailed in Section 220.6 of the National Coverage Determination Manual. See section 220.6 at http://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/ncd103c1_Part4.pdf.

A. Current Request

CMS received a formal written request from the Medical Imaging & Technology Alliance (MITA) for reconsideration of the NCD described above to permit local MACs to make determinations for PET using new proprietary FDA approved radio-pharmaceuticals. The requesters asked that “… CMS remove the current non-coverage language as it pertains to new PET radiopharmaceuticals that receive approval from the FDA.”

We note that the current request is not for positive national coverage of any specific use of PET or a new PET tracer. That is, the requester is seeking a change to the national coverage determination so that new PET radiopharmaceuticals would be subject to local contractor determinations under section 1862(a)(1)(A), rather than be automatically non-covered under the terms of section 220.6. Local contractors could choose to cover (or not cover) PET scans using tracers that are not specifically addressed in 220.6.

B. Benefit Category

Medicare is a defined benefit program. An item or service must fall within a benefit category as a prerequisite to Medicare coverage §1812 (Scope of Part A); §1832 (Scope of Part B) and §1861(s) (Definition of Medical and Other Health Services) of the Act. Positron emission tomography is considered to be within the following benefit category: other diagnostic tests §1861(s)(3).

Medicare regulations at 42 C.F.R. §410.32(a) state in part that “. . . diagnostic tests must be ordered by the physician who is treating the beneficiary, that is, the physician who furnishes a consultation or treats a beneficiary for a specific medical problem and who uses the results in the management of the beneficiary’s specific medical problem.”

IV. Timeline of Recent Activities

V. FDA Status

The history of other FDA approvals, as summarized in our December 15, 2000 decision memorandum, FDG Positron Emission Tomography (PET) (CAG-00065N) is briefly excerpted below.

FDA has reviewed and approved new PET radiopharmaceuticals other than FDG, ammonia N-13, rubidium Rb-82 and sodium fluoride (F-18). In recent months, FDA approved two new PET radiopharmaceuticals for diagnostic imaging as shown in the following table.

The current request suggests that, in addition to the two new PET radiopharmaceuticals noted above, other new PET tracers are undergoing clinical research, potentially for future FDA review for diagnostic imaging indications. The requesters explain this trend by noting in their letter that:

We understand, based on public announcements and communications with the PET stakeholder community, that the FDA has been reviewing new proprietary radioactive tracers for use in PET imaging.

VI. General Methodological Principles

As noted above, the external request and our review are not directed toward establishing positive national coverage for any specific use of PET. Thus, our analysis speaks to whether we believe that physician understanding of the role of PET imaging, and the evidence base on these uses as it has evolved since our first PET NCD, have reached a point where coverage may commonly be determined successfully at the local contractor level with respect to the use of potentially new radiopharmaceuticals.

Public commenters sometimes cite the published clinical evidence and provide CMS with useful information. Public comments that provide information based on unpublished evidence, such as the results of individual practitioners or patients, are less rigorous and, therefore, less useful for making a coverage determination. CMS uses the initial comment period to inform the public of its proposed decision. CMS responds in detail to the public comments that were received in response to the proposed decision when it issues the final decision memorandum.

VII. Evidence

This section explains how CMS will consider the current request.

B. Discussion of Evidence

In contrast to most national coverage analyses (NCAs), national coverage is not being sought by the requesters. CMS is instead being asked to reconsider the language resulting from a prior national coverage policy, not to add or remove a specific diagnostic PET imaging radiopharmaceutical or service, but to remove statements that have had the effect of denying the possibility of local coverage of certain uses of PET tracers, including radiopharmaceuticals that may be approved in the future.

The current request asks that CMS reconsider one part of the note in Section 220.6 (and related language in section 220.6.19(D)) of the Medicare National Coverage Determinations Manual (available on-line at http://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/Downloads/ncd103c1_Part4.pdf)”

In summary, CMS views the current request as a question of how best to administer the Medicare program in the face of rapidly changing technology rather than of the validity or utility of a specific diagnostic PET imaging device or service, and not as a question that can be answered by a traditional review of clinical evidence. Thus we considered whether or not the current imaging environment was sufficiently mature in various clinical areas that we could confidently delegate our local contractors to exercise coverage discretion.

CMS did not request an external technology assessment (TA) on this issue.

Given the nature of the external request, CMS staff could not design nor perform a traditional literature search for relevant clinical evidence about a particular radiopharmaceutical for a specific use in a population of interest. Rather, we searched for evidence that established the strength or weakness of the infrastructure of evidence based clinical guidelines for general clinical areas, e.g., oncologic imaging, cardiac imaging etc.

We believe that a robust and organized infrastructure of evidence based clinical guidelines will facilitate our contractors’ ability to efficiently develop consistent local coverage policies.

4. MEDCAC

A Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) meeting was not convened on this issue. However, some of the conclusions of prior MEDCAC (or MCAC) panel meetings may be relevant to CMS’ analysis (see Section VIII below).

5. Evidence-based guidelines

CMS searched the National Guideline Clearinghouse (www.guideline.gov) on September 28, 2012. We found 106 older adult guidelines than included consideration of the use of PET for oncologic, i.e. cancer related imaging. Guideline sponsors and developers include physician specialty societies, Canadian provincialgovernments, NICE, and other customary institutions. Collectively the scope of the guidelines is broad across many cancer types and the assessment of undifferentiated signs and symptoms that may prompt a diagnostic evaluation for occult cancer. Many of the guidelines focused specifically on PET rather than merely mentioning PET in a general topic review. We also note explicit acknowledgement of the limitations of imaging through statements such as “…[PET/CT] have value in selected patients but are not considered routine clinical practice at this time” in the American College of Radiology (ACR) Appropriateness Criteria for Low Back Pain.

We found 13 older adult guidelines pertaining to PET imaging for cardiology in adults in a search of National Guideline Clearinghouse (www.guideline.gov) on September 28, 2012. Guideline sponsors and developers included the ACR, the American College of Cardiology Foundation, the American Heart Association and various international institutions. These guidelines were not focused on PET, rather PET was one of many diagnostic modalities reviewed in a variety of cardiovascular disease contexts.

6. Professional Society Position Statements

We expect to receive professional society position statements on the proposed decision.

7. Expert Opinion

We did not receive expert opinions on the proposed decision during the initial public comment period.

8. Public Comments

Initial Comment Period: July 11, 2012 – August 10, 2012

CMS received 26 timely public comments during the first public comment period. Of these comments, most supported permitting the MACs to make the section 1862(a)(1)(A) coverage determination with respect to the use of new radiopharmaceuticals, though some also expressed a desire for presumptive positive coverage for FDA approved PET tracers.

Of those not supporting the request, three commenters believe that coverage of PET tracers should be determined at the national level rather than locally by the MACs. Two state that FDA approval is not sufficient for coverage and that use of PET tracers should be considered on a scan-by-scan basis rather than by national or local coverage determination processes.

Four commenters state that neurocognitive imaging agents, including florbetapir, should not be considered within the scope of this decision.

Two comments were outside the scope of the request.

Full text public comments without personal health information can be viewed at http://www.cms.gov/medicare-coverage-database/details/nca-view-public-comments.aspx?NCAId=261.

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 by Medicare (§1862(1) of the Act).

In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within part A or part B, and must not be otherwise excluded from coverage. Moreover, §1862 (a)(1) of the Act in part states that, with limited exception, no payment may be made under part A or part B for any expenses incurred for items or services:

When CMS first addressed diagnostic PET imaging coverage nationally more than a decade ago, PET was a relatively new technology searching for an integrated role among, or eventually in combination with, other advance diagnostic imaging modalities, e.g. CT or MRI. Since that initial assessment, much progress in PET functional performance has been achieved. Such progress has been demonstrated by:

• Improved technical performance of PET scanning systems, especially in integrating their images with those of computerized tomography (CT);
• Enhanced FDA regulation of nuclear medicine, as shown by more stringent requirements for PET/CT diagnostic equipment, for approval of radiopharmaceuticals, and for demonstrating clinical utility of diagnostic services; and
• Better training for those who interpret PET images.

Breadth of the Request

While there was some public comment supporting the core of the request, i.e., permitting coverage determinations to be made by local MACs, there was not a consensus on the breadth of the request. Specifically, several commenters ask us to separately consider PET for neurocognitive imaging. We agree with these latter comments and we have recently opened a national coverage analysis Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease to separately consider that issue. We noted this possibility in the tracking sheet. “We remind the reader that local determination of coverage would not preclude CMS from accepting internal or external requests to open a national coverage analysis (NCA) on any uses of PET.” Thus we will not discuss coverage of beta amyloid PET further in this proposed decision memorandum.

Newer imaging strategies increasingly attempt to correlate visual results with the activity of metabolic or other pathways that are thought to be relevant to the individual patient’s clinical presentation. A proliferation of radioactive PET tracers increases the risk that a patient may, even when PET is indicated, have the study performed with the “wrong” tracer. Absent widespread physician acceptance of evidence based diagnostic algorithms, there is a real risk that imaging may proceed in a haphazard manner. Thus we considered for this review whether evidence based guidelines could support the orderly and efficient determination of coverage by MACs for various indications of PET imaging.

We searched for evidence based guidelines to see whether a robust infrastructure is present to inform physicians’ imaging referral practices and support local MAC determinations of coverage. It is worth emphasis here that we are not in this current reconsideration being asked to grant expanded coverage for PET but to permit certain coverage determination to be made in the first instance by MACs. In that light, we were not looking specifically for guideline recommendations to support positive coverage. Indeed, in this context, a negative recommendation is as persuasive as a positive one. Looking toward PET tracers that may be FDA approved in the future, we believe that an established guideline infrastructure can be readily updated to include their review.

Our search of the National Guideline Clearinghouse identified over 100 evidence based guidelines relevant to PET imaging for oncology. The sponsors and developers reflected a balance of physician professional societies, governmental bodies and others. In many cases these guidelines specifically focused on PET. We believe this demonstrates a robust infrastructure to support a reasonably consistent consideration of the evidence by the MACs, and we propose to permit the MACs to determine whether (or not) coverage of PET scans using new radiopharmaceuticals are reasonable and necessary under section 1862(a)(1)(A).

The number of guidelines that consider PET imaging in cardiology was much smaller, reflected a narrower spectrum of sponsors and developers, and PET was generally one of many diagnostic modalities included in those reviews. Though we are not proposing to delegate cardiac PET imaging to the MACs, we are particularly interesting in public comment on this topic.

Our search for a body of guidelines on PET imaging for topics beyond oncology and cardiology was not productive.

Medicare Administrative Contractor (MAC) Determination

We agree with the commenters who wrote that FDA approval in and of itself should not result in de facto Medicare coverage. However, as we have noted elsewhere in this proposed decision, the current request is not for coverage but for permitting of MACs to determine whether or not PET scans using new radiopharmaceuticals should be covered in the first instance. The requesters suggest our current policy “will present a substantial barrier to beneficiary access to appropriate and well-validated diagnostic healthcare as new, rigorously-reviewed, FDA-approved PET radiopharmaceuticals become available. (External Request, March 30, 2012, at 5.)

The Program Integrity Manual at 13.7.1 provides general direction to the contractors about evidence supporting local coverage determinations (LCDs). While our proposed decision does not require MACs to publish LCDs, they may determine claims on a case by case basis as well; we believe that the practical implementation of the manual instructions would include generally consideration of the following factors when a diagnostic test is under review.

In consideration of diagnostic testing, including imaging, CMS weighs heavily on the impact of the test result on the management of the patient’s condition by the treating physician. Does the test lead the physician to reconsider the pre-test treatment plan and make appropriate modifications in light of the test result? What evidence is available to support assertions of benefit from testing?

We generally consider the evidence in the hierarchical framework of Fryback and Thornbury (1991) where Level 2 addresses diagnostic accuracy, sensitivity and specificity of the test; Level 3 focuses on whether the information produces change in the physician’s diagnostic thinking; Level 4 concerns the effect on the patient management plan, and Level 5 measures the effect of the diagnostic information on patient outcomes.

Commonly, studies have focused on test characteristics and have not considered health outcomes, such as mortality, morbidity or reduction of invasive testing. However, we believe that evidence of improved health outcomes is more persuasive than evidence of test characteristics. Please see Appendix A, General Methodological Principles of Study Design.

In evaluating diagnostic tests, Mol and colleagues (2003) reported: “Whether or not patients are better off from undergoing a diagnostic test will depend on how test information is used to guide subsequent decisions on starting, stopping or modifying treatment. Consequently, the practical value of a diagnostic test can only be assessed by taking into account subsequent health outcomes.” When a proven, well established association or pathway is available that demonstrates a virtually certain association between a well-defined, objectively assessed intermediate health outcome and one or more net beneficial patient outcomes of interest, intermediate health outcomes may also be considered. For example, if a particular diagnostic test result can be shown to change patient management, and other evidence has demonstrated that those patient management changes improve health outcomes, then those separate sources of evidence may be sufficient to demonstrate positive health outcomes from the diagnostic test.

Other Considerations

Apart from the need to order diagnostic PET imaging wisely, CMS originally recognized the additional challenge of evaluating PET scanners themselves. We were aware of the diverse technical components of these systems, including their software algorithms, as well as differences in the experience and ability of interpreting physicians who read the PET images.

The technical discussion as to whether PET imaging could be standardized quantitatively addressed an additional challenge: to enable meaningful comparison of a patient’s PET image taken in different facilities or at different times. Thus arose the concept of standard uptake value, SUV, particularly for oncologic imaging. A 1995 commentary titled “SUV: Standard Uptake Value or Silly Useless Value?” in the Journal of Nuclear Medicine concluded, “as currently applied, the SUV is, in fact a “silly useless value” and its continued application as a quantitative index for malignancy per se should be discouraged.” (Keyes). Fifteen years later, Visser and colleagues commenting in the same journal proposed “SUV: From Silly Useless Value to Smart Uptake Value.” They concluded, “ . . . it is necessary that advanced delineation algorithms become implemented into commercial nuclear medicine software packages and that consensus be achieved with regard to the preferred method. Standard procedures and phantoms should be defined to optimize these algorithms for different types of scanners and reconstruction algorithms, possibly with the support of PET scanner manufacturers.”

We are increasingly aware that new proprietary agents have been approved with training requirements for readers, and we expect that such training will decrease one of the contributing factors for misinterpretation and downstream patient harm. With proprietary radiopharmaceuticals we believe that gives the sponsor both the uniquely identifiable responsibility and the interest to facilitate the needed standardization.

The task of incorporating new radiopharmaceuticals into clinical practice raises additional challenges. Not only can physicians choose from an expanding palette of available diagnostic imaging technologies, but for an individual patient who presents with a constellation of symptoms, signs, and medical history findings relevant to the current complaint, the need for deliberate and efficient use of diagnostic imaging is increasingly clear. Avoiding diagnostic imaging lacking demonstrated clinical utility avoids needless delay in decision making and minimizes unnecessary exposure of the patient to radiation or contrast agents that may lead to increased risk of subsequent harms such as malignancy or kidney failure. Additional studies of potential harms deriving from inappropriate use of diagnostic PET imaging need to be undertaken, including those harms resulting from unnecessary and possibly harmful diagnostic or therapeutic procedures. CMS encourages such studies as useful adjuncts to any future diagnostic PET imaging coverage requests.

In light of so many intersecting technical and regulatory challenges, CMS (formerly the Health Care Financing Administration - HCFA) reserved past diagnostic PET imaging coverage determinations to national decisions. However, with various improvements in the technical, regulatory and professional aspects of PET imaging for diagnosis, we believe that it has become appropriate to recognize the role of local coverage determination for certain uses of diagnostic PET imaging, as it is for many other diagnostic items and services.

PET has been widely available for many years and we are unaware of specific safety concerns beyond those generally associated with radiation exposure from other advanced imaging, for example, computed tomography (CT); the relative radiation level exposure with PET is comparable to CT (Peck DJ, Samei E. "How to understand and communicate radiation risk." Published by the Imaging Wisely campaign, a project of the American College of Radiology, the Radiological Society of North American, the American Association of Physicists in Medicine and the American Society of Radiology Technologists. Undated. Downloaded on 11/7/2012 from http://www.imagewisely.org/Imaging-Professionals/Medical-Physicists/Articles/How-to-Understand-and-Communicate-Radiation-Risk?referrer=search). The diagnostic use of PET in patients with cancer is in contrast to screening applications where there is likely to be widespread exposure of many healthy individuals who are unlikely to personally experience a benefit to balance the accumulated risk over time.

A review of articles discussed above in this decision memorandum reveals no analysis of outcome by racial or ethnic categories. Any inference about relative benefits positron emission tomography in specific racial or ethnic groups would be, at best, speculative. CMS also notes the absence of evidence about benefits or harms related to other population classifiers that have been associated historically with healthcare access or outcome disparities, such as gender, sexual orientation, religion, and age, and encourages additional studies in which such associations might be studied.

CMS recognizes that recent publications may reflect additional interest in examining disparities in PET use among geographic or sociodemographic population subgroups. A recent retrospective article examined disparities in FDG PET use by Medicare beneficiaries with cancer (Onega et al., 2012). Using CMS files, Medicare claims for beneficiaries with any of five selected cancers (head and neck; lung; esophageal; colorectal; and lymphoma, based on ICD-9-CM coding of the claim) were tabulated and examined in relation to a number of economic and demographic factors. Beneficiaries in Medicare Advantage plans were excluded, as were beneficiaries less than 65 years old or more than 100 years old. The authors found that in the study population of cancer patients, the median age was 75 years, and 48% of study subjects were female. They found that PET use among beneficiaries with cancer increased from 2004 to 2008. In each of those years, PET use was higher among whites than among blacks. The authors concluded that the growth from 2004 to 2008 was not uniform across health care markets or patient populations.

CMS concludes that there is a need for additional evidence about racial and ethnic factors. In our view this evidence gap should be considered by trial designers when proposing clinical trial designs for PET scans under this NCD. All other factors being equal, CMS will prefer clinical study proposals in which data on racial and ethnic factors are specifically collected and analyzed.

Summary:

For the reasons noted earlier in this section, CMS proposes to modify Section 220.6 of the Medicare National Coverage Determination Manual as follows:

1. For labeled uses of FDA approved radiopharmaceuticals in addition to FDG, N-13, rubidium Rb-82 and sodium fluoride (F-18), Medicare coverage for diagnostic PET imaging for oncologic uses may be considered at the discretion of local contractors for uses that are not determined by NCD.

We emphasize each of the following points.

1. Changing the ‘restrictive’ language of prior PET decisions will not by itself suffice to expand Medicare coverage to new PET radiopharmaceuticals.
2. The scope of this change extends only to FDA approved indications for oncologic uses of PET tracers.
3. This change does not include screening uses of PET scanning.

CMS acknowledges the advances relating to the assessment of diagnostic performance and patient safety, as pioneered by FDA in its regulatory policies and guidelines for diagnostic PET imaging agents and systems during the past decade. We note for completeness that local coverage cannot be in conflict with NCDs or other national policies. Finally, we note that future CMS national coverage determinations, if any, regarding diagnostic PET imaging would not be precluded by this determination, if finalized.

IX. Conclusion

The Centers for Medicare & Medicaid Services (CMS) proposes that local Medicare Administrative Contractors (MACs) may determine coverage within their respective jurisdictions for positron emission tomography (PET) using radiopharmaceuticals for their labeled indications for oncologic imaging that are approved by the U.S. Food and Drug Administration (FDA).

The effect of this decision, if finalized without change, would be to remove the national noncoverage for any of these identified uses of these radiopharmaceuticals that have not been more specifically determined nationally. Thus this change would not apply to any use of PET using radiopharmaceuticals FDG (2-deoxy-2-[F-18] fluoro-D-Glucose (fluorodeoxyglucose)), NaF-18 (fluorine-18 labeled sodium fluoride), ammonia N-13, or rubidium Rb-82. This would not prevent CMS from determining national coverage for any of these uses in the future, and if such determinations are made, a future determination would supersede local contractor determinations under §1862(a)(1)(A) of the Social Security Act (the Act).

We are requesting public comments on this proposed decision pursuant to §1862(l) of the Act. After consideration of these public comments and any additional evidence, we will issue a final determination responding to the public comments consistent with §1862(l)(3) of the Act.

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

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

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

Assessing Individual Studies

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

• 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 help ensure adequate numbers of patients are enrolled 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. One of the goals of our determination process is to assess health outcomes. We are interested in the results of changed patient management not just altered management. These outcomes include resultant risks and benefits such as increased or decreased morbidity and mortality. In order to make this determination, it is often necessary to evaluate whether the strength of the evidence is adequate to draw conclusions about the direction and magnitude of each individual outcome relevant to the intervention under study. In addition, it is important that an intervention’s benefits are clinically significant and durable, rather than marginal or short-lived. Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.

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

Assessing the Relative Magnitude of Risks and Benefits

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

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