Transvenous (Catheter) Pulmonary Embolectomy

The Centers for Medicare & Medicaid Services (CMS) is proposing to remove the National Coverage Determination (NCD) for Transvenous (Catheter) Pulmonary Embolectomy (NCD § 240.6), permitting Medicare coverage determinations for Transvenous (Catheter) Pulmonary Embolectomy to be made by Medicare Administrative Contractors (MACs) under § 1862(a)(1)(A) of the Social Security Act (the Act).

See Appendix B for proposed NCD manual language.

TO: 		Administrative File: CAG-00457R

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

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

		JoAnna Baldwin, MS
		Acting Director, Division of Policy and Evidence Review
	
		Melissa Evans, PhD, MSAE
		Deputy Director, Division of Policy and Evidence Review

		David Dolan, MBA
		Lead Analyst

		Joseph Dolph Hutter, MD, MA
		Lead Medical Officer

SUBJECT: 	Proposed decision memorandum to remove Transvenous (Catheter) Pulmonary Embolectomy National Coverage Determination (NCD) (§ 240.6)

DATE: 		August 11, 2021

I.  Proposed Decision

The Centers for Medicare & Medicaid Services (CMS) is proposing to remove the National Coverage Determination (NCD) for Transvenous (Catheter) Pulmonary Embolectomy (NCD § 240.6), permitting Medicare coverage determinations for Transvenous (Catheter) Pulmonary Embolectomy to be made by Medicare Administrative Contractors (MACs) under § 1862(a)(1)(A) of the Social Security Act (the Act).

See Appendix B for proposed NCD manual language.

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:

ACC - American College of Cardiology
AdvaMed - Advanced Medical Technology Association
AHA - American Heart Association
ASA - American Stroke Association
AVF - American Venous Forum
CMS - Centers for Medicare & Medicaid Services
CT - Computed Tomography
DVT - Deep Vein Thrombosis
FDA - Food and Drug Administration
MAC - Medicare Administrative Contractor
MDMA - Medical Device Manufacturers Association
MRA - Magnetic Resonance Angiography
NBCA - National Blood Clot Alliance
NCA - National Coverage Analysis
NCD - National Coverage Determination
PE - Pulmonary Embolism
PERC - Pulmonary Embolism Rule Out Criteria
PERT - Pulmonary Embolism Response Team
PESI - Pulmonary Embolism Severity Index
SCAI - Society of Cardiovascular Angiography and Interventions
SIR - Society of Interventional Radiology
SVM - Society of Vascular Medicine
SVS - Society of Vascular Surgeons
TA - Technology Assessment
TPE - Transvenous (Catheter) Pulmonary Embolectomy
US - Ultrasound
VQ - Ventilation Perfusion
VTE - Venous Thromboembolism

Overview of Pulmonary Embolism

Pulmonary embolism (PE) occurs when a thrombus (clot) that forms in the body, such as in the deep veins of the legs (deep venous thrombosis, or DVT) breaks loose, travels through the venous system, and gets lodged in one or more pulmonary arteries feeding the lungs.  Both DVT and PE are a continuum of a single disease process: venous thromboembolism (VTE).  While small emboli lodged in peripheral pulmonary arteries may occur frequently with little to no clinical significance, larger emboli that lodge more centrally in the pulmonary arterial tree can cause acute symptoms, such as chest pain and shortness of breath, and are potentially life threatening (Dobler 2019). 

Deaths in the U.S. due to VTE are at least 100,000 annually (CDC 2020, SG 2008), and could be greater as many cases of sudden cardiac death may be due to pulmonary embolism.  The mortality rate in patients with acute PE is high.  One large study (N=31,656) reported a 3.9% mortality rate at 30 days and 12.9% at 1 year, with rates climbing with increasing age.  Patients with cancer-associated thromboembolism had 1- and 5-year survival rates of 66% and 46% (Alotaibi 2016).  Other studies estimate that 10%–30% of all VTE patients suffer mortality within 30 days, when including PE cases that present as sudden death (Beckman 2010, including citations 6-10).

Diagnosis of Pulmonary Embolism

The clinical workup and diagnosis of patients with acute PE typically involves some combination of:

• a validated clinical prediction tool, such as Wells’ Criteria, Geneva Protocol, or Pulmonary Embolism Rule Out Criteria (PERC) (van Bell 2006, Douma 2009, Klok 2008, Kline 2004);
• a high-sensitivity plasma D-dimer test (Kearon 2019); and
• imaging, typically computed tomography (CT) pulmonary angiography (Moore 2018, Meinel 2015) but also in special circumstances a nuclear medicine ventilation-perfusion (VQ) scan, catheter-directed angiography, or magnetic resonance angiography (MRA).

Treatment of Pulmonary Embolism

Appropriate treatment of patients with acute PE is guided by risk stratification.  Depending on the risk of death, treatment escalates from standard anticoagulation (to prevent future clots from forming), to systemic thrombolysis (intravenous drugs such as tissue plasminogen activator [t-PA] that break up existing clots), and then to catheter-directed therapies as an alternative to more invasive surgical embolectomy.

While risk-stratification of patients with acute PE is evolving (Giri 2019), generally patients are categorized as having low-risk PE, intermediate-risk (also called “submassive”) PE, or high-risk (“massive”) PE.[1]  Prognostic models contribute to risk stratification.  While a dozen such models exist, the most common and validated test is the Pulmonary Embolism Severity Index (PESI).  PESI uses 11 variables, including age, comorbidities, and clinical parameters (e.g., respiratory rate) to classify patients according to increasing risk for mortality.  The simplified PESI (sPESI), which uses fewer variables, identifies risk of 30-day mortality and classifies patients as low risk (score 0) or high risk (score ≥1) (Yamashita 2020).  Both PESI and sPESI have been integrated into current guidelines (Konstantinides 2019).

Under current evidence-based guidelines, low-risk patients with acute PE are defined by the absence of right heart strain, myocardial necrosis, and systemic arterial hypotension (by imaging, laboratory, and clinical parameters), and may be treated with standard anticoagulation if there are no contraindications (Konstantinides 2019, Kuo 2018, Kearon 2016). 

Intermediate-risk patients have acute right ventricular dysfunction and myocardial injury but are hemodynamically stable (have normal blood pressure), and with European Society of Cardiology (ESC) criteria, have an sPESI score of one or more.  According to 2019 ESC guidelines, these patients are further categorized as “intermediate-low risk” (abnormal right ventricular function or elevated serum troponin), or “intermediate-high risk” (abnormal right ventricular function and elevated serum troponin).  Intermediate-risk patients who fail standard anticoagulation and decompensate clinically may be treated with systemic thrombolysis, which has been associated with decreased hemodynamic collapse and mortality (Kearon 2016, Konstantinides 2019, Meyer 2014, Chopard 2019, Giri 2019).

High-risk patients with acute PE are those who are, or are likely to imminently become, hemodynamically unstable, and may descend into shock.  For high-risk patients for whom systemic thrombolysis has failed or is contradicted due to risk of severe bleeding, current evidence-based guidelines recommend consideration of catheter-directed therapies as an alternative to more invasive surgical embolectomy (Konstantinides 2019, Giri 2019, Kuo 2018, Kearon 2016). 

Catheter-directed therapies consist of: (a) transvenous (catheter) pulmonary embolectomy (TPE), also called percutaneous pulmonary thrombectomy, mechanical thrombectomy, and catheter embolectomy (and herein referred to as “catheter embolectomy”), and (b) catheter-directed thrombolysis.  The former involves catheter-directed extraction of the clot.  The latter involves injection of lytic drugs locally in a pulmonary artery to dissolve a clot, at lower doses than used in systemic thrombolysis, with the goal of decreasing bleeding risk.     

Catheter-directed thrombolysis and catheter embolectomy are thus distinct procedures, but can be used in combination; i.e., by breaking up and/or dissolving a clot and then aspirating out what is left (Piazza 2015, De Gregorio 2019).  Adjunctive interventions to catheter-directed therapies exist.  Catheter-directed ultrasound, in which sound waves are used with the intent of improving catheter-directed thrombolysis/fibrinolysis by allowing better access of lytic drugs to the fibrin within a thrombus, has been studied (Kucher 2014, Piazza 2015), but the partial contribution of ultrasound is undefined.  Inferior vena cava (IVC) filters (to catch clot emboli from the lower extremities before they reach the lungs) have been used alone or in combination with other interventions in certain clinical scenarios. 

The scope of this national coverage analysis (NCA) is limited to TPE. 

III.  History of Medicare Coverage

Currently, Transvenous (Catheter) Pulmonary Embolectomy is noncovered through a longstanding NCD (NCD 240.6).

A.  Current Request

CMS internally generated this NCA reconsideration based upon stakeholder feedback. We received three requests for CMS to remove the NCD using the expedited process established in the August 7, 2013 Federal Register (78 FR 48164).  We also received nine comments on the 2021 Medicare Physician Fee Schedule Proposed Rule recommending that CMS consider removing this NCD in the future.  85 Fed. Reg. 84,472, 84,801 (December 28, 2020).

B.  Benefit Category

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 Act.

Transvenous (Catheter) Pulmonary Embolectomy qualifies as:

• Physicians’ services (§ 1861(s)(1))

Note:  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 FDA has cleared medical devices that are catheter-directed therapies, such as continuous flush and catheter embolectomy devices, for the treatment of pulmonary embolism.  FDA cleared the Ekosonic Endovascular System (EKOS Corporation) in 2011 (K111705), with an indication for use of infusion of solutions into the pulmonary arteries.  Additional iterations of the device were subsequently cleared under K140151, K162771, K182324, K183361, K191119, and K200648 with variations in trade/brand name, and with a revised indications for use of ultrasound facilitated, controlled, and selective infusion of physician specified fluids, including thrombolytics, into the vasculature for the treatment of pulmonary embolism, and infusion of solutions into the pulmonary arteries.

FDA also cleared the Inari Medical Flowtriever Retrieval/Aspiration System (K180466) in 2018, which is indicated for use in the peripheral vasculature and for the treatment of pulmonary embolism; for the non-surgical removal of emboli and thrombi from blood vessels; and injection, infusion, and/or aspiration of contrast media and other fluids into or from a blood vessel.  Subsequent iterations of the Flowtriever Retrieval/Aspiration System (including the Triever Catheter but excluding the Flowtriever 2 Catheter) have been cleared under K181694, K182233, K183198, K191368, K191710, K202345, K203333, K210195, and K211013.

The FDA has also cleared the Penumbra Indigo Aspiration System (K192833), which is indicated for the removal of fresh, soft emboli and thrombi from vessels of the peripheral arterial and venous systems, and for the treatment of pulmonary embolism.  Subsequent iterations of this device have been cleared under K200771, K202821, K210083, and K210323. 

All three devices are in clinical use presently.

VI.  Public Comment

Public comments sometimes cite the 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. 

CMS uses the initial public comments to inform its proposed decision.  CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum.  The tracking sheet for this NCD noted that CMS was seeking public comments on the evidence speaking to the health outcomes attributable to the use of TPE.  All comments that were submitted without personal health information may be viewed in their entirety by using the following link https://www.cms.gov/medicare-coverage-database/details/nca-view-public-comments.aspx?NCAId=303. 

Initial Public Comment Period:  04/13/2021 – 05/13/2021

During the 30-day comment period following the release of the tracking sheet, CMS received 28 comments.  All of the commenters requested that the current non-coverage for TPE be removed, with most of the commenters suggesting to remove the current NCD.

The comments included 15 from physicians, and one from a medical device company.  We also received 12 comments representing 13 national associations/professional societies, including the American College of Cardiology (ACC), Advanced Medical Technology Association (AdvaMed), American Heart Association (AHA), American Stroke Association (ASA), Ascension, Medical Device Manufacturers Association (MDMA), National Blood Clot Alliance (NBCA), Pulmonary Embolism Response Team (PERT), Society of Cardiovascular Angiography and Interventions (SCAI), Society of Interventional Radiology (SIR), Society of Vascular Medicine (SVM), Society of Vascular Surgeons (SVS), and the American Venous Forum (AVF).

VII.  General Methodological Principles

When making national coverage determinations, CMS generally evaluates relevant clinical evidence to determine whether 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 CMS uses to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A.

VIII.  Evidence

The evidence summarized in this section includes the peer-reviewed, published clinical research pertinent to the use of catheter embolectomy in patients with acute PE.  Our assessment focuses on the key evidence question below.

1.  Evidence Question

• Is the evidence sufficient to conclude that use of transvenous (catheter) pulmonary embolectomy improves health outcomes for Medicare beneficiaries?

2.  External Technology Assessments

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

3.  Internal Technology Assessment

Literature Search Methods

A clinical librarian performed literature searches to identify peer-reviewed studies on TPE, also called percutaneous pulmonary thrombectomy, published between January 1, 2005 and February 12, 2021, using Embase and Scopus (both of which include Medline), NICE, and Cochrane CENTRAL (which pulls articles from PubMed, Embase, CINAHL, and trials listed in ClinicalTrials.gov and in the WHO trials database).

Articles were included if they conformed to the following eligibility criteria:

Inclusion criteria:

• Studies using transvenous or percutaneous devices for pulmonary embolectomy or thrombectomy
• Articles published in scientific journals
• Technology assessments, guidelines, or consensus statement
• English language
• Adult
• Human
• Literature from United States, Canada, the United Kingdom, Europe, and Australia

Exclusion criteria:

• Non-English language articles
• Technical, nonclinical articles (e.g., animal, biomechanical, cadaver)
• Conference abstracts
• Studies conducted outside the countries listed above
• Studies published before 2005
• Studies with less than 50 participants
• Studies not related to transvenous pulmonary (catheter) embolectomy

Evidence Table 1.  Key Contemporary Studies on Catheter Embolectomy

* PICO: Population, Intervention, Control, Outcomes.  ~ PE: pulmonary embolism. ° RV/LV: right ventricular / left ventricular.  ** NR: not reported.  ⁺ AE: adverse events. ⁺⁺ 92 patients with embolectomy alone; 398 total combining embolectomy and thrombolysis.

IX.  CMS Analysis

Introduction:

The term “national coverage determination” is defined by statute and means a determination by the Secretary of the Department of Health and Human Services (Secretary) with respect to whether or not a particular item or service is covered nationally under Title XVIII of the Act, Section 1862(l)(6).  NCDs are controlling authorities for Medicare contractors and adjudicators as described more fully in 42 CFR § 405.1060.

In the absence of an NCD, Medicare contractors may establish a local coverage determination (LCD) (defined in section 1869(f)(2)(B) of the Act) or adjudicate claims on a case-by-case basis. The case-by-case adjudicatory model permits consideration of a beneficiary's particular factual circumstances described in the medical record.  The case-by-case model affords more flexibility to consider a particular individual's medical condition than is possible when the agency establishes a generally applicable rule.

With relatively few exceptions, the statute provides in section 1862(a)(1) of the Act that no payment may be made under Part A or Part B for any expenses incurred for items or services which “are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.” The Supreme Court has recognized that “[t]he Secretary's decision as to whether a particular medical service is ‘reasonable and necessary’ and the means by which she implements her decision, whether by promulgating a generally applicable rule or by allowing individual adjudication, are clearly discretionary decisions.” Heckler v. Ringer, 466 U.S. 602, 617 (1984).  See also, Almy v. Sebelius, 679 F.3d 297, 303-04 (4^th Cir. 2012) (“The Medicare statute preserves this discretion for the Secretary, leaving it to her judgment whether to proceed by implementing an NCD, by allowing regional contractors to adopt an LCD, or by deciding individual cases through the adjudicative process.”); International Rehabilitative Services Inc. v. Sebelius, 688 F.3d 994, 1001 (9^th Cir. 2012) (“But while the agency may make coverage determinations via up-front rules, it is not required to do so; rather, the agency has discretion in whether to make coverage determinations by up-front rulemaking or by case-by-case adjudication.”)

Evidence Review Summary:

For this reconsideration of the NCD on TPE, CMS focused on the following question:

• Is the evidence sufficient to conclude that use of TPE improves health outcomes for Medicare beneficiaries?

Most publications have consisted of case reports and small, observational studies, often with heterogeneous populations (i.e., patients with different risk levels), and no comparative arm. There were no randomized controlled trials.

Catheter embolectomy has been used in combination with thrombolysis and/or other interventions in the same study (e.g., Pieri 2007, Cuculi 2012), and the partial effect of each intervention is often unknown.  Such studies are of limited value to our assessment, which focuses on catheter embolectomy alone as this is the sole procedure that is nationally noncovered by the existing NCD.

The literature reveals that catheter embolectomy comprises a few similar but distinct procedures all aimed at physical extraction of a clot lodged in a pulmonary artery.  These procedures include rheolytic embolectomy (Chechi 2009, Kuo 2009), rotational or manual pigtail embolectomy (Kuo 2009, Skaf 2007), and aspiration (suction) embolectomy (Tu 2019, Sista 2021).  Procedural categories overlap: the first two can involve aspiration, while currently the third category exclusively uses aspiration as the technique.

Quality and Strength of Evidence

Our analysis focuses on this last technique, aspiration embolectomy, as it represents the latest-generation technology and was used in two recent studies, the results for which lent impetus to our decision to reconsider this NCD.  These are the prospective, single-arm, multicenter studies, FLARE (Tu 2019) and EXTRACT-PE (Sista 2021), which evaluate aspiration catheter embolectomy in an intermediate-risk population.

Though based on scant evidence, current societal guidelines recommend consideration of catheter embolectomy only for high-risk, hypotensive patients who have substantial bleeding risk, have failed thrombolysis, or are in shock (Konstantinides 2019, Kearon 2016, Giri 2019). These are decompensating, clinically unstable patients for whom immediate extraction of the embolus may be a last resort.

The question of how to manage acute PE in patients in less dire circumstances – those with intermediate risk – is less clear. Yet this group represents a significant portion of the PE population.  By some estimates, intermediate-risk PE represents 25–40% of the PE population and has a mortality rate of between 3% and 21% at 3 months (Meyer 2014, Reis 2018).  This is why these two recent prospective studies target this intermediate-risk group.

The FLARE and EXTRACT-PE studies are similar in design and produce similar results. Both studies demonstrate significant improvement in RV/LV ratio and minimal major bleeding (see study details in Table 1).

These two studies stand out because:

• They are larger (N>100), prospective, multicenter, investigational device exemption (IDE) studies, in a field littered with very small, retrospective studies.
• They are contemporary.  Both studies use latest-generation catheter-guided, mechanical aspiration technology (two similar products from competing companies, the large-bore FlowTriever system from Inari, and the small-bore Indigo system from Penumbra).
• They isolate the intervention this NCD addresses: catheter embolectomy.  In both studies, only two patients (1.9% in FLARE, and 1.7% in EXTRACT-PE) received adjunctive thrombolysis.  If the argument is that catheter embolectomy can benefit patients with acute PE while avoiding the bleeding risk posed by thrombolytics, this procedure needs to be tested without adjunctive thrombolytics – as these studies do.

However, these two studies also share significant limitations:

• The primary endpoint is a surrogate measure: the RV/LV ratio, an indicator of right-heart strain. While prior observational studies have suggested an association between RV/LV ratio and mortality (Trujillo-Santos 2013), we are aware of no prospective study demonstrating that interventions to improve that ratio in turn reduce mortality, or any other patient health outcome (Desai 2021, Giri 2019). 
• The studies are not powered for short or long-term health outcomes themselves.  As PE is a life- threatening disease, mortality is a logical primary study outcome.
• There is no randomization with an active-comparator arm (however, the authors of one of these studies acknowledge their conclusions should be further evaluated with a prospective randomized controlled trial; Sista 2021).

Summarizing the evidence for all catheter-based interventions for acute PE, the 2019 AHA Statement concludes, “the primary aims of advanced therapies are to avert possible hemodynamic collapse and death resulting from progressive right-sided heart failure and to expedite symptom resolution.  Although these represent the rationale for device use, to date, no prospective study has demonstrated a mortality benefit associated with the use of any interventional therapy in any population of patients with PE” (Giri 2019).  Commenting further on trial design, the authors state, “To date, no trials have been carried out that have had the power to assess potential benefits in short-term mortality or hemodynamic decompensation with the use of CDL [catheter-directed thrombolysis] or catheter-based embolectomy devices” (Giri 2019).

We believe the above assessment remains accurate after FLARE and EXTRACT-PE, both published after the 2019 AHA Statement.  While the published clinical research reveals that this procedure is no longer “experimental,” the evidence is insufficient to build broad criteria for a national coverage determination.

In sum, the contemporary use of catheter embolectomy in high-risk patients, and recommendations by society guidelines, support that this procedure is no longer “experimental.”  However, the scant evidence in the peer-reviewed, published medical literature is insufficient to inform specific criteria for national coverage.  As for use in intermediate-risk patients, the two recent studies, FLARE and EXTRACT-PE, support that the procedure may benefit some patients.  However, the limitations of these studies (detailed above), similarly preclude their ability to inform broad national coverage for intermediate-risk patients.

NCD Removal

Allowing MACs to determine coverage of catheter embolectomy for patients with acute PE is clinically appropriate and in the best interest of our beneficiaries.  The evidence is promising, but it is based largely on small, observational studies that lack a comparative arm, and is insufficient for informing criteria for national coverage.  Additionally, we anticipate low numbers of procedures in the future (although we do not have complete historical claims data to predict future usage as the existing NCD provides for noncoverage).

Due to the expected small number of patients involved and the need for careful patient selection, we believe that coverage of TPE is an appropriate determination made by the MACs.  The MACs are structured to be able to take into account local patient, clinician and institutional factors, which are especially important when the overall prevalence is low.  Thus, we are proposing to remove our national coverage determination at § 240.6.  In the absence of a national coverage determination, MACs would make the coverage determination under § 1862(a)(1)(A) of the Social Security Act.

Health Disparities

Studies addressing TPE did not directly address health disparities. 

X.   Conclusion

The Centers for Medicare & Medicaid Services (CMS) is proposing to remove the National Coverage Determination (NCD) for Transvenous (Catheter) Pulmonary Embolectomy (NCD 240.6), permitting Medicare coverage determinations for Transvenous (Catheter) Pulmonary Embolectomy to be made by Medicare Administrative Contractors (MACs) under §1862(a)(1)(A) of the Social Security Act (the Act).

See Appendix B for proposed NCD manual language.

When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether 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 unlikely 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.

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