This is a limited coverage policy for molecular biomarker tests to guide
targeted therapy selection in Rheumatoid Arthritis (RA).

**Coverage criteria:**

  1. The patient is an adult with a confirmed diagnosis of moderately to severely active RA.
  2. The patient has a history of failure, contraindication, or intolerance to at least one first-line therapy for the treatment of RA (i.e., conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs)) despite adequate dosing.
  3. The patient has not initiated a biologic or targeted synthetic therapy (b/tDMARD) for RA (i.e., Tumor Necrosis Factor-?? inhibitor [TNFi], Janus Kinase [JAK] inhibitor, etc.) OR has initiated b/tDMARD therapy and is being considered for an alternate class of targeted therapies as a result of failure, contraindication, or intolerance to the initial targeted therapy despite adequate dosing.
  4. The test predicts response and/or non-response to at least one class of targeted or biologic therapies for RA according to multiple validated response/remission criteria (a) with an accuracy that exceeds that which can be obtained from the combination of existing clinical and other data AND (b) with demonstrated reproducibility across clinical study cohorts.
  5. Testing using molecular biomarkers has not been previously performed for predictive therapy selection in RA.
  6. Testing is performed according to the intended use of the test in the intended patient population for which the test was developed and validated.
  7. The test demonstrates analytical validity (AV), clinical validity (CV) and clinical utility (CU), establishing a clear and significant biological/molecular basis for stratifying patients and subsequently selecting (either positively or negatively) a clinical management in a clearly defined population.
  8. Clinical validity of any analytes (or expression profiles) measured must be established through a study published in the peer-reviewed published literature for the intended use of the test in the intended population.
  9. If the test relies on an algorithm, the algorithm must be validated in a cohort that is not a development cohort for the algorithm.
  10. The lab providing the test is responsible for clearly indicating to treating physicians the population and indication(s) for test use.
  11. The test successfully completes a Molecular Diagnostic Services Program (MolDX) Technical Assessment that ensures that AV, CV, and CU criteria set in this policy are met to establish the test as Reasonable and Necessary.
  12. If applicable, performance characteristics are equivalent or superior to the average performance of other similar tests (for the same intended use) evaluated by this contractor upon successful completion of a technical assessment.

Since the clinical utility of predictive testing is largely dependent upon
consensus-based management recommendations, this coverage decision is subject
to change pending changes in the literature and in consensus guidelines.

Finally, new tests that become available with significantly improved
performance may render older tests no longer compliant with this policy.

Rheumatoid arthritis (RA) is complex and heterogeneous inflammatory autoimmune
disease, with a multifactorial etiology.1-3 An estimated 1.3 million adults in
the United States live with RA and though the disease affects both sexes, the
incidence is higher in women than in men (53/100,000 vs 29/100,000
population).4 Left improperly treated, it can progress and become a
debilitating disease with significant morbidity as well as increased
mortality.2,5,6

RA treatment response is defined in terms of disease activity or remission
scores. Commonly used are the American College of Rheumatology (ACR) and the
European League Against Rheumatism (EULAR) response criteria.7-10 EULAR
response criteria are based on changes in the Disease Activity Score (DAS),
while the ACR improvement scores of ACR20, ACR50, and ACR70, represent the
percent improvement in a standard set of indices, including clinical factors
as well as laboratory markers (i.e. acute-phase reactants).11,12 A 50%
response (ACR50) is needed for most patients to reach low disease activity.3
The ACR and EULAR criteria have been reported to have comparable validity.13
However, given that their components and requirements are different, and that
there is known variability in patient disease assessments (PDAs) and patient-
reported outcome measures (PROMs) as well as in the composite of clinical
metrics used that are included in the response criteria, some patients who are
classified as responders by one criterion may not be classified as responders
by another criterion.9,14-16 For example, differences are seen among the
various EULAR response criteria, depending on which of the composite measures
is used (i.e. disease activity score using 28 joint counts (DAS28)/Erythrocyte
Sedimentation Rate (ESR) vs DAS28/C-reactive protein (CRP)).17,18 Other
scores, namely the clinical disease activity index (CDAI), and the simplified
disease activity index (SDAI), are also commonly used in clinical care and
correlate with outcomes such as progression and functional impairment.19

Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such
as methotrexate are considered first-line therapy for many patients with RA.20
However, up to 60% of patients fail to achieve treatment targets on
csDMADRs.21 For them, biologic and targeted synthetic DMARDs (b/t DMARDs), are
often recommended.20,22 These include tumor necrosis factor-alpha inhibitors
(anti-TNFs, or TNFis), Janus Kinase tyrosine kinases (JAKs), Interleukin-6
(Il-6) inhibitors, T- and B-cell therapies. The various b/tDMARDs have, on the
whole, shown similar efficacy and safety profiles; as such, many guidelines
have not preferred or prioritized among them.20,23,24 Despite the fact that
there are multiple classes of targeted therapies available, TNFis remain the
predominant first-line b/tDMARDs in the majority of patients with RA for a
variety of reasons, including long-term established efficacy and safety
profiles, the comfort level of ordering physicians, and insurance policy
requirements.25-29 However, up to two-thirds of patients will fail to achieve
ACR50 within 6 months of therapy with their first TNFi, and more than 60% will
require a third DMARD.19,30,31 After patients fail their first TNFi therapy,
they are approximately 12-30% more likely to inadequately respond to their
second targeted medication.32-35 Over time, up to 75% of patients may
eventually reach treatment targets with multiple trial-and-error sequential
approaches to treatment.19

When TNFi therapy is ineffective or results in adverse effects, patients may
'cycle' to another TNFi or to 'switch' to a drug with a different mechanism of
action (MOA). The ACR conditionally recommends 'switching' over 'cycling,'
based on evidence supporting greater improvement in disease activity when
patients switch drug classes, rather than cycle between them.20,32,36-38
However, a claims analysis-based study found that most (~64%) patients still
often cycle to a second TNFi before switching to a non-TNFi, and that patients
who switch to a non-TNFi are significantly older with more comorbidities.39
These trial-and-error attempts using various drugs and drug classes, often
with inadequate disease response and with drug-induced side-effects, can
result in continued disease progression, as effective therapy (which is
important early in RA to delay or prevent debilitating disease outcomes) is
delayed.5,20

Despite the availability of multiple treatment options, there is no certain
way to predict which patients will respond to the various available therapies.
Certain characteristics, including obesity and sex, have been associated with
a lack of response to TNFis in some studies but not in others.40-44 Moreover,
up to 30% of RA patients do not have rheumatoid factor (RF) or anti-
citrullinated protein antibodies (ACPA), and researchers remain divided on
whether to subdivide and manage RA differently based on autoantibody
status.45,46 For example, there have been conflicting reports regarding
whether seronegative patients have less active disease at baseline and less
radiographic progression than seropositive patients.46-49 Moreover, distinct
genetic factors have been associated with seronegative patients, indicating
that there may be distinct pathogenic mechanisms involved.50,51 Further,
studies have found that treatment choice is influenced by the presence of
autoantibodies and that patients with autoantibodies may require biologics to
achieve remission more frequently than seronegative patients.47,52
Additionally, in some multivariable analyses, RF has been negatively
associated with biologic therapy survival and ACPA with the inability to taper
or discontinue TNFis after remission.37 However, other studies, including
meta-analyses, have not found these associations; rather, they report that
both seropositive and seronegative types of RA may require similar intensive
treat-to-target therapies.49,53-55 Differences in study findings may be due to
different classification schemes used (i.e. RA diagnosed using ACR 2010 vs
older criteria) as well as on the inclusion PDAs and PROMs, which are varied
and prone to inherent subjectivity. Nevertheless, there remain unanswered
questions regarding the management of different sub-populations with RA. As
such, there is an unmet clinical need for a test that can accurately predict
which patients will or will not respond to targeted and biologic therapies.

**Predictive Biomarker Tests**

A number of molecular biomarker tests have been proposed that can predict
response (or non-response) to certain classes or multiple classes of drugs in
RA treatment.56-63 Some are based on genetic markers found in blood, some on
genetic markers in combination with clinical and laboratory factors, and
others on transcriptomics within the synovium. One observational cohort
evaluated the differential expression and methylation of DNA to predict
response to two different TNFi drugs adalimumab (ADA) and etanercept (ETN) in
patients with RA. A machine learning model found divergent transcriptomic
signatures in ADA and ETN responders that predicted drug response with an
accuracy of up to 85-88%.57 Interestingly, in that study the majority of the
patients did not respond to both drugs but had the potential to respond to
either ADA or ETN. However, a prior study evaluating DNA methylation in RA
found different methylation sites than those reported by Tao et al.64 The
differences may have been due to the different cell types interrogated as well
as different response criteria used. However, these studies were limited by
small sample sizes and have not been externally validated using larger sample
sizes.

The above-mentioned studies evaluated a decision regarding the choice of TNFi
(ADA vs ETN). Other biomarker tests have been proposed to assist in the
decision regarding which _class_ of drug to use - i.e., whether to use a TNFi
versus a drug with an alternate mechanism of action (alt-MOA, or non-TNFi).
The one such test that is most widely published is a molecular signature
response classifier (MSRC) from Scipher Medicine (Waltham, MA) that can be
performed prior to the start of targeted or biologic therapy to predict non-
response (NR) to TNFis.59,65 This test is performed on whole blood and
includes 10 single-nucleotide polymorphisms (SNPs) associated with RA, 8 gene
transcripts, 2 traditional laboratory tests (CRP and anti-CCP), and 3 clinical
parameters (sex, body mass index (BMI), and patient disease assessment
(PDA)).52,59 The raw output of the model is transformed into a continuous
variable between 1 and 25 with higher numbers indicating a greater likelihood
of non-response to TNFis.66

In a clinical validity study of 175 prospectively collected samples from RA
patients in the CERTAIN trial, the top 23 ranked biomarkers were found to
identify ACR50 non-responders with a sensitivity of 50.0%, specificity of
86.8%, and a positive predictive value (PPV) of 89.7%.59,67 The overall TNFi
response rate was 30.3%, whereas patients predicted to be non-responders (NRs)
by the test had a TNFi response rate of 10.3% (7/68) by ACR50.59 Conversely,
lack of a NR signature did not predict response, as nearly 60% of patients
with this result did not meet ACR50 response criteria when treated with a
TNFi.59 Another prospective clinical study (NETWORK-004) also reported that
patients with a molecular signature of NR were less likely to achieve therapy
targets with TNFis than those lacking the signature with odds ratios (ORs) of
3.4-8.8 for b/tDMARD-naive (n=146) and 3.3-26.6 for TNFi-exposed patients
(n=113) (notably, the OR of 26 was in previously TNFi-exposed patients).65 In
this study, a NR signature was detected in nearly 45% of patients at
baseline.65 Importantly, both of these studies were observational and test
results were not actually used to inform treatment selection. Additionally,
treatment selection was at the physician's discretion and may have been
influenced by multiple clinical and non-clinical factors, as outlined above.

A prospective multi-institutional cohort study using a clinical database of RA
patients (Study to Accelerate Information of Molecular Signatures [AIMS] in
Rheumatoid Arthritis) evaluated outcomes in patients for who a b/tsDMARD
treatment decision was informed by MSRC testing.68 Patient eligibility did not
consider baseline disease activity, prior biological exposure, or csDMARD use.
The primary endpoint was therapeutic responsiveness defined by achievement of
ACR50 at 24-weeks. According to questionnaire responses, therapy selection was
informed by the test results for 73.5% (277/377) of patients.68 However, only
85 patients completed a 24-week follow-up visit. Patient responses to
treatment (informed by the MSRC) at 24 weeks in predicted non-responders who
received an alternate drug (alt-MOA) (n=23 patients) and in predicted non-
responders who received a TNFi despite their NR signature (n=29 patients) were
34.8% and 10.3% by ACR50; by CDAI they were 56.2% and 15.4%, respectively.68
ACR50 response to TNFis in patients lacking the NR signature was only 45.8%.68
Patients with and without a molecular signature of NR who received an alt-MOA
had a nearly equivalent responses (33-34%) by ACR50.68 Notably, the number of
evaluable patients at 24 weeks in each sub-group was small and despite access
to the test results, more patients with predicted NR to TNFis were still
prescribed TNFis rather than alt-MOAs, once again highlighting the multiple
variables associated with physician prescribing practices. A second interim
analysis of AIMS that included a larger number of patients (N=274) with
moderate or severe RA similarly showed that absolute changes in CDAI scores
from baseline were improved when treatment was informed by the MSRC test.69
Finally, a comparative cohort study compared a MSRC-tested arm from AIMS with
an external control arm from a United States electronic health records
database.70 This study validated the reported test performance characteristics
of the MSCR (i.e. PPV 88%) but again noted that physicians prescribed test-
aligned therapies only 70% of the time. Despite this incomplete adherence to
test results, patients in the MSRC arm were nearly 3 times more likely to
achieve remission than those in the standard-of-care control arm.70
Importantly, the authors reported that after cohort matching, 57% of patients
in the MSRC-tested arm (N=489 with clinical outcomes data at 6 months) had not
been included in the 2 prior interim analyses, thus providing data independent
of the two prior AIMS-based cohort studies.70

There are other predictive biomarker tests that are 'biopsy-driven,'
evaluating the transcriptomic signature of the synovium in RA patients as an
indicator for therapy response and clinical outcomes.69,70 R4RA (rituximab vs
tocilizumab in anti-TNF inadequate responder patients with rheumatoid
arthritis) was a multicenter randomized trial evaluating RA patients with
inadequate responses to TNFis.69 RNA sequencing-based identification of
patients with a low or absent B cell gene expression signature in synovial
tissue significantly correlated with a greater response to tocilizumab (63%)
than rituximab (36%), suggesting that in patients with a low or absent B cell
expression gene signature in synovial tissue, an alternative therapy may be
preferred over rituximab.69 Another longitudinal study of the synovial
transcriptome reported differentially expressed genes in DMARD-naive early-RA
patients versus advanced RA patients.70 Results from the synovial
transcriptome studies have not yet been replicated in external validation
cohorts. Moreover, studies have shown pronounced heterogeneity in the synovial
tissue of RA patients, mirroring the general heterogeneity seen in this
inflammatory disease.71 Finally, synovial fluid is not readily available for
testing to inform therapy decisions in routine clinical practice settings.
Nonetheless, it remains an active area of exploration for both the
pathogenesis as well as the response to therapy in RA.

Though various candidate polymorphisms have been proposed to be associated
with TNFi treatment response in RA patients, multiple genome-wide association
studies (GWAS) have not identified such predictive genetic variants in a
consistent or reproducible manner.72 An 'open challenge' comparing prediction
models developed by 73 research groups found that, despite a "genetic
heritability estimate of treatment non-response trait," SNP data do not
significantly contribute to the prediction of response to therapy above that
which was obtained by available clinical predictors.73 Specifically, this
analysis did find that certain available clinical features, including sex,
age, the specific TNFi, and methotrexate use, did provide a level of
prediction that performed significantly better than random.73 The authors
conclude that "these results suggest that future research efforts focused on
the incorporation of a richer set of clinical information--including
seropositivity, treatment compliance and disease duration--may provide
opportunity to leverage these methods in clinically meaningful ways. In
addition, the identification of data modalities that are more effective than
genetics in capturing heterogeneity in RA disease progression--whether
clinical, molecular or other--may also improve predictive performance."73

Drug treatments themselves have been reported to alter the molecular profile
of RA patients, both in terms of normalization of the profile (which has been
associated with clinical remission), and in terms of resistance to
treatments.60,74 A multi-omics analysis found that normalization and
resistance are also heterogeneous, which may be explained by an imbalance of
white blood cell subsets. It remains unclear, however, whether these
signatures are also found in the inflamed synovium.60

Finally, the EULAR and others have reported (and cautioned) on the variability
inherent in the existing big data sources, on the tolerance of poor quality
data in large registries used in RA biomarker studies, on the heterogeneous
methods used between studies to analyze big data, and on the lack of external
validation of some of the tests.58,75-77 These issues lend themselves to the
risks of 'quantitative fallacy,' bias, overfitting of predictive models, and
the inability to generalize results.75,78 EULAR has called for comprehensive
and harmonized standards, open data platforms, and interdisciplinary
collaboration, such that artificial intelligence (AI) can safely and
effectively be implemented in the clinical practice of RA.76

**Contractor Advisory Committee (CAC)**

A Contractor Advisory Committee (CAC) meeting on the topic of predictive
testing in RA was held in December 2021. Similar to findings from a published
survey of 248 USA-based rheumatologists, the CAC subject matter expert (SME)
panelists noted that physicians would welcome predictive tests to guide
targeted therapy in RA patients and find them useful if they could help
minimize the trial-and-error approach of current therapy.79 However, though
the panelists were aware of early and emerging data, they were not aware that
any such tests had been rigorously validated for routine clinical use at the
time of the CAC. Additionally, the panelists expressed the opinion that TNFis
are the most commonly prescribed biologic therapies in RA for two primary
reasons - (1) they were the first biologics available for RA patients and
therefore physician and patient comfort levels may be higher with this class
of drug over 'newer' therapies with similar safety and efficacy profiles and
(2) insurance companies often require a trial of 1-2 TNFis before covering
other targeted therapies. There was consensus that the requirement by
insurance companies for patients to fail multiple TNFis prior to paying for an
alternate targeted therapy is unreasonable.

Finally, during the Comment period, we received letters from our SMEs in
support of the use of predictive biomarker tests for a limited RA population.

TNFi therapies are often the first biologic therapy used to treat RA patients
who have not responded to csDMARDs for several reasons, some of which are not
evidence based. However, many patients do not adequately respond to TNFis.
Therefore, a test that can accurately predict response to such therapies would
help inform therapeutic decision-making, lessen unnecessary trial-and-error
approaches, eliminate or reduce the time to effective therapy, and improve
patient outcomes.

Multiple studies have pointed to the presence of a molecular signature
underlying the pathophysiology of TNFi response in RA. RA is a heterogeneous
disease in terms of pathogenesis as well as treatment response. Additionally,
baseline demographic and clinical patient characteristics such as obesity,
female sex, and the presence of RF, have each been associated with a lack of
response to TNFi therapy.42,80,81 In published studies, these factors may have
impacted observed treatment responses as well as provider treatment decisions
independently of any test result. Despite this, the MSRC has recently
demonstrated through a multivariable analysis that it is a better predictor of
ACR50 nonresponse to TNFi therapy than any single clinical feature or
combination of clinical features, confirming that the genomic component of the
test contributes to the test performance above the contributions from the
available clinical, demographic and laboratory parameters that are included as
part of the test.84

Our review of the current literature demonstrates that there are multiple
limitations not only of the current biomarker tests for RA therapy selection,
but also of the disease response assessments against which they are measured.
First, physician and patient assessments of disease activity can be
considerably variable. For example, the DAS28-CRP has been reported to
significantly underestimate disease activity and overestimate improvements
compared with DAS28-ESR.82 It is imperative, therefore, that any biomarker
test is clinically validated according to _multiple_ validated response
outcome criteria (including ACR50, DAS28-CRP and CDAI) in order to perform as
a robust predictor.59,65,66 Second, PDAs and PROMS are subjective, have
inherent variability, and are not well-defined in the tests that use them as
components. They also lack important measures of disease assessment. For
example, a systematic review found a lack of adequate PROMs to evaluate and
define symptoms such as stiffness and sleep problems, both common in RA.15,16
Further, it is unclear how patients with various levels of symptoms, flares,
and periods of remission were accounted for in studies that included PDAs in
their analyses. Finally, these disease assessments themselves have been
reported to differentiate TNFi responders from non-responders.83 As such, the
extent of impact from all of these variables on claimed test accuracy across
the published studies is as-yet unknown, and any discordance observed in the
various disease activity measures and PROMS must be thoroughly investigated,
rather than eliminating such results from analysis, as has been done in some
of the published literature.66 In fact, researchers have called for agreed
prioritization across stakeholders about the most important metrics to collect
for clinical decision-making and in clinical trials, and the ACR recently
provided recommendations for Functional Assessment Instruments in RA suitable
for routine clinical use.16,84,85

The current literature illuminates many limitations of the evaluated evidence
supporting the use of these RA biomarker tests. One major issue is that they
consider responses to TNFis as a class but it is not clear whether only one or
a few drugs within the class account for most of the impact observed regarding
disease response. It is also unknown whether certain variables impact certain
TNFis more than others within the class. For example, one study found that the
most important clinical factors associated with TNFi response were age for
adalimumab, rheumatoid factor for etanercept, erythrocyte sedimentation rate
for infliximab and golimumab, disease duration for abatacept, and C-reactive
protein for tocilizumab.86 Finally, as some of the tests do not discriminate
between TNFi agents, patients may be considered non-responders to the entire
class of TNFis when in fact, the NR signature may be heavily skewed toward a
specific TNFi, unnecessarily limiting patients' treatment options.

There are also limitations in the various studies that may have significantly
influenced the treatments provided and conclusions drawn by the authors,
including but not limited to the following: patients with conflicting
information in the AIMS database relative to primary source documents were
excluded without further investigation; patients in the CERTAIN trial were
allowed to contribute multiple sets of observations if they initiated
different biologics over the study period and if they did so, a new 'baseline'
visit was established; patients who switched to a new biologic, even if for
reasons of safety rather than efficacy were considered as non-responders; in
the CERTAIN trial, the reasons for discontinuation were not systematically
collected for all of the years of the study period, and discontinuation may
have occurred for a variety of reasons unrelated to efficacy; most authors of
the MSRC papers were Scipher Medicine employees or had heavy financial ties to
the company.

The MSRC only provides information regarding response to TNFi therapies and
does not provide information regarding the various alternate therapies that
are available. Moreover, the test will only identify about 55% of the TNFi
non-responders.59 The remaining half of true NR patients will still likely be
treated with TNFis and most of them will not achieve clinical disease response
or remission. Additionally, many patients who are not predicted to be non-
responders to TNFis will still fail to achieve an adequate response to TNFi
therapy for reasons that may be unrelated to their molecular signature, such
as the development of anti-drug antibodies (which have been reported for all
TNFi therapies and are known to decrease TNFi response in RA).91 Therefore,
the utility of a test like the MSRC is limited to only a subset of the RA
population. It is thus evident that limited sample sizes, the complexity of
gene expression data analysis, the uncertain combinatorial effects of
serologic and other laboratory markers with clinical variables, and the
variability in validated disease assessments and in patient reported
assessments of disease activity have all proven to be challenges in the
development of robust predictive biomarker tests that are generalizable across
RA patient cohorts.80,90 For many of these reasons, international, national,
and society guidelines have not yet endorsed predictive (for response to
therapy) biomarker testing in RA.

Despite the many limitations of predictive biomarker tests, a review of the
evidence, as imperfect as it may be, supports the limited use of these
services given their demonstrated validity and utility. When a NR signature is
obtained by the MSRC, nearly 90% of those patients will prove to not
clinically respond to TNFi therapies using multiple validated disease response
criteria including the ACR50 and CDAI.59 In these patients, a non-TNFi is
likely the best therapeutic option. While the high PPV of this test is also a
function of the high (~60-70%) prevalence of true TNFi- non-responders in this
population, the incremental (~20%) improvement over the already known high
prevalence of NR at baseline (uninformed by the test) is still considered an
improved outcome by this contractor despite its marginal benefit to these
patients. Further, although there is no guarantee that the use of a non-TNFi
in a patient with a NR-signature will result in improved disease outcomes, as
only about 35% of these patients respond to alternate therapies by ACR50,
similar to the response rate to TNFis reported in the overall population at
baseline (though 56.2% of these patients respond to the alt-MOA therapies when
the CDAI measure of disease activity is used),68 this change in management
would ultimately serve to avoid time on an unnecessary therapy and shorten the
time to an appropriate therapy. Despite this, additional challenges remain as
studies have shown that (a) physicians still prescribe TNFis in many patients
with NR signatures, (b) many patients will still often cycle to a second TNFi
before switching to a non-TNFi (despite ACR guidelines) and (c) patients who
begin or switch to a non-TNFi tend to be older with more comorbidities.
Therefore, it is not immediately clear that the use of this test will, in
fact, result in a significant shift in physician prescribing even in the
appropriate TNFi-NR populations.

There is an apparent need to identify appropriate (or inappropriate) targeted
therapies for RA patients. While the current data on the use of these services
is very limited, a review of the published evidence to date demonstrates a
marginal but pragmatic value to the use of some RA therapy selection tests in
a limited setting. However, it is imperative to underscore that the utility of
the reviewed tests remains limited to only half of the true TNFi-NR population
and that even in this group, there is no guarantee that the alternate (non-
TNFi) therapies prescribed as a result of the test will result in improved
disease activity or remission. Therefore, it is likely that future tests will
add substantially more benefit than the current services offered and reviewed
by this contractor.

Finally, while this contractor does not believe it appropriate that patients
continue classes of therapy that they have already failed due to payor
preference, it is also not appropriate to perform testing to avoid such
preferences that is not grounded in evidence.

This contractor will continue to monitor the evidence and may modify coverage
based on new information in the pertinent literature and society
recommendations.