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Notification Issue Date:



Medical Policy Bulletin


Title:Measurement of Serum Antibodies to and Measurement of Serum Levels of Biologics

Policy #:06.02.39d

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract. The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

The intent of this policy is to communicate that measurement of serum antibodies to and measurement of serum levels using Anser™ or DoseAssure™ Tests are considered experimental/investigational.

For information on policies related to this topic, refer to the Cross References section in this policy.

Measurement of antibodies to infliximab and measurement of serum infliximab levels in an individual receiving treatment with infliximab, either alone or as a combination test (i.e., Anser™IFX) are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

Measurement of antibodies to adalimumab and measurement of serum adalimumab levels in an individual receiving treatment with adalimumab, either alone or as a combination test (i.e., Anser™ADA) are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

Measurement of antibodies to ustekinumab and measurement of serum ustekinumab levels in an individual receiving treatment with ustekinumab, either alone or as a combination test (i.e., Anser™UST) are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

Measurement of antibodies to vedolizumab and measurement of serum vedolizumab levels in an individual receiving treatment with vedolizumab, either alone or as a combination test (i.e., Anser™VDZ) are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

DoseASSURE Test Portfolio (i.e.: DoseASSURE™ IFX, DoseASSURE™ IFX (Serial Monitor), DoseASSURE™ VDZ, DoseASSURE™ UST, DoseASSURE™ ADL, DoseASSURE™ RTX, DoseASSURE™ CTZ, DoseASSURE™ GOL, DoseASSURE™ ADL (Serial Monitor), and DoseASSURE™ ETN (Serial Monitor)) are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature. [Key: IFX = Infliximab, VDZ = Vedolizumab, UST = Ustekinumab, ADL = Adalimumab, CTZ = Certolizumab, RTX = Rituximab, GOL = Golimumab, & ETN = Etanercept]
Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, the tests/services addressed in this policy bulletin, (i.e., measurement of serum antibodies to and measurement of serum levels using Anser™ or DoseAssure™ Tests) are not eligible for payment under the medical benefits of the Company’s products because the service is considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are a benefit contract exclusion for all products of the Company. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

The services discussed in this policy bulletin are laboratory procedures developed by laboratories and are not regulated by the US Food and Drug Administration (FDA).

Clinical Laboratory Improvement Amendments (CLIA) laboratory establishes quality standards for all laboratory testing. Manufacturers of the discussed tests are CAP-accredited (CLIA) laboratories.

Description

BACKGROUND OF INFLIXIMAB AND ADALIMUMAB IN AUTOIMMUNE DISEASES

Infliximab is a chimeric (mouse/human) anti-tumor necrosis factor α (TNF-α) monoclonal antibody. Adalimumab is a fully human monoclonal antibody to TNF-α. Therapy with monoclonal antibodies has revolutionized therapy in individuals with inflammatory diseases such as inflammatory bowel disease (IBD; Crohn disease, ulcerative colitis), rheumatoid arthritis, and psoriasis. These agents are generally given to individuals who fail conventional medical therapy, and they are typically highly effective for induction and maintenance of clinical remission. However, not all individuals respond, and a high proportion of individuals lose response over time. An estimated one-third of individuals do not respond to induction therapy (primary nonresponse), and among initial responders, response wanes over time in approximately 20% to 60% of individuals (secondary nonresponse). The reasons for therapeutic failures remain a matter of debate but include accelerated drug clearance (pharmacokinetics) and neutralizing agent activity (pharmacodynamics) due to antidrug antibodies (ADA). ADA are also associated with injection site reactions (adalimumab) and acute infusion reactions and delayed hypersensitivity reactions (infliximab). As a fully human antibody, adalimumab is considered less immunogenic than chimeric antibodies, such as infliximab.

DETECTION OF ANTIDRUG ANTIBODIES (ADA)

The detection and quantitative measurement of ADA has been fraught with difficulty, owing to drug interference and identifying when antibodies likely have a neutralizing effect. First-generation assays, (i.e., enzyme-linked immunosorbent assays [ELISA]) can measure only ADA in the absence of detectable drug levels, due to interference of the drug with the assay. Other techniques available for measuring antibodies include the radioimmunoassay (RIA) method, and more recently, the homogenous mobility shift assay (HMSA) using high-performance liquid chromatography. Disadvantages of the RIA method are associated with the complexity of the test and prolonged incubation time, and safety concerns related to the handling of radioactive material. The HMSA has the advantage of being able to measure ADA when infliximab is present in the serum. Studies evaluating the validation of results among different assays are lacking, making interstudy comparisons difficult. One retrospective study in 63 individuals demonstrated comparable diagnostic accuracy between 2 different ELISA methods in individuals with IBD (i.e., double antigen ELISA and antihuman lambda chain-based ELISA) (Kopylov et al 2012). This study did not include an objective clinical and endoscopic scoring system for validation of results.

ANSER™IFX AND ANSER™ADA

Prometheus® Laboratories Inc. offers nonradiolabeled, fluid-phase homogenous mobility shift assay (HMSA) tests called Anser™ IFX for infliximab and Anser™ ADA for adalimumab. Neither test is ELISA based, and each can measure antidrug antibodies in the presence of detectable drug levels, improving upon a major limitation of the ELISA method. Both tests measure serum drug concentrations and antidrug antibodies. Other proprietary commercial and/or academic labs may offer similar testing.

These tests were developed and their performance characteristics determined by Prometheus Laboratories Inc. Although the US Food and Drug Administration (FDA) has not been involved in the regulation of laboratory procedures historically, recently, the FDA is reported to be involved in the evaluation of certain lab tests. Anser™IFX and Anser™ADA have not been cleared or approved by the U.S. Food and Drug Administration.

TREATMENT OPTIONS FOR INDIVIDUALS WITH SECONDARY LOSS RESPONSE TO ANTI-TNF THERAPY

A diminished or suboptimal response to infliximab or adalimumab can be managed in several ways: shortening the interval between doses, increasing the dose, switching to a different anti-TNF agent (in individuals who continue to have loss of response after receiving the increased dose), or switching to a nonanti-TNF agent.

SYSTEMATIC REVIEWS RELATED TO ANSER™IFX AND ANSER™ADA

The systematic review and meta-analysis by Pecoraro et al (2017) selected 34 studies (total N=4273 individuals), including randomized controlled trials (RCTs; n=4), prospective observational (n=22), retrospective observational (n=6), and cross-sectional (n=2). Studies evaluated rheumatoid arthritis (RA; n=18), ulcerative colitis (n=2), Crohn disease (CD; n=5), psoriatic arthritis (n=4), ankylosing spondylitis (n=5), plaque psoriasis (n=4), and spondyloarthritis (SpA; n=1). Most individuals (45%) received infliximab, 35% received adalimumab, and 21% received etanercept. None received golimumab or certolizumab. Reviewers identified studies published through August 2016 and rated study quality as good (n=17), fair (n=16), or poor (n=1). The effect of ADA was evaluated in 19 studies, showing a significant (p<0.05) reduction of response(relative risk [RR], =0.43; 95% confidence interval [CI], 0.3 to 0.63) in ADA-positive individuals relative to ADA-negative individuals, with adalimumab therapy demonstrating a greater reduction (RR=0.40; 95% CI, 0.25 to 0.65; p<0.001) than infliximab (RR=0.37; 95% CI, 0.2 to 0.7; p<0.001). Measures of heterogeneity were 84%, 57%, and 79%, respectively. Fourteen studies reported on the effect of ADA on clinical response (see Table 4). Eleven studies found the risk of developing ADA to be significantly (p=0.03) lower in individuals treated with concomitant methotrexate therapy relative to treated those without methotrexate (RR=0.65; 95% CI, 0.47 to 0.9). Studies comparing treatment response with nonresponse (n=15) found responders to have a significantly (p<0.001) lower risk of developing ADA relative to nonresponders (RR=0.31; 95% CI, 0.18 to 0.52). The presence of ADA was associated with a significant reduction of anti-tumor necrosis factor α (TNF-α) serum concentration. Of the 20 studies (n>2800 individuals) reporting data on adverse events, 31% (n=2 studies) developed infections, 18% (n=12 studies) developed injection-site reactions, 8% (n=11 studies) discontinued treatment due to adverse events, and 5% (n=1 study) developed serious adverse events. Although ADA significantly reduced TNF-α response, the results should be viewed cautiously due to reported study limitations, including small numbers of studies assessed and considerable heterogeneity.

The systematic review and meta-analysis by Thomas et al (2015) included 68 studies (total N=14651 individuals). individuals had RA (n=8766), SpA (n=1534), or IBD (n=4351). Immunogenicity was examined for infliximab (39 comparisons), adalimumab (15), etanercept (5), golimumab (14), and certolizumab (8). Reviewers identified studies published through December 2013 and included 38 RCTs and 30 observational studies (study quality rated as good [n=32], moderate [n=26], poor [n=10]). The pooled prevalence of ADA varied by disease and drug (see Table 1, highest with infliximab: 25.3%). Duration of exposure (reported in 60 studies) was examined for its potential effect on the development of ADA, and most studies employed enzyme-linked immunosorbent assays (ELISA). The presence of ADA was associated with lower odds of response across most drugs and diseases. An exception was in studies of IBD. Use of immunosuppressive agents substantially decreased the risk of ADA (odds ratio [OR], 0.26; 95% CI, 0.21 to 0.32). Finally, infusion reactions and injection-site reactions were more common when ADA were detectable (OR=3.25). Evaluation of potential publication bias and overall assessment (e.g., GRADE or similar) for the body of evidence were not reported. Additionally, no measures of heterogeneity were reported.

The systematic review by Meroni et al (2015) searched PubMed through March 2013 and included 57 studies of infliximab (n=34), adalimumab (n=18), and etanercept (n=5). Studies primarily included individuals with IBD and RA, but also SpA and psoriasis. Most had prospective cohort designs (n=42), and a formal assessment of study quality (bias) was not reported. Reviewers noted considerable variability in the time from drug administration to ADA and drug bioavailability testing across studies. Various antibody testing assay methods were used and included solid-phases radioimmunoassay (RIA), traditional ELISA, fluid-phase RIA, and bridging ELISA; cutoffs for positive test results were also inconsistently reported. The ranges of individuals with detectable ADA varied substantially but were consistent with other reviews. Qualitatively, the presence of ATI was associated with lower levels of infliximab and lower risk of disease control or remission. The presence of ATI also increased the risk of infusion reactions. When ascertained, the time to development of ATI varied from as little as 16 weeks to over a year. The time to ATA positivity varied (e.g., 50% of individuals with detectable ATA at 28 weeks to a median time of 1 year). Finally, for both infliximab and adalimumab, immunosuppression was associated with less ADA positivity. Reviewers concluded that “…the lack of homogeneity in study design and methodologies used … limited the opportunity to establish the time-course and clinical consequences of anti-drug antibody development....” Although qualitative, reviewers included many studies and provided a detailed review of each not reported by the other meta-analyses.

Nanda et al (2013) conducted a meta-analysis of studies that reported on clinical outcomes according to the presence or absence of antibodies to infliximab (ATI) in individuals with IBD. Several databases were searched to February 2012 (one was searched to August 2012). Eleven studies involving 707 individuals were selected. Six studies (2 RCTs, 1 prospective cohort study, 3 retrospective cohort studies) were included. Selected studies failed at least 1 quality domain (study eligibility criteria, measurement of exposure and outcome, control for confounders, completeness of follow-up), and all studies had a high risk of bias. The prevalence of detectable ATI in the included studies ranged from 22.4% to 46%. The outcome of interest was a loss of response to infliximab, defined as “relapse of clinical symptoms in individuals who were in clinical remission from, or had responded to, infliximab.” Measures of loss of response varied across studies and included clinician assessment, standardized scales (Crohn’s Disease Activity Index [CDAI], Harvey-Bradshaw Index, Simple Clinical Colitis Activity Index), and the requirement for surgery or presence of a nonhealing fistula. individuals with ATIs had a 3-fold greater risk of loss of response than those without ATIs (RR=3.2; 95% CI, 2.0 to 5.0; (RR of clinical response in treated vs untreated individuals to allow comparison with other meta-analyses)). This result was influenced primarily by 532 individuals with CD (RR=3.2; 95% CI, 1.9 to 5.5); pooled results for 86 individuals with ulcerative colitis were not statistically significant (pooled RR=2.2; 95% CI, 0.5 to 9.0). (Eighty-nine individuals with unspecified IBD also were included in the meta-analysis.) In addition to potential bias in included studies and heterogeneity in outcome assessment, the meta-analysis was limited by variability in the method of ATI detection (double-antigen ELISA, antihuman lambda chain-based ELISA, fluid-phase RIA).

Garces et al (2013) performed a meta-analysis of studies of infliximab and adalimumab used to treat RA, IBD, SpA, and psoriasis. Databases were searched to August 2012, and reviewers selected 12 prospective cohort studies involving 860 individuals (540 with RA, 132 with SpA, 130 with IBD, 58 with psoriasis). The outcome of interest was a response, assessed using standard assessment scales for rheumatologic diseases (e.g., European League Against Rheumatism criteria for RA; Assessment in Ankylosing Spondylitis 20% response criteria, or Ankylosing Spondylitis Disease Activity Score for spondyloarthritis; Psoriasis Area and Severity Index for psoriasis) and clinician assessment for IBD. Overall, detectable ADA were associated with a 68% reduction in drug response (pooled RR=0.32). Significant heterogeneity was introduced by varying use of immunosuppressant therapy (e.g., methotrexate) across studies. To assess ADA, most studies used RIA, which is less susceptible than ELISA to drug interference and may be more accurate.

Lee et al (2012) conducted a meta-analysis of individuals with IBD receiving infliximab to estimate the prevalence of ATI, the effect of ATI on the prevalence of infusion reactions, and the effect of ATI on disease remission rates. Databases were searched through October 2011, and 18 studies (total N=3326 individuals) were selected. Studies included 9 RCTs, 5 prospective cohort studies, and 4 retrospective cohort studies. The prevalence of ATI was 45.8% when episodic infusions of infliximab were given and 12.4% when maintenance infliximab was given. individuals with ATI were less likely to be in clinical remission, but this finding was not statistically significant (RR=0.90; p=0.10). Rates of infusion reactions were significantly higher in individuals with ATI (RR=2.07; see Table 3). Immunosuppressants resulted in a 50% reduction in the risk of developing ATI (p<0.001). Reviewers concluded that individuals with IBD who test positive for ATIs are at an increased risk of infusion reactions but have rates of remission similar to individuals who test negative for ATIs.

ANALYTIC AND CLINICAL VALIDATION OF ANSER™IFX AND ANSER™ADA

Cludts et al (2017) conducted a single-center retrospective cohort analysis of individuals with RA (n=18), psoriatic arthritis (n=9), or ankylosing spondylitis (n=12) in Italy. Serum samples were taken prior to adalimumab therapy and after 12 and 24 weeks of treatment. Psoriatic arthritis and ankylosing spondylitis individuals were grouped together (SpA) due to axial involvement in all psoriatic arthritis individuals. Although adalimumab levels varied among individuals (0 to 30 mg/mL), median levels were significantly lower at 12 and 24 weeks in ATA-positive samples, and antibody formation was associated with decreasing levels of circulating adalimumab. A reporter gene assay detected neutralizing antibodies against TNF antagonists in ATA-positive, therapeutic-negative individuals; however, neutralization could not be confirmed in all ATA-positive samples due to adalimumab interference. There was a negative correlation between ATA levels and adalimumab in all groups, with 43.6% and 41% of the adalimumab-treated individuals developing antibodies at 12 and 24 weeks, respectively. These percentages increased to 48.7% and 46% after subjecting the samples to acid treatment. There was a negative correlation between adalimumab trough levels and Disease Activity Score in 28 joints (DAS28) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores (p<0.001). There were no significant differences in BASDAI scores between ATA-positive and ATA-negative individuals at 12 or 24 weeks. Study findings are consistent with others, suggesting that adalimumab levels can serve as an indicator of ATA; however, limitations included small sample size, retrospective research design, and failure to confirm neutralization in all ATA-positive samples.

Using an observational, cross-sectional study design, Ara-Martin et al (2017) analyzed the impact of immunogenicity on response to anti-TNF therapy in 137 adults with moderate-to-severe plaque psoriasis at 35 centers in Spain between 2012 and 2014. All individuals experienced secondary nonresponse to adalimumab (n=65), etanercept (n=47), and infliximab (n=19) after 6 or more months of treatment. Serum ADA was identified in 48%, 0%, and 42% of individuals treated with adalimumab, etanercept, and infliximab, respectively. Loss of efficacy was assessed using the Psoriasis Area and Severity Index (PASI; >5), 75% improvement in PASI score from baseline (PASI75), and/or the Physician Global Assessment (>2). Physician Global Assessment values for ADA-positive vs ADA-negative individuals were significantly worse in the adalimumab group (3.7 vs 3.2; p=0.02) but not in the infliximab group. There was a significant negative linear correlation between serum drug concentrations and ADA in the adalimumab group (p=0.001) and among the 3 groups combined (p=0.001), and a significant (p=0.019) correlation between serum ADA titer and body surface area. Unlike the other studies, in this study, the use of concomitant antirheumatic drugs was not associated with anti-TNF immunogenicity in any of the groups. This study provided evidence of antibody development against adalimumab and infliximab (not against etanercept) in individuals with psoriasis, with ADA formation accounting for half of the secondary nonresponse associated with these therapies. However, conclusions were limited due to the cross-sectional study design, use of ELISA to detect ADAs due to drug interference, the potential presence of neutralizing antibodies as confounding factors, and limited information about individuals’ health status prior to the study period.

A case-control, longitudinal study by Lombardi et al (2016) evaluated possible confounding factors by analyzing adalimumab treatment for psoriasis in 5 distinct groups, including individuals who received: biologic therapies after switching from adalimumab (n=20); ongoing adalimumab therapy (n=30); novel adalimumab therapy (n=30); biologic therapies other than adalimumab (n=15); and no treatment with immunosuppressants or biologics (n=15), serving as a quasi-control. The clinical severity of psoriasis was scored using the PASI. At 12-month follow-up, ADA was highest (87%) in individuals who received biologic therapies after switching from adalimumab. The false-positive rate was 23% for adalimumab detection and 22% for anti-adalimumab antibodies in individuals who were never treated with adalimumab. There were no significant differences in median PASI scores between the anti-adalimumab antibody-negative individuals (1.1) and the anti-adalimumab antibody-positive individuals (4.0). There was no association between PASI score or TNF-á concentration and the presence of anti-adalimumab antibodies in individuals receiving adalimumab. Additionally, there were no significant differences in TNF-á and C-reactive protein concentrations. Study limitations included the observational design, small sample size, use of ELISA to measure ADA, and high variability of results. The authors concluded that the assay has limited clinical utility.

Arstikyte et al (2015) prospectively evaluated the association between ADA and adverse events, clinical response, and serum drug levels in 143 symptomatic individuals (62 with RA, 81 with SpA; mean age, 45 years) treated with TNF blockers in Lithuania. All individuals receiving adalimumab or infliximab were tested and 1 in 3 individuals was given etanercept (because it is more commonly used). A response in RA individuals was defined as either good, moderate, or low using European League Against Rheumatism criteria; SpA disease activity was considered inactive, moderate, high, or very high by established criteria,15, with inactive and moderately active disease defined as a response. At least 3 months after therapy initiation, a single serum sample was obtained prior to dosing between 2012 and 2013; disease activity and other patient characteristics (e.g., symptom duration, health status) were assessed concurrently. Serum adalimumab, infliximab, and etanercept levels were obtained; ADA was assayed using a bridging ELISA. Of 57 individuals receiving infliximab, 14 (24.6%) had detectable antibodies, with 13 of the 14 undetectable infliximab trough levels. Disease activity at baseline was unassociated with the development of ADA in either disease. In individuals achieving a response, infliximab and adalimumab trough levels were higher, but not significantly (p=0.09 and p=0.14, respectively). However, adalimumab concentrations were significantly higher in nonresponders (p<0.001). ATI were associated with infusion reactions but with little certainty (OR=5.9; 95% CI, 1.0 to 33.3) as was stopping infliximab treatment or changing agent. Study strengths included its prospective design, standardized assessments, and responder definition. Limitations were the small number of nonresponders and lack of specificity on whether any eligible participants declined enrollment.

Jani et al (2015) measured ADA and RIA together, with drug levels in 331 RA individuals treated with adalimumab (n=160) or etanercept (n=171) between 2008 and 2013. individuals were participants in the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate, conducted in 60 centers across the United Kingdom. Disease activity was assessed using the DAS28. Response was evaluated using European League Against Rheumatism response criteria or change in DAS28 score. Following 12 months of adalimumab therapy, ADA were detectable in 24.8% of individuals (almost all were detectable by 6 months) and were associated with lower serum drug levels. Both routine (nontrough) drug levels and ATA were associated with DAS28 scores at 12 months. In predicting European League Against Rheumatism nonresponse, the area under the curve for an adalimumab concentration less than 5 mg/mL at 3 months was 0.66 (95% CI, 0.55 to 0.77) and 0.68 (95% CI, 0.54 to 0.81) for the presence of ADA. None of the etanercept individuals developed detectable ADA. Although derived from a well-established observational study designed to examine predictors (genetic and other) of treatment response, ADA serum levels were not used to inform treatment decisions. Study results corroborated other research findings.

Frederiksen et al (2014) conducted a single-center retrospective cohort study of IBD individuals treated with infliximab (n=187) or adalimumab (n=57) in Denmark. ADA were assayed using fluid-phase RIA; 49% of infliximab-treated individuals developed antibodies compared with 21% of those treated with adalimumab. Development of ATA was associated with secondary nonresponse: the positive predictive value was 91% (95% CI, 59% to 100%), sensitivity was 50% (95% CI, 27% to 73%); the negative predictive value was 74% (95% CI, 57% to 87%), and specificity was 97% (95% CI, 82% to 100%) (values varied by adalimumab trough levels). The authors also reported that individuals switching from infliximab to adalimumab who had antibodies were more likely to develop ATA. These findings are consistent with other studies and evaluation of ADA using RIA (a strength of this study). Conclusions were limited by the retrospective design and sample size.

While many studies have evaluated the clinical validity using single ADA measurements, at least one assessed their persistence over time. Vande Casteele et al (2013) analyzed infliximab trough and ATI levels using a homogeneous mobility shift assay with banked serum obtained from 90 IBD individuals treated between 1999 and 2011. ATI levels had been previously assayed using an ELISA-based test. A total of 1232 samples were evaluated (mean, 14 per patient). Treatment decisions were made solely on clinical evaluation and C-reactive protein levels. ATI were detected in 53 (59%) of 90 individuals but subsequently were nondetectable in 15 (28%) of the 53. Persistent ATIs were associated with discontinuation of infliximab (RR=5.1; 95% CI, 1.4 to 19.0), but the wide CI reflects considerable uncertainty. Although the transience of ATI in IBD has not been carefully scrutinized, if replicated, these results would suggest interpreting a single ATI result cautiously.

A large body of evidence has evaluated the clinical validity of ADA testing. ADA has been associated with secondary nonresponse in RA, SpA, and possibly IBD. The presence of ADA has been consistently associated with an increased risk of an infusion-site reaction related to infliximab and injection-site reactions related to adalimumab. A concomitantly administered immunosuppressant agent may reduce the risk of developing ADA. Although ADA significantly reduced TNF-α response in a recent meta-analysis, considerable heterogeneity limits those findings. In addition, a recent observational study found no association between concomitant immunosuppressants and anti-TNF immunogenicity in individuals with psoriasis; and a second cohort study found no association between PASI score or TNF-α concentration and the presence of anti-adalimumab antibodies in individuals receiving adalimumabto treat psoriasis.

CLINICAL UTILITY OF ANSER™IFX AND ANSER™ADA

Several algorithms have been developed to manage individuals with IBD, and RA22, who have relapsed during TNF-inhibitor therapy. These algorithms are generally based on evidence that has indicated an association between ADA, reduced serum drug levels, and relapse. None of the algorithms has included evidence demonstrating improved health outcomes, such as reduced time to recovery from relapse (response).

Steenholdt et al (2014) reported on results of a noninferiority trial and cost-effectiveness analysis of 69 individuals with CD who relapsed (CDAI ≥220 and/or ≥1 draining perianal fistula) during infliximab therapy. individuals were randomized to infliximab dose intensification (5 mg/kg every 4 weeks) or algorithmic treatment based on serum infliximab level and ATI. individuals with subtherapeutic infliximab level (<0.5 ìg/mL24) had the infliximab dose increased if ATI were undetectable or were switched to adalimumab if ATI were detectable; individuals with therapeutic infliximab level underwent repeat testing of infliximab and ATI levels if ATI were detectable or diagnostic reassessment if ATI were undetectable. Serum infliximab and ATI levels were measured in all individuals using RIA in single-blind fashion (individuals were unaware, but investigators were aware of test results). Randomized groups were similar at baseline; overall, 55 (80%) of 69 individuals had nonfistulizing disease. Most individuals (70%) had therapeutic serum infliximab levels without detectable ATI; revised diagnoses in 6 (24%) of 25 such individuals in the algorithm arm25, included bile acid malabsorption, strictures, and irritable bowel syndrome. In both intention-to-treat and per-protocol analyses, similar proportions of individuals in each randomized group achieved clinical response at week 12, defined as a minimum 70-point reduction from baseline CDAI score for individuals with nonfistulizing disease and a minimum 50% reduction in active fistulas for individuals with fistulizing disease (intention-to-treat, 58% in the algorithm group vs 53% in the control group; p=0.810; per-protocol, 47% in the algorithm group vs 53% in the control group; p=0.781). Only the intention-to-treat analysis fell within the prespecified noninferiority margin of -25% for the difference between groups.

Conclusions on the noninferiority of an algorithmic approach compared with dose intensification from this trial are limited. The noninferiority margin was arguably large and was exceeded in the conservative per-protocol analysis. Dropouts were frequent and the differential between groups; 17 (51%) of 33 individuals in the algorithm group and 28 (78%) of 36 individuals in the control group completed the 12-week trial. A large proportion of individuals (24%) in the algorithmic arm were potentially misdiagnosed (i.e., CD flare was subsequently determined not to be the cause of relapse); the comparable proportion in the control arm was not reported. In most individuals (80% who had nonfistulizing disease), only a subjective measure of treatment response was used (minimum 70-point reduction from baseline CDAI).

Roblin et al (2014) conducted a single-center, prospective observational study of 82 individuals with IBD (n=45 CD, n=27 ulcerative colitis) with clinical relapse (CDAI score >220 or Mayo Clinic score >5) during treatment with adalimumab 40 mg every 2 weeks. For all individuals, trough adalimumab levels and ADA were measured in a blinded fashion using ELISA, and adalimumab dose was optimized to 40 mg weekly. Those who did not achieve clinical remission (CDAI score <150 or Mayo score <2) within 4 months underwent repeat trough adalimumab and anti-adalimumab antibody testing and were switched to infliximab. Clinical and endoscopic responses after adalimumab optimization and after infliximab therapy for 6 months were compared across 3 groups: (1) those with a therapeutic adalimumab level (>4.9 ìg/mL27), (2) those with a subtherapeutic adalimumab level and undetectable ATA; and (3) those with a subtherapeutic adalimumab level and detectable ATA. After adalimumab optimization, more group 2 individuals achieved clinical remission (16 [67%] of 24 individuals) than group 1 (12 [29%] of 41 individuals; p<0.01 vs group 2) and group 3 (2 [12%] of 17 individuals; p<0.01 vs group 2) individuals. Duration of remission was longest in group 2 (mean, 15 months) compared with group 1 (mean, 5 months) and group 3 (mean, 4 months; p<0.01 for both comparisons vs group 2). At 1 year, 13 (52%) of 24 individuals in group 2 maintained clinical remission compared with no individuals in groups 1 or 3 (p<0.01 for both comparisons vs group 2). Results were similar when remission was defined using calprotectin levels (<250 ìg/g stool) or endoscopic Mayo score (<2).

Fifty-two individuals (n=30 CD, n=22 ulcerative colitis) who failed to achieve clinical remission after adalimumab optimization were switched to infliximab. More individuals in group 3 achieved clinical remission (12 [80%] of 15 individuals) than in group 1 (2 [7%] of 29 individuals) or group 2 (2 [25%] of 8 individuals; p<0.01 for both comparisons vs group 3). Duration of response after switching to infliximab was longest in group 3 (mean, 14 months) compared with group 1 (mean, 3 months) and group 2 (mean,5 months; p<0.01 for both comparison vs group 3). At 1 year, 8 (55%) of 15 individuals in group 3 maintained clinical remission compared with no individuals in groups 1 or 2 (p<0.01 for both comparisons vs group 3). Results were similar using objective measures of clinical remission (calprotectin level, endoscopic Mayo score).

These results suggested that individuals with IBD who relapse on adalimumab and have subtherapeutic serum adalimumab levels may benefit from a higher adalimumab dose if ATA are undetectable or from a change to another TNF inhibitor if ATA are detectable. Relapsed individuals who have therapeutic serum adalimumab levels may benefit from change to a different drug class. Strengths of the study included its use of subjective and objective measures of remission and blinded serum drug level and ATA monitoring. However, results were influenced by the small sample size, use of ELISA for antibody testing, and lack of ADA levels for decision making. A subsequent study comparing the management using the algorithm proposed with usual care is needed. Finally, the lead author of the study received lecture fees from the ADA test provider (Theradiag).

Afif et al (2010) evaluated the clinical utility of measuring ATI (referred to as human antichimeric antibodies in the study) and infliximab concentrations by retrospectively reviewing patient medical records. Record review from 2003 to 2008 identified 155 individuals who had had ATI, had data on infliximab concentrations, and met the study inclusion criteria. A single physician ordered 72% of the initial tests. The authors retrospectively determined clinical response to infliximab. Forty-seven percent of individuals were on concurrent immunosuppressive medication. The main indications for testing were a loss of response to infliximab (49%), partial response after initiation of infliximab (22%), and possible autoimmune or delayed hypersensitivity reaction (10%). ATI were identified in 35 (23%) individuals and therapeutic infliximab concentrations in 51 (33%) individuals. Of 177 tests assessed, the results impacted treatment decisions in 73%. In ATI-positive individuals, change to another anti-TNF agent was associated with a complete or partial response in 92% of individuals, whereas dose escalation occurred in 17%.

The authors concluded that measurement of ATI and infliximab concentration had a clinically useful effect on patient management. The strategy of increasing infliximab dose in individuals with ATI was ineffective whereas in individuals with subtherapeutic infliximab concentrations this strategy was a good alternative to changing to another anti-TNF agent.28, Study limitations included the retrospective design and use of ELISA testing for ATI. Because there was no control group, one cannot determine what changes in management would have been made absent ATI measurement. Because clinicians are likely to change management for individuals who do not achieve or maintain a clinical response, it is important to understand how these management decisions differ when ATI are measured. Because the clinical validity of testing anti-TNF-α inhibitor ATI or ATA in this population has not been established, a chain of evidence supporting clinical utility cannot be constructed.
Convincing evidence for the clinical utility of ADA testing is currently lacking. Uncontrolled retrospective studies in IBD have demonstrated the impact of ADA testing on treatment decisions but cannot demonstrate improved patient outcomes compared with a no-testing strategy. Additional limitations of these studies included a lack of clinical follow-up after treatment decisions were made and lack of clinical assessments to guide treatment decisions. Additionally, determination of a clinically relevant threshold for ADA level is complicated by the use of various assay methods. A small, nonrandomized prospective study suggested that ADA levels may be informative in relapsed individuals with IBD who have low serum adalimumab levels, but this finding requires confirmation in larger, randomized trials. Methodologic flaws, including relapse misclassification, limit conclusions from the RCT in individuals with relapsed IBD. Direct or indirect evidence for clinical utility in individuals with RA or SpA was not identified. Finally, although ADA are associated with increased risk of infliximab infusion- and adalimumab injection-site reactions, whether testing for ADA can reduce that risk is unclear. For example, the Lichtenstein (2013) systematic review of infliximab-related infusion reactions concluded: “…there is a paucity of systematic and controlled data on the risk, prevention, and management of infusion reactions to infliximab.”

ANSER™ UST AND ANSER™ VDZ

Anser® UST simultaneously measures ustekinumab (UST) and antibodies to ustekinumab (UST) levels in serum. Anser® VDZ simultaneously measures vedolizumab (VDZ) and antibodies to vedolizumab (ATV) levels in serum at any time during therapy. There is lack of published peer-reviewed literature, which specifically establishes the technical/analytic validity, clinical validity, and clinical utility of Anser® UST & Anser® VDZ. Both of these tests are offered by Prometheus® Laboratories Inc.


DoseASSURE Test Portfolio

Tests in the DoseASSURE Portfolio measure a specific drug and ADA for it. There are no pieces of published peer-reviewed literature, which specifically address the technical/analytic validity, clinical validity, and clinical utility of any of the tests for nine biologics, (i.e.: DoseASSURE™ IFX, DoseASSURE™ IFX (Serial Monitor), DoseASSURE™ VDZ, DoseASSURE™ UST, DoseASSURE™ ADL, DoseASSURE™ RTX, DoseASSURE™ CTZ, DoseASSURE™ GOL, DoseASSURE™ ADL, and DoseASSURE™ ETN) in this portfolio. Currently, Laboratory Corporation of America® (LabCorp) does not cite specific and direct peer-reviewed published evidence for any of the tests from this portfolio on its official website. [Key: IFX = Infliximab, VDZ = Vedolizumab, UST = Ustekinumab, ADL = Adalimumab, CTZ = Certolizumab, RTX = Rituximab, GOL = Golimumab, & ETN = Etanercept]

PRACTICE GUIDELINES AND POSITION STATEMENTS

Current clinical guidelines from the American College of Gastroenterology, the American College of Rheumatology, and the European League Against Rheumatism (EULAR) do not include recommendations for testing for ADA in individuals treated with tumor necrosis factor inhibitors. An important question included in the EULAR research recommendations was: “Is measurement of serum drug and/or drug antibody levels useful in clinical practice?” The National Institute for Health and Care Excellence has not formally released draft guidance regarding ADA, but a press release indicates an “in research only” recommendation. More details are as follow:

AMERICAN COLLEGE OF GASTROENTEROLOGY

The American College of Gastroenterology Institute (2017) published guidelines on therapeutic drug monitoring in inflammatory bowel disease. The guidelines note that “When anti-drug antibodies are detected, it is unclear what antibody level is clinically meaningful…. the reporting of anti-drug antibodies is variable between commercial assays, with some assays being very sensitive for detecting very-low-titer antibodies of limited clinical significance. Uniform thresholds for clinically relevant antibody titers are lacking. At this time, it is unclear how antibodies affect drug efficacy when both active drug and antibodies are detected. In cases of low trough concentrations and low or high anti-drug antibodies, the evidence to clarify optimal management is lacking.”

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

The National Institute for Health and Care Excellence (2016) issued guidance on therapeutic monitoring of tumor necrosis factor α inhibitors in the treatment of individuals with Crohn disease. The Institute recommended that laboratories monitoring tumor necrosis factor α inhibitors in individuals with Crohn disease who have lost response to the treatment should “work with clinicians to collect data through a prospective study, for local audit, or for submission to an existing registry.”


SUMMARY

Infliximab (Remicade®; Janssen Biotech) is an intravenous tumor necrosis factor α (TNF-α) blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis (RA), Crohn disease (CD), ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and ulcerative colitis. Adalimumab (Humira®; AbbVie) is a subcutaneous TNF-α inhibitor that is FDA-approved for treatment of these indications (CD and ulcerative colitis [UC] in adults only) and juvenile idiopathic arthritis. Following primary response to infliximab and adalimumab, some individuals become nonresponders (secondary nonresponse). The development of antidrug antibodies (ADA) is considered to be a cause of secondary nonresponse.

The evidence for measuring anti-TNF-α inhibitor antibodies in individuals who have rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis; inflammatory bowel diseases (Crohn disease, ulcerative colitis); ankylosing spondylitis; or plaque psoriasis includes multiple systematic reviews, a single randomized controlled trial, and other observational studies. Relevant outcomes are test accuracy and validity, change in disease status, health status measures, quality of life, and treatment-related morbidity. Antibodies-to-infliximab (ATI) or to adalimumab (ATA) develop in a substantial proportion of treated individuals and are believed to neutralize or enhance clearance of the drugs. Considerable evidence demonstrates an association between ADA and secondary nonresponse as well as injection site and infusion reactions. The clinical usefulness of measuring ADA hinges on whether test results inform management changes, thereby leading to improved outcomes, compared with management directed by symptoms, clinical assessment, and standard laboratory evaluation. Limited evidence describes management changes after measuring ADA. A small, randomized controlled trial in individuals with CD comparing ATI-informed management of relapse with standard dose escalation did not demonstrate improved outcomes with the ATI-informed approach. Additionally, many different assays—some having significant limitations—have been used in studies; ADA threshold values that are informative for discriminating treatment responses have not been established. The evidence for all the ANSER™ tests, (i.e., ANSER™ IFX, ANSER™ ADA, ANSER™ UST, ANSER™ VDZ), and all the tests that are part of DoseASSURE Test Portfolio is insufficient to determine the effects of these technologies on health outcomes.
References


Afif W, Loftus EV, Jr., Faubion WA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in individuals with inflammatory bowel disease. Am J Gastroenterol. May 2010;105(5):1133-1139. PMID 20145610

Ara-Martin M, Pinto PH, Pascual-Salcedo D. Impact of immunogenicity on response to anti-TNF therapy in moderate-to-severe plaque psoriasis: results of the PREDIR study. J Dermatolog Treat. Nov 2017;28(7):606-612. PMID 28274164

Arstikyte I, Kapleryte G, Butrimiene I, et al. Influence of immunogenicity on the efficacy of long-term treatment with TNF alpha blockers in rheumatoid arthritis and spondyloarthritis individuals. Biomed Res Int. Jun 2015;2015:604872. PMID 26064930

Bendtzen K. Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factor-alpha antagonists. Discov Med. Apr 2013;15(83):201-211. PMID 23636137

Castillo-Gallego C, Aydin SZ, Marzo-Ortega H. Clinical utility of the new ASAS criteria for spondyloarthritis and the disease activity score. Curr Rheumatol Rep. Oct 2011;13(5):395-401. PMID 21748416

Cludts I, Spinelli FR, Morello F, et al. Anti-therapeutic antibodies and their clinical impact in individuals treated with the TNF antagonist adalimumab. Cytokine. Aug 2017;96:16-23. PMID 28279855

Eser A, Primas C, Reinisch W. Drug monitoring of biologics in inflammatory bowel disease. Curr Opin Gastroenterol. Jul 2013;29(4):391-396. PMID 23703367

Feuerstein JD, Nguyen GC, Kupfer SS, et al. American Gastroenterological Association Institute Guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. Sep 2017;153(3):827-834. PMID 28780013

Frederiksen MT, Ainsworth MA, Brynskov J, et al. Antibodies against infliximab are associated with de novo development of antibodies to adalimumab and therapeutic failure in infliximab-to-adalimumab switchers with IBD. Inflamm Bowel Dis. Oct 2014;20(10):1714-1721. PMID 25069030

Garces S, Antunes M, Benito-Garcia E, et al. A preliminary algorithm introducing immunogenicity assessment in the management of individuals with RA receiving tumour necrosis factor inhibitor therapies. Ann Rheum Dis. Jun 2014;73(6):1138-1143. PMID 23666932

Garces S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis. Dec 2013;72(12):1947-1955. PMID 23223420

Jani M, Chinoy H, Warren RB, et al. Clinical utility of random anti-tumor necrosis factor drug-level testing and measurement of antidrug antibodies on the long-term treatment response in rheumatoid arthritis. Arthritis Rheumatol. May 2015;67(8):2011-2019. PMID 26109489

Khanna R, Sattin BD, Afif W, et al. Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease. Aliment Pharmacol Ther. Sep 2013;38(5):447-459. PMID 23848220

Kopylov U, Mazor Y, Yavzori M, et al. Clinical utility of antihuman lambda chain-based enzyme-linked immunosorbent assay (ELISA) versus double antigen ELISA for the detection of anti-infliximab antibodies. Inflamm Bowel Dis. Sep 2012;18(9):1628-1633. PMID 22038899

LabCorp official website: https://www.labcorp.com/assets/16791 Accessed 05/29/2019.

LabCorp official website: https://www.labcorp.com/search/site/doseassure Accessed 05/29/2019.

Lee LY, Sanderson JD, Irving PM. Anti-infliximab antibodies in inflammatory bowel disease: prevalence, infusion reactions, immunosuppression and response, a meta-analysis. Eur J Gastroenterol Hepatol. May 27 2012;24(9):1078-1085. PMID 22647738

Lichtenstein GR. Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response. Therap Adv Gastroenterol. Jul 2013;6(4):269-293. PMID 23814608

Lombardi G, Perego S, Sansoni V, et al. Anti-adalimumab antibodies in psoriasis: lack of clinical utility and laboratory evidence. BMJ Open. Dec 09 2016;6(12):e011941. PMID 27940624

Meroni PL, Valentini G, Ayala F, et al. New strategies to address the pharmacodynamics and pharmacokinetics of tumor necrosis factor (TNF) inhibitors: A systematic analysis. Autoimmun Rev. Sep 2015;14(9):812-829. PMID 25985765

Minar P, Saeed SA, Afreen M, Kim MO, & Denson LA. Practical Use of Infliximab Concentration Monitoring in Pediatric Crohn Disease. J Pediatr Gastroenterol Nutr. 2016 May;62(5):715-22.

Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in individuals with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol. Jan 2013;108(1):40-47; quiz 48. PMID 23147525

National Institute for Health and Care Excellence (NICE). Therapeutic monitoring of TNF-alpha inhibitors in Crohn’s disease (LISA-TRACKER ELISA kits, IDKmonitor ELISA kits, and Promonitor ELISA kits) [DG22]. 2016; https://www.nice.org.uk/guidance/dg22/chapter/1-Recommendations. Accessed October 28, 2018.

Pecoraro V, De Santis E, Melegari A, et al. The impact of immunogenicity of TNFalpha inhibitors in autoimmune inflammatory disease. A systematic review and meta-analysis. Autoimmun Rev. Jun 2017;16(6):564-575. PMID 28411169

Prometheus official website: https://www.anserifx.com/about.aspx Accessed 05/29/2019.

Prometheus official website: https://www.anserifx.com/clinical-support.aspx Accessed 05/29/2019.

Roblin X, Marotte H, Rinaudo M, et al. Association between pharmacokinetics of adalimumab and mucosal healing in individuals with inflammatory bowel diseases. Clin Gastroenterol Hepatol. Jan 2014;12(1):80-84 e82. PMID 23891927

Roblin X, Rinaudo M, Del Tedesco E, et al. Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases. Am J Gastroenterol. Aug 2014;109(8):1250-1256. PMID 24913041

Rubin DT, Naik S, Kondragunta V, Rao T, & Jain A. Detection of adalimumab and antibodies to adalimumab using a homogeneous mobility shift assay. Curr Med Res Opin. 2017 May;33(5):837-843. Epub 2017 Mar 2.

Steenholdt C, Bendtzen K, Brynskov J, et al. Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn's disease. Scand J Gastroenterol. Mar 2011;46(3):310-318. PMID 21087119

Steenholdt C, Brynskov J, Thomsen OO, et al. Individualised therapy is more cost-effective than dose intensification in individuals with Crohn's disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. Jun 2014;63(6):919-927. PMID 23878167

Tan M. Importance of defining loss of response before therapeutic drug monitoring. Gut. Mar 2015;64(3):516-517. PMID 25031226

Thomas SS, Borazan N, Barroso N, et al. Comparative immunogenicity of TNF inhibitors: impact on clinical efficacy and tolerability in the management of autoimmune diseases. a systematic review and meta-analysis. BioDrugs. Aug 2015;29(4):241-258. PMID 26280210

van Gestel AM, Prevoo ML, van 't Hof MA, et al. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum. Jan 1996;39(1):34-40. PMID 8546736

Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. Jun 2013;108(6):962-971. PMID 23419382

White CM, Ip S, McPheeters M, et al. Using Existing Systematic Reviews to Replace De Novo Processes in Conducting Comparative Effectiveness Reviews Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; 2008.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

EXPERIMENTAL/INVESTIGATIONAL


80145

80187

80230

80235

80280

80285


THE FOLLOWING CODE IS USED TO REPRESENT PROMETHEUS® ANSER™ IFX TESTING, PROMETHEUS® ANSER™ ADA TESTING, PROMETHEUS® ANSER™ VDZ TESTING, and PROMETHEUS® ANSER™ UST TESTING

84999

THE FOLLOWING CODES ARE USED TO REPRESENT DoseASSURE™ IFX, DoseASSURE™ IFX (Serial Monitor), DoseASSURE™ VDZ, DoseASSURE™ UST, DoseASSURE™ ADL, DoseASSURE™ RTX, DoseASSURE™ CTZ, DoseASSURE™ GOL, DoseASSURE™ ADL (Serial Monitor), and DoseASSURE™ ETN (Serial Monitor)

80299

82397

[Key: IFX = Infliximab, VDZ = Vedolizumab, UST = Ustekinumab, ADA or ADL = Adalimumab, CTZ = Certolizumab, RTX = Rituximab, GOL = Golimumab, & ETN = Etanercept]



Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

N/A


HCPCS Level II Code Number(s)

N/A


Revenue Code Number(s)

N/A


Misc Code

N/A:

N/A


Coding and Billing Requirements


Cross References


Policy History

Revisions from 06.02.39d
01/01/2020This version of the policy will become effective on 01/01/2020 due to coding updates.

The following procedure codes are being added to the policy:

80145
80187
80230
80235
80280
80285

Revisions from 06.02.39c
07/01/2019This version of the policy will become effective on 07/01/2019.

Policy title was changed from Measurement of Serum Antibodies to and Measurement of Serum Levels of Infliximab and Adalimumab TOMeasurement of Serum Antibodies to and Measurement of Serum Levels of Biologics.

The following tests are are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature:
  • Anser™UST
  • Anser™VDZ
  • DoseASSURE™ IFX
  • DoseASSURE™ IFX (Serial Monitor)
  • DoseASSURE™ VDZ
  • DoseASSURE™ UST
  • DoseASSURE™ ADL
  • DoseASSURE™ RTX
  • DoseASSURE™ CTZ
  • DoseASSURE™ GOL
  • DoseASSURE™ ADL
  • DoseASSURE™ ETN

[Key: IFX = Infliximab, VDZ = Vedolizumab, UST = Ustekinumab, ADA or ADL = Adalimumab, CTZ = Certolizumab, RTX = Rituximab, GOL = Golimumab, & ETN = Etanercept]

Anser™IFX and Anser™ADA continue to be considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

06.02.39b
11/21/2018This policy has been reissued in accordance with the Company's annual review process.
11/22/2017This policy has been reissued in accordance with the Company's annual review process.


Effective 10/05/2017 this policy has been updated to the new policy template format.


Version Effective Date: 01/01/2020
Version Issued Date: 12/31/2019
Version Reissued Date: N/A

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