917 Form

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Medical Policy Therapeutic Drug Monitoring for Biologic Agents
Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History
• Endnotes Policy Number: 917 NCD/LCD: N/A Related Policies
Immune Modulating Drugs, #004 Policy1 Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

Measurement of serum TNF inhibitor levels and anti-drug antibodies for infliximab and adalimumab in patients being treated with these drugs, are considered MEDICALLY NECESSARY.

The use of serum TNF inhibitor levels and anti-drug antibodies for other biologics (including but not limited to ustekinumab, vedolizumab, risankizumab) are considered INVESTIGATIONAL.

Prior Authorization Information
Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

Outpatient Commercial Managed Care (HMO and POS) Prior authorization is not required. Commercial PPO and Indemnity Prior authorization is not required. Medicare HMO BlueSM Prior authorization is not required. Medicare PPO BlueSM Prior authorization is not required.

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CPT Codes / HCPCS Codes / ICD Codes
Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list.

The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue: CPT Codes CPT codes:

Code Description 80145 Adalimumab 80230 Infliximab

The following CPT codes are considered investigational for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

CPT Codes CPT codes:

Code Description 0514U Gastroenterology (irritable bowel disease [IBD]), immunoassay for quantitative determination of adalimumab (ADL) levels in venous serum in patients undergoing adalimumab therapy, results reported as a numerical value as micrograms per milliliter (µg/mL) 0515U Gastroenterology (irritable bowel disease [IBD]), immunoassay for quantitative determination of infliximab (IFX) levels in venous serum in patients undergoing infliximab therapy, results reported as a numerical value as micrograms per milliliter (µg/mL)

Description Infliximab, Adalimumab, Vedolizumab, Risankizumab, and Ustekinumab in Autoimmune Diseases Biologic agents (e.g. infliximab, adalimumab, vedolizumab, risankizumab or ustekinumab) are used to treat multiple inflammatory conditions, including rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis; inflammatory bowel disease (eg, Crohn disease, ulcerative colitis), ankylosing spondylitis, and plaque psoriasis. These agents are generally given to patients who fail conventional medical therapy, and they are typically highly effective for the induction and maintenance of clinical remission. However, not all patients respond, and a high proportion of patients lose response over time. It is estimated that 1 in 3 patients do not respond to induction therapy (primary nonresponse); further, among initial responders, response wanes over time in approximately 20% to 60% of patients (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).1,Antidrug antibodies are also associated with injection-site reactions and acute infusion reactions and delayed hypersensitivity reactions.

Detection of Antidrug Antibodies The detection and quantitative measurement of ADA is difficult, owing to drug interference and identifying when antibodies likely have a neutralizing effect. First-generation assays (ie, enzyme-linked immunosorbent assays [ELISA]) can measure only ADA in the absence of detectable drug levels, due to Commented about CPT codes for B12 injection?

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the interference of the drug with the assay. Other techniques available for measuring antibodies include the radioimmunoassay method and, more recently, the homogenous mobility shift assay using high- performance liquid chromatography. Disadvantages of the radioimmunoassay method are associated with the complexity of the test and prolonged incubation time, along with safety concerns related to the handling of radioactive material. The homogenous mobility shift assay measures ADA when infliximab is present in serum. Studies evaluating the validation of results among different assays are lacking, making interstudy comparisons difficult. One retrospective study by Kopylov et al (2012), which evaluated 63 patients, demonstrated comparable diagnostic accuracy between 2 different ELISA methods in patients with inflammatory bowel disease (ie, double-antigen ELISA and antihuman lambda chain-based ELISA).2, This study did not include an objective clinical and endoscopic scoring system for validation of results. Treatment Options for Secondary Nonresponse to Biologic Agents A diminished or suboptimal response to infliximab, adalimumab, vedolizumab, risankizumab or ustekinumab can be managed in several ways: shortening the interval between doses, increasing the dose, switching to a different biologic agent (in patients who continue to have a loss of response after receiving the increased dose), or switching to a non-biologic agent.

Summary Biologic agents used to treat autoimmune diseases include infliximab, adalimumab, vedolizumab, risankizumab and ustekinumab. Infliximab (Remicade) is an intravenous tumor necrosis factor α blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, Crohn disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and ulcerative colitis.
Adalimumab (Humira) is a subcutaneous tumor necrosis factor α inhibitor that is FDA approved for the treatment of rheumatoid arthritis, Crohn disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis in adults and those with juvenile idiopathic arthritis, hidradenitis suppurativa, and uveitis. Vedolizumab (Entyvio) is an intravenous integrin receptor antagonist that is FDA approved for treatment of ulcerative colitis and Crohn disease in adults. Risankizumab (Skyrizi) is an intravenous and subcutaneous human interleukin-23 antagonist that is FDA approved for treatment plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis in adults. Ustekinumab (Stelara) is an intravenous and subcutaneous human interleukin-12 and -23 antagonist that is FDA approved for the treatment of Crohn disease and ulcerative colitis in adults, and psoriatic arthritis and plaque psoriasis in children and adults. Following the primary response to these medications, some patients become secondary nonresponders. The development of antidrug antibodies is considered a cause of this secondary nonresponse.

For individuals who have rheumatoid arthritis, psoriatic arthritis, or juvenile idiopathic arthritis; inflammatory bowel disease (eg, Crohn disease, ulcerative colitis); ankylosing spondylitis; or plaque psoriasis who receive evaluation for serum antibodies to infliximab, adalimumab, vedolizumab, risankizumab or ustekinumab, the evidence includes multiple systematic reviews, randomized controlled trials, and observational studies. Relevant outcomes are test validity, change in disease status, health status measures, quality of life, and treatment-related morbidity. Antibodies to biologic agents develop in a substantial proportion of treated patients and are believed to neutralize or enhance clearance of the drugs. Considerable evidence has demonstrated an association between antidrug antibodies and secondary nonresponse as well as injection-site and infusion-site reactions. The clinical usefulness of measuring antidrug antibodies 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. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Policy History Date Action 1/2026 Policy revised. Policy statements on infliximab and adalimumab changed from investigational to medically necessary based on expert opinion. Measurement of serum TNF inhibitor levels and anti-drug antibodies for infliximab and adalimumab are

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medically necessary. The use of serum TNF inhibitor levels and anti-drug antibodies for other biologics are investigational. Clarified coding information. Effective 1/1/2026.
1/2025 Annual policy review. References updated. Policy statements unchanged. 10/2024 Clarified coding information.
1/2024 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2023 Annual policy review. References updated. Minor editorial refinements to policy statements; intent unchanged. 1/2022 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2021 Updated terminology throughout the policy to reflect the addition of the interleukin-2 and -23 antagonist ustekinumab. Policy statement otherwise unchanged. 1/2020 Annual policy review. Investigational policy statement reworded to include currently FDA-approved TNF blocking agents. Policy title changed to
Measurement of Serum Antibodies to Selected Biologic Agents. Clarified coding information. 1/2019 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 1/2018 Annual policy review. New references added. 12/2016 Annual policy review. New references added. 1/2016 Annual policy review. New references added. 12/2014 Annual policy review. New references added. 3/2014 Annual policy review. New references added. 3/2013 New policy describing non-coverage. Effective 3/1/2013.
Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

References

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18. 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): 1714-21. PMID 25069030
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Mediated Inflammatory Diseases: A Randomized Clinical Trial. JAMA. May 04 2021; 325(17): 1744-

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      Endnotes

      1 Based on expert opinion