Appeal type: Experimental/Investigational
Decision: Overturned

Diagnosis: Crohn's Disease.
Treatment: Lab Work/Blood Tests- therapeutic drug monitoring.
The insurer denied Lab Work/Blood Tests- therapeutic drug monitoring.
The determination is overturned.

This patent has Crohn's disease and is requesting the service of testing serum adalimumab levels and antibodies to adalimumab. The patient has developed antibodies to adalimumab and had evidence of active Crohn's disease on colonoscopy. The attending gastroenterologist hence escalated the dose of Humira to weekly and added an immunomodulator (methotrexate). Subsequent therapeutic drug monitoring has showed therapeutic levels of adalimumab and no antibodies to adalimumab. The patient's methotrexate was stopped due to an infection. The attending gastroenterologist ordered adalimumab levels and antibodies to adalimumab to ensure that the patient had adequate levels of adalimumab and no antibodies to adalimumab after stopping the immunomodulator. At issue is the proposed health service or treatment of laboratory services to monitor therapeutic drug levels.

The proposed health service or treatment laboratory services is likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease.

Therapeutic drug monitoring offers a rational approach to the management of secondary failure to adalimumab. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomized controlled trials. The Anser adalimumab (ADA) test which measures serum trough levels of adalimumab and antibodies to adalimumab is medically necessary when a provider is considering either a dose adjustment or making a switch to a different anti-tumor necrosis factor (TNF) agent. Although not completely understood, the development of antibodies to anti-tumor necrosis factor (TNF) agents may have important clinical implications in patients with inflammatory bowel disease (IBD). Antibody formation lessens the bioavailability of the anti-tumor necrosis factor (TNF) agent and may compromise the ability of anti-tumor necrosis factor (TNF) agents to reduce inflammation, potentially compromising clinical response. Up to 50 percent of patients lose response to treatment (secondary non-responders) and up to 30 percent do not respond at all (primary non-responders).

The rationale for lack or loss of response is multi-factorial but is related to the molecular structures and complex pharmacokinetics (PK) and pharmacodynamics of the medications, including the development of anti-drug antibodies. One of the proposed strategies when patients lose response to an anti-tumor necrosis factor (TNF) is switching to another drug in the same or different class. Another strategy is to empirically increase the dose, hoping to overcome increased drug clearance. Unfortunately, this can lead to significant adverse events including hypersensitivity reactions. A third potential tactic is to measure drug levels and antibodies, trying to identify those patients who will benefit from dose escalation and those who will be best served by switching to an alternate drug class. This latter strategy has been proven to be more cost effective when compared to the former and highlights the importance and usefulness of measuring levels in these patients. There is growing evidence that such testing improves patient outcomes and is cost-effective.

Favorable clinical outcome is the consequence of sustained therapeutic drug levels, and the current literature supports a practice of dose adjustments. When immunogenicity develops to a single biological agent, response can be regained by introduction of an alternative biological agent of the same or different class. Efficacy is reduced with second-line agents either within or across classes compared with naive patients. In the absence of direct measurement of drug levels and anti-drug antibodies, clinical judgment is necessary to assess the mechanisms of loss of response, and more empiric decision making may be necessary to determine the choice of second-line biological agents. Current data suggests that there is a significant association between serum levels of anti-tumor necrosis factor agents and levels of mucosal healing. Serum levels of 6-10 microgram (g) /milliliter (mL) for infliximab and 8-12 microgram (g) /milliliter (mL) for adalimumab are required to achieve mucosal healing in 80-90 percent of patients with inflammatory bowel disease (IBD), and that this could be considered as a "therapeutic window." Exceeding these levels produces only a negligible gain in proportion of patients with mucosal healing.