Appeal type: Experimental/Investigational
Decision: Overturned

Diagnosis: Ulcerative Colitis
Treatment: Lab testing to determine response to Humira (adalimumab)
The insurer denied lab testing to determine response to Humira (adalimumab).
The determination is overturned.

The patient has ulcerative colitis (UC) managed with Humira. She had symptoms suggestive of a flare of her UC and increased diarrhea and blood in her stool. The attending provider was concerned that this patient may have developed antibodies to adalimumab or had low adalimumab trough levels. Rather than empirically increase the dose of adalimumab or switch to another agent, the attending provider ordered antibodies to adalimumab and adalimumab trough levels, since a dose increase would have been futile if this patient had antibodies to adalimumab. At issue is whether the lab testing to determine response to Humira (adalimumab) is likely to be more beneficial than any standard treatment or treatments for the insured's life threatening or disabling condition or disease.

The proposed health service or treatment lab testing to determine response to Humira (adalimumab) was 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 is now considered the standard of care in patients who appear to be losing response to a biological agent and is endorsed by national practice guidelines. 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-TNF agents may have important clinical implications in patients with inflammatory bowel disease (IBD). Antibody formation lessens the bioavailability of the anti-TNF agent and may compromise the ability of anti-TNF agents to reduce inflammation, potentially compromising clinical response. Up to 50% of patients lose response to treatment (secondary non-responders) and up to 30% do not respond at all (primary non-responders) The rationale for lack or loss of response is multi-factorial, but is likely 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-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. However, 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.

Favorable clinical outcome appears to be 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. New data suggests that there is a significant association between serum levels of anti-tumor necrosis factor agents and level of mucosal healing. Serum levels of 6-10 micrograms per milliliter (g/mL) for infliximab and 8-12 g/mL for adalimumab are required to achieve mucosal healing in 80%-90% of patients with IBD, and this could be considered as a "therapeutic window." Exceeding these levels produces only a negligible gain in a proportion of patients with mucosal healing.