Appeal type: Experimental/Investigational
Decision: Overturned

Diagnosis: Digestive System/Gastrointestinal. 
Treatment: Labwork/Blood Tests. 
The insurer denied Adalimumab antibody testing. 
The denial is overturned. 

The patient is a female who has Crohn's disease managed with Humira. The attending provider was concerned that this patient may have developed antibodies to adalimumab or had low adalimumab trough levels since she had symptoms suggestive of a flare of Crohn's disease despite being on adequate dosing of Humira. 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. 

The subject under review is whether the adalimumab antibody testing is likely to be more beneficial for this patient than standard treatment.

The proposed health service or treatment Adalimumab antibody testing 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 is more beneficial than empiric dose escalation or empiric switching to another biological agent. These tests are now considered the standard of care when patients on biological therapy are not doing well either clinically or in lab or endoscopic parameters.

Therapeutic drug monitoring, both proactive and reactive, is well accepted practice in monitoring response to therapy to biological medications used to treat inflammatory bowel disease (IBD), endorsed by national practice guidelines and meets the definition of medical necessity below. 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 randomised 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 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. 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. The Anser ADA test, which is a proprietary test developed by Prometheus Laboratory, measures adalimumab levels and antibodies to adalimumab levels in patients with inflammatory bowel disease who are demonstrating decreased response to adalimumab. 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 that this could be considered as a "therapeutic window." Exceeding these levels produces only a negligible gain in proportion of patients with mucosal healing.