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 upheld.

The patient has ulcerative colitis and is requesting adalimumab laboratory testing. Drug level and antibody testing was performed. The appeal letter describes the need to assess for therapeutic level to make sure she was not building up resistance to the medication.

She was doing well, with solid stool, and the last colonoscopy showed no active inflammation except in the distal rectum. Recently she had had some frequency, cramping, diarrhea, and was given a prednisone taper. She was feeling much better and was on a tapering dose of prednisone. Her body mass index (BMI) was 22.86. 
There was a documented drug level, and the presence of antibodies at a low titer.
She was weaning off prednisone, with increased stress at school, feeling well, with one bowel movement a day. She takes probiotics for bloating. The last colonoscopy showed normal mucosa in the entire colon. The last 6 colonoscopy evaluations all showed normal mucosa in the entire colonic mucosa. She continued Humira every other week. BMI was 23.59.

An appeal letter describes diffuse colitis, recurrent flare, testing drug levels of adalimumab to see if the medication was working for her. "This helps me decide if we should increase her dose or change to a different therapy". At issue is whether 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.

Despite the detection of a low titer of antibodies to adalimumab the patient was doing well, with formed stool, after completing a prednisone taper. Multiple colonoscopy evaluations over the last several years had shown the patient to be in endoscopic remission with normal mucosa. There was no documentation of a failure to respond to the drug that required assessment of antibodies or drug levels. There are no randomized control studies or well-designed cohort studies that show an improvement in health outcomes of ulcerative colitis patients with the use of adalimumab drug/antibody testing to guide management. The clinical presentation of the patient decides management and not drug levels. The patient's reported symptoms, colonoscopy data, pathology data, and hemoglobin data is likely to be more beneficial then adalimumab drug/antibody assessment.

Although antibodies to Adalimumab can occur and lead to resistance to therapy, routine assay of antibody levels to Adalimumab has not been proven to improve health outcomes. The decision to continue, or increase the dose of Adalimumab, are based upon the clinical response of the patient. Whether to continue or discontinue Adalimumab is determined by the patient's clinical status and not based on antibody assays to Adalimumab. A diminished or suboptimal response to Adalimumab can be managed in several ways: shortening the interval between doses, increasing the dose, switching to a different anti-tumor necrosis factor (TNF) agent, or switching to a non-anti-TNF agent. Data regarding the clinical utility of Anser adalimumab (ADA) and Anser infliximab (IFX) is still emerging. There is no clear evidence at this time that these tests improve health outcomes over standard clinical management. It is also unclear what, if any, different decisions physicians would make for their patients based on anti-drug antibody levels as opposed to their current approach of managing the drug based on the patient's clinical response. Some studies have shown changes to management after antibody measurement. However, no controls were used and there is no comparison to changes made when management is based on clinical findings alone. Measurement of antibodies to Adalimumab in a patient receiving treatment with Adalimumab, either alone or as a combination test which includes the measurement of serum Adalimumab levels, is not proven for this diagnosis. Studies evaluating the validation of the results between different assays are lacking, making interstudy comparisons difficult. Antibodies to Adalimumab are present in a substantial number of patients treated with Adalimumab, and there may be a correlation between the level of these antibodies and clinical response. However, the clinical utility of measuring anti-Adalimumab antibody concentrations has not been established, as it is not known how patient management would change based on test results. Limited evidence describes changes in management after measurement of antibody, but does not compare these management changes to those made in the absence of antibody measurement. In addition, there are technical factors relating to the use of different assay methods across studies; it has not yet been established whether the use of threshold levels aids in the discrimination of response to Adalimumab, or has the optimal timing of when to measure antibody levels been established. There is no consensus on the clinical significance of the presence of antidrug antibodies. Limited data are available regarding the relationship between adalimumab drug levels and serum/fecal markers of gut inflammation.

Reinhold, calling for more study based on a retrospective review: "The majority of patients treated with anti-tumor necrosis factor (TNF) therapy develop anti-drug antibodies (ADAs), which might result in loss of treatment efficacy. Strict guidelines on measuring trough levels (TLs) and ADA in clinical routine do not exist. TDM [Therapeutic Drug Monitoring] showed significant treatment adaptations in patients with subtherapeutic TL. Conversely, in patients with therapeutic and supratherapeutic TLs, reasons for adaptations were based on considerations other than TL, such as clinical disease activity. Further studies should focus on decision-making in patients presenting with supratherapeutic TL in remission."

Chaparro, in a study with limitations of drug monitoring: "Objectives: (a) To evaluate the diagnostic accuracy of anti-TNF trough levels to predict mucosal healing in inflammatory bowel disease (IBD); (b) to determine the best cut-off point to predict mucosal healing in inflammatory bowel disease (IBD) patients treated with anti-TNF.
There was an association between anti-TNF trough levels and mucosal healing in IBD patients; however, the accuracy of the determination of infliximab and adalimumab concentrations able to predict mucosal healing was suboptimal."

Wright, et al, in a study with limitations of drug monitoring: "Anti-TNF prevents postoperative Crohn's disease recurrence in most patients but not all. This study aimed to define the relationship between adalimumab pharmacokinetics, maintenance of remission and recurrence. Adalimumab concentration in patients treated with adalimumab to prevent symptomatic endoscopic recurrence postoperatively is, for most patients, well within the therapeutic window, and is not significantly lower in patients who develop recurrence compared with in those who remain in remission. Mechanisms of anti-TNF failure to prevent postoperative recurrence remain to be determined in these patients."

Dose escalation is based on the clinical presentation of the patient and not based on drug levels. Dosing based on drug levels does not have definite evidence of improving health outcome in patients that have achieved an improvement in their clinical status, such as in this case.

Papamichael summarized limitations of drug monitoring: "Anti-tumour necrosis factor (TNF) therapies, such as infliximab, adalimumab, certolizumab pegol and golimumab, have been proven to be effective for the treatment of patients with Crohn's disease and ulcerative colitis. However, 10%-30% of patients with inflammatory bowel disease (IBD) show no initial clinical benefit to anti-TNF therapy (primary non-response), and over 50% after an initial favourable outcome will lose response over time (secondary loss of response (SLR)). Numerous recent studies in IBD have revealed an exposure-response relationship suggesting a positive correlation between high serum anti-TNF concentrations and favourable therapeutic outcomes including clinical, biomarker and endoscopic remission, whereas antidrug antibodies have been associated with SLR and infusion reactions. Currently, therapeutic drug monitoring (TDM) is typically performed when treatment failure occurs either for SLR, drug intolerance (potential immune-mediated reaction) or infusion reaction (reactive TDM). Nevertheless, recent data demonstrate that proactive TDM and a treat-to-target (trough) therapeutic approach may more effectively optimize anti-TNF therapy efficacy, safety and cost. However, implementing TDM in real-life clinical practice is currently limited by the diversity in study design, therapeutic outcomes and assays used, which have hindered the identification of robust clinically relevant concentration thresholds."

There was no treatment failure, drug intolerance (potential immune-mediated reaction) or infusion reaction documented in this case that would warrant drug/antibody testing for Humira.