Therapeutic monitoring of TNF-alpha inhibitors in Crohn's disease (LISA-TRACKER ELISA kits, IDKmonitor ELISA kits, and Promonitor ELISA kits)

Evidence-based recommendations on therapeutic monitoring of tumour necrosis factor (TNF)alpha inhibitors (LISATRACKER, IDKmonitor and Promonitor ELISA kits) in people with Crohns disease.

# Recommendations
The LISATRACKER, IDKmonitor and Promonitor enzymelinked immunosorbent assay (ELISA) kits show promise for therapeutic monitoring of tumour necrosis factor (TNF)alpha inhibitors in people with Crohn's disease but there is insufficient evidence to recommend their routine adoption across the NHS.
Laboratories currently using LISATRACKER, IDKmonitor and Promonitor ELISA kits for therapeutic monitoring of TNFalpha inhibitors in people with Crohn's disease whose disease loses response to TNFalpha inhibitors should:
have specialist expertise in immunoassay analysis, including an understanding of the technical factors that may affect the results of the ELISA kits
work closely with the treating or referring clinician, in a network, to ensure appropriate use of the tests and interpretation of the results
work with clinicians to collect data through a prospective study, for local audit, or for submission to an existing registry. (The IBD Registry is being adapted to receive data on TNFalpha inhibitor levels and antibodies against TNFalpha inhibitors. When this facility is available, all data should be entered onto the database; see section 7.2).
Further research is recommended on the clinical and cost effectiveness of using LISATRACKER, IDKmonitor and Promonitor ELISA kits for therapeutic monitoring of TNFalpha inhibitors in people with Crohn's disease whose disease responds to treatment with TNFalpha inhibitors (see section 7.3).
This guidance considers ELISA kits for therapeutic monitoring of TNFalpha inhibitors in 2 different populations:
people with Crohn's disease, whose disease loses response to treatment with TNFalpha inhibitors (that is, people whose disease first responds to treatment, but stops responding over time, so may need a higher dose of TNFalpha inhibitor to try to recover a clinical response)
people with Crohn's disease, whose disease responds to treatment with TNFalpha inhibitors (that is, people whose disease responds well to treatment and who may continue having the same level of treatment).
People whose disease does not respond to treatment in the induction phase of treatment are not considered in this assessment.
NICE's technology appraisal guidance on vedolizumab for treating moderately to severely active Crohn's disease after prior therapy was published while this guidance was in development.  NICE will consider adding vedolizumab into the economic model as a treatment option in the care pathway of people with Crohn's disease when the diagnostics guidance is reviewed for the need to update.# The technologies
The LISATRACKER, IDKmonitor, and Promonitor enzymelinked immunosorbent assay (ELISA) kits are intended to be used for measuring the levels of tumour necrosis factor (TNF)alpha inhibitors and antibodies against TNFalpha inhibitors in the blood of people having TNFalphainhibitor treatment for Crohn's disease. TNFalpha is a cell signalling protein that promotes inflammatory responses. Dysregulation of TNFalpha production can contribute to inflammatory diseases, such as Crohn's disease. TNFalpha inhibitors, such as infliximab and adalimumab, are given to people with Crohn's disease to inhibit TNFalpha production and suppress the inflammatory response.# Clinical need and practice

# The problem addressed
Although tumour necrosis factor (TNF)alpha inhibitors can help many people with Crohn's disease, there are some people whose disease does not respond to treatment. Also, many people whose disease first responds to treatment find that their disease stops responding over time (loss of response). This loss of response may be caused by:
changes in disease characteristics over time
inflammation unrelated to TNFalpha concentrations
antibodies to TNFalpha inhibitors
fluctuations in circulating drug levels.
The concentration of TNFalpha inhibitor in the blood immediately before the next dose of TNFalpha inhibitor is due (referred to as the 'trough level') can vary widely between people who have had the same previous dose. These variations can be caused by:
differences in drug pharmacokinetics between individuals
antibodies that bind to the TNFalpha inhibitor, neutralising its activity and leading to increased clearance
concomitant treatment with some immunosuppressive drugs, such as methotrexate.
Currently, treatment decisions for people with Crohn's disease are based on clinical judgement and 'trial and error', so adapting treatment to suit the person may be difficult. People whose disease responds well to a TNFalpha inhibitor may continue having the same level of treatment even when it may be possible to reduce the dose or withdraw the treatment without having any detrimental effect on clinical outcomes. This continued treatment may lead to people having side effects of the treatment unnecessarily. People whose disease loses response are typically treated with a higher dose of TNFalpha inhibitor to try to recover a clinical response. This approach can be successful for some people, but for others, the intensified treatment regimen is not effective because they continue to have an expensive drug that gives them no benefit and they may have unnecessary treatment side effects.
The symptoms of Crohn's disease can vary widely between people. The personal preferences of clinicians and patients also make it difficult to establish a standardised pathway for people with Crohn's disease. Measuring levels of TNFalpha inhibitors and antibodies against TNFalpha inhibitors in a person's blood could help clinicians to identify the best treatment strategy for a person with Crohn's disease.
The purpose of this assessment is to evaluate the clinical and cost effectiveness of using ELISA kits (LISATRACKER, IDKmonitor and Promonitor) to test levels of TNFalpha inhibitors and antibodies to TNFalpha inhibitors in people with Crohn's disease:
whose disease responds to treatment with a TNFalpha inhibitor
whose disease loses response to maintenance treatment with a TNFalpha inhibitor.

# The condition
Crohn's disease is a chronic inflammatory disease that affects the gastrointestinal tract, most commonly the large intestine or the last section of the small intestine. The prevalence of Crohn's disease in the UK is estimated to be 157 per 100,000 population (Steed et al. 2010). The condition can affect people of all ages, but most develop it between the ages of 16 and 30 years. Many also develop it between the ages of 60 and 80 years. Although the cause of Crohn's disease is unknown, it is likely that a genetic predisposition, smoking and intercurrent infection increase the risk of it developing.
The clinical course of Crohn's disease is marked by relapses (when the disease flares up) and remission (when there are few or no signs or symptoms). During relapses, people can have diarrhoea, abdominal pain, fatigue and weight loss.
There is no cure for Crohn's disease, so treatment is directed at symptom relief. The 2 main aims of treatment are inducing remission (active treatment of acute disease) and maintaining remission (preventing relapse). Complications of Crohn's disease include:
Intestinal stricture: inflammation may cause scar tissue to form, resulting in a narrowing of the affected area of the intestine. This can cause an obstruction leading to pain and vomiting.
Perforation: stricture can cause rupture of the bowel resulting in infection.
Fistula: inflammation may cause an ulcer to develop in the lining of the gastrointestinal tract, which can deepen over time and become a channel to another hollow organ or the skin, known as a fistula.
Cancer: Crohn's disease is associated with a small increase in the risk of developing colorectal cancer in later life.
Osteoporosis: weakening of the bones because of poor absorption of nutrients from food and the use of steroid medication.
Problems with growth and development in children with Crohn's disease, because their bodies are not absorbing enough nutrients.

# The diagnostic and care pathways
Treatments for Crohn's disease aim to reduce symptoms and maintain or improve quality of life, while minimising toxicity related to drugs over both the short and long term. Managing Crohn's disease in adults, young people and children is covered in the NICE guideline on Crohn's disease. See also the NICE topic page on inflammatory bowel disease..
The World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organisation's London Position Statement (published in the American Journal of Gastroenterology) provides support to clinicians on when to start and stop therapy, which drug to choose, and how to predict response to biological therapy. The paper states:
A diminished or suboptimal response to infliximab can be managed by:
shortening the interval between dosing
increasing the dose to 10 mg/kg.
A diminished or suboptimal response to adalimumab can be managed by weekly dosing (shortened from every other week).
Patients who continue to have a diminished or loss of response after increasing the dose may benefit from switching to a different TNFalpha inhibitor.
When TNFalpha inhibitors fail, switching treatment to an agent with a different mechanism of action is logical.
Tests for the therapeutic monitoring of TNFalpha inhibitors and antibodies to TNFalpha inhibitors may be done in 2 ways:
Concurrent testing: tests for TNFalphainhibitor drug levels and antibodies to TNFalpha inhibitors are done at the same time.
Reflex testing: the test for TNFalphainhibitor drug levels is done first and the result used to guide followup testing by the laboratory without a further request from the treating clinician. If the drug is undetectable, testing for antibodies to the TNFalpha inhibitor would be done. If TNFalpha inhibitor is present in the sample, then testing for antibodies would not be done.# The diagnostic tests

# The interventions

## LISATRACKER ELISA kits
LISATRACKER enzymelinked immunosorbent assay (ELISA) kits are manufactured by Theradiag and distributed in the UK by Alpha Laboratories. There are 6 LISATRACKER ELISA kits relevant to this assessment. Two kits measure the levels of free antibodies to tumour necrosis factor (TNF)alpha inhibitor, 2 kits measure the levels of free TNFalpha inhibitor and 2 kits measure the levels of both free TNFalpha inhibitor and antibodies to TNFalpha inhibitor.
The LISATRACKER ELISA kits consist of precoated strips of microtitre plate (96 wells), reagents, wash buffer, standards and controls. The assays can be run simultaneously or individually on any manual or automated standard ELISAbased processor platform.

## IDKmonitor ELISA kits
IDKmonitor ELISA kits (previously called Immundiagnostik TNFblocker ELISA kits) are manufactured by Immundiagnostik AG and distributed in the UK by Biohit Healthcare. There are 6 IDKmonitor ELISA kits relevant to this assessment. Two kits measure the levels of free antidrug antibodies, 2 kits measure the levels of total antidrug antibodies (free antibodies and antibodies bound to the drug), and 2 kits measure the levels of free TNFalpha inhibitor.
The kits consist of strips of precoated microtitre plate (96 wells), reagents, buffers, standards (drug level ELISAs only) and controls. The ELISAs can be done manually or run on an automated ELISA processor.

## Promonitor ELISA kits
Promonitor ELISA kits are manufactured by Proteomika and distributed in the UK by Grifols UK. There are 4 Promonitor ELISA kits relevant to this assessment. Two of these kits measure the levels of free antidrug antibodies and 2 kits measure the levels of free TNFalpha inhibitor.
The kits consist of strips of precoated microtitre plate (96 wells), reagents, buffers, standards, controls and ELISA cover films. The ELISAs can be done manually or run on an automated ELISA processor.

# The comparator: no testing
The comparator for this assessment is treatment decisions based on clinical judgement without measuring levels of TNFalpha inhibitor or antibodies to TNFalpha inhibitor.# Outcomes
The Diagnostics Advisory Committee (section 10) considered evidence from a number of sources (section 11). Full details of all the evidence are in the committee papers.

# How outcomes were assessed
The External Assessment Group (EAG) conducted a systematic review of the evidence on tests to monitor levels of tumour necrosis factor (TNF)alpha inhibitors and antibodies to TNFalpha inhibitors in people with Crohn's disease treated with infliximab or adalimumab. The review had 4 key objectives:
compare the performance of the different tests available
compare optimal cutoff thresholds identified in different studies
analyse the correlation between test results and clinical state
describe and compare testinformed algorithms used in studies, and review the clinical effectiveness of these testinformed algorithms compared with standard care (no testing done).
For the purpose of this assessment and to aid understanding, tests have been split into 3 groups: index tests, alternative tests, and other tests. The 6 different tests are summarised in table 1. Because there were no direct clinical outcome data for the index tests (LISATRACKER enzymelinked immunosorbent assay  kits, IDKmonitor ELISA kits and Promonitor ELISA kits), the clinicaleffectiveness review considered alternative tests for which clinical outcome data were available. Evidence on the comparative performance of the index tests and the alternative tests was then sought in order to make a link between the index tests and the clinical outcomes. Other tests are also mentioned in the review because they form an indirect link between the index tests and clinical outcomes through the alternative tests.
Test group
Name of test
Use in the assessment
Index tests
LISATRACKER enzymelinked immunosorbent assay  (ELISA) kits
Promonitor ELISA kits
IDKmonitor ELISA kits
Named in the scope and are subject to recommendations by the Diagnostics Advisory Committee.
Alternative tests
Prometheus ELISA and homogeneous mobility shift assay (HMSA)
Leuven inhouse ELISA
Form a link between the index tests and clinical outcomes.
Other tests
Amsterdam Sanquin inhouse ELISA and radioimmunoassay
Form a link between the index tests and the alternative tests.

# Evidence on clinical outcomes
Three studies were identified that implemented a testinformed algorithm in managing Crohn's disease treated with infliximab or adalimumab and reported clinical outcomes.

## Steenholdt et al. 2014 and 2015
This was a singleblind randomised controlled trial of 69 adults with Crohn's disease on maintenance infliximab treatment whose disease had lost response to treatment. Patients were randomised to either an infliximab intensified arm (n=36) or to an algorithm arm (n=33). In the infliximab intensified arm, the dose frequency of 5 mg/kg infliximab was increased from every 8 weeks to every 4 weeks. In the algorithm arm, patients had treatment according to a defined algorithm based on serum concentrations of infliximab and of antibodies to infliximab. Samples were taken immediately before infliximab infusion and were analysed by radioimmunoassay. The algorithm categorised patients into one of 4 groups and guided treatment as described in table 2.
Group
Drug levels
Antibody levels
Treatment
Intention to treat population
Group 1
Subtherapeutic infliximab
Detectable antiinfliximab antibodies
Change to a different tumour necrosis factor  (TNF)alpha inhibitor (adalimumab).
Group 2
Subtherapeutic infliximab
Undetectable antiinfliximab antibodies
Intensify infliximab treatment.
Group 3
Therapeutic infliximab
Undetectable antiinfliximab antibodies
Discontinue treatment with TNFalpha inhibitors. Review of condition.
Group 4
Therapeutic infliximab
Detectable antiinfliximab antibodies
Repeat testing. If results are unchanged act as for group 3.
In the doseintensification arm, all patients had treatment according to the protocol. In the algorithm arm, 14 of 33 patients did not have treatment according to the algorithm (13 in group 3; 1 in group 4). Most of these 14 patients continued to have infliximab. There were 2 withdrawals from the algorithm arm and 8 withdrawals from the dose intensification arm.
In the intention to treat population (n=69), clinical response at week 12 was seen in 53% of patients in the dose intensification arm and in 58% of patients in the algorithm arm (relative risk  1.09; 95% confidence interval  0.713 to 1.673; p=0.810). At week 20, clinical response was seen in 56% of the dose intensification arm and in 76% of the algorithm arm (RR 1.4; 95% CI 1.0 to 1.9; p=0.128). Remission was achieved at week 20 in 39% of patients in the dose intensification arm and in 55% of patients in the algorithm arm (RR 1.4; 95% CI 0.8 to 2.4; p=0.232).

## Vaughn et al. 2014
This was a retrospective observational pilot study of patients with inflammatory bowel disease in clinical remission who were having infliximab. Patients were identified from records and classified into those who had proactive drug monitoring and those who did not (control group). Samples were analysed first by ELISA (Prometheus) and later with a homogenous mobility shift assay (HMSA; Prometheus). In the proactive monitoring group, serum trough levels of infliximab guided dose change to achieve target drug levels according to the algorithm presented in table 3. Reactive testing was done in both groups if the disease lost response or there was a concern for side effects because of antibody formation.
Test result
Treatment
Undetectable trough levels of infliximab
Infliximab dose increased to 7.5 mg/kg and next infusion given after 6 weeks, then future infusions given every 8 weeks.
Detectable trough level of infliximab, but less than 5 micrograms/ml
Infliximab dose increased by 50 mg or 100 mg.
Trough levels of infliximab of greater than 10 micrograms/ml on at least 2 occasions
Infliximab dose reduced.
Trough drug level between 5 micrograms/ml and 10 micrograms/ml
No changes made.
There were 48 patients in the proactive drug monitoring group and 78 patients in the control group. In the proactive drug monitoring group, infliximab dose was adjusted in 35% of patients after initial testing (71% dose escalation, 18% dose decrease, and 12% stopped infliximab). After subsequent proactive tests, the dose was adjusted in 25% of patients (80% dose escalation and 20% dose decrease).
After 5 years, the probability of staying on treatment was 86% in the proactive drug monitoring group and 52% in the control group (hazard ratio 0.3; CI 0.1 to 0.6; p=0.0006). In the control group, the main reasons for stopping infliximab treatment were recurrence of symptoms and acute infusion reactions. In the proactive drug monitoring group, the main reasons for stopping infliximab treatment were adverse events and high antibody levels.

## Vande Casteele et al. 2015  the TAXIT trial
This was a randomised controlled trial of 251 patients with inflammatory bowel disease (173 with Crohn's disease and 78 with ulcerative colitis). Patients were randomised to clinicallybased dosing or to infliximab troughlevelbased dosing. Before randomisation, patients were screened and had an optimisation treatment phase, to identify patients whose trough levels of infliximab could be brought to the target range. Therefore, all randomised patients entered the maintenance phase of the study with trough infliximab levels in the target range of 3 to 7 micrograms/ml. In the clinicallybased dosing arm, all subsequent infliximab dosing was according to clinical symptoms and Creactive protein levels. In the troughlevelbased dosing arm, all subsequent infliximab dosing was according to the algorithm presented in table 4. Samples were analysed using Leuven inhouse ELISAs.
Test result
Treatment
Trough level infliximab greater than 7 micrograms/ml
Dose decrease (by 5 mg/kg) to 5 mg/kg or increase dosing interval by 2 weeks.
Trough level infliximab less than 7 micrograms/ml but greater than 3 micrograms/ml
No dose adaption.
Trough level infliximab less than 3 micrograms/ml
Decrease dosing interval by 2 weeks (to minimum of 4 weeks) or increase dose (by 5 mg/kg) to a maximum of 10 mg/kg.
Trough level infliximab less than 3 micrograms/ml with antibodies to infliximab less than 8 micrograms/ml
Decrease dosing interval by 2 weeks (to minimum of 4 weeks) or increase dose (by 5 mg/kg) to a maximum of 10 mg/kg.
Trough level infliximab less than 3 micrograms/ml with antibodies to infliximab greater than 8 micrograms/ml
Stop treatment with infliximab.
In the optimisation phase, 74% of patients with Crohn's disease were in remission before dose optimisation, and 80% were in remission after optimisation. Dose escalation was done in 43 of 178 patients and the percentage of patients in remission in this group increased from 65% to 88%. Dose reduction was done in 51 of 178 patients and the percentage of patients in remission in this group decreased from 80% to 69%. For the dose escalation group, an average of 2.1 optimisations were needed to reach target trough infliximab levels, and at the end of optimisation the median infusion interval was 6 weeks (range 48 weeks). For the dosereduction group an average of 1.4 optimisations were needed and the median infusion interval was 8 weeks (range 612 weeks).
In the maintenance phase, similar rates of clinical remission were seen in both groups: 69% in the concentrationbased dosing group, and 66% in the clinicallybased dosing group. When restricted to patients with Crohn's disease, rates of clinical remission were 63% in the concentrationbased dosing group, and 55% in the clinicallybased dosing group.
There was little difference between groups in the probability of maintaining durable remission (26% in the concentrationbased dosing group and 27% in the clinicallybased dosing group). More patients in the concentrationbased dosing group than in the clinicallybased dosing group (74% compared with 57%) had an infliximab trough concentration between 3 micrograms/ml and 7 micrograms/ml. The risk of patients in the clinicallybased dosing group having undetectable trough levels of infliximab was statistically significantly greater than in the concentrationbased dosing group (RR 3.7; 95% CI 1.7 to 8.0; p<0.001). None of the patients in the concentrationbased dosing group were positive for antidrug antibodies, but 3 patients in the clinicallybased dosing group had antidrug antibodies.
No deaths occurred in either group. However, 2 patients in the clinicallybased dosing group needed hospital admission: one for acute appendicitis and the other for ileostomy complications. There were 12 discontinuations in the clinicallybased dosing group and 13 discontinuations in the concentrationbased dosing group. More patients in the clinicallybased dosing group (17%) relapsed and needed rescue therapy than in the concentrationbased dosing group (7%; RR 2.4; 95% CI 1.2 to 5.1; p=0.018).

## Summary
Key conclusions from the 3 studies are summarised in table 5.
Study
Methods
Tests used
Author conclusions
Steenholdt et al. (2014 and 2015)
Patients whose disease lost response to infliximab were randomised to either an algorithm group (patients had treatment according to a defined algorithm based on serum concentrations of infliximab and antibodies to infliximab) or a doseintensification group (patients had 5 mg/kg infliximab every 4 weeks).
Samples were first analysed by radioimmunoassay and retrospectively analysed by ELISA and homogenous mobility shift assay (HMSA; Prometheus).
The clinical response in the testalgorithm group was similar to the clinical response in the doseintensification group.
Vande Casteele et al. (2015)
Patients with inflammatory bowel disease and stable response to infliximab were randomised to a testalgorithm group or a control group. In the testalgorithm group, the infliximab dose was adjusted based on trough levels of infliximab to target an infliximab trough level of 37 micrograms/ml. In the control group, the infliximab dose was guided by clinical symptoms and Creactive protein levels.
Samples were analysed using the Leuven inhouse ELISA.
Clinical response was similar in the testalgorithm group and in the control group.
Vaughn et al. (2014)
Patients with inflammatory bowel disease in clinical remission, who were having infliximab, were retrospectively identified. Patients were classified into those who had dose changes guided by trough levels of infliximab (proactive drug monitoring group) and those who did not (control group).
Samples were first analysed using ELISA (Prometheus Laboratories) and later with homogenous mobility shift assay (HMSA; Prometheus).
Proactive monitoring of trough levels of infliximab resulted in a greater probability of staying on infliximab compared with no monitoring.

# Evidence on the comparative performance of different tests
The comparative performance of the index tests (LISATRACKER ELISA kits, IDKmonitor ELISA kits or Promonitor ELISA kits) with alternative tests that did have data on clinical outcomes was reviewed. Data comparing the performance of the 3 index tests were also assessed. There were 14 studies that had relevant test comparisons, of which 5 reported concordance as numerical data or Cohen's kappa. In addition, an unpublished analysis of data was provided by a company.

## Comparisons between the index tests
Based on limited evidence on the correlation between the 3 index tests, it appears that the LISATRACKER ELISAs have the most variation in test results compared with the IDKmonitor ELISAs and Promonitor ELISAs. However, it is not clear how this would affect test results at clinically meaningful cutoff thresholds.
One analysis provided by a company compared the correlation of the 3 different ELISAs. The results of this analysis are commercial in confidence.
In an analysis using both patient samples and spiked samples, test results differed between the Promonitor ELISA and the LISATRACKER ELISA, and Pearson R2 was 0.83. Results show that the Promonitor ELISA gave higher adalimumab levels than the LISATRACKER ELISA (Nagore et al. 2015).
One analysis provided by a company compared the correlation of the 3 different ELISAs. The results of this analysis are commercial in confidence.
The analysis by Nagore et al. (2015) reports a Cohen's kappa of 0.8 between the Promonitor ELISA and the LISATRACKER ELISA.
One analysis provided by a company compared the correlation of the 3 different ELISAs. The results of this analysis are commercial in confidence.
In an analysis using both patient samples and spiked samples, test results differed between the Promonitor ELISA and the LISATRACKER ELISA, and Pearson R2 was 0.98. Results show that the Promonitor ELISA gave lower infliximab levels than the LISATRACKER ELISA (Nagore et al. 2015).
A study of 66 patient samples showed that results from the IDKmonitor ELISA were on average 1.8 micrograms/ml lower than results from the Promonitor ELISA, with 95% of measurements by the Promonitor ELISA 10.8 micrograms/ml lower to 7.1 micrograms/ml higher than measurements by the IDKmonitor ELISA (Daperno et al. 2013).
One analysis provided by a company compared the correlation of the 3 different ELISAs. The results of this analysis are commercial in confidence.
The analysis by Nagore et al. (2015) reports a Cohen's kappa of 1.0 between the Promonitor ELISA and the LISATRACKER ELISA, indicating complete agreement.
The study by Daperno et al. (2013) found that test results from the IDKmonitor ELISA and the Promonitor ELISA were 'identical' in only 6 out of 63 cases.

## Comparisons between the index tests and the alternative tests
There was insufficient evidence for linking any of the index tests (LISATRACKER ELISA kits, IDKmonitor ELISA kits or Promonitor ELISA kits) to any of the alternative tests with links to clinical outcomes (Prometheus HMSA, radioimmunoassay, Prometheus ELISA, or Leuven inhouse ELISA).
One study was identified that has data on the LISATRACKER ELISAs and the Leuven inhouse ELISAs for infliximab and antibodies to infliximab (Vande Casteele et al. 2012). This study also included the Amsterdam Sanquin ELISA and radioimmunoassay. A mix of clinical and spiked samples was used. Results suggest that the LISATRACKER ELISA may give some false positive results for infliximab levels in the presence of antibodies to infliximab or adalimumab. However, Parussini disputed these results in a nonpeerreviewed letter to the editor (2012), which was not included in the systematic review because it did not meet the inclusion criteria. For detecting antibodies to infliximab, the LISATRACKER ELISA gave fewer positive results than the radioimmunoassay, but a greater number of positive results than the Leuven inhouse ELISA (Vande Casteele et al. 2012). However, it is not clear if these results are true positives.
There were no data linking the LISATRACKER ELISAs to any of the alternative tests for detecting adalimumab or antibodies to adalimumab.
One study compared the Promonitor ELISAs with the Amsterdam Sanquin ELISA and radioimmunoassay (RuizArguello et al. 2013), and a further study compared the Amsterdam Sanquin ELISA and radioimmunoassay with the Leuven inhouse ELISA (Vande Casteele et al. 2012), giving an indirect link between the index test and the alternative test.
RuizArguello et al. (2013) used spiked samples and results suggested that for drug levels, although the analytical sensitivity of the Amsterdam Sanquin ELISA was higher than that of the Promonitor ELISA, the Amsterdam Sanquin ELISA may overestimate drug levels at higher drug concentrations. For antidrug antibodies, the analytical sensitivity of the Promonitor ELISA was higher than that of the Amsterdam Sanquin radioimmunoassay.
Vande Casteele et al. (2012) reported that the Amsterdam Sanquin ELISA and the Leuven inhouse ELISA for drug levels performed similarly across all cutoffs used. However, the Amsterdam Sanquin radioimmunoassay gave a greater number of positive results for antidrug antibodies than the Leuven inhouse ELISA.
Two studies compared the IDKmonitor ELISAs with the Prometheus HMSA (Eser et al. 2013a and 2013b). The Immundiagnostik ELISAs were compared with the Amsterdam Sanquin ELISA and radioimmunoassay in 1 study (Schatz et al. 2013), and Vande Casteele et al. (2012) compared the Amsterdam Sanquin ELISA and radioimmunoassay with the Leuven inhouse ELISAs.
Eser et al. (2013a and 2013b) used patient samples and reported that the Prometheus HMSA could detect antiinfliximab antibodies in the presence of infliximab, whereas the IDKmonitor ELISA returned inconclusive results because of interference from infliximab.
Schatz et al. (2013) used patient samples and reported agreement between the IDKmonitor ELISA and the Amsterdam Sanquin ELISA for infliximab levels with a Cohen's kappa of 0.792. A greater number of positive results were returned by the Amsterdam Sanquin tests than the Immundiagnostik ELISAs for both infliximab levels and antibodies to infliximab.
There were no data linking the IDKmonitor ELISAs to any of the alternative tests for detecting adalimumab or antibodies to adalimumab.

# Evidence on optimal cutoff thresholds
Receiver operating characteristic threshold analyses to determine optimal cutoff thresholds predictive of clinical response for infliximab, adalimumab or both were reported in 24 studies. Different studies used different markers to assess clinical response. When identifying optimal cutoffs, some studies aimed for high sensitivity (0.90) at the expense of specificity (0.37), whereas others favoured high specificity (1.00) at the expense of sensitivity (0.33). Reported cutoffs for infliximab ranged from 0.6 to 7 micrograms/ml. Reported cutoffs for adalimumab ranged from 3 micrograms/ml to 6.85 micrograms/ml.
The range of cutoff thresholds reported across the included studies shows that no validated threshold has been established. Cutoff thresholds strongly depend on the assay used, the drug measured, the clinical marker investigated and the time of testing.

# Evidence on the correlation between test results and clinical state
The review identified 34 studies that reported on the relationship between test results and the clinical status of patients with Crohn's disease or inflammatory bowel disease. Of these, 3 were systematic reviews that included a metaanalysis, and 31 were primary studies.
The test accuracy of druglevel tests and antidrug antibodies tests as predictors of clinical status was moderate. Positive and negative predictive values across clinical prevalence ranges showed that 20% to 30% of test results were wrong.
Nanda et al. (2013) included 11 studies in a metaanalysis and reported a 3fold greater risk of the disease losing response in patients with a positive antidrug antibodies test result compared with patients who had a negative antidrug antibodies test result (RR 3.16; 95% CI 2.00 to 4.98). Hierarchical metaanalysis gave a sensitivity of 0.70 (95% CI 0.55 to 0.82) and specificity of 0.81 (95% CI 0.67 to 0.89) for the antidrug antibody test in predicting loss of response. At a loss of response prevalence of 34.7%, the positive predictive value was 65% and the negative predictive value was 84%.
Lee et al. (2012) included 10 studies in a metaanalysis and reported no statistically significant decrease in rates of remission in patients with a positive test result for antidrug antibodies compared with patients with a negative test result for antidrug antibodies (RR 0.96; 95% CI 0.77 to 1.19). Hierarchical metaanalysis gave a sensitivity of 0.42 and specificity of 0.69 for the antidrug antibody test in predicting remission.
Lee et al. (2012) also examined the association between developing antidrug antibodies and having immunosuppressant therapies. Metaanalysis of 11 studies indicated a 50% reduction in risk of developing antidrug antibodies when immunosuppressants were administered (0.50; 95% CI 0.42 to 0.59).
Paul et al. (2014) included 3 studies in adults and 2 studies in children and reported statistically significantly greater odds of a lack of clinical response in patients with subtherapeutic adalimumab levels compared with patients with therapeutic levels of adalimumab (odds ratio 2.60; 95% CI 1.79 to 3.77). They also reported statistically significantly greater odds of a lack of clinical response in patients with antibodies to adalimumab compared with patients who had no antibodies to adalimumab (odds ratio 10.15; 95% CI 3.90 to 26.40).

# Systematic review of costeffectiveness evidence
The External Assessment Group (EAG) conducted a search to identify studies investigating the cost effectiveness of LISATRACKER ELISA kits, IDKmonitor ELISA kits, and Promonitor ELISA kits for measuring levels of TNFalpha inhibitors and of antidrug antibodies.
Four relevant studies were identified. All studies indicated that a testing strategy might be cheaper than a notesting strategy. However, studies reported variable small effects on effectiveness, with some indicating small reduced benefits and some indicating small increased benefits.
Vande Casteele et al. (2015) conducted a randomised controlled trial to determine whether concentrationbased infliximab dosing is more cost effective than clinicallybased infliximab dosing in people with moderate to severe Crohn's disease or ulcerative colitis (TAXIT trial). The time horizon of the model was 1 year and the perspective was that of the thirdparty payer. The basecase results showed that concentrationbased dosing was slightly less effective (0.8227 qualityadjusted life years  compared with 0.8421 QALYs) and less costly (20,700 compared with 21,000) than clinicallybased dosing, but overall differences were small.
Steenholdt et al. (2014) assessed the costeffectiveness of having treatment based on serum concentrations of infliximab and antibodies to infliximab compared with having infliximab at an increased dose frequency of 5 mg/kg every 4 weeks. In all patients, the disease lost response to infliximab while the patient was having maintenance treatment. The authors reported that costs at 12 weeks were statistically significantly lower in the algorithm group than in the infliximab intensification group. Mean costs in the intention to treat population at 12 weeks were 6038 in the algorithm group compared with 9178 in the infliximab intensification group (p<0.001).
Steenholdt et al. (2015) conducted a followup to the original study (Steenholdt et al. 2014), which extended the time horizon to 1 year to assess the longterm costs of treating Crohn's disease that lost response to infliximab maintenance therapy. Costs were assessed at 20 weeks and at 1 year. The authors reported that the algorithm group had significantly lower costs than the infliximab intensification group at 20 weeks and this was maintained throughout the year. At 20 weeks, the average costs in the algorithm group were US$11,900 compared with US$17,200 in the infliximab intensification group. At 1 year, the average costs in the algorithm group were US$22,100 compared with US$29,100 in the infliximab intensification group.
Velayos et al. (2013) used a decision analytical model to assess the cost effectiveness of a testingbased strategy compared with an empiricdoseescalation strategy for patients with moderate to severe Crohn's disease whose disease lost response to infliximab. The study had a third party payer perspective and a 1year time horizon. The basecase results showed that that the testing strategy was cheaper and marginally more effective than the empiric doseescalation strategy.

# Economic analysis

## Model structure
The EAG constructed 2 new economic models designed to assess the cost effectiveness of monitoring levels of TNFalpha inhibitor and antidrug antibody compared with standard care in patients with Crohn's disease. The first model focuses on patients whose disease responds to infliximab maintenance therapy and the second model focuses on patients whose disease loses response to infliximab maintenance therapy.
Both models have a 10year time horizon, a 4week cycle length and assume a cohort of people aged 30 years with moderate to severe Crohn's disease. In each model, patients can have either standard care, treatment according to an algorithm based on concurrent testing, or treatment according to an algorithm based on reflex testing.
Patients in the responder model enter in the responder health state, that is, their disease responds to treatment with maintenance infliximab. Patients may stay in this state or their disease may lose response to infliximab, that is, a recurrence of active symptoms while on maintenance infliximab treatment. After a dose change or switch in the TNFalpha inhibitor, the disease may regain response or may continue to lose response and the TNFalphainhibitor treatment is stopped. Disease that regains response may continue to respond or may lose response again. Patients who stop TNFalphainhibitor treatment will have best supportive care and some may need surgery. After surgery, patients move to a postsurgery health state and may have a TNFalpha inhibitor, immunosuppressant, a combination of TNFalpha inhibitor and immunosuppressant or no treatment. Patients who have a TNFalpha inhibitor alone or in combination will reenter the model in the regain response state or the loss of response state. Patients who have an immunosuppressant or no treatment will stay in the postsurgery state until they need further surgery or they die.
Patients in the loss of response model enter the model in the loss of response to TNFalpha inhibitor state, that is, active symptoms have recurred while on maintenance infliximab treatment. The model then follows the same structure as the responder model.
In the standard care pathway:
people whose disease is categorised as a responder continue having infliximab maintenance therapy every 8 weeks until they lose response
people whose disease loses response will have an increased dose; as a result, the disease may regain response or continue with loss of response
people whose disease continues to lose response will have another drug in addition to their current treatment; as a result, the disease may regain response or continue with loss of response
people whose disease continues to lose response will switch TNFalphainhibitor treatment
people whose disease does not respond to a different TNFalpha inhibitor will be considered for surgery.
In the concurrenttesting scenario, tests for infliximab levels and antibodies to infliximab would be done at the same time. Patients would fall into one of 4 categories:
drug absent and antibodies present
drug and antibodies absent
drug and antibodies present
drug present and antibodies absent.
In the reflextesting scenario, a test for infliximab levels is done first. If the drug is absent, a test for antibodies to infliximab would be done. If the drug is present, no further testing would be done. Patients would fall into one of 3 categories:
drug absent and antibodies present
drug and antibodies absent
drug present.
For patients whose disease is in the responder state, treatment options for each of the categories are based on the algorithm used in the TAXIT trial by Vande Casteele et al. (2015); table 6.
Category
Treatment
Drug absent, antibodies present (greater than 8 mg/ml)
Switch tumour necrosis factor (TNF)alpha inhibitor.
Drug absent, antibodies absent (less than 8 mg/ml)
Increase dose of current TNFalpha inhibitor.
Drug present, antibodies present
If the trough level is below the target range  decrease the dosing interval.
If the trough level is within the target range  no dose change.
If the trough level is above the target range  increase the dosing interval.
Drug present, antibodies absent
If the trough level is below the target range  decrease the dosing interval.
If the trough level is within the target range  no dose change.
If the trough level is above the target range  increase the dosing interval.
For patients whose disease loses response, treatment options for each of the categories are based on the algorithm used in the study by Steenholdt et al. (2014); table 7.
Category
Treatment
Drug absent and antibodies present
Switch tumour necrosis factor (TNF)alpha inhibitor.
Drug and antibodies absent
Increased dose of current TNFalpha inhibitor.
Drug and antibodies present
TNFalpha inhibitor stopped and best supportive care provided.
Drug present, antibodies absent

## Model inputs
The model was populated with data from the clinicaleffectiveness review and supplemented with information from secondary sources and values from clinical experts.
For patients whose disease is in the responder state, the proportions that fall into each of the test categories were sourced from Imaeda et al. (2012). For patients whose disease is in the loss of response state, the proportions in each test category were taken from Steenholdt et al. (2014). For patients with detectable trough drug levels, the proportions with below target range, within target range and above target range were based on the study by Vande Casteele et al. (2015). The proportions of patients having different postsurgery treatment options were based on a study by Van der Have et al. (2014).
Costs were obtained from standard sources such as the British National Formulary (BNF) and NHS Reference cost database. The test costs used in the model were based on the LISATRACKER ELISA kit costs provided by the company; but costs of the other index tests were similar (table 8).
Test
Price
Patient samples tested
Cost per patient
LISATRACKER drug level ELISA
LISATRACKER antidrug antibodies ELISA
LISATRACKER Duo
IDKmonitor drug level ELISA
IDKmonitor antidrug antibodies ELISA
IDKmonitor total antidrug antibodies ELISA
Promonitor drug level ELISA
Promonitor antidrug antibodies ELISA
Utility values were taken from published literature (table 9). The utility values reported in Velayos et al. (2013) were from the study done by Gregor et al. (1997).
Health state
Utility
Source
Responder
Velayos et al. (2013)
Loss of response
Gregor et al. (1997)
Regain response
Assumption
Surgery
Marchetti et al. (2014)
Postsurgery
Velayos et al. (2013)

## Model assumptions
The following assumptions were applied in the basecase analysis:
Patients have had intravenous infusions of infliximab of 5 mg/kg at weeks 0, 2 and 6.
Patients weigh more than 70 kg.
Patients whose disease regained response have the same utility as those whose disease is categorised as a responder.
People with Crohn's disease are not at increased risk of dying from the disease over the lifetime of the model, and there is no difference in mortality between the testalgorithm group and the standardcare group.
For people who have had surgery, there is an increased risk of 0.0015 of dying from the procedure.
The treatment effects for people having a dose increase (from 5 mg/kg to 10 mg/kg of infliximab) and a decreased interval (from 8week to 6week intervals) are the same.
People whose disease is categorised as a responder and who have trough concentrations within the range that the treatment algorithm suggests receive no dose change.
Transition probabilities in the testalgorithm group are the same as the transition probabilities in the standardcare group for the following transitions:
loss of response to infliximab maintenance therapy (Juillerat et al. 2015)
loss of response with dose escalation (Ma et al. 2014)
loss of response to adalimumab maintenance therapy (Karmaris et al. 2009).
People whose disease stays in the loss of response health state (TNFalpha inhibitor stopped) have symptoms of Crohn's disease that in time may need surgery. People will have best supportive care until active symptoms develop that need surgery.
The testing schedules in the basecase models were:
In the responder model, testing was done every 3 months while patients' disease was responding to a TNFalpha inhibitor. If patients' disease lost response to a TNFalpha inhibitor they would also be tested every 3 months until the TNFalpha inhibitor was stopped.
In the loss of response model, patients whose disease lost response were tested on entry into the model. If their disease regained response they would then enter onto the 3monthly testing regimen. If their disease continued to lose response to a TNFalpha inhibitor they would also be tested every 3 months until the TNFalpha inhibitor was stopped.
Two sets of basecase results were provided. The first basecase results use nonconstant hazard timetoevent transition probabilities. The second basecase results use exponential transition probabilities (which assume constant hazard of timetoevent transition probabilities). These different sets of transition probabilities reflect different assumptions on the time taken for people with Crohn's disease to leave one health state and pass to another in the model. The EAG states that the constant hazard transition probabilities appear to be more appropriate for the model.

## Results  responder model
The second basecase results for the responder model show that the testing strategies are cheaper but less effective than the standard care strategy. Incremental costs (savings) compared with no testing are 11,800 for reflex testing and 10,700 for concurrent testing. Incremental QALYs (lost) compared with no testing are 0.2323 for reflex testing and 0.2447 for concurrent testing. Incremental costeffectiveness ratios (ICERs) show that if testing strategies were adopted, savings of between 43,700 and 50,800 would be made for each QALY lost.
Scenario analyses of the responder model included:
testing done annually in patients whose disease responds to treatment with a TNFalpha inhibitor
testing done first at 3 months and then annually in patients whose disease responds to treatment with a TNFalpha inhibitor
testing done only at 3 months in patients whose disease responds to treatment with a TNFalpha inhibitor, and in patients whose disease regains response after loss of response to TNFalphainhibitor treatment
testing done only at 3 months in patients whose disease responds to treatment with a TNFalpha inhibitor (no testing of patients whose disease regains response after losing response to TNFalphainhibitor treatment).
Results of scenario analyses show that the testing strategies are cheaper and less effective than the standardcare strategy. Incremental costs (savings) compared with no testing range from 36,400 (annual testing) to 48,500 (testing at 3 months only in people whose disease responds). Incremental QALYs (lost) compared with no testing range from 0.2694 (testing at 3 months in people whose disease responds or regains response) to 0.2823 (annual testing). ICERs show that if testing strategies were adopted, savings of between 126,600 and 176,300 would be made for each QALY lost.

## Results  loss of response model
The second basecase results for the loss of response model show that the testing strategies are cheaper but less effective than the standardcare strategy. Incremental costs (savings) compared with no testing are 84,800 for reflex testing and 86,100 for concurrent testing. Incremental QALYs (lost) compared with no testing are 0.2985 for reflex testing and 0.3154 for concurrent testing. ICERs show that if testing strategies were adopted, savings of between 273,000 and 284,100 would be made for each QALY lost.
A scenario analysis of the loss of response model examined a test schedule in which patients whose disease lost response to a TNFalpha inhibitor are tested, but patients whose disease regains response to treatment with a TNFalpha inhibitor are not tested. Testing is done every 3 months until the patient's disease regains response to the TNFalpha inhibitor, or the patient stops treatment with the TNFalpha inhibitor. Results show that the testing strategies are cheaper but less effective than the notesting strategy. Incremental costs (savings) compared with no testing are 118,100 for reflex testing and 119,600 for concurrent testing. Incremental QALYs (lost) compared with no testing are 0.3331 for reflex testing and 0.3508 for concurrent testing. ICERs show that if testing strategies were adopted, savings of between 340,900 and 354,500 per QALY lost could be made.

## Sensitivity analyses
In addition to the scenario analyses, a range of univariate sensitivity analyses were done. These included:
Changing the time horizon from 10 years to 1 year.
In the notesting strategy arm, transition probabilities derived from Juillerat et al. (2015) were used for people whose disease lost response after dose escalation.
In the responder model, transition probabilities derived from Vande Casteele et al. (2015) were used.
Reducing the proportion of people with infliximab and antibodies to infliximab from 0.7878 to 0.200.
Changing the transition probabilities from exponential transition probabilities (which assume a constant hazard rate over time) to timetoevent transition probabilities.
Patients whose disease did not regain response after best supportive care.
Most of these changes had no impact on the direction of the results. However, changing the transition probabilities from exponential transition probabilities to timetoevent transition probabilities resulted in the testing strategies becoming more costly and less effective than the notesting strategy. Also, in the responder model, if patients' disease was assumed not to regain response after best supportive care, this resulted in the notesting strategy becoming cheaper than the testing strategies. Incremental QALYs also reduced, but the notesting strategy remained slightly more effective than the testing strategies.
In further sensitivity analyses, key model input parameters were varied to determine which inputs influence the ICER. Results showed that the models are stable to most changes, but sensitive to a 10% increase in the utility value for people whose disease regains response.
Probabilistic sensitivity analyses were done on the revised basecase models. In the responder model, the scatterplot shows considerable uncertainty around both the incremental costs and incremental QALYs. The costeffectiveness acceptability curve suggests that there is a 50% probability of the notesting strategy being cost effective if the maximum acceptable ICER is 20,000 per QALY gained. It should be noted however, that this analysis is of the basecase model in which testing was done every 3 months.
In the loss of response model, the scatterplot shows less uncertainty in the incremental costs but considerable uncertainty in the incremental QALYs. The costeffectiveness acceptability curve suggests that there is no preference between a notesting strategy and a testing strategy if the maximum acceptable ICER is 20,000 per QALY gained. However, if the maximum acceptable ICER is greater than 30,000 per QALY gained, a notesting strategy is likely to be the most costeffective strategy. Again, it should be noted that this analysis uses the basecase model in which patients whose disease regained response to a TNFalpha inhibitor were tested every 3 months, in addition to testing of patients whose disease lost response.# Considerations
The Diagnostics Advisory Committee considered the impact of Crohn's disease on a person's life. It heard from a clinical expert on the Committee that the disease most often presents in early adulthood, but can occur at any age. It heard that severe Crohn's disease can have devastating effects on a person's life, such as extreme weight loss, fistulas and abscesses, the need for surgery, and enteral or parenteral nutrition. The Committee heard from a patient expert that even mild or moderate Crohn's disease can have a substantial impact on a person's daytoday quality of life in the form of fatigue, fever, anaemia, diarrhoea and joint pain. It also heard that having Crohn's disease can result in a person needing substantial time off work and can restrict their participation in activities with their family. The Committee concluded that Crohn's disease substantially impacts the quality of life of the person with Crohn's disease and their family.
The Committee considered the complexity of managing Crohn's disease. It heard from a clinical expert that many different factors influence the development and progression of Crohn's disease, including genes and the environment. It also heard that because of these different influences, adapting treatment to suit individual patients can be difficult and there are limited options for treatment, particularly in those with severe disease. The Committee concluded that managing Crohn's disease is extremely complex and that new tests that can help clinical decisionmaking could improve management of the condition and improve outcomes for the patient.
The Committee reviewed the evidence available on the clinical and cost effectiveness of using enzymelinked immunosorbent assay (ELISA) kits (LISATRACKER, IDKmonitor, and Promonitor) to test levels of tumour necrosis factor (TNF)alpha inhibitors and antibodies to TNFalpha inhibitors in the following 2 populations:
people with Crohn's disease whose disease responds to treatment with a TNFalpha inhibitor
people with Crohn's disease whose disease loses response during maintenance treatment with a TNFalpha inhibitor.The Committee noted that no clinical outcome data were available on the 3 index tests (LISATRACKER, IDKmonitor and Promonitor ELISA kits) and therefore the results of the economic model were based on the results from studies of alternative tests (Prometheus ELISA, Prometheus homogeneous mobility shift assay ), radioimmunoassay and Leuven in house ELISA).
The Committee considered the test performance of the ELISA kits (LISATRACKER, IDKmonitor and Promonitor) compared with the alternative tests that have direct clinical outcome data (Prometheus ELISA, Prometheus HMSA, radioimmunoassay and Leuven inhouse ELISA). It noted that the evidence base on comparative test performance was very small, which led to great uncertainty in the comparability of the different tests. The Committee heard from clinical experts that most testing in the UK is done in a few centres with each using different test kits or laboratorydeveloped methods. The Committee concluded that because of the absence of clinical data, it was uncertain which of the tests would be most clinically useful in both scenarios. It concluded further, that in the absence of robust positive or negative evidence linking the index tests to the alternative tests, the outcomes of the economic model can be applied to the index tests (LISATRACKER, IDKmonitor and Promonitor ELISA kits), and the Committee noted the uncertainty in making this assumption.
The Committee considered the analytical validity of the ELISA kits (LISATRACKER, IDKmonitor and Promonitor). It heard from experts on the Committee that measuring TNFalpha inhibitor levels can be problematic if antibodies to TNFalpha inhibitors are also present in the sample. It heard further that tests measuring antibodies to TNFalpha inhibitors do not distinguish between transient antibodies (antibodies that disappear and reappear over time) and stable antibodies (antibodies that stay at high levels), but that the type of antibody is clinically important and could affect treatment decisions. The Committee noted that some ELISAs for antibodies to TNFalpha inhibitors are quantitative and others are semiquantitative, and concluded that it was uncertain which would be most clinically useful. The Committee questioned whether the ELISAs would work with biosimilar versions of TNFalpha inhibitors. It heard from an expert on the Committee that studies have been done that show the ELISAs do work with biosimilars, but these studies are currently unpublished. The Committee also heard from a clinical expert that there is no formal external quality assurance programme for measuring levels of TNFalpha inhibitors and antibodies to TNFalpha inhibitors, but that some laboratories take part in sampleexchange programmes as a form of quality assurance. The Committee concluded that further research into the analytical performance of the ELISAs is needed.
The Committee considered the evidence on the optimal cutoff thresholds for use with the ELISA kits (LISATRACKER, IDKmonitor and Promonitor). It noted that the informationforuse documents for each of the kits do not specify thresholds to guide interpretation of test results. So each laboratory is expected to identify and validate a threshold for use with the tests. The Committee heard from clinical experts that the same thresholds should not be used between different kits, making it difficult to compare the results from different kits. It also heard that thresholds for infliximab levels were better established than thresholds for adalimumab levels, and that thresholds for TNFalphainhibitor levels were better established than thresholds for antibodies to TNFalpha inhibitors. The Committee noted that a precise threshold was less critical for people whose disease loses response, because the objective of testing was to identify the presence or absence of the TNFalpha inhibitor. It noted further that a precise threshold was more important in people whose disease was responding to treatment with a TNFalpha inhibitor in whom the objective of testing was to titrate the dose of the TNFalpha inhibitor to achieve a trough level in a target range. The Committee therefore concluded that further research is needed to establish clinically meaningful thresholds for each of the ELISAs, and considered that laboratories currently doing these tests should have specialist expertise in immunoassay analysis and should be interpreting the results with caution.
The Committee considered the accuracy of the ELISA kits (LISATRACKER, IDKmonitor and Promonitor) for predicting the clinical state of Crohn's disease. The Committee noted that evidence suggested that the ability of these tests to classify clinical state is poor, which could result in misclassification of clinical state in people with Crohn's disease. The Committee concluded that the uncertainty in the accuracy of these tests would lead to uncertainty in the model, and that further research is needed on the clinical validity of the ELISA kits.
The Committee considered the outcomes used to assess the response of Crohn's disease to treatment with TNFalpha inhibitors. It heard from an expert on the Committee that the outcomes often used to assess response include blood serum biomarkers and mucosal healing (through endoscopy). It heard further that the outcome most important to people with Crohn's disease is that they feel better. The Committee noted that the levels of TNFalpha inhibitor needed to achieve mucosal healing are higher than the levels of TNFalpha inhibitor needed for the person to feel better. It concluded that future studies should include patientreported outcomes measures.
The Committee considered the assumptions used in the economic models. It noted that 2 different sets of transition probabilities were used to generate 2 sets of basecase results. The first base case used timedependent transition probabilities, whereas the second base case used exponential transition probabilities. The Committee heard from the External Assessment Group (EAG) that the timedependent transition probabilities best reflect the data from the key studies used to provide inputs for the model. However, the exponential transition probabilities assume that people progress through the model at a constant rate over time, and this better reflects how people move through the care pathway, given the modelling methods that were used. The Committee concluded that the results of the second base case were the most plausible.
The Committee considered the test schedules assessed in the models. It noted that in the base case, people whose disease responded to TNFalphainhibitor treatment were tested for TNFalphainhibitor levels and antibodies to TNFalpha inhibitors every 3 months. The Committee heard from a clinical expert that in UK practice the most likely testing strategy is to test for TNFalphainhibitor levels and antibodies to TNFalpha inhibitors once a year and on loss of response. The Committee concluded that the most plausible ICER for the responder model was from the 'annual testing' scenario (126,600 saved per QALY lost for concurrent testing compared with no testing), and the most plausible ICER for the loss of response model was from the 'testing only on loss of response' scenario (340,900 saved per QALY lost for concurrent testing compared with no testing).
The Committee considered the QALY losses resulting from the economic model that were spread over 10 years. It noted that in the responder model with annual testing, the QALY losses compared with a notesting strategy were 0.280 for a reflextest strategy and 0.288 for a concurrenttest strategy. It also noted that in the loss of response model, when testing was done only in people whose disease lost response to a TNFalpha inhibitor, the QALY losses compared with a notesting strategy were 0.333 for a reflextest strategy and 0.351 for a concurrenttest strategy. The Committee considered that these QALY losses are quite large and unexpected, given the low quality of life experienced by people with Crohn's disease that loses response to a TNFalpha inhibitor. The Committee also heard from a clinical expert on the Committee that the quality of life of people with Crohn's disease can be difficult to value, and that utility values used in the model may not fully reflect the quality of life of people with Crohn's disease. The Committee concluded further that research into the quality of life of people with Crohn's disease treated with TNFalpha inhibitors would be useful.
The Committee considered the reasons for the QALY losses. It heard from the EAG that one reason was the high proportion (79%) of people in the model in the loss of response health state with TNFalpha inhibitor present and antibodies to TNFalpha inhibitors absent. This proportion was taken from the study by Steenholdt et al. (2014). A clinical expert on the Committee advised that the proportion of patients in the UK with loss of response, TNFalpha inhibitor present and no antibodies to TNFalpha inhibitors is much lower than 79%. The Committee also heard from the EAG that these people in the model, with a testing strategy, would stop TNFalphainhibitor treatment and have best supportive care, which would eventually include surgery. A notesting strategy would result in these patients staying on TNFalphainhibitor treatment longer before stopping the TNFalpha inhibitor and having best supportive care. The Committee also noted its conclusion that the uncertainty in the accuracy of the ELISA kits for predicting clinical state could lead to misclassifying clinical state in some people with Crohn's disease (section 6.7). It noted further that if clinical state in people with Crohn's disease is being misclassified by the test results this may explain some of the QALY losses seen in the economic model. The Committee concluded that the QALY losses in the models were uncertain and may not reflect clinical practice in the NHS.
The Committee considered the cost savings resulting from the economic model. It noted that the cost savings in the testing strategies compared with the notesting strategy were driven by reduced use of TNFalpha inhibitor in the testing strategies, particularly by:
not increasing the dose of TNFalpha inhibitor in people whose disease loses response and who have high levels of antibodies to TNFalpha inhibitor
stopping treatment with, or reducing the dose of TNFalpha inhibitor in people whose disease is in remission and have undetectable or low trough level of TNFalpha inhibitor.The Committee heard from an expert on the Committee that biosimilars for infliximab and adalimumab are likely to be introduced soon. The Committee noted that biosimilar drugs are cheaper than the original drugs, which would be likely to reduce the cost savings in the model. The Committee concluded that the small evidence base led to uncertainties in the modelling, which resulted in uncertainty in the cost savings.
The Committee considered the probabilistic sensitivity analyses done by the EAG. It noted that the scatterplots for both the loss of response model and the responder model showed considerable uncertainty in the QALY losses, and that there was overlap between the results of the testing strategies and the notesting strategy in terms of QALY losses. The Committee also noted that the scatterplot for the responder model showed considerable uncertainty in the cost savings, and there was overlap between the results of the testing strategies and the notesting strategy in terms of cost savings. However, the scatterplot for the loss of response model showed slightly less uncertainty in the cost savings, and there was no overlap between the results of the testing strategies and the notest strategy in terms of cost savings. The Committee concluded that there was greater uncertainty in the cost savings in people whose disease was responding to TNFalphainhibitor treatment compared with people whose disease loses response to TNFalphainhibitor treatment.
The Committee considered the current UK use of testing for TNFalpha inhibitors and antibodies to TNFalpha inhibitors in Crohn's disease. It heard from clinical experts on the Committee that approximately a third to a half of all centres are referring samples for testing to help manage the treatment of Crohn's disease, especially in people whose disease loses response to a TNFalpha inhibitor. The Committee noted that there is a lot of interest in using these tests to support decisionmaking in Crohn's disease, and that clinicians find them useful. It was concerned however, that the complexities in interpreting the results without a defined cutoff threshold (section 6.6) and the potential for misclassification (section 6.7) meant that tests could be incorrectly used by clinicians without specialist knowledge of the tests. The Committee therefore concluded that at this time, the number of laboratories using these tests should not increase beyond current numbers, unless the tests are used in the context of data collection or a research study.
The Committee considered the different scenarios for using the ELISA kits, that is, in people whose disease loses response to TNFalphainhibitor treatment, and in people whose disease is responding to TNFalphainhibitor treatment. The Committee noted the differences in the ICERs between the 2 scenarios, and that using the ELISA kits in people whose disease loses response to TNFalphainhibitor treatment was associated with greater savings per QALY lost compared with using the ELISA kits in people whose disease is responding to TNFalphainhibitor treatment (section 6.10). It also noted that there was less uncertainty in the cost savings in people whose disease loses response to TNFalphainhibitor treatment compared with people whose disease was responding to TNFalphainhibitor treatment (section 6.14). The Committee further noted that people with Crohn's disease with loss of response to TNFalpha inhibitors have a low quality of life (section 6.11) and limited treatment options (section 6.2). The Committee concluded that in people whose disease loses response to TNFalphainhibitor treatment, the ELISA kits should be used in laboratories alongside data collection through a relevant registry or audit. The Committee also concluded that only laboratories that are currently using these tests and have expertise in immunoassay analysis and a thorough understanding of the technical factors that may affect the results should continue to use them. These laboratories should work closely in a network with the treating or referring clinician to ensure the appropriate use of the tests and interpretation of the results. The Committee also concluded that in people whose disease responds to TNFalphainhibitor treatment, the ELISA kits should be used only in research.
The Committee considered the use of ELISA kits (LISATRACKER, IDKmonitor, and Promonitor) in children with Crohn's disease and noted that no evidence on children was identified in the assessment. It heard from a clinical expert on the Committee that the effect of Crohn's disease on children can be slightly different to that in adults, for example, resulting in growth delay and psychiatric problems. It heard further that there is growing interest from paediatric clinicians in using these tests to help guide treatment in children with Crohn's disease. The Committee therefore encouraged data collection and further research into using ELISA kits (LISATRACKER, IDKmonitor and Promonitor) to support decisionmaking in children with Crohn's disease.
The Committee considered the advantages and disadvantages of concurrent testing and reflex testing. It heard from a clinical expert on the Committee that most centres in the UK use a concurrenttesting strategy. The Committee noted that when a concurrenttesting strategy is used, some tests may be wasted because samples with TNFalpha inhibitor present are unlikely to have free antibodies to TNFalpha inhibitor present (which is what most of the antidrug antibody ELISAs measure). However, a reflextest strategy may cause an unacceptable delay in giving results because fewer samples would be tested for antibodies to TNFalpha inhibitor and a laboratory would often wait for a full batch of samples before doing the test. The Committee noted that the ICER for the concurrenttest strategies and the reflextest strategies were similar. It concluded that either test strategy could be used in research.
The Committee considered the research being conducted on tests to measure levels of TNFalpha inhibitors and antibodies to TNFalpha inhibitors in Crohn's disease. The Committee heard from a clinical expert that this is a fastmoving area and a lot of research is being done. It also noted that the UKbased PANTS  Personalised AntiTNF Therapy in Crohn's Disease  study should provide relevant data; but results are not expected until the end of 2016. The Committee concluded that data from this ongoing research are likely to be important when the guidance is considered for updating in the future.# Recommendations for further research
Further research into the analytical and clinical validity of the enzymelinked immunosorbent assay (ELISA) kits (LISATRACKER, IDKmonitor and Promonitor) is recommended, specifically on:
the best methods to measure tumour necrosis factor (TNF)alphainhibitor levels in the presence of antibodies to TNFalpha inhibitors
developing primary reference standards
the accuracy for predicting clinical state
clinically meaningful thresholds.
Further research is recommended on clinical outcomes associated with using the ELISA kits (LISATRACKER, IDKmonitor and Promonitor) in people whose Crohn's disease is losing response to a TNFalpha inhibitor. This could be through a prospective study, for local audit, or for submission to a registry. (The IBD Registry is being adapted to receive data on TNFalpha inhibitor levels and antibodies against TNFalpha inhibitors).
Further research is recommended on clinical outcomes associated with using the ELISA kits (LISATRACKER, IDKmonitor and Promonitor) to monitor TNFalphainhibitor levels and antibodies to a TNFalpha inhibitor in people with Crohn's disease whose disease responds to treatment with TNFalpha inhibitors. This should be evaluated using prospective studies.# Review
NICE updates the literature search at least every 3 years to ensure that relevant new evidence is identified. NICE will contact product sponsors and other stakeholders about issues that may affect the value of the diagnostic technology. NICE may review and update the guidance at any time if significant new evidence becomes available.
Andrew Dillon Chief Executive February 2016