Therapeutic monitoring of TNF-alpha inhibitors in rheumatoid arthritis

4.6 INGEBIO was a prospective, non-randomised, non-inferiority, multicentre pragmatic study. It assessed the efficacy and cost of implementing therapeutic monitoring to guide treatment decisions in people with different rheumatic diseases taking adalimumab. The comparator was standard care in Spain, where treatment decisions (including dose reduction) are based on clinical judgement only.

4.7 It recruited a mixed population of 169 people with rheumatoid arthritis (n=63; 37%), psoriatic arthritis (n=54; 32%) and ankylosing spondylitis (n=52; 31%). They had treatment with adalimumab and had remained clinically stable for at least 6 months (Ucar et al. 2017).

4.8 In the study, everyone had therapeutic monitoring using Promonitor adalimumab and anti-adalimumab antibody kits, but test results were only revealed to clinicians in the intervention arm. They were not obliged to follow any therapeutic algorithm based on the test results but could use it to inform their judgement on treatment. In contrast, therapeutic monitoring test results were not revealed to clinicians in the control arm. This reflected standard care in Spain where treatment decisions are based on clinical judgement only, without knowing the drug levels and antidrug antibodies of people with rheumatoid arthritis.

4.9 The frequency of testing was once every 2 to 3 months. People were assessed for up to 18 months for change in disease response and health-related quality-of-life outcomes.

4.10 Results were reported in 3 conference abstracts. During consultation on the draft guidance, Grifols provided the full study report (commercial in confidence). Table 2A and B show the baseline characteristics and 18‑month clinical outcomes reported in INGEBIO. Ucar et al. (2017) reported intention-to-treat analysis, whereas Arango et al. (2017) reported per-protocol analysis, which excluded 19 people who were lost to follow up. The full study report provided further details on the per-protocol analysis. In the intention-to-treat analysis:

Notes: The rate of flares per patient-year reported in Ucar et al. (2017) is the same as in Arango et al. (2017) even though these sources reported outcomes for different numbers of people and different follow-up periods. This could be because of an error in 1 of the abstracts.

The difference in duration of follow up between the 2 abstracts is most likely because of the exclusion of 19 people who were lost to follow up (and so had a shorter follow-up time) rather than a longer data collection period.

Abbreviations: NR, not reported.

4.11 Using ROBINS-I criteria, INGEBIO was judged to be at serious risk of bias, because of baseline imbalance in disease activity between the intervention and control groups. The full study report highlighted additional important differences in baseline characteristics between the 2 study groups. Also, the findings may not be generalisable to the UK rheumatoid arthritis population because:

4.12 The study was initially identified as a conference abstract (Pascual-Salcedo et al. 2013). However, during consultation Sanquin provided a full-text article (Pascual-Salcedo et al. 2015) that was not indexed in any database and therefore not identified in the systematic literature review. Although results were presented for slightly different populations, the 2 sources were generally in line.

4.13 This was a single-centre observational study of daily clinical practice comparing clinical outcomes. The conference abstract included 88 people (43 with rheumatoid arthritis and 45 with spondyloarthritis) and the full-text publication included 77 people (36 with rheumatoid arthritis and 41 with spondyloarthritis). They had treatment with TNF‑alpha inhibitors (infliximab, adalimumab and etanercept) before and after introducing therapeutic monitoring of TNF‑alpha inhibitors (capture ELISA by Sanquin). Inclusion and exclusion criteria were reported only in the full-text publication.

4.14 The study compared outcomes in the same cohort of people in 2 periods: before introducing therapeutic monitoring, from 2006 to 2009 (full-text publication: 2007 to 2009) and after introducing therapeutic monitoring, from 2010 to 2012. Everyone was in sustained remission or had low disease activity for at least 6 months (defined in rheumatoid arthritis as disease activity score [DAS28] less than 3.2), and had treatment with the same TNF inhibitor throughout the entire study.

4.15 There were statistically significant changes after introducing therapeutic monitoring of TNF‑alpha inhibitors for all 3 drugs (reported in the conference abstract and the full-text publication):

4.16 Everyone had stable clinical activity in both periods. In people with rheumatoid arthritis, the mean (± standard deviation [SD]) DAS28 was 2.31±0.52 after introducing therapeutic monitoring of TNF‑alpha inhibitors compared with 2.51±0.85 before (p=0.061). In the full-text publication the mean DAS28 was 2.37±0.50 and 2.28±0.47, respectively (p=0.2).

4.17 The study was an open-label, randomised, parallel-group, non-inferiority trial done in the Netherlands. It assessed clinical outcomes in people with rheumatoid arthritis with high serum adalimumab concentrations (above 8 mg/litre) who had dose-interval prolongation, compared with people who continued standard dosing.

4.18 The trial considered people with rheumatoid arthritis who had treatment for at least 28 weeks and had no indication for adjustment of adalimumab treatment, discontinuation or a scheduled surgery in the next 6 months. A total of 55 people were randomised and 54 included for analyses.

4.19 The mean DAS28 after 28 weeks decreased by 0.14 (SD 0.61) in the interval prolongation group and increased by 0.30 (SD 0.52) in the continuation group. The difference in the mean change in DAS28 was 0.44 (95% CI 0.12 to 0.76; p=0.01) in favour of the prolongation group.

4.20 The authors concluded that the frequency of adalimumab dosing can be safely extended without loss of disease control. However, because of the small sample size and comparable median adalimumab doses at week 28 in both groups, the EAG did not include this study in the economic assessment.

4.21 The EAG identified 5 studies investigating the cost effectiveness of ELISA tests used to measure drug levels and antidrug antibodies for monitoring response to TNF‑alpha inhibitors. There were 3 studies that were model-based economic evaluations (cost-effectiveness models) and 2 were observational (Pascual-Salcedo et al. 2013 reported costs and Arango et al. 2017 reported costs and quality-adjusted life years [QALYs]).

4.22 In INGEBIO (see sections 4.6 to 4.11 for study details), the mean QALYs during the 18‑month follow-up period were 1.076 in the control (standard care) group and 1.145 in the intervention group (therapeutic monitoring of TNF‑alpha inhibitors). This was a gain of 0.069 QALYs compared with control (Arango et al. 2017). The average per patient-year costs of adalimumab were €10,665 in the control group and €9,856 in the intervention group. This was a cost saving of €808 (8% of cost). Other healthcare costs were not reported. Data in the full study report (commercial in confidence) were generally in line with the findings in the conference abstract.

4.23 In the observational study by Pascual-Salcedo et al. (2013; see sections 4.12 to 4.16 for study details), introducing therapeutic monitoring of TNF‑alpha inhibitors resulted in lower monthly acquisition costs of TNF‑alpha inhibitors, compared with the monthly costs of the drugs before monitoring. The monthly cost saving was €92 per person on infliximab (assuming a mean weight of 70 kg), €324 per person on adalimumab, and €257 per person on etanercept. In the full-text publication the monthly cost saving was €143, €215, and €136 per person, respectively (Pascual-Salcedo et al. 2015).

4.24 Krieckaert et al. (2015) considered the cost effectiveness of a personalised treatment algorithm in people with rheumatoid arthritis taking adalimumab in the Netherlands. This was based on clinical response and drug levels (in-house ELISA tests, Sanquin) at 6 months of treatment, compared with standard care. The study population included all people who had treatment for 6 months, regardless of disease response. For 272 people starting adalimumab treatment over the period of 3 years, a test-based treatment strategy would:

4.25 Laine et al. (2016) assessed the cost effectiveness of routine monitoring of serum drug concentrations and antidrug antibodies in people with rheumatoid arthritis who had TNF‑alpha inhibitors (adalimumab and infliximab), compared with standard care in Finland. Routine monitoring of both drug and antibody levels was estimated to be cost saving, assuming that it would improve treatment decisions for 2.5% to 5% of people who would otherwise have non-optimal treatment for 3 to 6 months in the standard care scenario.

4.26 Gavan (PhD thesis 2017; personal communication with the EAG) assessed the cost effectiveness of using ELISA testing (no test specified) for monitoring people with rheumatoid arthritis taking adalimumab. The analysis considered 10 different testing scenarios and 2 scenarios in which adalimumab doses were halved without previous testing. Routine adalimumab testing (either drug levels alone or drug levels plus antidrug antibodies) was generally cost effective compared with current practice. But it was unlikely to be cost effective relative to dose reduction (without testing) for people in remission.

4.27 The EAG developed a de novo economic model designed to estimate the health and economic outcomes of adding therapeutic monitoring of TNF‑alpha inhibitors to usual practice to guide treatment decisions in people with rheumatoid arthritis who had reached treatment target (remission or low disease activity). The model was based on the INGEBIO results, so it considered Promonitor tests for measuring adalimumab drug and antibody levels. Several analyses were done:

4.28 Exploratory analyses were done to assess the health and economic outcomes of the Promonitor tests to measure drug levels and antidrug antibodies for TNF‑alpha inhibitors other than adalimumab (that is, infliximab and etanercept). These assumed similar clinical effectiveness across the TNF‑alpha inhibitors and similar performance of the Promonitor tests used for measuring the drug and antibody levels of all TNF‑alpha inhibitors.

4.29 Economic analyses for ELISA tests other than Promonitor were not done because of the lack of evidence to inform the models.

4.30 Economic assessment for the population with primary or secondary non-response was not possible because of the lack of evidence.