Y-ECCO Literature Review: Jennie Clough

Jennie Clough

Tight control for Crohn’s Disease with adalimumab-based treatment is cost-effective: An economic assessment of the CALM trial

Panaccione R, Colombel J-F, Travis SPL, Bossuyt P, Baert F, Vaňásek T, Danalıoğlu A, Novacek G, Armuzzi A, Reinisch W, Johnson S, Buessing M, Neimark E, Petersson J, Lee W-J, D’Haens GR GR

Gut 2019 Jul 8. doi: 10.1136/gut-jnl-2019-318256 [Epub ahead of print].


Jennie Clough picture small
Jennie Clough
© Jennie Clough

It is widely accepted that a ‘treat-to-target’ (T2T) approach of continual assessment against established biomarkers and early treatment optimisation is important in preventing progression in Crohn’s Disease (CD) [1], and in 2015 the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) programme was initiated to define a T2T approach for CD [2].

CALM was an open-label, multicentre, randomised controlled phase 3 study comparing the outcome of a ‘tight control’ (TC) adalimumab-based treatment strategy against standard clinical symptom-based management (CM) for patients with early CD [3]. Treatment of patients in the TC arm was escalated in a stepwise manner in response to elevated C reactive protein (CRP) or faecal calprotectin, even in the absence of symptoms. A significantly higher proportion of patients in the TC group achieved the primary endpoint of mucosal healing (CDEIS<4) at 48 weeks compared to the CM group (46% vs 30%).

Perhaps unsurprisingly, a TC approach led to higher rates of adalimumab usage than a conventional approach [3]. Biologics constitute a significant cost in managing Inflammatory Bowel Disease, with other major cost drivers being hospital admission and surgical management [4]. As rates of surgery and hospitalisation have decreased with the advent of biologics [5, 6], costs have shifted to outpatient care, drug acquisition and infusion unit management [7].

This study sought to model the costs of a TC versus a conventional approach, to determine whether the increased biologic costs could be offset by a reduction in hospital attendance and need for surgery, and enhanced economic outputs associated with increased wellbeing.  


The authors developed a computational model to compare TC and CM strategies based on a UK public payer health system, using patient observation data from the 244 patients enrolled in the original CALM trial. The model was a stochastic or ‘Markov’ model, in which patients were assigned to a ‘health state’ based on disease severity, as defined by CDAI score. Patients were able to move between disease states based on transition probabilities. Outcomes were modelled at 48 weeks and 5 years.

CALM trial data were analysed to derive inputs for the model for baseline health states, hospitalisation rates and transition probabilities between health states. Direct medical costs taken into account included laboratory, radiology, emergency department attendance, non-biologic drugs and clinician visits. Efforts were also made to deduce indirect cost measures, including assessment of work absenteeism through subjects’ responses to work productivity and quality of life questionnaires.

Key Findings

The proportion of patients in each health state (moderate/severe/very severe) was not significantly different between TC and CM arms of the study. Patients in the TC arm had a greater likelihood of maintaining or moving to a less severe health state than those in the CM arm, and there were twice as many hospitalisations in the CM arm. The model predicted that 58.2% of patients treated according to TC strategy were in clinical remission at 48 weeks, compared to 46.8% in the CM group.

Over the course of 48 weeks, a TC strategy equated to an extra 77.5 hours of work attendance per patient and reduced the costs of absenteeism by £3962, compared to £2748 per patient in the CM arm (calculated from the Office for National Statistics 2017 UK wage rates).

A TC strategy was deemed cost-effective compared to CM in modelled scenarios in which half of patients were in severe and half in very severe health states at baseline, and when all study patients were in a moderate health state at baseline.


This study reinforces the findings of the CALM trial, that use of adalimumab according to a tight control strategy brings significant clinical benefit. In addition, the modelled data provide reassurance that this is also a viable strategy from an economic point of view. Additional costs associated with greater use of adalimumab and more frequent biomarker testing in the TC group were offset by reduced hospital attendances and improvements in quality of life, including resumption of work activity.

There are limitations to the trial. Although patient data from the CALM cohort were used to derive inputs for the model, several resources were not measured in the trial and were sourced from a study that stratified resource by disease severity. Outcomes are therefore derived from modelling of predicted resource use for patients taking part in a randomised controlled trial, rather than real-world observational data. Of note, the costs of adalimumab were calculated from 2017 NHS pricing, prior to the launch of biosimilar products in October 2018. The reduced cost of biosimilar adalimumab would further enhance the favourable cost-effective profile of a TC strategy.

The CALM cohort represents an uncomplicated CD population with a short disease duration (mean 2.6 months), and it is unclear whether the economic benefits can be extrapolated to a population with more advanced disease. Other important considerations include the enhanced costs of provision of intravenous therapy compared to self-administered subcutaneous injection, and the use of newer biologic agents without available biosimilars. In addition, it is unclear whether a TC approach would also be economically favourable in an insurer provider healthcare model.

The economic impact of suboptimal biologic therapy is substantial [8]. Adhering to proactive therapeutic drug monitoring (TDM) in combination with a T2T approach may reduce long-term biologic costs [9], through early cessation of ineffective therapy and identification of over/under-dosing.

Overall, this study provides further justification for use of a proactive T2T approach in patients with Crohn’s Disease, and corroborates previous studies which have found the use of anti-TNFα agents in IBD to be cost-effective [10, 11]. In assessing costs of treatment, measures of the impact of indirect costs are likely to be conservative, and may fail to adequately quantify the value of an enhanced quality of life and the ability to enjoy leisure time, which are likely to be vitally important to CD patients.


      1. Colombel J-F, D’haens G, Lee W-J, Petersson J, Panaccione R. Outcomes and strategies to support a treat-to-target approach in inflammatory bowel disease: a systematic review. J Crohn’s Colitis. 2019. doi:10.1093/ecco-jcc/jjz131 [Epub ahead of print].
      2. Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110:1324–38.
      3. Colombel J-F, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn’s disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet. 2018;390:2779–89.
      4. Park KT, Bass D. Inflammatory bowel disease-attributable costs and cost-effective strategies in the United States. Inflamm Bowel Dis. 2011;17:1603–9.
      5. Bernstein CN, Loftus E V, Ng SC, Lakatos PL, Moum B. Hospitalisations and surgery in Crohn’s disease. Gut. 2012;61:622–9.
      6. Frolkis AD, Dykeman J, Negrón ME, et al. Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and meta-analysis of population-based studies. Gastroenterology. 2013;145:996–1006.
      7. Valk ME van der, Mangen M-JJ, Leenders M, et al. Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study. Gut. 2014;63:72–9.
      8. Rubin DT, Mody R, Davis KL, Wang C-C. Real-world assessment of therapy changes, suboptimal treatment and associated costs in patients with ulcerative colitis or Crohn’s disease. Aliment Pharmacol Ther. 2014;39:1143–55.
      9. Vande Casteele N, Gils A. Preemptive dose optimization using therapeutic drug monitoring for biologic therapy of Crohn’s Disease: avoiding failure while lowering costs? Dig Dis Sci. 2015;60:2571–3.
      10. Dretzke J, Edlin R, Round J, et al. A systematic review and economic evaluation of the use of tumour necrosis factor-alpha (TNF-α) inhibitors, adalimumab and infliximab, for Crohn’s disease. Health Technol Assess (Rockv). 2011;15:1–244.
      11. Tang DH, Harrington AR, Lee JK, Lin M, Armstrong EP. A systematic review of economic studies on biological agents used to treat Crohn’s disease. Inflamm Bowel Dis. 2013;19:2673–94.


Jennie is a gastroenterology registrar working at Guy’s and St Thomas NHS Trust in London. She is currently undertaking research into regulatory T cells in IBD and is involved in the delivery of the MRC-funded TRIBUTE trial in Crohn’s Disease.

Posted in ECCO News, Y-ECCO Literature Reviews, Committee News, Y-ECCO, Volume 14, Issue 4