Technologies scoping report

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1 Technologies scoping report In response to an enquiry from NHS Greater Glasgow and Clyde Number 18 October 2013 What is the clinical effectiveness, cost effectiveness and implications for safety of assessing anti-tumour necrosis factor (TNF)α drug levels and antibodies in children with moderate to severe inflammatory bowel disease (IBD) compared with existing clinical strategies in use in What is a scoping report? Scoping reports ascertain the quantity and quality of the published clinical and cost-effectiveness evidence on health technologies under consideration by decision makers within NHSScotland. They also serve to clarify definitions related to the research question(s) on that topic. They are intended to provide an overview of the evidence base, including gaps and uncertainties, and inform decisions on the feasibility of producing an evidence review product on the topic. Scoping reports are undertaken in an approximately 1-month period. They are based upon a high-level literature search and selection of the best evidence that Healthcare Improvement Scotland could identify within the time available. The reports are subject to peer review. Scoping reports do not make recommendations for NHSScotland, however the Scottish Health Technologies Group (SHTG) produce an Advice Statement to accompany all evidence reviews. Further information on scoping reports is available at Key definitions Inflammatory bowel diseases (IBD): chronic inflammatory disorders defined by distinctive clinical, pathological, endoscopic and radiological features. The most common are Crohn s disease (CD) and ulcerative colitis (UC). Anti-tumour necrosis factor (TNF)α medications: novel biological therapies ( biologics ) for immune-mediated diseases. Trough levels: lowest levels of medication detectable in serum immediately prior to administration of the next scheduled dose. Background The incidence of paediatric IBD in Scotland is the highest in the United Kingdom and has risen rapidly over recent decades. One analysis suggests that for children younger than 16 years, the incidence of CD rose by 66% between the periods and , and that there was a 30% increase in the incidence of UC across that timeframe 1. In the period there were 436 new diagnoses of paediatric IBD in Scotland giving an adjusted incidence of 7.82/100,000/year 1. Anti-TNFα medications, infliximab and adalimumab, are recommended as third-line treatments, which may offer an alternative to surgery for children with IBD 2,3. The Scottish Medicines Consortium (SMC) advises that: infliximab (Remicade ) is accepted for use within NHSScotland for the treatment of severe, active CD in paediatric patients aged 6 17 years, who have not responded to conventional therapy including a corticosteroid, an immunomodulator and primary nutrition therapy; or who are intolerant to or have contraindications for such therapies 4. infliximab (Remicade ) is accepted for restricted use within NHSScotland for treatment of severely active UC in children and adolescents aged 6 17 years who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine or azathioprine, or who are intolerant to or have medical contraindications for such therapies. SMC restricted infliximab as an alternative to ciclosporin in patients with acute, severe paediatric UC (rescue therapy) who are steroid refractory 5. adalimumab (Humira ) is accepted for the treatment of severe active CD in paediatric patients of 6 to 17 years of age who have had an inadequate response to conventional therapy including primary

2 Technologies scoping report 2 nutrition therapy, a corticosteroid, and an immunomodulator, or who are intolerant to or have contraindications for such therapies. SMC restricted prescription of adalimumab to specialists in paediatric gastroenterology 6. Up to 70% of patients treated with anti-tnfαα medications who initially respond to treatment subsequently lose clinical response 7 and it is suggested that this is related to development of antibodies to the medications. The possibility of using antibody status and serum drug concentration measurements to optimise treatment outcomes and predict which patients will respond to intensification of treatment (through dose increase or reduction in treatment interval) and which will require a change of drug agent is hypothesised At present, management decisions are largely empiric and based on clinical judgment supported by assessment of faecal biomarkers (principally faecal calprotectin) and inflammatory markers in blood (eg erythrocyte sedimentation rate, C-reactive protein). Infusion reactions can be an important reason for withdrawal from anti-tnf α treatment and it is further proposed that testing for antibodies may facilitate identification of patients at greatest risk of adverse immune reactions 12,13. The evidence base is primarily focused on infliximab in part due to the availability of commercial assays for detection of anti-infliximab antibodies (ATIs). The following questions were scoped: 1. What is the clinical utility of assessing anti-tnfα antibodies (ATAs) in children being treated for moderate to severe IBD compared with existing clinical strategies in use in 2. What is the clinical utility of assessing anti- TNFα drug levels in children being treated 3. What are the implications for safety of assessing anti-tnfα drug levels and anti- TNFα antibodies in children being treated 4. What is the cost effectiveness of assessing anti-tnf α drug levels and anti-tnfα antibodies in children being treated Methods A systematic search of the secondary literature was carried out between 4 19 March 2013 to identify systematic reviews, health technology assessments and other evidence-based reports. Medline, Medline in process, Embase and Web of Knowledge databases were searched for systematic reviews and meta-analyses. The primary literature was systematically searched between March 2013 using the following databases: Medline, Medline in process, Embase, and Web of Knowledge. Results were limited to English language studies on paediatric populations published between Key websites were searched for guidelines, policy documents, clinical summaries, economic studies and ongoing trials (ongoing trials search 1 5 May 2013). Websites of organisations related to this topic, for example British Society for Gastroenterology, Academy for Paediatric Gastroenterology, British Society for Paediatric Gastroenterology Hepatology and Nutrition, were also searched. Concepts used in all searches included: inflammatory bowel diseases, anti-tumour necrosis factor, drug monitoring, and antibody monitoring. A full list of resources searched and terms used is available on request. Evidence base Table 1 Included evidence sources Publication type Number of publications References Meta-analysis 2 7,13 Narrative review Findings 1. What is the clinical utility of assessing ATA in children being treated for moderate to severe IBD compared with existing clinical strategies in use in No systematic reviews or meta-analyses were identified which directly addressed the question. Two meta-analyses examined the development of ATIs and their association with both drug level and clinical response.

3 Technologies scoping report 3 A meta-analysis of data from nine randomised controlled trials, five prospective and four retrospective cohort studies published up to October 2011 included 3,326 patients with CD or UC receiving treatment with infliximab 13. Two small cohort studies (total n=62) in a paediatric population were included. ATIs were tested for in 2,350 patients across all studies and the mean prevalence was 20.8% (95% confidence interval (CI) 19.2% to 22.5%). Episodic treatment was associated with greater risk of developing ATIs than maintenance treatment (45.8% versus 12.4%, relative risk (RR)=3.71, 95% CI 3.16 to 4.35, p<0.0001). Combining 10 studies (including the two in children), there was no strong evidence of a difference in rates of remission between patients who developed ATIs and those who did not (RR= 0.90, 95% CI 0.79 to 1.02; p=0.10). Patients on concomitant immunosuppressant therapy were less likely to develop ATIs than those not on immunosuppressants (RR=0.50, 95% CI 0.42 to 0.59, p< ), although for this outcome there was evidence of publication bias. Another meta-analysis extracted data only for adult patients on maintenance (scheduled) treatment with infliximab 7. Thirteen studies were identified (n=1,378). Loss of clinical response to infliximab was associated with presence of ATIs (RR=3.16, 95% CI 2.00 to 4.98, p<0.0001). On analysis of study quality, there were components in all the included studies which were judged as introducing high risk of bias. There was also evidence of publication bias. The meta-analysis identified three studies examining the association of ATI status with serum infliximab trough levels. All three studies reported significantly lower trough serum levels in patients with detectable ATIs. Both meta-analyses highlighted heterogeneity in assay methods used to determine antibody status 7,13. There is no gold standard for this assessment and the most commonly used assay (solid phase enzyme-linked immunosorbent assay (ELISA)) is unable to measure antibody status in the presence of infliximab resulting in up to 72% of assessments classed as ATI inconclusive 13. In addition to this, analysis of ATI as a dichotomous variable may not be clinically relevant. The timing of measurement of antibodies was also a source of variation, in that ATI status may be transient, latent or sustained 13. Reviews identified two studies examining the development of antibodies to adalimumab in patients with CD. In both studies (Sandborn, 2007 and West, 2008) the presence of antibodies to adalimumab were associated with reduced clinical response 9, What is the clinical utility of assessing anti- TNFα drug levels in children being treated No systematic reviews or meta-analyses were identified which directly addressed the question. A meta-analysis identified six studies in adults which reported on loss of response according to infliximab trough level 7. In four of the studies, lower trough levels were associated with loss of response whilst in two studies there was no association. All of the studies were assessed as having a high risk of bias in at least two of four quality domains. Pooling of the data was not possible 7. Reviews identified two studies (Karmiris, 2009 and Li, 2010) examining the association between serum adalimumab levels and clinical response 9,10. Findings were inconclusive as to the association with short and long-term clinical outcomes. 3. What are the implications for safety of assessing anti-tnfα drug levels and anti- TNF α antibodies in children being treated No systematic reviews or meta-analyses were identified which directly addressed the question. A meta-analysis of data from seven studies (one in children) reporting rates of infusion reactions found that these were higher in patients with ATIs (RR=2.07, 95% CI 1.61 to 2.67; p< ) 13. There was no information as to the severity of the reactions or whether reactions led to discontinuation of therapy. 4. What is the cost-effectiveness of assessing anti-tnfα drug levels and anti-tnfα antibodies in children being treated for moderate to severe IBD compared to existing clinical strategies in use in No cost-effectiveness studies were identified.

4 Summary Technologies scoping report 4 Data on the associations between clinical response, development of ATAs and serum levels of anti- TNFα medications are complex and conflicting, and there is a lack of standardisation of assays or outcome measures. No prospective comparative studies were identified assessing the utility of the measures in directing clinical decision making in a paediatric population. Ten ongoing trials, of which the majority are in adults, were identified as outlined in Table 2. Table 2 Ongoing clinical trials Identifier Title Subjects Country Timeframe NCT Study to determine relationship between serum infliximab and efficacy in luminal Crohn's disease patients (cross-sectional) Adults Canada April 2011 (Final data collection) NCT Association of serum infliximab and antibodies toward infliximab (ATI) to clinical outcomes in Crohn's disease Age 7+ USA October 2013 NCT NCT Use of combined measurements of serum infliximab and antiinfliximab antibodies in the treatment of patients with Crohn s disease failing infliximab therapy Improving treatment of inflammatory bowel diseases through better understanding infliximab drug and antibody levels (OPTIMIZE) Adult Denmark February 2014 Adult Canada September 2015 NCT A randomised controlled trial investigating tailored treatment with infliximab for active luminal Crohn's disease Adult France November A randomised prospective trough level monitoring study with real-time therapeutic adaptations: Trough level Adapted infliximab Treatment scheme (TAXIT) Adult Belgium June 2011

5 Technologies scoping report 5 Identifier Title Subjects Country Timeframe JPRN-UMIN Analysis of the correlation between the blood concentration of infliximab and therapeutic effect for refractory ulcerative colitis No age limit specified Japan August Utilising drug levels and anti-drug antibodies to predict response to treatment in patients with inflammatory bowel disease Adult UK October 2012 JPRN-UMIN NTR3943 Prediction of therapeutic efficacy of infliximab for refractory ulcerative colitis by analysing and measuring serum concentration of cytokines and infliximab Cost-effectiveness of trough level-based dose reduction during infliximab maintenance treatment in Crohn's disease REDIX No age limit specified Japan March 2013 Adult Holland June 2013 Further work for Healthcare Improvement Scotland Given the large number of trials in progress, an evidence review of the primary literature should be considered in 2 years. Equality and diversity Healthcare Improvement Scotland is committed to equality and diversity in respect of the nine equality groups defined by age, disability, gender reassignment, marriage and civil partnership, pregnancy and maternity, race, religion, sex, and sexual orientation. As a scoping report summarises information and does not provide recommendations a full EQIA assessment is not deemed necessary. The scoping report process has been assessed and no adverse impact across any of these groups is expected. The completed equality and diversity checklist is available on

6 Technologies scoping report 6 Acknowledgements Healthcare Improvement Scotland and the Scottish Health Technologies Group (SHTG) acknowledge the contribution of Dr Richard Russell, Consultant Paediatric Gastroenterologist, who acted as a clinical advisor for this topic. Healthcare Improvement Scotland invited the following individuals and organisations to peer review the draft technologies scoping report: Dr Anne M Griffiths, Division Head, Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Canada, independent clinical advisor Professor David Wilson, Professor of Paediatric Gastroeterology and Nutrition, University of Edinburgh, independent clinical advisor Declarations of interest were sought from the clinical advisor and all peer reviewers. All contributions from peer reviewers were considered by the group. However the peer reviewers had no role in authorship or editorial control and the views expressed are those of Healthcare Improvement Scotland. Healthcare Improvement Scotland development team: Lorna Thompson, Author/Health Services Researcher Jenny Harbour, Information Scientist Emma Riches, Medical Writer Marina Tudor, Team Support Administrator Members of the SHTG evidence review committee Healthcare Improvement Scotland 2013 ISBN X NICE has accredited the process used by Healthcare Improvement Scotland to produce its evidence review products. Accreditation is valid for 5 years from January More information on accreditation can be viewed at References 1. Henderson P, Hansen R, Cameron FL, Gerasimidis K, Rogers P, Bisset WM, et al. Rising incidence of pediatric inflammatory bowel disease in Scotland. Inflamm Bowel Dis. 2012;18(6): Sandhu BK, Fell JM, Beattie RM, Mitton SG, Wilson DC, Jenkins H, et al. Guidelines for the management of inflammatory bowel disease in children in the United Kingdom. J Pediatr Gastroenterol Nutr. 2010;50(Suppl 1):S Turner D, Levine A, Escher JC, Griffiths AM, Russell RK, Jenkins H, et al. Management of pediatric ulcerative colitis: joint ECCO and ESPGHAN evidence-based consensus guidelines. J Pediatr Gastroenterol Nutr. 2012;2012(55):3. 4. Scottish Medicines Consortium. SMC advice: infliximab (Remicade) [cited 17 July 2013]; Available from: infliximab_100mg_powder Remicade_/infliximab Remicade_ 5. Scottish Medicines Consortium. SMC advice: infliximab (Remicade) [cited 17 July 2013]; Available from: Remicade/infliximab_Remicade

7 Technologies scoping report 7 References continued 6. Scottish Medicines Consortium. SMC advice: adalimumab (Humira) [cited 17 July 2013]; Available from: Humira_Crohns_ABBREVIATED/adalimumb_Humira 7. Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol. 2013;108(1): Ben-Horin S, Chowers Y. Review article: loss of response to anti-tnf treatments in Crohn's disease. Aliment Pharmacol Ther. 2011;33(9): Chaparro M, Guerra I, Muñoz-Linares P, Gisbert JP. Systematic review: antibodies and anti-tnf-α α levels in inflammatory bowel disease. Aliment Pharmacol Ther. 2012;35(9): Colombel JF, Feagan BG, Sandborn WJ, Van Assche G, Robinson AM. Therapeutic drug monitoring of biologics for inflammatory bowel disease. 2012;18(2): Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol. 2011;106(4): Cassinotti A, Travis S. Incidence and clinical significance of immunogenicity to infliximab in Crohn's disease: a critical systematic review. Inflamm Bowel Dis. 2009;15(8): Lee LY, Sanderson JD, Irving PM. Anti-infliximab antibodies in inflammatory bowel disease: prevalence, infusion reactions, immunosuppression and response, a meta-analysis. Eur J Gastroenterol Hepatol. 2012;24(9):