Barbara Mascialino, Hiroshi Iwamaru, Anagh Vora

The pre-endoscopic screening test EliA Calprotectin 2 is a cost-saving technique compared to serological markers and colonoscopy: the Japanese perspective Barbara Mascialino, Hiroshi Iwamaru, Anagh Vora ImmunoDiagnostics, Thermo Fisher Scientific, Uppsala, Sweden ImmunoDiagnostics, Thermo Fisher Scientific, Tokio, Japan ImmunoDiagnostics, Thermo Fisher Scientific, Portage, MI, USA

Outline • InflammatoryBowelDiseases • IrritableBowelSyndrome • Diagnostic Challenges • Health Economics Assessments on F-Calprotectin • NHS Health Economics Evaluation (2010) • Mindemark and Larsson (2013) • Ourmodel (2013 version) • Why a model for Japan? • Adaptation ofourmodel to the Japanese scenario • Results • Conclusions

Outline • Inflammatory Bowel Diseases • IrritableBowelSyndrome • Diagnostic Challenges • Health Economics Assessments on F-Calprotectin • NHS Health Economics Evaluation (2010) • Mindemark and Larsson (2013) • Ourmodel (2013 version) • Why a model for Japan? • Adaptation ofourmodel to the Japanese scenario • Results • Conclusions

Inflammatory Bowel Diseases (IBD) • The majority of lower gastrointestinal disorders exhibit a limited number of overlapping symptoms. • Ulcerative colitis (UC) and Crohn’s disease (CD) represent the two major forms of the Inflammatory Bowel Diseases (IBD), a group of disorders characterized by chronic inflammationof the gastrointestinal tract. • Among IBD’s symptoms, abdominal pain, increased stool frequency and decreased stool consistency can be listed; these are rather unspecific symptoms. • Based on symptoms only, IBD diagnosis can be challenging for both the gastroenterologist and the primary care physician(Sands, 2004); in the past, in some extreme cases the time from the beginning of the symptoms to a definitive IBD diagnosis could be as long as 20 years(Admans et al., 1980).

The Burden of IBD • A recent study on the Swiss IBD cohort study has shown that diagnosis delay still exists: still exists: 75% of the UC patients considered were diagnosed within 12 months, and the same proportion of CD patients were diagnosed only within 24 months, with a significant diagnosis delay for 25% of the CD subjects (Vavricka et al., 2012). • IBD is nowadays considered to be second only to rheumatoid arthritis for what concerns its chronicity (Elkjaer, 2012). • The disease chronicity, together with an early onset in life, reduced productivityand long periods of absenteeism increase substantially the healthcare costs related to IBD (Bodger, 2002). => IBD can nowadays be considered as a global emerging disease.

The Prevalence of IBD • IBD is mostly prevalent in the Western world (especially in Canada and in Europe), while it can be considered as a rare diseasein developing countries. • In Europe: • the highest reported prevalence values are 505 cases per 100 000 inhabitants for Ulcerative Colitis in Norway (Begtson et al., 2009), and 322 cases per 100 000 inhabitants for Crohn’s Disease in Italy (Cottone et al., 2006). • In a survey conducted during the year 1996 in United Kingdom, 122 cases per 100 000 inhabitants with Ulcerative Colitis and 214 cases per 100 000 inhabitants with Crohn’s Disease (Loftus, 2004) were identified.

The Incidence of IBD • Despite of its rather low prevalence, IBD’s incidence is significantly and steadily increasing since the 1930s (Molodecky et al., 2012) with a North-South gradient (Loftus, 2004). • Nowadays, IBD’s incidence is estimated in 24.3 new Ulcerative Colitis cases every year per 100 000 inhabitants in Iceland (Shivananda et al., 1996), and in 10.6 new Crohn’s Disease cases every year per 100 000 in the United Kingdom (Thompson et al., 1998). This phenomenon is particularly evident in pediatric IBD patients. • In the past 14 years, the pediatric IBD incidence has tripled in Spain (Martín-de-Carpi et al., 2012). Scotland has registered a 76% increase of pediatric IBD cases since the mid-1990s, and IBD in children is progressively being diagnosed at a younger age (Henderson et al., 2012). • In Eastern Denmark, IBD in children has been constantly increasing over the past 12 years, with 6.4 new pediatric cases per 100 000 inhabitants in the period 2007-2009 (Jakobsen et al., 2011).

Outline • InflammatoryBowelDiseases • Irritable Bowel Syndrome • Diagnostic Challenges • Health Economics Assessments on F-Calprotectin • NHS Health Economics Evaluation (2010) • Mindemark and Larsson (2013) • Ourmodel (2013 version) • Why a model for Japan? • Adaptation ofourmodel to the Japanese scenario • Results • Conclusions

Irritable Bowel Syndrome (IBS) • The irritable bowel syndrome (IBS) is a prevalent functional disorder, causing frequent medical consultations. • IBS brings about abdominal pain, abdominal discomfort, and abnormalities in stool form and frequency, symptoms very similar to IBD. • Nowadays, there is limited evidence that genetic factors play a role in IBS (Camilleri and Katzka, 2012). • On the other hand, there is proof that this syndrome is often driven by psychological factors(Surdea-Blaga et al., 2012), including anxiety and/or depression (Ladabaum et al., 2012). • De facto, IBS treatment is still challenging, with few directed therapies available.

The Burden of IBS • IBS patients experience the same poor Quality of Life(QoL) as other major diseases, such as diabetes, hyptertension, or kidney disease (El-Serag et al., 2002; Gralnek et al., 2000). • IBS represents a burden to the societybecause it is associated to high expenditures and diminished work productivity. • IBS patients have a reduced social functioning, and experience significant QoL impairment. • Every year, IBS accounts for $1.6 billionin direct and for $19.2 billionin indirect costs in the United States (Ladabaum et al., 2012). • In adults, indirect costs are related to both missing work 3-5% of the work week (Spiegel et al., 2008), and impaired work performance and productivity, 26-31% of the work week w.r.t. 6-11% reported by non-IBS patients (Dean et al., 2005). • Agarwal and Spiegel (2011) have estimated the loss to be equivalent to 14 hours of lost productivity per 40-hour work week.

The Prevalence of IBS • The prevalence of IBS is high and it varies between 10% and 20%in the general population in the United States (Bellini et al., 2011). • In the United Kingdom, it is estimated that 2.34 millionsof people are affected by IBS (NICE clinical guideline, 2008). • These figures may be affected by the fact that there is no gold standardcase definition of IBS. • IBS diagnostic criteria have not been standardized over time, and they have a large margin of error in their application.

Diagnostic Challenges • IBD and IBS often present with the same symptoms, making diagnosis very difficult in primary care. • In many countries, in clinical practice the patterns currently adopted to diagnose and manage IBD/IBS are not well described, nor to which extent are IBS patients diagnosed by a general practitioner, or by a gastroenterologist. • For these patients an accurate diagnosis is crucial, as a wrong IBD diagnosis might result in inappropriate or even contraindicated treatment. • In children, a prompt IBD diagnosis is even more important, as the disease might affect growth and sexual maturation (Canani et al., 2006).

Colonoscopy • Endoscopy is still considered the Gold Standardprocedure for detecting and quantifying IBD, but it allows acquiring information limited to the mucosal surface, and it cannot always be complete (Ordás et al., 2012). • Moreover, colonoscopy is expensive, uncomfortableand riskyfor the patients. • Selecting patients for endoscopy based only on symptomsis not a reliable method (Burri et al., 2012): due to the low prevalence of IBD, endoscopy would turn negative in most of the cases with intestinal complaints (Larsson et al., 2004). • Therefore, the correct identification of the IBS cases is pivotal, as for them colonoscopy is unnecessary. => This represents the current diagnostic challenge in this domain.

Serologic and Faecal Biomarkers • Ideally, a test to rule out IBD should be: • non-invasive, • inexpensive, • sensitive, i.e. reliable in detecting intestinal inflammation, • with a good specificity, in order to avoid unnecessary endoscopies. Nowadays, other diagnostic tools than endoscopy are available, to diagnose and stratify patients, and IBS patients could be identified at the General Practitioner level using the appropriate diagnostic tools.

Serologic Markers: CRP and ESR • Serologic biomarkers, such as C-Reaction Protein (CRP) and Erythrocyte Sedimentation Rate (ESR), can be helpful in determinining patient active inflammation. • Therefore, their sensitivity for IBD / IBS is considered as rather low(Dotan, 2010), and often further investigations (including imaging and endoscopy) are required for precise diagnosis. • The thresholds adopted for CRP and ESR are 5,0 mg/L and 10 mm/h respectively (Tibble et al, 2002).

Faecal Markers: F-Calprotectin • Gastrointestinal diseases can also be screened, diagnosed and controlled over time using faecalmarkers. • Because of their direct contact with the intestinal mucosa, faecalmarkers may be more accurate in determining gastrointestinal inflammation. • Overall, faecal markers are considered more accuratethan serologic markers for IBD/IBS precise diagnosis (Abraham and Kane, 2012). • Faecal calprotectin (F-Calprotectin) is a faecal marker of intestinal inflammation. • IBD patients exhibit F-Calprotectin levels significantly higherthan the general population. F-Calprotectin levels do notdiffer significantly in IBS patients from healthy controls (von Roon et al., 2007). =>The F-Calprotectin test can be used as a pre-endoscopic technique to differentiate between IBD and IBS.

Faecal Markers: F-Calprotectin • The physiological values of F-Calprotectin decrease significantly with age. • In adults, the suggested test threshold for the test is 50 µg/g, but a global agreement on this value was not found yet. • Some studies available in the literature discuss the usage of different thresholds, ranging between 30 µg/g and 150 µg/g; the value chosen is often based on their own receiver operating curves(Tibble, 2000; Schroder 2007). • In adults, F-Calprotectin values above 500 µg/g seem to be associated with active IBD (Srinivas et al, 2011). • Some authors recommend the usage of the recommended threshold (50 µg/g) also in children aged from 4 to 17 years (Fagerberg, 2003). • In children, the adoption of a threshold equal to 500 µg/g seems to be useful to distinguish between children at high- and low- risk of symptomatic disease relapse (van Rheenen, 2012).

NHS Health Economics Evaluation (2010) In 2010, the NHS in the United Kingdom has published an economic report (NHS, CEP09041, 2010) showing the valueof F-Calprotectin in diagnosing IBD/IBS in primary careversus the standard practice, i.e. the usage of serologic markers, such as the combined usage of CRP and ESR. York Health Economics Consortium University of York

PICO (part of CEP09041) • Population: • 1000 patients with lower GI symptoms suggestive of IBS enter the model • Patients <45 years • Absence of anaemia, weight loss or rectal bleeding (red flags according to Rome criteria) • Intervention: • Faecal Calprotectin, threshold 50 µg/g • Theoretical evaluation • Comparator: • Serological markers (combinedusage of CRP and ESR) • Outcome: • Number of correctly diagnosed IBD and IBS patients

Input data to the Markov model • The diagnostic accuracy* used in the NHS model are: ► F-Calprotectin: sensitivity = 90%; specificity = 80% (Tibble et al, 2002) ► CRP+ESR:sensitivity = 35%; specificity = 73% (Tibble et al, 2002) • Prevalence data used in the model (from clinical expert opinion): IBD = 10% IBS = 90% • The thresholds adopted for CRP and ESR are 5,0 mg/L and 10 mm/hrespectively (Tibble et al, 2002). The threshold for F-Calprotectin is 50 µg/g. • NHS perspective, no indirect costs. * The sensitivity and specificity of each test determines the percentage of true IBS/IBD positives, false IBS/IBD positives, true IBS/IBD negatives, false IBS/IBD negatives

Input costs to the Markov model

The Markov models

The F-Calprotectin model in detail • Cut-off: 50 µg/g • Patients with results <50 µg/g: suspected to have IBS, follow algorithm as suggested in the negative arm • Patients with results > 250 µg/gare IBD suspected, follow positive arm and will be directly sent to colonoscopy • Patients with results between 50 µg/gand 250 µg/gare retested before being sent to colonoscopy

Results of the NHS model: F-Calpro vs ESR+CRP Tibble et al, 2002 Tibble et al, 2002 Results clearly show that the F-Calprotectin strategy leads to more correct diagnoses, and to fewer unnecessary colonoscopies(63 additional correctly diagnosed IBS cases, and 55 additional correctly diagnosedIBDcases) at a lower price(£13.46 per patient saved).

Conclusions • The benefits of the usage of F-Calprotectin in terms of its potential for screening outmoreIBScases in primary care thanother tests for inflammation havebeen demonstrated • Reductionin the number of unnecessaryreferrals to secondary care for endoscopy • F-Calprotectin has a higher diagnostic accuracythan CRP+ESR for distinguishingIBS from IBD => F-Calprotectin is less costlyand moreeffective in terms of diagnostic accuracy

Mindemark M and Larsson A (2012) The aim of the study was to use cost-minimization analysis to assess the cost-effectiveness of using F-calprotectin tests as a filter to minimize unnecessary diagnostic procedures and set direction for the overall diagnostic approach by ruling out patients that most likely do not have IBD. The purpose was to estimate the short-term cost avoidanceand reduction in demand for colonoscopies.

PICO • Population: • Retrospective study • 3639 patients, 60% children • Samples collected prior to colonoscopy • Patients 0-99 years old • Intervention: • Screening with Faecal Calprotectin, twothresholdsapplied (50 µg/g and 100 µg/g) • Theoretical evaluation on real data • Comparator: • Directreferral for endoscopy • Outcome: • Colonoscopies reduction • Cost avoidance

The Markov model and results

Conclusions • F-Calprotectin is a simple, reliable, non-invasive diagnostic tool • It is a valuable supplementto otherclinical diagnostic procedures • F-Calprotectin couldsubstantiallyreducethe number of invasivemeasurementsnecessary in the diagnostic work-up of patients withsuspectedIBD • 49.8%and 66.9% of the F-Calprotectin tests performed would result below the cut-off value chosen (50 µg/g and 100 µg/grespectively); this means that, respectively, 18 428and 24750colonoscopies per year could be potentially avoided in Sweden with an estimated cost-avoidance equal to 17-23 millions of Euros. • A reduction of expenses and invasive diagnostic procedures in combination with a more rapid management of patientswithsuspectedIBDwould benefit health care budgets as well as patients.

Outline • InflammatoryBowelDiseases • IrritableBowelSyndrome • Diagnostic Challenges • Health Economics Assessments on F-Calprotectin • NHS Health Economics Evaluation (2010) • Mindemark and Larsson (2013) • Our model (2013 version) • Why a model for Japan? • Adaptation ofourmodel to the Japanese scenario • Results • Conclusions

Mascialino et al (2013)

Aim of the study The aim of the present study is double-fold: • to evaluate the cost implicationsrelated to the usage of F-Calprotectin tests compared to the standard pre-endoscopic tests routinely used to distinguish IBD from IBS in the United Kingdom using a refined Markov modelfor F-Calprotectin, and new test sensitivity and specificityvalues; • to derive the HRQoL values for IBD and IBS patients from the published literature, transform these measures in quality-adjusted life years (QALYs) by means of transfer-to-utility techniques, and to use the refined Markov model developed to evaluate the incremental-cost-effectiveness ratio(ICER).

PICO • Population: • 1000 patients with lower GI symptoms suggestive of IBS enter the model • Patients <45 years • Absence of anaemia, weight loss or rectal bleeding (red flags according to Rome criteria) • Intervention: • FaecalCalprotectin (new sensitivity and specificityvaluesevaluatedwith a SLR and meta-analysis) • Theoreticalestimation, refinementbased on real life data • Comparator: • Serological markers (combinedusageof CRP and ESR) • Outcome: • Cost per correctlydiagnosed patient • Cost per QALY (ICER)

Diagnostic meta-analysis(2013) POOLED SENSITIVITY = 96% (95% C.I. 95-98%) POOLED SPECIFICITY = 96% (95% C.I. 94-97%) Update of van Rheenen et al., 2010

A limitation of the NHS model • 16% of patients have a F-Calprotectin test results between 50 µg/gand 250 µg/gfall in the “grey area”, andare usually retested before being sent to colonoscopy • The cost of the second F-Calprotectin test is included in the model BUT the outcome of the test is assumed to be negative in all the cases, and the subjects are not further followed over time => UNDERESTIMATION OF THE COST SAVINGS

Refined Markov modelfor F-Calprotectin (2013) data from 4 640 patients (61% F, 2-95 years old) 42% 58%

Costs input to the model

Cost savings * from CEP09041 Results clearly show that the F-Calprotectin strategy leads to more correct diagnoses, and to fewer unnecessary colonoscopies (207 additional correctly diagnosed IBS cases, and 61additional correctly diagnosedIBDcases) at a lower price (£113.17 per patient saved).

IBD in Asia • Both incidence and prevalence of IBD have been increasing rapidly in Asia over the last two decades, mostly in association with urbanisation. • Knowledge on IBD has not been properly disseminated in a vast area of Asia, and IBD patients still do not receive a timely diagnosis and appropriate treatment. • Health care for IBD patients has not received sufficient attention yet.

Why a model for Japan? • In Japan, IBD’sprevalencewasestimatedas • 24 x 100 000 persons in 1991 (Morita et al., 1995), • nowadaysaccording to the Japanese National Insurance Health Care System it is as high as 152 x 100 000persons, i.e., morethan200 000 IBD patients(Ng et al., 2016). • In Japan: IBS prevalence = 10%-13%(Miwa, 2008) • Canthesechallengesbecome an opportunity? • CanweempowerAsiandoctors to achievemorediagnostic and therapeuticskills for managing IBD?

Outline • InflammatoryBowelDiseases • IrritableBowelSyndrome • Diagnostic Challenges • Health Economics Assessments on F-Calprotectin • NHS Health Economics Evaluation (2010) • Mindemark and Larsson (2013) • Ourmodel (2013 version) • Why a model for Japan? • Adaptation of our model to the Japanese scenario • Results • Conclusions

Aim of the study The aim of the present study is many-fold: • to evaluate the cost implicationsrelated to the usage of F-Calprotectin tests compared to the standard pre-endoscopic tests routinely used to distinguish IBD from IBS in the United Kingdom using a refined Markov modelfor F-Calprotectin, and new test sensitivity and specificityvalues; • to evaluate the costs ascribable to colonoscopy-related complications, and to patient inadequate colon preparation.

PICO • Population: • 1000 patients with lower GI symptoms suggestive of IBS enter the model • Patients <45 years • Absence of anaemia, weight loss or rectal bleeding (red flags according to Rome criteria) • Intervention: • EliACalprotectin 2 • Theoretical estimation, refinementbased on real life data • Comparator: • Serological markers (combinedusage of CRP and ESR) • Directreferral to colonoscopy • Outcome: • Cost per correctlydiagnosed patient • Costofcolonoscopy-relatedcomplications and of patient inadequate colon preparation

Colonoscopy-related Complications and Inadequate Colon Preparation • A recent article has quantifiedcolonoscopy-related complications(EmergencyRoom visits, Hospitalisation and eventualsurgery) in 1.6%of all the colonoscopiesperformed (Ranasinghe et al., 2016). • Inadequate colon preparationoccurs in 23%of the colonoscopies (Kilgore et al., 2011). • In caseofinadequate colon preparation, often a diagnosis is not possible, and in 30.3%of the cases the colonoscopy must be repeated (Hendry et al., 2006).

Refined Markov model for F-Calprotectin (2013) data from 4640 patients (61% F, 2-95 years old)

The NHS CRP+ESR Markov Model (2010)

Barbara Mascialino, Hiroshi Iwamaru, Anagh Vora