DIAGNOSTICS ASSESSMENT PROGRAMME

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1 National Institute for Health and Clinical Excellence DIAGNOSTICS ASSESSMENT PROGRAMME Evidence overview SeHCAT (tauroselcholic [ 75 selenium] acid) for the investigation of diarrhoea due to bile acid malabsorption This overview summarises the key issues for the Diagnostics Advisory Committee s consideration. It includes a brief description of the topic, a description of the analytical structure and model, a discussion of the analytical difficulties, and a brief summary of the results. It is not a complete summary of the diagnostics assessment report, and it is assumed that the reader is familiar with that document. This overview contains sections from the original scope and the diagnostics assessment report, as well as referring to specific sections of these documents. 1 Background 1.1 Introduction SeHCAT was referred by the Medical Technologies Advisory Committee (MTAC) for recommendations on its use for the investigation of diarrhoea caused by bile acid malabsorption. The purpose of the meeting of the Diagnostics Advisory Committee on 4 July 2012 is to formulate provisional recommendations on the clinical and cost effectiveness of using SeHCAT in diagnosing bile acid malabsorption in England. NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 1 of 52

2 1.2 The condition Bile acid malabsorption/diarrhoea The target condition/indication for this assessment is chronic diarrhoea due to bile acid malabsorption. Diarrhoea is defined as the abnormal passage of loose or liquid stools more than 3 times daily and/or a volume of stool greater than 200 g/day. Diarrhoea is considered to be chronic if it persists for more than 4 weeks. Chronic diarrhoea is one of the most common reasons for referral to a gastrointestinal clinic and can account for as many as 1 in 20 referrals. Estimates of the prevalence of chronic diarrhoea in western populations are between 4 and 5%. The cause of chronic diarrhoea in adults is difficult to ascertain and patients may undergo several investigations without a definitive cause being identified. Bile acid malabsorption is one of several causes of chronic diarrhoea (see box 1). Bile acids are synthesised in the liver from cholesterol before being transferred in conjugated form to the bile ducts where they accumulate and are stored in the gall bladder. After a meal the gall bladder contracts and bile acids flow into the intestinal lumen. Most of the bile acids are then reabsorbed by the distal ileum into the portal circulation and returned to the liver. The bile acids are later secreted into the bile again as part of a recycling process called enterohepatic circulation. Although a small proportion of bile acids (3%) are excreted in the faeces, about 97% of bile acids are recycled. In people with bile acid malabsorption, excess bile in the colon stimulates electrolyte and water secretion which results in chronic watery diarrhoea. Bile acid malabsorption causes diarrhoea by one of the following mechanisms: inducing secretion of sodium and water, particularly at a concentration above 3 mmol/litre increasing colonic motility stimulating defecation inducing mucus secretion damaging the mucosa, thereby increasing mucosal permeability. NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 2 of 52

3 Bile acid malabsorption has been divided into 3 types depending on aetiology: type 1: following ileal resection, disease or bypass of the terminal ileum type 2: primary idiopathic malabsorption type 3: associated with cholecystectomy, peptic ulcer surgery, chronic pancreatitis, coeliac disease and diabetes mellitus. Type 2 (idiopathic) bile acid malabsorption, which has no obvious cause, occurs in both men and women, mostly between the ages of 30 and 70 years. There is a history of diarrhoea which can be either continuous or intermittent. Although not life threatening, it can have a significant impact on lifestyle and quality of life because the increased frequency of bowel motions often limits the person s ability to travel or leave the house. Bile acid malabsorption has commonly been regarded as a rare condition and of limited importance in clinical practice. It is often only considered after conditions such as inflammatory bowel disease, colonic cancer, coeliac disease and colonic infections have been excluded. It is also often misdiagnosed as diarrhoea-predominant irritable bowel disease (IBS-D), with some figures showing that 30 50% of people with unexplained diarrhoea may have bile acid malabsorption. The two conditions associated with bile acid malabsorption that have been included in this assessment are IBS-D and Crohn s disease (without ileal resection). NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 3 of 52

4 Box 1 Causes of diarrhoea Colonic Colonic neoplasia Ulcerative and Crohn s colitis Microscopic colitis Small bowel Coeliac disease Crohn s disease Other small bowel enteropathies (for example, Whipple s disease, tropical sprue, amyloid, intestinal lymphangiectasia) Bile acid malabsorption Disaccharidase deficiency Small bowel bacterial overgrowth Mesenteric ischaemia Radiation enteritis Lymphoma Giardiasis (and other chronic infections) Pancreatic Chronic pancreatitis Pancreatic carcinoma Cystic fibrosis Endocrine Hyperthyroidism Diabetes Hypoparathyroidism Addison s disease Hormone secreting tumours (VIPoma, gastrinoma, carcinois) Other Factitious diarrhoea Surgical causes (e.g. small bowel resection, internal fistulae) Drugs Alcohol Autonomic neuropathy Irritable bowel syndrome Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders. It is a chronic, relapsing and often life-long disorder, characterised by abdominal pain/discomfort associated with defecation, a change in bowel habit together with disordered defecation (constipation or diarrhoea, or both) and the sensation of abdominal distension. It can include associated non-colonic symptoms such as dehydration, lack of sleep, anxiety NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 4 of 52

5 and lethargy, with consequences such as time taken off work, avoidance of stressful or social situations and significant reduction in quality of life. IBS most commonly presents for the first time between the ages of 20 and 30 years and is twice as common in women as in men. People with IBS are the largest group of patients seen in a general gastroenterology clinic (1 in 20 referrals). The prevalence of the condition in the general population is estimated at between 10 and 20%. Recent trends indicate that there is also a significant prevalence of IBS in older people; therefore IBS should be considered when an older person presents with unexplained abdominal symptoms. The true prevalence of IBS in the whole population may be higher than estimated, because it is thought that many people with IBS symptoms do not seek medical advice. NHS Direct online data suggest that 75% of people using this service who have IBS symptoms rely on self-care. In England and Wales, the number of people consulting for IBS is extrapolated to between 1.6 and 3.9 million. There are 3 types of IBS namely: IBS with constipation (IBS-C), IBS with diarrhoea (IBS-D) and IBS with alternating constipation and diarrhoea (IBS-A). People with chronic diarrhoea are often given a diagnosis of IBS-D if a definitive cause has not been identified. There is evidence that suggests a high prevalence of bile acid malabsorption (up to one-third) in people with a diagnosis of IBS-D. On this basis, approximately half a million patients in the NHS who are currently treated for IBS-D may actually have bile acid malabsorption for which potential diagnosis and treatment are available. Crohn s disease Crohn s disease and Ulcerative colitis are the two most common forms of inflammatory bowel disease (IBD). Ulcerative colitis is limited to the colon (large intestine). Crohn's disease is a chronic severe condition characterised by inflammation, ulcers and bleeding that may affect any part of the gastrointestinal tract, but mostly commonly the small intestine and/or colon. Both Ulcerative colitis and Crohn s disease directly cause chronic diarrhoea. NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 5 of 52

6 Together these long-term conditions are estimated to affect about 240,000 people in the UK, approximately 400 per 100,000 population. Bile acid malabsorption is associated with Crohn s disease. There are approximately 60,000 people in the UK with this condition. Crohn s disease is sometimes treated by ileal resection. The prevalence of bile acid malabsorption among people with Crohn s disease who have had ileal resection and are in clinical remission is 97%. In people in clinical remission without ileal resection, the prevalence is 54%. Because the prevalence of bile acid malabsorption is high among people with Crohn s disease that have had ileal resection, this group was excluded from this assessment. 1.3 Diagnostic and care pathways In current practice, the main pathway that includes SeHCAT is set out in the British Society of Gastroenterology (BSG) guideline for the investigation of chronic diarrhoea (figure 1). During early scoping, 2 issues arose regarding the BSG pathway. First, all experts agreed that SeHCAT needs to be placed earlier in the pathway so that a firm diagnosis can be obtained at an earlier stage. However, expert opinion varied as to where SeHCAT should be placed in the pathway. Some felt that it should be available to GPs for use in all patients with chronic bowel problems and a tendency to diarrhoea, whereas others felt that it more appropriate for use in secondary care. Second, the BSG guideline does not take into account the prevalence of bile acid malabsorption in people with a diagnosis of IBS-D and places SeHCAT at the end of the diagnostic algorithm (position C in figure 1). Possible alternatives identified at scoping were: SeHCAT as part of the basic investigations for all patients presenting with chronic diarrhoea (position A in figure 1) SeHCAT for all patients presenting with chronic diarrhoea and symptoms suggesting functional disease (that is, age under 45 years and normal basic investigations) (position B1 in figure 1); and also for patients with a NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 6 of 52

7 history of findings suggesting colonic or terminal ileal disease (position B2 in figure 1). Figure 1 British Society of Gastroenterology guideline for the investigation of chronic diarrhoea (Thomas et al. 2003) Including SeHCAT as part of the basic investigations (position A in figure 1) means that all patients presenting with chronic diarrhoea will be tested with SeHCAT. However, during the scoping workshop clinical experts advised that a positive SeHCAT test at this stage does not rule out the possibility of organic disease. Because no subsequent tests for organic disease are made redundant, it was thought unlikely that SeHCAT in position A would be more cost effective than in position B1 and a decision was made for the assessment to focus on position B1. NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 7 of 52

8 The same applies to SeHCAT in position B2. A positive SeHCAT test in position B2 is not likely to stop clinicians from doing subsequent tests such as sigmoidoscopy, barium enema or colonoscopy. Therefore, in the assessment using SeHCAT in position B2 and in position C was considered to have the same effect on the care pathway. This leaves two possible populations for investigation: people presenting with chronic diarrhoea of unknown cause and symptoms suggesting functional disease for whom SeHCAT is considered in position B1 people with Crohn s disease and chronic diarrhoea of uncertain cause (that is, before resection of the terminal ileum) for whom SeHCAT is considered in position C. Treatment After a definitive diagnosis, patients may be treated with bile acid sequestrants which bind with bile acids in the small bowel and prevent the secretory action of bile acids on the colon. There are currently three bile acid sequestrants available: cholestyramine, colestipol and colesevelam. Cholestyramine and colestipol are anion exchange resins that form complexes with bile acids with high affinity. The main disadvantage of cholestyramine and colestipol is an unpleasant taste, which can lead to intolerability and poor adherence. Other side effects include constipation, nausea, borborygmi, flatulence, bloating and abdominal pain. Colesevelam is a new bile acid sequestrant that forms a polymeric gel in the gastrointestinal tract. It binds bile acid with higher affinity than cholestyramine or colestipol. It is available in tablet form which makes it more acceptable than cholestyramine, which is only available in powder form. Colesevalam is significantly more expensive than cholestyramine and colestipol. It is also not licensed to treat bile acid malabsorption. NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 8 of 52

9 The response to bile acid sequestrants varies among people with diarrhoea due to bile acid malabsorption. For people with Crohn s disease and ileal resection, the response to bile acid sequestrants was 60%; with a response of 40% in those with Crohn s disease without ileal resection and 70% in those with a diagnosis of IBS-D. NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 9 of 52

10 2 The technology SeHCAT (GE Healthcare) is a radiopharmaceutical that is licensed for use in measuring bile acid pool loss and investigating bile acid malabsorption. It may also be used to assess ileal function, to investigate inflammatory bowel disease and chronic diarrhoea and to study the enterohepatic circulation. SeHCAT consists of a capsule containing a synthetic analogue of the natural conjugated bile acid tauroselcholic acid and 75 Se (a gamma-emitter). The radionuclide tracer atom allows SeHCAT to be easily detected in a whole body scan using a standard gamma camera. The technology is used to test the function of the bowel by measuring how well the compound is retained or lost from the body into the faeces. It is claimed that SeHCAT is the only test available to diagnose bile acid malabsorption. The test involves two scans 1 week apart, and these are carried out as outpatient appointments. During the first appointment, SeHCAT is administered orally and, once localised in the body (after approximately 1 3 hours), the radionuclide tracer atom is detected in a whole-body baseline scan using a standard gamma camera. This gives an initial count, which is used to provide a zero-time or 100% value. During the second appointment, the patient is scanned to produce a second count and the retained activity is expressed as a percentage of the original value. Retention values of less than 15% have been considered abnormal and indicative of bile acid malabsorption. However, there is no definitive cut-off between normal and abnormal. In this assessment, 3 cut-off points were evaluated, 5%, 10% and 15%. Although the models used by the External Assessment Group assume no treatment differences based on SeHCAT results, the 5, 10 and 15% have also been used by clinicians to grade the severity of the bile acid malabsorption as follows: i) retention value of 10 15% (mild bile acid malabsorption) NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 10 of 52

11 ii) iii) retention value of 5 10% (moderate bile acid malabsorption) retention value of 0 5% (severe bile acid malabsorption). Appendix B contains the summary of product characteristics of SeHCAT. 2.1 Comparators There is no direct comparator for this diagnostic test. Current diagnostic options include analysis of a patient s history, investigations to exclude red flag symptoms and a variety of other diagnostic tests such as blood tests and lactose tolerance tests. Trial of treatment is used, with mixed results, to diagnose bile acid malabsorption. However, it is not widely used in current practice. The main comparator for the assessment will be tests and clinical observations contained in the BSG guidelines for the investigation of chronic diarrhoea. 2.2 Trial of treatment In the absence of diagnostic tests, a therapeutic trial of bile acid sequestrants is sometimes employed to diagnose bile acid malabsorption. The value of this approach has not been studied. A trial of treatment with bile acid sequestrants lacks diagnostic accuracy because the optimal dose is not predictable and false negative rates of 25% have been reported. Discussions at the scoping workshop and the assessment subgroup meeting affirmed that trial of treatment is not a routine diagnostic technique in the NHS and that bile acid sequestrants are not always tolerated by patients. Moreover, most clinicians were of the opinion that the result of a SeHCAT test is essential for titrating the dose of bile acid sequestrants. NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 11 of 52

12 3 The evidence 3.1 Evidence Assessment Group model A de novo model was constructed by the External Assessment Group to assess the clinical and cost effectiveness of SeHCAT in people presenting with symptoms suggesting functional disease (IBS-D) and people with Crohn s disease without ileal resection. A systematic literature review was undertaken to obtain parameters for the model. Below is a description of the model, the systematic review, the parameters and the analyses undertaken Modelling approach This model consists of 2 parts: a decision model reflecting the diagnostic and initial treatment phase and a Markov model to estimate long-term costs and effects. This model was used for both the IBS-D and Crohn s populations albeit with different parameter values. Two types of analysis were performed. In the first, labelled the short-term model in the diagnostics assessment report, the model only compares the number of treatment responders to IBS-D treatment and to bile acid sequestrant treatment. This analysis was done as there was some data available to inform the short-term, but no data for the long term extrapolation. This analysis is helpful if dominance is shown, but does not provide an estimate of overall cost effectiveness. The second analysis, called the long-term model in the diagnostics assessment report, creates true cost effectiveness ratios and incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves (CEAC) Model structure Decision tree component of the model The decision tree component of the model (labelled short term in the diagnostics assessment report) uses response to treatment, dependent on test outcome, to compare 2 no-sehcat strategies with 3 SeHCAT strategies in the IBS-D population. The 3 SeHCAT strategies were percentage reabsorption at cut-off points of less than 5%, less than 10% and less than NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 12 of 52

13 15%. The two strategies that excluded the use of SeHCAT were no SeHCAT (meaning everybody was treated for IBS-D) and trial of treatment. In the Crohn s population, the outline of the truncated model (decision tree component only) is in effect the same as that for the IBS-D model with 2 exceptions. First, if no-sehcat is used, if the test is negative, or if there is no response to trial of treatment, patients are treated for Crohn s disease (controlling the non bile acid malabsorption diarrhoea) instead of IBS-D. Second, the truncated model (for the Crohn s population) did not include the SeHCAT strategy at less than 5% because no data on the probability of a positive test result were available for this cut-off point. Figures 2 and 3 below show the structure of the decision tree for the IBS-D and Crohn s population. NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 13 of 52

14 Figure 2: Diagnostic and initial treatment model: IBS-D NICE Diagnostic Assessment Programme: overview SeHCAT (Tauroselcholic [75 Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption. Page 14 of 52

15 Figure 3: Diagnostic and initial treatment model: Crohn s Selenium} Acid) for the investigation of diarrhoea due to bile acid malabsorption.

16 3.1.3 Markov component of the model The Markov component of the model allowed for the assessment of the costs and effects of the various strategies throughout the patient s life span. Patients who responded to treatment enter the Markov model in the no diarrhoea state and patients who did not respond enter in the diarrhoea state. Because the model is a lifetime horizon, the third state is death. Patients can move between the no diarrhoea state and the diarrhoea state from 1 cycle to another, stay the same or die. The cycle length used is 6 months. The general Markov component of the model is parameterised according to treatment, yielding multiple models based on the same structure. This means in the IBS-D population, patients who received bile acid sequestrants enter the bile acid sequestrant Markov model and those who received IBS-D treatment enter the IBS-D Markov model. Likewise, in the Crohn s population, patients who received bile acid sequestrants enter the bile acid sequestrant Markov model and those who received treatment for Crohn s with chronic diarrhoea enter the Crohn s Markov model. Each Markov model consists of 6 transition probabilities. These are from diarrhoea to no diarrhoea from no diarrhoea to diarrhoea, from diarrhoea to death, from no diarrhoea to death and to stay in diarrhoea or to stay in no diarrhoea.

17 3.1.4 Comparator The scope clearly defined a no-sehcat strategy as the comparator. The External Assessment Group did not exclude trial of treatment as an option and presented 2 sets of results: 1 with trial of treatment as a comparator and 1 without trial of treatment Systematic review for parameter values The External Assessment Group undertook a systematic review of the evidence to identify the parameters for inclusion in the model. Full details of the systematic review can be found in chapter 4 of the diagnostics assessment report. Based on the searches undertaken by the External Assessment Group, 24 publications of 21 studies met the inclusion criteria and were included in the review. Twenty of the studies provided data either on the accuracy of SeHCAT in predicting treatment response (where treatment response is the reference standard), or on treatment effect in SeHCAT-positive and negative groups. Out of the 20 SeHCAT studies, 19 included people with chronic diarrhoea with unknown cause and 2 studies included people with Crohn s disease and chronic diarrhoea. The remaining study was a randomised controlled trial that compared treatment with the bile acid sequestrant colesevelam with placebo for patients with IBS-D. The results of the systematic review are summarised below. Accuracy of SeHCAT for detecting bile acid malabsorption None of the studies evaluated in the diagnostic assessment report was included in the review as diagnostic test accuracy studies, because they either did not use an acceptable reference standard or they included a population not in line with the scope (that is, they included healthy volunteers or people with ileal resection). Therefore the assessment focused on the value of SeHCAT in predicting the response to treatment with bile acid sequestrants.

18 Accuracy of SeHCAT for assessing response to treatment in people with chronic diarrhoea Of the 20 studies with information on the relationship between SeHCAT and response to bile acid sequestrant treatment, 19 were in people with chronic diarrhoea. These studies were divided based on the reliability of their results. Fifteen studies did not provide, or had very limited information about respondents with a negative SeHCAT test and were considered to have a flawed design for the purpose of the review. They were considered not to be reliable enough to assess the relationship between SeHCAT and response to treatment. Four studies had data for all respondents with a negative SeHCAT test. However, in 2 of these studies (Fellous et al, and Merrick et al, 1985), it was unclear why certain patients were treated and others not. The study by Fellous et al. was not included because it had substantially more people who did not receive treatment. This leaves 3 studies for assessing the relationship between the SeHCAT test and treatment with cholestyramine: Merrick et al (1985). estimated the sensitivity of SeHCAT in predicting a positive response as (95% confidence interval [CI] to 0.957) and the specificity as (95% CI to 0.999) using a cut-off of 8% for the test. Using a cut-off of 15%, the sensitivity was (95% CI to 1.000) and the specificity (95% CI to 0.981). Sciaretta et al. (1986) estimated the sensitivity of SeHCAT in predicting a positive response as (95% CI to 0.996) and the specificity as (95% CI to 1.000) using a cut-off of 5% for the test. However, only 13 patients were included in this analysis. Sciaretta et al. (1987) estimated the sensitivity of SeHCAT in predicting a positive response as (95% CI to 0.999), and the specificity as (95% CI to 0.999) using a cut-off of 8% for the test.

19 Accuracy of SeHCAT for assessing response to treatment in people with Crohn s disease Only 2 studies looked at this population. Neither presented data for people with a negative SeHCAT test. Moreover, neither study explained why certain people received treatment and others did not. Effectiveness of bile acid sequestrants for the treatment of people with chronic diarrhoea One controlled clinical trial compared colesevelam (a bile acid sequestrant) with placebo for people with IBS-D. No controlled trials that assessed the effectiveness of bile acid sequestrants in terms of bowel function in patients with chronic diarrhoea of unknown cause were identified. In addition to the randomised controlled trial, data on the effectiveness of bile acid sequestrants for the treatment of bile acid malabsorption were also obtained from the 19 studies described above. All the 19 studies provided data on the effectiveness of bile acid sequestrants given a positive SeHCAT test. Only 3 of the studies provided data on the effectiveness of bile acid sequestrants given a negative SeHCAT test (see tables 9 and 10 on pages of the diagnostic assessment report). A narrative synthesis was used because formal meta-analysis was considered inappropriate because of the small number of studies with varying diagnostic thresholds and between study heterogeneity in other study design categories. Nevertheless, it was deemed necessary for the economic model to calculate average response rates given a positive tests at different cut-offs. Therefore, the External Assessment Group presented the best available evidence, but this is still highly uncertain given the heterogeneity between studies. Table 11 on page 70 of the diagnostic assessment report shows the average response rates given a positive and negative SeHCAT test at all different cutoffs using all available data for patients with chronic diarrhoea of unknown cause. Data were grouped in cut-off thresholds of 5%, 10% and 15% (table 12, page 7 of the diagnostic assessment report).

20 Effectiveness of bile acid sequestrants for the treatment of people with Chron s disease Two studies looked at this population although neither presented data for people with a negative SeHCAT test. In addition, it was not clear why certain people were treated and others were not. From both studies, those with a positive SeHCAT test had a response rate of 95% at a cut-off of 5% and 87% at a cut-off of 10% (table 15, page73 of the diagnostic assessment report) Systematic review of cost-effectiveness evidence Searches were undertaken to identify studies of cost effectiveness of SeHCAT in the diagnosis of bile acid malabsorption and the use of bile acid sequestrants. Three health economic models for IBS were identified. The first assessed the cost effectiveness of endoscopy in IBS only in the diagnostic phase and did not consider the long-term costs and effects. No relevant information could be extracted from this paper. The second model investigated the cost effectiveness of screening for coeliac disease in people with symptoms of IBS and consisted of a diagnostic part until final diagnosis and a long-term part in which life expectancy of patients is multiplied with overall annual costs for IBS treatment and with a utility value. A utility of was applied to IBS patients in this paper. This value is slightly lower than the value of derived for the SeHCAT model. The models were not considered useable by the External Assessment Group for this evaluation and the de novo model was constructed Additional model parameters Probabilities The decision tree was populated with probabilities that were obtained from the systematic review as well as expert opinion. These probabilities are: Probability of a positive SeHCAT test: For the IBS-D population, this was estimated from the studies listed in tables 9 and 10 on pages of the diagnostics assessment report. Based on the data retrieved, a random effects meta-analysis was performed to find a pooled estimate for each of

21 the three cut-off values (see tables on pages of the diagnostics assessment report). Only 2 studies included in the review reported results specifically for patients with Crohn s disease without ileal resection. There were no studies identified with a SeHCAT 5% cut-off in this population thus pool estimates were derived only for SeHCAT 10% and 15% cut-offs (see tables on page 95 of the diagnostics assessment report). Probability of response to bile acid sequestrants: Patients with a positive SeHCAT test result are considered to have bile acid malabsorption which is treated with cholestyramine. The response rate to bile acid malabsorption differs between the various cut-off points. This is due to the fact that the severity of bile acid malabsorption increases as the cut-off value is lowered. The studies listed in tables 9 and 10 on pages of the diagnostic assessment report were again used to estimate the response rate to bile acid sequestrants using random effects meta-analysis (see tables on pages of the diagnostic assessment report). For the Crohn s population, there were no data available on the response in patients with a positive SeHCAT test. The External Assessment Group therefore assumed that the response rate would be the same as in people with idiopathic bile acid malabsorption (see tables 21 and 22 on pages 85 6 of the diagnostics assessment report). Probability of a positive response to treatment (IBS-D or Crohn s diarrhoea) in patients with no SeHCAT test: IBS-D treatment varies greatly and may be in the form of a variety of drugs, dietary advice and psychological treatment. Because of this variation, the External Assessment Group was unable to obtain rates of response to treatment for IBS-D from the literature. A questionnaire (appendix 9 of the diagnostics assessment report) was sent to approximately thirty two specialists asking what percentage of patients would eventually be successfully treated with the usual IBS-D treatment options, and the plausible range for this percentage.

22 Seven specialists responded and the results are presented in table 23 of the diagnostics assessment report. For the no-sehcat population, a pooled mean of 52% response to IBS-D treatment was calculated. In the strategies in which a SeHCAT test was performed, only those with a negative SeHCAT test received IBS-D treatment. This implies that most patients who actually have bile acid malabsorption are no longer part of the group receiving IBS-D treatment. The External Assessment Group assumed that the response rate to IBS-D treatment in the SeHCATnegative population may therefore be higher than in the no SeHCAT population. In the base-case analysis, a subjective assumption was made that at a cut-off point of 15%, 10% and 5%, the response rate to IBS-D treatment in the SeHCAT-negative population is higher by 10%, 8% and 5% respectively. In the trial of treatment strategy, it was assumed that the response rate to IBS-D treatment is the same as in the SeHCAT 15% strategy. Because these estimates are subjective, the impact on the outcomes was explored through scenario analyses. For the Crohn s population, the equivalent probability is that of response to diarrhoea treatment. There were no data from the literature as to how many people with Crohn s without ileal resection will respond to such treatment. The External Assessment Group asked clinical experts which percentage of patients would be eventually treated. The responses are presented in table 30 on page 96 of the diagnostic assessment report. For the Crohn s population, a pooled mean of 62% response to treatment was calculated. The External Assessment Group assumed that response to diarrhoea treatment may be higher in SeHCAT-negative Crohn s patients than in the no-sehcat population. No data were available to justify this assumption.

23 The External Assessment Group made the same assumption as they did in the IBS-D population, that is, 10% point higher than in the no-sehcat population for a cut-off of 15% and 8% higher for a cut-off of 10%. Again, because of the subjective nature of this estimate, the impact on the outcomes was explored through scenario analyses. Probability of response for bile acid sequestrants given as trial of treatment to all patients: The External Assessment Group assumed that, for both IBS- D and Crohn s populations, the 28% of people who responded to bile acid sequestrants in the SeHCAT strategy is the percentage that would be found when giving all patients a trial of bile acid sequestrants. Probability of death: The External Assessment Group assumed that there is no excess mortality associated with IBS-D and bile acid malabsorption and concluded that the overall mortality in the UK population is relevant. These were derived from England and Wales Interim Life Tables to In addition, the average age and gender distribution in the model cohort was assumed to be 47 years and a ratio of male to female of For the Crohn s population, no reports were found that suggest the chronic diarrhoea leads to excess mortality. People with Crohn s disease however, have a shorter life expectancy compared with the general population. A meta analysis by Canavan et al () showed a pooled estimate of the standardized mortality ratio (SMR) of 1.52 (Confidence interval: 1.32 to 1.74) which was applied to the overall majority in the UK population, for which the England and Wales Interim Life Tables to was used. The average age and gender distribution in the model cohort was assumed to be 39 years and a ratio of male to female of Probability of transition from diarrhoea to no diarrhoea (and vice versa): for people receiving bile acid sequestrants and also for those receiving IBS-D treatment, the transition probabilities from diarrhoea to no diarrhoea and vice versa were impossible to quantify. A range of plausible scenarios with

24 various values, were used to show the impact of the assumptions on outcomes. The first of these cases was treated as a base case even though there is no reason to believe it is more plausible than the others. Quality of life For the IBS-D population, the following utilities were estimated: For the health state diarrhoea, utility was For the health state no diarrhoea (IBS_D), utility was For the health state no diarrhoea (BAM), utility was For the Crohn s population, the following utilities were estimated: For the health state diarrhoea, utility was For the health state no diarrhoea (IBS_D), utility was For the health state no diarrhoea (bile acid malabsorption), utility was 0.74.

25 Costs Table 1 Costs used in the model Description Mean value ( ) Cost per day of IBS-D medication 0.17 Diet costs per 6 months associated with IBS-D Psychological costs per 6 months associated with IBS-D Cost per day of BAS medication (IBS-D model) 0.63 Cost SeHCAT capsule 195 Cost for administering SeHCAT test 186 Maintenance and service costs of SeHCAT test 0 Cost per day associated with health state diarrhoea 0.06 IBS-D medication cost per day associated with health state no diarrhoea BAS cost per day associated with health state no diarrhoea (IBS-D model) Cost per day of Crohn s medication 1.78 Cost per day of BAS medication (Crohn s model) 0.63 Crohn s medication cost per day associated to health state no diarrhoea BAS cost per day associated to health state No diarrhoea (Crohn s model) BAS=bile acid sequestrant Results of clinical and cost-effectiveness analysis Results of analysis for IBS-D For the IBS-D population, results are given for both the truncated model (called short-term in the diagnostics assessment report) and the complete model (called long-term in the diagnostics assessment report). The results are presented first without trial of treatment as a comparator and then with trial of treatment as a comparator. The truncated model only looks at costs and the number of responders whereas the full model provides results in terms of overall costs and quality-adjusted life years (QALYs). The full model provides full cost-effectiveness ratios, whereas the truncated model can provide information about cost per responder which allows dominance to be detected.

26 Truncated model results IBS-D (decision tree) In the truncated model, ICERs were estimated as cost per additional responder to treatment in the short term (6 months). NICE methods permit this because if one strategy dominates at this stage, it is entirely likely that it will remain dominant if the outcomes used are QALYs. As mentioned previously, various assumptions regarding probabilities had to be made when neither literature nor expert opinion were available. In addition there was uncertainty about the costs of IBS-D treatment and to a lesser extent the exact costs of SeHCAT testing. To offset these uncertainties, the EAG formulated several scenarios which have been reproduced in table 2. Table 2 Overview of scenarios explored for short term IBS-D Scenario SeHCAT service cost Prob. Response to IBS-D treatment in SeHCAT negative patients IBS_D treatment costs SeHCAT capsule cost A No A Yes A Yes A No A Yes A multiply by Yes A divide by Yes A divide by No A No A Yes A Yes 1 Cost multiplied by 2 from base level 2 Cost divided by 2 from base level Dominated Table 34 in the diagnostics assessment report represents the probabilistic outcomes of the base-case decision tree for the IBS-D population (scenario A1 in table 2). It is clear that based on the assumptions in scenario A1, the

27 SeHCAT 15% strategy dominates the other two SeHCAT strategies. Also SeHCAT 15% is more expensive than no SeHCAT test- treat as IBS-D but it generates more responders (ICER of 2378 per additional responder). In scenario A2 and A3, the service costs of SeHCAT were increased by 55 and 105 respectively. This did not impact on the results of the base case. In scenario A4, the probability of response rate to IBS-D treatment in SeHCAT-negative patients was reduced to The results showed that number of responders in the SeHCAT strategy decrease (compared with the base case) and that the SeHCAT 10% strategy dominates the other SeHCAT strategies. When the cost of IBS-D treatment is reduced by 50% from the base case (scenario A8) SeHCAT 10% remains dominant (table 37 of the diagnostics assessment report). This shows that the impact of treatment costs for IBS-D in the short term is limited. In scenario A9, the cost of SeHCAT was reduced to 100. The results show that SeHCAT 15% strategy now dominates the other SeHCAT strategies, albeit with minimal overall impact (table 38 of the diagnostics assessment report). The CEAC for scenario A9 (figure 13) is similar to that of the base case (figure 10) indicating that the impact of lowering the cost of SeHCAT is minimal on short-term results Lifetime results IBS-D (Markov model) For the full model results, ICERs were estimated as cost per additional QALY in the long term (lifetime). No information was available to estimate the transition probabilities in the Markov models other than the all-cause mortality rates. Thus, various scenarios with different transition probabilities no diarrhoea to diarrhoea (for bile acid malabsorption), diarrhoea to no diarrhoea (for bile acid malabsorption),, no diarrhoea to diarrhoea (for IBS-D) and diarrhoea to no diarrhoea (for IBS-D) were formulated. There were two additional scenarios regarding the utility in the no diarrhoea health state; this is either the utilities of BAS and IBS-D are the same or utility of BAS responders is lower than for IBS-D responders. Table 39 of the diagnostics assessment report provides an

28 overview of all scenarios explored. Because many yielded the same results, only a selection of the scenarios were presented, as indicated in table 3. Table 3 Overview of IBS-D scenarios explored for the long term analysis, no ToT Scenario IBS-D P( IBS-D BAM BAM utility BAS no diarrhoea BAS<IBS Yes BAS<IBS Yes BAS<IBS Yes BAS<IBS Yes Results presented BAS<IBS No, same as BAS<IBS No, same as BAS<IBS No, same as BAS=IBS Yes BAS=IBS No, same as BAS=IBS No, same as BAS=IBS No, same as BAS=IBS Yes BAS=IBS No, sme as BAS=IBS No, same as 7 Scenario 1 assumes that the all 4 transition probabilities are 5% per cycle and the utility of BAS responders is lower than that of IBS-D responders. The results show that all 3 SeHCAT strategies were dominated by the no SeHCAT strategy (table 40 of the diagnostics assessment report). The cost effectiveness acceptability curve (figure 14) shows that no SeHCAT has the highest probability of being cost effective. Scenario 2 assumes that all 4 transition probabilities are 0% per cycle and the utility of BAS responders is lower than that of IBS-D responders. The results (table 41 of the diagnostic assessment report) show that the ICER

29 of SeHCAT 5% compared with no SeHCAT is The ICER for SeHCAT 15% versus SeHCAT 5% is 31,031. The CEAC (Ffigure 16) shows that for small thresholds, the no SeHCAT strategy has the highest probability of being cost effective whereas for higher thresholds (around 10,000) SeHCAT 5% has the highest probability of being cost effective. Scenario 3 assumed that the transition probabilities from no diarrhoea to diarrhoea for both IBS-D and BAM are 5% and 0% for diarrhoea to no diarrhoea. The utility of BAS responders is assumed to be lower than that of IBS-D responders. Table 42 of the diagnostic assessment report shows that for this scenario SeHCAT 5% has a favourable ICER compared with no SeHCAT, and the ICER for SeHCAT 15% compared with SeHCAT 5% may also be considered acceptable given a threshold of 30,000. The CEAC Figure 17 of the diagnostic assessment report) shows that for lower threshold values (< 20,000) no SeHCAT has the highest probability of being cost effective whereas for higher threshold values (> 30,000), all 3 SeHCAT strategies have a higher probability of being cost effective than no SeHCAT. Scenario 4 assumes that the transition probability from no diarrhoea to diarrhoea in the IBS model is 5% per cycle with all others being 0. It also assumes that the utility of BAS responders is lower than that of IBS-D responders. The results (table 43 of the diagnostics assessment report) show that SeHCAT 15% compared to no SeHCAT yields an ICER of 4782 whereas the other 2 SeHCAT strategies are extendedly dominated by SeHCAT 15%. The CEAC ( figure 19 of the diagnostic assessment report,) shows that for low thresholds the no SeHCAT strategy has the highest probability of being cost effective whereas for higher thresholds (around 5000) SeHCAT 15% has the highest probability of being cost-effective. Scenario 8 is the same as scenario 1, and assumes that the all 4 transition probabilities are 5% per cycle. The difference is that here the utilities for IBS-D and BAM the same. The results (table 44 of the diagnostics assessment report) show that SeHCAT 5% has an ICER of 20,976 compared with no SeHCAT, and the ICER for SeHCAT 15% compared with

30 SeHCAT 5% is 24,265. The CEAC (figure 20) shows that for lower threshold values no SeHCAT has the highest probability of being costeffectivewhereas at a threshold between 20,000 and 30,000, the 3 SeHCAT strategies have approximately the same probability of being costeffective. Scenario 12 is the same as scenario 5, and assumes that the transition probability from diarrhoea to no diarrhoea in the IBS model is 5% per cycle whereas all others are 0, but with utilities for IBS-D and BAM the same. Because of the higher utility for BAM responders, SeHCAT 5% now has an ICER of 25,567 per QALY gained compared with no SeHCAT. The CEAC (figure 22) shows that for lower threshold values no SeHCAT has the highest probability of being cost-effective whereas at a threshold between 20,000 and 30,000, SeHCAT 5% has the highest probability of being cost-effective Truncated model results (decision tree) IBS-D with trial of treatment The probabilistic outcomes of the base-case decision tree for the IBS-D population when trial of treatment is also considered as comparator are presented in table 46 of the diagnostics assessment report. Results are presented in order of increasing number of responders and show that the trial of treatment strategy dominates all other strategies: it leads to the highest number of responders for the lowest costs. Of the 3 SeHCAT scenarios the 15% cut-off dominates the other two cut-offs. The CEAC (figure 23) shows that the trial of treatment strategy has the highest probability of being cost effective over the whole range of possible threshold ICERs. In addition, various scenarios regarding transition probabilities, cost of IBS-D treatment and total costs of SeHCAT were formulated in order to compensate for the lack of data in the literature (table 47 of the diagnostics assessment report). None of these scenarios led to results different from the base case, in which trial of treatment is the dominant strategy. For all scenarios trial of treatment had the highest probability of being cost effective; this probability

31 was for most scenarios around 90% but decreased to 50% for some scenarios Lifetime results IBS-D with trial of treatment The same 14 scenarios for transition probabilities and the utility of the no diarrhoea health state used in the Markov model without trial of treatment were used here (table 48 of the diagnostics assessment report). Because the results of some of the scenarios are similar, only results of 5 of the scenarios are presented. Scenario 1 assumes that all four transition probabilities are 5% per cycle. All SeHCAT strategies and trial of treatment are dominated by no SeHCAT (table 49). The CEAC (figure 24), shows that no SeHCAT has the highest probability of being cost effective for the whole range of thresholds. Scenario 2 assumes that all four transition probabilities are 0% per cycle, meaning that all patients remain in the same state. The ICER for trial of treatment compared with no SeHCAT is 5064, whereas all SeHCAT strategies are dominated by trial of treatment. The CEAC (figure 27) shows that for low thresholds the no SeHCAT has the highest probability of being cost effective whereas for higher thresholds (around 5000) trial of treatment has the highest probability of being cost effective. Scenario 7 assumes that the transition probability for diarrhoea to no diarrhoea in the BAM model is 5% per cycle whereas all others are 0. Trial of treatment compared with no SeHCAT has an ICER of 5060 the ICER is 13,295 when SeHCAT 15% is compared with trial of treatment. The CEAC (figure 27), shows that that for low thresholds the no SeHCAT strategy has the highest probability of being cost effective; for thresholds between 5000 and 15,000 trial of treatment has the highest probability for being costeffective and for thresholds higher than 15,000 SeHCAT 15% has the highest probability of being cost effective. Scenario 8 is the same as scenario 1, but with utilities for IBS-D and BAM the same. Trial of treatment has an ICER of 10,344 compared with no SeHCAT, whereas all the SeHCAT strategies are dominated by trial of