Consultee Section no. Comment Response

Transcription

1 Consultee Response 1. Consultee 1 NHS Professional 2. Consultee 2 Representative of the British Nuclear Medicine Society 1 on 1: Provisional recommendations 1 on 1: Provisional recommendations This should be stronger in confirming the CLINICAL effectiveness of SeHCAT in diagnosing bile acid malabsorption (BAM) in patients with chronic diarrhoea (otherwise diagnosed as IBS-D). Please note the aim is to determine both clinical and cost effectiveness. The data on cost effectiveness is lacking, not clinical effectiveness. We are very concerned at these recommendations. There are very few clinicians who are experts with experience of using SeHCAT. Most of these have been excluded from the assessment process because they acted together about 5 years ago to persuade GE healthcare to save SeHCAT and so have obtained honoraria from the company which excluded them from the NICE process. This is a major flaw in the entire process. In a situation where there is very little / no level A (randomised controlled trial) or level B (outcomes research) evidence to define optimal management of these patients then level C (case series) and level D (expert The Committee felt that there is insufficient evidence to ascertain the clinical effectiveness of SeHCAT for the diagnosis of bile acid malabsorption. The diagnostic assessment programme adheres to NICE s code of practice for declaring and dealing with conflicts of interest. Those clinicians that are excluded from being Specialist Committee Members can still participate in the evaluation by registering as stakeholders. In addition, the external assessment group can approach any clinican for their expert opinion. NICE does look at lower evidence 1

2 Consultee Response 3. Consultee 3 Pharmaceutical industry 1 on 1: Provisional recommendations opinion, physiological and laboratory studies) data are entirely valid sources of evidence. All level D (expert evidence) has been excluded, but as this is central to the decision making process in this scenario. We would suggest that NICE should invite some of the excluded expert clinicians to present their evidence. There is a risk that NICE reaches a false conclusion as a result of not appreciating the issues clearly because they have failed to listen to expert clinical evidence, because of the percieved conflict of interest. 1.1 : SeHCAT is a potentially clinically important test for diagnosing BAM??. GE :We would suggest that the Committee consider changing the wording of this statement to SeHCAT is a clinically important test. There is currently no other readily accessible test for the diagnosis of BAM and while the evidence to fully determine clinical and cost-effectiveness still has some gaps we feel there is sufficient evidence to confirm the clinical importance of this test for diagnosis of BAM. levels when necessary but does not afford them the same weight. The existence of lower levels of evidence supporting the use of a technology may not reduce the uncertainty sufficiently for the Committee to accept that the technology is clinically and cost effective. The Committee recognised the potential importance of SeHCAT as a diagnostic test. However, the Committee felt that additional evidence is needed to demonstrate this. 2

3 Consultee Response 4. Consultee 2 Representative of the British Nuclear Medicine Society 2 on 2: The technology There has been a large increase in the use of SeHCAT scanning recently, as determined by a survey of UK clinical practice carried out by the British Nuclear Medicine Society (BNMS) and presented at the BNMS annual meeting by Smith and Perkins in May This is a direct result of clinical appreciation of the benefit arising from the use of the investigation. This survey also highlighted the need for standardisation of the test. The Committee acknowledged the fact that there has been an increase in SeHCAT usage in the past few years. This has been mentioned in the DCD. Unpublished data / audits of SeHCAT usage in expert hands suggest that it diagnoses bile acid malabsorption in 40-60% of patients tested, many of whom have had their symptoms for many years, seen many clinicians and had multiple often repeated investigations particularly expensive endoscopies (not including a previous SeHCAT). SeHCAT almost certainly should be a test available to primary care physicians which would save vast amounts of unnecessary referrals to secondary care. Instead this NICE assessment has focused on secondary and tertiary care settings. At the scoping phase, it emerged that a positive SeHCAT test would not preclude additional tests. For this reason, the decision was made that this assessment should focus on the use of SeHCAT in secondary care. Expert clinical opinion suggests that this is 3

4 Consultee Response because it is such a simple diagnostic test which really changes management. 5. Consultee 1 NHS Professional 3 on 3: Clinical need and practice In 3.2 (or in 3.5) a definition of bile acidinduced diarrhoea (malabsorption) should use the gold standard of excessive faecal bile acids. Some mention in 3.5 should be made of secondary BAs and different potencies in stimulating diarrhoea. These mechanisms in 3.5 can be cumulative and not "by 1 of the following...". Thank you for your comments. Ammendments have been made to these sections. 3.7 Probably better to use " Type 2, primary or idiopathic, bile acid malabsorption..." Age range is larger and is not needed. 3.9 In populations not considered, radiationinduced bowel damage and UC do not have a "very high" likelihood of BAM. Otherwise this sentence is OK Please comment that BSG Guidance is from 2003 and is being updated The approved UK spelling in "colesevelam". 4

5 Consultee Response 6. Consultee 2 Representative of the British Nuclear Medicine Society 3 on 3: Clinical need and practice While the focus on IBS is important (data suggest 500,000 patients in the UK who actually have BAM are misdiagnosed as having BAM) and BAM is clearly missed often in Crohns. Why has the committee ignored the literature on other large groups of patients eg those after upper GI resectional surgery, post cholecystectomy diarrhoea, during pelvic radiotherapy, after pelvic radiotherapy, post right hemicolectomy diarrhoea, after pancreatitis, after vagotomy, diabetics, those with microscopic colitis etc. At the very least, this report should acknowledge that these groups are large and this exercise perhaps made a mistake in excluding these other populations. During and after pelvic radiotherapy, in particular, there are excellence incidence and prevalence data in many published studies. Most of these groups constitute much bigger populations than those with Crohns. So why, the focus on Crohns? Thank you for your comments. These groups were not included in the evaluation because of the very high likelihood of bile acid malabsorption in these patients leading to a reduced need for testing prior to treatment.the guidance relates only to people with chronic diarrhoea considered likely to have IBS-D and people with chronic diarrhoea who have been diagnosed with Crohn s disease and have not had an ileal resection. 7. Consultee 3 Pharmaceutical industry 3 on 3: Clinical need and practice 3.15: In current practice, the main pathway that includes SeHCAT is set out in the British Society of Gastroenterology (BSG) guidelines for the investigation of chronic diarrhoea. GE comment:it has been recognised that the current 2003 BSG guidelines are out of date Thank you for your comments. This section has been amended. 5

6 Consultee Response and are being updated. It may be relevant to note this within the document to guide people to look for the new guidelines when available to support their own decision making. 8. Consultee 1 NHS Professional 4 on 4: The diagnostic test 3.18: An important disadvantage of colestyramine and colestipol is an unpleasant taste, which can lead to poor tolerance of and adherence to treatment. GE :While published literature does note possible compliance issues with these drugs, we also heard from the IBS Network representative at the 1st Committee meeting that with the right encouragement and given a definitive diagnosis the compliance with these products could be considerably higher than previously reflected in publications. We would suggest to the Committee that the importance of a definitive diagnosis and the importance of encouragement and working with patients to improve compliance should be noted. 4.5 Better to say that "There is no WIDELY AVAILABLE comparator for this diagnostic test of bile acid malabsorption. Faecal bile acid measurements, bile acid breath tests, and bile acid precursor assays are used only in limited research settings. Current diagnostic 6.5 of the DCD deals with the issue of improved compliance with BAS treatment if clinicians encourage people. 4.5 has been amended. 6

7 Consultee Response considerations include ruling out other diagnoses by analysis..." 9. Consultee 2 Representative of the British Nuclear Medicine Society 10. Consultee 3 Pharmaceutical industry 4 on 4: The diagnostic test 4 on 4: The diagnostic test Note the External Assessment Group used Trial of Treatment as a comparator, for which there is no published evidence. Since the test itself is the most appropriate method for assessing BAM there is a lack of methodology for comparison. Whilst further information is required we object strongly to limiting its future use in research only. 4.4: clinicians have used SeHCAT results to grade the severity of the bile acid malabsorption as follows:?.. GE :We would ask the Committee to also indicate the importance to the clinician of being able to grade the severity of BAM. As previously noted, the knowledge of severity of BAM coupled with an assessment of the clinical symptoms of the patient may suggest to the clinician that pharmaceutical intervention it not currently required and dietary control could be the best initial choice. The importance of grading the severity of BAM has been considered by the Committee (section 6.5 of the DCD). 7

8 Consultee Response 4.5:There is no direct comparator?. GE :It seems contradictory to note that there is no direct comparator for SeHCAT yet still include the trial of treatment comparison conducted by the External Assessment Group as noted in 5.3. This confuses the document. 5.3 describes the model structure which did include trial of treatment. Results of analyses that used trial of treatment as a comparator were not included in the guidance. 11. Consultee 1 NHS Professional 5 on 5: Outcomes The External Assessment Group report has been the subject of detailed criticism before. The use of Trial of Treatment for comparison and the exclusion of many early formative papers are major flaws. This cost analysis is detailed but impaired by lack of significant data on the disutility of failing to diagnose BAM. Results of analyses that used trial of treatment as a comparator were not included in the guidance. Also, the EAG has given reasons for excluding papers in comments 12, 14 and 16 below. 12. Consultee 2 Representative of the British Nuclear Medicine Society 5 on 5: Outcomes All outcome data in the published trials are flawed. a) there has been no standardisation in the literature as to what constitutes a positive SeHCAT scan or how it should be carried out Thank you for your comments. Below is the EAG response to the comments you have raised. 8

9 Consultee Response b) there is almost no appreciation in the literature that severity of symptoms in bile acid malabsorption are a reflection of dietary fat intake. There is not a single published study which correlates outcome with a measure of dietary fat intake, which suggests that the literature is uninterpretable. c) There is only one retrospective study of colesevelam published which is a much more effective bile acid sequestrant than colestyramine. Excellent evidence says that this is the case. Hence to base conclusions on published therapeutic studies using colestyramine which cannot be tolerated by 25% of patients (i.e. a second rate, outdated agent with poor tolerance) is seriously flawed when level D expert opinion of colesevelam usage in BAM suggests that effective treatment is available. EAG comments: We are not aware of any RCTs comparing colevasalam with cholestyramine; nor of any other RCTs involving BAS treatments in the population of interest, apart from the study by Odunsi et al. which was included in the review. The study by Odunsi did not test participants for BAM. In all studies involving SeHCAT, patients were treated with cholestyramine. d) there are no dietary intervention studies in patients with bile acid malabsorption. Expert opinion suggests that a substantial group of patients can benefit from being taught how to use a low fat diet. 9

10 Consultee Response 13. Consultee 3 Pharmaceutical industry 5 on 5: Outcomes 5.3:The 2 strategies that excluded the use of SeHCAT were?no-sehcat? (meaning everybody was treated for IBS-D) and?trial of treatment? with bile acid sequestrants. GE : In 4.5 (the comparator) it is noted that there is no direct comparator to SeHCAT and that the main comparison is therefore with the protocol of tests and clinical observations contained in the BSG guidelines. It is therefore very confusing for the reader to see trial of treatment as a comparison especially when this does not represent good medicine, it is not routinely used in the NHS and there is no clinical evidence to support this option at all. Results of analyses that used trial of treatment as a comparator were not included in the guidance. 5.14:The probability of a positive SeHCAT? Consultee 1 NHS Professional 6 on 6: GE :The probability of a positive SeHCAT test is noted incorrectly for the 10% and 15% cut-off points. From the DAR these probabilities should read 36% and 38% for the 10% and 15% cut-off points respectively. Many of these considerations appear to focus around poor information rather than expert opinion: This has been corrected. Below is the EAG s response 10

11 Consultee Response Considerations 6.1 Primary BAM is distinct from secondary BAM. Roughly 30% of patients otherwise diagnosed as IBS-D have PRIMARY IDIOPATHIC BAM [Wedlake APT : 707]. BAM is the cause of decreased colonic transit, there is little primary BA absorption in the colon, many patients with diarrhoea have normal faecal bile acid and SeHCAT values [Pattni Gut (S1):A88, and submitted]. 6.2 There is extensive literature validating SeHCAT. Faecal bile acids are the gold standard for BAM diarrhoea, and taurocholate breath tests were previously used. See Thaysen Gut : 862 Nyhlin Gastro : 63 Sciarretta Gut : 970 Jazrawi Gastro : 164 van Tilburg J Nucl Med : SeHCAT values do NOT vary over time in patients with primary BAM. See Rossel Scand J Gastro : 587 Bajor Dig Dis Sci : There are in fact many papers giving evidence of the clinical effectiveness of BA outlining why the papers were excluded from the evaluation. EAG comments: The systematic review is indeed based on poor quality published evidence. Most of the studies did not differentiate between primary or secondary BAM. Where possible we tried to include only data from primary BAM patients. All of these studies were assessed for inclusion in the systematic review: - Wedlake and Patni are not primary studies, but reviews. - Sciaretta and Borghede were included. We even contacted the authors of Borghede for additional 11

12 Consultee Response sequestrants e.g. recently Borghede Eur J Int Med : e137. This Box is too small to complete all criticisms. e.g no harm of SeHCAT known. information. Borghede is a retrospective study and does not include a control group and is therefore not useful to assess the effectiveness of treatment. - Nyhlin - The population did not fulfil the inclusion criteria: 45 patients including healthy controls and Crohn s disease with ileal resection. - Van Tilburg Aim of the study was to re-evaluate the recommended reference values for the SeHCAT test, used in the analysis of chronic diarrhoea. Data were not reported in a useful way for this review (no number of pos SeHCAT at a certain cutoff) - Thaysen The population did not fulfil the inclusion criteria: 8 patients without gastrointestinal complaints 12

13 Consultee Response and 30 patients with various gastrointestinal disorders (no further details). Bajor 2008 does address the reproducibility of SeHCAT, but not it s accuracy or the relationship with treatment outcome. Five other publications by Bajor et al. were also excluded. Rossel was excluded from the SR because of study design (Only those followed up with pos Sehcat and response to BAS). It was later used in the economic evaluation to assess the probabibility of a positive response in SeHCAT positives. Jazrawi compares SeHCAT with [14C]taurocholate in 5 healthy individuals 13

14 Consultee Response 15. Consultee 2 Representative of the British Nuclear Medicine Society 6 on 6: Considerations Throughout the NICE documenation, it is suggested that patients with undiagnosed BAM are likely to present with chronic diarrhoea?. This is a fundamental error which is repeated continually in the literature and is simply not correct. Patients with BAM may present with chronic diarrhoea, but MUCH more common is to present with erratic bowel function which sometimes is loose / diarrhoea. Some patients actually have episodes of constipation between the diarrhoea episodes. Thank you for your comments. The Committee recognises that SeHCAT is a potentially important test in diagnosing bile acid malabsorption. The Committee, however, believes that more evidence is needed to ascertain the clinical and cost effectiveness of the test. For NICE to come to a conclusion which would allow commissioners not to fund such an essential test would be very retrogressive. To hinder funding because there is no evidence that it is useful, because the published studies are inadequate would be unacceptable. Where is the evidence that it doesnt make a difference? There is none. The people who are arguing against SeHCAT are producing level D evidence to say that a trial of a bile acid sequestrant is as good in their opinion. This is hugely unfair as the experts who would argue that SeHCAT is enormously valuable have all 14

15 Consultee Response been excluded from the process. 16. Consultee 3 Pharmaceutical industry 6 on 6: Considerations 6.2:The Committee was informed that there are not clinical validity results for SeHCAT?? GE :We would still argue that there is data to demonstrate the clinical validity of SeHCAT. Validation from faecal bile acids which were the gold standard (at that time) prior to SeHCAT were extensively used and evidence can be found in the following references. Nyhlin 1983 Gastroenterology 84: 63 8 van Tilburg J Nucl Med 1991, vol 32 (6): Sciarretta Gut 1987, Aug. 28(8): These were studies for which the licence approval for SeHCAT were obtained. 6.3:The Committee was informed that, in people with IBS-D, the result of a SeHCAT test may vary. Thank you for your comments. The EAG has provided the following comments below to illustrate why these studies were excluded. EAG comments All of these studies were assessed for inclusion in the systematic review. - Nyhlin - The population did not fulfil the inclusion criteria: 45 patients including healthy controls and Crohn s disease with ileal resection. - Van Tilburg Aim of the study was to re-evaluate the recommended reference values for the SeHCAT test, used in the analysis of 15

16 Consultee Response GE :We would suggest to the Committee that the SeHCAT test is very accurate. It has a high repeatability. See the following references: Ung KA et al. Scand J Gastroenterol 2001, Jun 36(6): Bajor A, Dig Dis Sci 2008 (53): :The Committee was informed by the manufacturer that 30 40% of gastrointestinal centres in the country use SeHCAT and that the number is rising. GE :Considering more recent internal data, we would suggest that SeHCAT is actually procured and used in 40 chronic diarrhoea. Data were not reported in a useful way for this review (no number of pos SeHCAT at a certain cutoff) Sciaretta was included in the review. Bajor see above. Ung reinvestigated 27 patients with collagenous colitis after 3 years to study whether bile acid malabsorption is a permanent finding. One of the inclusion criteria for the SR is people with unknown cause chronic diarrhoea. Patients with collagenous colitis (BAM is common in collagenous colitis) were therefore excluded. 16

17 Consultee Response 17. Consultee 1 NHS Professional 18. Consultee 2 Representative of the British Nuclear Medicine Society 19. Consultee 3 Pharmaceutical industry 7 on 7: Proposed recommendations for further research 7 on 7: Proposed recommendations for further research 7 on 7: Proposed recommendations for further research 7.1 As discussed above, there is no deficit in knowledge of the "[clinical] validity and accuracy of the SeHCAT test". This has been well established, unlike cost analysis. I welcome the recommendation for potential alternative technologies and research into the nature of the disorder. This will benefit a large population. Although we can not disagree with the conclusions based solely on the published evidence we have to state that current experience and practice, although diverse does strongly indicate that there is a clinical use for this diagnostic test beyond that of a mere research application. The BNMS would be pleased to assist with any future research in this area. 6.7:The Committee was informed by the manufacturer that 30? 40% of gastrointestinal centres in the country use SeHCAT and that the number is rising. GE :Considering more recent internal data, we would suggest that SeHCAT is actually procured and used in 40?45% of Nuclear Medicine Centres. It is worth noting that not all hospitals have the facility to perform 6.7 has been amended. 17

18 Consultee Response SeHCAT scans on-site and so a?hub and spoke? system is used in many cases. The definitive number of GI centres currently referring for SeHCAT scans is not known. Our data also suggests that it is inaccurate to state that SeHCAT is mostly used in teaching hospitals and universities as there are many District General Hospitals that use SeHCAT. 20. Consultee 1 NHS Professional 21. Consultee 2 Representative of the British 8 on 8: Implementation 9 on 9: 6.9:..and potential harms of using SeHCAT and?.. GE :There have been very few adverse event reports for SeHCAT ever since gaining marketing authorisation in Canada in the 1980?s. The safety profile of SeHCAT is very robust, as reflected in the Summary of Product Characteristics, therefore we would suggest that there is no need for additional research for SeHCAT specifically for this. The recommendation for further research into SeHCAT is a positive outcome of this review. No The Committee feels that any research protocol should look for potential harms arising from the test including any arising from subsequent treatment. 18

19 Consultee Response Nuclear Medicine Society 22. Consultee 1 NHS Professional 23. Consultee 2 Representative of the British Nuclear Medicine Society Related NICE guidance 10 on 10: Review 10 on 10: Review I support the review of this guidance when new evidence has been produced, as much of the interpretation of the evidence by the External Assessment Group shows a poor understanding of the literature from the 1980s and the nature of the clinical problem. No Thank you for your comments. 19