National Institute for Health and Care Excellence. Single Technology Appraisal (STA)

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1 Single Technology Appraisal (STA) Eluxadoline for treating irritable bowel syndrome with diarrhoea Response to consultee and commentator comments on the draft remit and draft scope (pre-referral) Please note: Comments received in the course of consultations carried out by NICE are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that NICE has received, and are not endorsed by NICE, its officers or advisory committees. Comment 1: the draft remit Appropriateness Allergan Allergan believes that this topic is appropriate for an appraisal by NICE. This is justified by the prevalence of IBS-D, its impact on patients quality of life and on the health economy, the current unmet needs that eluxadoline could cover and the fact that eluxadoline would be the first licensed drug for the treatment of IBS-D. Thank you for your comment. No action required. Wording Allergan Yes Timing Issues Allergan **************************************************************************************** ************************************************************************* Additional comments on the draft remit Royal College of Nursing The Royal College of Nursing welcome this draft consultation and overall we feel the proposals are reasonable Thank you for your comment. No action required. Page 1 of 8

2 Comment 2: the draft scope Background information Allergan The epidemiology data presented are consistent with accepted sources. We would like to clarify a few points: According to Spiller et al. (2007), 33-90% of sufferers do not consult. Prevalence estimates are based on postal questionnaires which means that the actual number of patients consulting for IBS would be lower than these prevalence figures. In the article mentioned above, the authors estimate that 50% of IBS patients in the UK are diagnosed. The prevalence of IBS varies between men and women with a ratio of 1:2 often reported. It is correct that neither tricyclic antidepressants nor selective serotonine reuptake inhibitors have a UK marketing authorisation for IBS. We believe it is important, however, also to note that loperamide is not licensed in the UK for the treatment of IBS either. Thank you for your comment. No action required. Comment noted. The background section of the scope has been updated. Some formulations of loperamide have marketing authorisations for the symptomatic treatment of acute episodes of diarrhoea associated with Irritable Bowel Syndrome. Therefore no changes were made to the background section of the scope. The technology/ Allergan The description of the technology is not complete as only the effect on gut motility is described. The effect on pain, which is an important aspect of IBS- Comment noted. The technology section of Page 2 of 8

3 intervention D, is missing. Eluxadoline is a locally active, mixed mu opioid receptor (μor) agonist/delta opioid receptor (δor) antagonist with low oral bioavailability with a proposed indication for the treatment of abdominal pain and diarrhoea in adult patients irritable bowel syndrome with diarrhoea (IBS-D). Eluxadoline has a dual effect on the symptoms of IBS-D as it improves stool consistency and also reduces abdominal pain. the scope has been updated to state that eluxadoline could reduce pain and improve stool consistency for people with irritable bowel syndrome. Population Allergan The population described is in line with the population treated in the randomised clinical trials (RCTs) of eluxadoline and is thus consistent with the indication submitted to the EMA. Comparators Allergan Allergan anticipates that the place of eluxadoline in the patient pathway will be for patients whose symptoms are not adequately relieved by over the counter (OTC) treatments. Therefore we do not believe that such treatments (ie loperamide and antispasmodics, both of which can be available OTC) constitute appropriate comparators for this appraisal. According to NICE CG61, the majority of patients with IBS are between 20 and 30 when they are diagnosed. Spiller et al. reported mean durations of disease in clinical trials of 5, 10 and 13 years. Although the average duration of disease was not reported in the RCTs for eluxadoline, we believe that it is likely that patients for whom treatment is appropriate, and who are seeking medical advice, may not only have been living with IBS-D for some years, but also to have tried OTC remedies. This belief is consistent with our proposed positioning for eluxadoline. Comment noted. Following consultation comments and the scoping workshop the comparators have been updated to: best standard care without eluxadoline (such as antispasmodics, antimotility agents and tricyclic antidepressants). The comparator arm in the eluxadoline RCTs was placebo. Patients were, however, allowed to use loperamide as rescue therapy, in both arms of the Page 3 of 8

4 study, for acute treatment of uncontrolled diarrhoea. For this reason, the placebo arm of the eluxadoline RCTs can be argued to be representative of best standard of care in the above described population. Outcomes Allergan Faecal incontinence is an important outcome to consider and we would suggest adding it to the list. Daily bowel incontinence episodes and daily incontinence free days are two measures of faecal incontinence. We would also suggest combining some of the outcomes proposed into a composite score to reflect the requirements of the FDA and the EMA in the assessment of this condition. Composite responder: a patient who met the daily pain response AND the daily stool consistency response criteria on at least 50% of days with diary entries during the 26 weeks. A patient must have met both of the following criteria on a given day to be a daily responder: Daily pain response: worst abdominal pain scores in the past 24 hours improved by 30% / 40% / 50% compared to Baseline (average of daily worst abdominal pain the week prior to randomization) Daily stool consistency response: BSS score <5 OR a diary response indicating the absence of a bowel movement accompanied by 30% improvement in worst abdominal pain compared to Baseline pain We believe the other key aspects of IBS-D, which include urgency, pain and quality of life are already captured in the outcomes listed in the scope. Comment noted. The outcomes section of the scope has been updated to include faecal incontinence and a composite response of daily pain and stool consistency. Economic analysis Allergan We plan to provide a within trial analysis looking at on treatment effect. We believe that our data will allow us to follow the reference case described in the guide to the methods of technology appraisal and that our economic analysis will comply with this frame. Page 4 of 8

5 Equality and Diversity Allergan No change to the proposed remit and scope are needed. Innovation Allergan Eluxadoline is first in class and the first licenced prescription treatment for IBS-D. It has a unique dual mechanism of action which allows targeting both gut motility and pain with a single twice daily treatment. In an area where patients have long sought effective alternatives to OTC treatments, eluxadoline will offer a potential solution for those patients whose symptoms remain troublesome and who are seeking further medical support. Moreover, eluxadoline will also provide physicians with a first licensed therapy to address the population of IBS-D patients with a high unmet clinical need. The true innovative nature of this product is linked to the existence, and the size, of clinical trials in IBS-D. Both doctors and patients will now have a treatment developed specifically for this disease. This innovation could result in a change in mentalities about a disease which lacks recognition. Comments noted. The technology section of the scope has been updated to reflect the dual mode of action of eluxadoline. Other considerations Questions for consultation Allergan None Allergan 1. What proportion of people with irritable bowel syndrome with diarrhoea in England are likely to receive pharmaceutical treatment for their condition? 81% of the English population is over 15yo (ONS): 54.3M x 81% = M Page 5 of 8

6 11% of the adult population has IBS: 44M x 11% = 4.84M of which 30% is IBS-D: 4.84M x 30% = 1.45M 1.45 million people could be IBS-D sufferer. Spiller et al. estimate that 50% of IBS sufferer patients are diagnosed: 1.45M x 50% = 725,720 Not all diagnosed patients receives treatment for IBS-D. Of those receiving treatment, an important proportion would take OTC medicines. Therefore the above number is vastly overestimating the number of IBS-D patients receiving prescription drugs. 2. Is eluxadoline likely to be administered in clinical practice as monotherapy or in combination with other treatments (best standard care)? We believe most patients will use eluxadoline as a monotherapy. Some patients in the RCT used loperamide as a rescue medication for acute treatment of uncontrolled diarrhoea but they were a minority. Comment noted. The 3. Are tricyclic antidepressants and selective serotonin reuptake comparators have been Page 6 of 8

7 inhibitors also used as part of best standard care? These two treatments are recommended in the NICE CG61 after loperamide. In practice, doctors can find it difficult to start discussing/prescribing antidepressant treatments with/to IBS patients who are not satisfactorily relieved by loperamide because of the stigma that these treatments may suggest. We do not know what proportion of patients receive these treatment for their IBS-D. We do know that the available evidence of their efficacy is limited which would prevent any reliable indirect comparison. updated to include the full range of comparators that may be appropriate in primary and secondary care which include antispasmodic an antimotility agents and tricyclic antidepressants. Selective serotonin reuptake inhibitors were not considered an appropriate comparator because they are not routinely used for the treatment of IBS-D and an undesirable effect of their use is diarrhoea. Additional comments on the draft scope Allergan Comments on the provisional matrix of consultees and commentators We noticed that the patient association named CORE ( was listed as a commentator but not as a consultee. We thought they would be relevant as consultee given the importance of the patient voice in this under-recognised condition. Comment noted. Page 7 of 8

8 The following consultees/commentators indicated that they had no comments on the draft remit and/or the draft scope Department of Health Page 8 of 8