Lead team presentation Eluxadoline for treating irritable bowel syndrome with diarrhoea (STA)

Transcription

1 Public slides Lead team presentation Eluxadoline for treating irritable bowel syndrome with diarrhoea (STA) 1 st Appraisal Committee meeting Committee B, 25th January 2017 Lead team: Nigel Westwood, Anne Joshua and Ruairidh Milne Company: Allergan Chair: Amanda Adler Evidence Review Group: Aberdeen HTA group NICE team: Henry Edwards, Jasdeep Hayre, Melinda Goodall

2 Eluxadoline MARKETING AUTHORISATION Adults for the treatment of irritable bowel syndrome with diarrhoea (IBS-D) KEY RESULTS Clinical data 3 placebo controlled RCTs Composite endpoint based on pain and stool consistency Eluxadoline vs placebo weeks 1-26 IBS-3001: 29.3% v 19.0% IBS-3002: 32.7% v 20.2% Cost effectiveness ICERs Company = 9,213/QALY ERG = 38,779/QALY KEY ISSUES Positioning Company positions eluxadoline after failure of standard of care Generalisability Patients in trial not typical of NHS clinical practice Stopping treatment Would doctors stop treatment if it didn t work? QALY gain Eluxadoline increase utility not length of life Model structure ERG questions structure of model Relative benefits Modelled treatment stopping might overestimate benefit Costs, resource use ICER sensitive to small changes in costs

3 Key issues: clinical effectiveness Where will eluxadoline be used in the treatment pathway? Will eluxadoline be initiated in primary or secondary care? What treatment comparators are most appropriate? Is the trial population generalisable to those that are intolerant to or unresponsive to best supportive care? to UK clinical practice? Are the outcome measures used reflective of important outcomes in NHS clinical practice? Does committee consider eluxadoline to be more effective than placebo? How long does it take to get benefit? When is it appropriate to stop eluxadoline treatment? Is the drug likely to continue working in the long run or does it wane? 3

4 Key issues: cost effectiveness Is the model structure appropriate? Should the model split adequately relieved and inadequately relieved health states by response? Is a 5 year time horizon sufficient to capture all costs and consequences? Is a stopping rule is appropriate? If so, when? Are the source and validity of utility values appropriate? What health benefits and costs should apply to people who stop eluxadoline? Which resource use estimates are appropriate - GP Survey or Fisher et al or other? Should the model include cost of adverse events? 4

5 Irritable bowel syndrome (IBS) A chronic functional bowel disease characterised by abdominal pain and/or discomfort Diagnostic guidelines, such as Rome III and Rome IV criteria, categorise patients into 3 groups: IBS with constipation, IBS with diarrhoea (IBS-D) Mixed IBS About 1/3 of people with IBS have IBS-D with an estimated prevalence in the UK of 3-7% Most frequent symptoms of IBS-D include gas, abdominal pain, urgency, and diarrhoea Range and frequency of symptoms can vary considerably IBS diagnosed by exclusion currently no reliable laboratory tests 5

6 Eluxadoline (Truberzi) Marketing authorisation Administration & dose Mechanism of action Cost Indicated in adults for the treatment of irritable bowel syndrome with diarrhoea (IBS-D) (September 2016) Administered as an oral therapy, 200 mg daily in adults (100 mg tablet, twice daily) An opioid receptor agonist and delta-opioid receptor antagonist that binds to opioid receptors in the digestive system and slows down the movement of food through the gut Eluxadoline 75 mg and 100 mg: per pack 56 tablets (Company submission, section 2.3) 6

7 Treatment pathway Line of treatment IBS-D 1 st Lifestyle management Dietary advice Exercise Antispasmodic e.g. mebeverine, hyoscine Antimotility e.g. loperamide Psychological intervention e.g. CBT, hypo therapy 2 nd Antidepressant TCAs e.g. amitriptyline SSRIs, e.g. citalopram Psychological intervention e.g. CBT, hypo therapy 3 rd Adapted from NICE Clinical Guideline (CG61) Eluxadoline? Where will eluxadoline be used in the treatment pathway? Will eluxadoline be initiated in primary or secondary care? Abbreviations: CBT, cognitive behavioural therapy; SSRI, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressant 7

8 Patient and professional feedback Disease Symptoms can have a devastating impact on quality of life Symptoms can vary in severity, and may not be predictable Current treatments Follow NICE Clinical Guideline: Irritable bowel syndrome in adults: diagnosis and management (CG61) Education, dietary interventions and pharmacotherapy Loperamide (an antimotility) is a current alternative to eluxadoline but poor evidence base for the efficacy of loperamide in IBS-D Limited pharmacologic options in IBS-D unmet need Eluxadoline should be used in people who meet Rome IV criteria 8

9 Decision problem NICE scope Company changes Justification Pop Adults with IBS-D Adults with IBS-D who have not responded adequately to or cannot tolerate pharmacological therapy Int Eluxadoline Matches NICE scope Com Out BSC without eluxadoline (e.g. antispasmodics, antimotility and tricyclic antidepressants) Listed in the premeeting briefing BSC without eluxadoline (BSC does not include pharmacological therapy) Matches NICE scope with the addition of adequate relief of symptoms Adequate relief: How would you rate your IBS symptoms overall over the past 7 days What treatment comparators are most appropriate? Clinical advice about its use in clinical practice Clinical advice about its place in the clinical pathway Adequate relief is the primary response criteria used in the UK Abbreviations: BSC, best supportive care; Pop, population; Int, intervention; Com, comparators; Out, outcomes 9

10 Scope vs evidence vs decision problem Scope decision problem Trials IBS-D Company decision problem IBS-D IBS-D Eluxadoline + BSC (only rescue therapy) Placebo + BSC (only rescue therapy) Intolerant or unresponsive to BSC (including pharmacological therapies) Eluxadoline BSC (including pharmacological therapies) Eluxadoline BSC (excluding pharmacologi cal therapies) Is the trial population generalisable to those intolerant to or unresponsive to best supportive care (including pharmacological therapies)? BSC, Best standard care: antispasmodics, antimotility agents and tricyclic antidepressants 10

11 Pivotal trials IBS-2001, IBS-3001 & IBS-3002 IBS-2001 Phase 2 n=807 Rome III US based Mean age 45 Eluxadoline (5, 25, 100, or 200 mg BID) 12 weeks Placebo Composite response Change in daily pain score Change in stool consistency IBS-3001 Phase 3 Double blind n=1281 Rome III Mainly US Mean age 45 IBS-3002 Phase 3 Double blind n=1146 Rome III Mainly US Mean age 45 Eluxadoline (75 or 100 mg BID) 26 weeks Placebo Composite response Change in daily pain score Change in stool consistency Is the trial population (e.g. age) generalisable to UK clinical practice? If so, is it likely to effect relative effectiveness? 11

12 Composite response Required to meet pain and stool consistency response criteria for ½ of the days with diary entries Stool consistency response: Bristol Stool Scale score <5 or the absence of a bowel movement Yes No Pain response: Worst abdominal pain (WAP) scores in the past 24 hours improved by 30% compared to baseline (average of daily WAP the week prior to randomisation) Yes No Pain + diarrhoea better Composite response Pain not better, diarrhoea better Pain better, diarrhoea not better Neither better Does composite response reflect important outcomes in NHS clinical practice? 12

13 Clinical efficacy Composite response IBS-2001 Responder, n (%) p-value Eluxadoline 5 mg BID 13 (12.4) <0.10 Eluxadoline 25 mg BID 20 (12.0) <0.05 Eluxadoline 100 mg BID 18 (11.0) <0.10 Eluxadoline 200 mg BID 22 (13.8) <0.05 Placebo 9 (5.7) - IBS-3001 Responder, n (%) p-value Eluxadoline 75 mg BID 100 (23.4) Eluxadoline 100 mg BID 125 (29.3) <0.001 Placebo 81 (19.0) - IBS-3002 Responder, n (%) Eluxadoline 75 mg BID 116 (30.4) <0.001 Eluxadoline 100 mg BID 125 (32.7) <0.001 Placebo 77 (20.2) - 13

14 Clinical efficacy Percentage of daily composite response (%): IBS-3002 % of daily composite responders Composite response by day. Eluxadoline 200 mg Eluxadoline 150 mg Placebo arm Study day When is it appropriate to stop eluxadoline treatment? Is the drug likely to continue working in the long run or does it wane? 14

15 Meta-analysis Pooled results from IBS-2001, IBS-3001 and IBS-3002 for eluxadoline vs placebo Standardised mean difference change in baseline [95% CI]: 12 weeks 26 weeks* Bristol Stool Scale score Stool consistency 1 7; where 1=hard, 7=watery stools Daily pain score Pain 0 10; where 0=no pain,10=worst pain imaginable IBS Quality of Life Total Score Qol 0 100; where=lowest, 100=highest Global symptom score (GSS)* IBS-GSS 0 4; to How would you rate your IBS symptoms overall over the past 7 days? Adequate relief of IBS symptoms Yes/No to How would you rate your IBS symptoms overall over the past 7 days xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx xxxx Do these changes reflect important clinical differences? Is eluxadoline more effective than placebo? How long does it take to get benefit? *Pooled results from IBS-3001 and IBS-3002 only; ** Odds Ratios (OR) 15

16 Adverse events Pooled safety data from the IBS-3001 and IBS-3002 for common adverse events Most common treatment-emergent adverse in patients on eluxadoline are gastrointestinal including nausea, constipation Event Placebo (n=808) Combined groups (75mg and 100mg twice daily) (n=1,666) All adverse events (%) 450 (55.7) 986 (59.2) Serious Adverse Events (%) 24 (3.0) 75 (4.5) Cardiac Events (%) 8 (1.0) 75 (4.5) Pancreatitis (%) 0 5 (0.3) Adapted from ERG report, table 13 16

17 Cost effectiveness 17

18 Company s model structure Adequately Relieved (Responder) Adequately Relieved (Non- Responder) Dead Enter the model as inadequately relieved Inadequately Relieved Adapted from Figure 41, Company s submission Markov state-transition model Company s clinical experts suggested that outcome measures in trials are not used in clinical practice & patient s subjective belief for symptoms was better correlated to improvement from baselines of at least 14 points in IBS-QoL Transition to other health states based on ability to achieve: adequate relief 14 improvement in IBS-QoL (a responder ) <14 (a non-responder ) Time horizon: 5 years 4 week cycle 18

19 ERG s comments Model structure Definition of adequate relief Splitting the adequately relieved by the IBS-QoL response Defined differently in the clinical study report and the submission: Economics section: Over the past week have you had adequate relief of your IBS symptoms? Clinical section/clinical study report: patients with a weekly response of Yes to adequate relief of their IBS symptoms for 50% of the total weeks during 1-12 weeks and 1-26 weeks 4 previous studies use IBS-QoL 14 change from baseline as the measure of response none use it to split adequate relief data as conducted by the company Other measures could have been used company s justification unclear Inadequate relief not split by IBS-QoL ERG unclear why 19

20 Model structure: Company vs preferred ERG structure ERG splits both adequate relief and inadequate relief Company model ERG s referred model structure Adequately Relieved (Responder) Inadequately Relieved Adequately Relieved (Non- Responder) Dead Should adequately relieved and inadequately relieved health states be split by quality of life ( response )? Is a 5 year time horizon sufficient to capture all the costs and consequences? 20

21 Clinical data used in the model Used for transition probabilities 0-28 weeks Pooled data from IBS-2001, IBS and IBS-3002 Used to calculate probability of moving between health states at 4 weekly intervals Beyond trial data Last observation carried forward for adequate relief i.e. transition probability from weeks reused thereafter 4 week stopping rule applied Time Stopping rule Those that move into inadequately relieved state in the final week of the cycle considered to have stopped treatment 260 weeks Is it appropriate to apply a 4-week clinical stopping rule? 21

22 Adequately Relieved (Responder) Discontinue? Adequately Relieved (Non- Responder) Dead Adapted from figure 41, Company s submission ERG s comments Discontinuing eluxadoline Inadequately Relieved Company: Assumed that patients who stop taking eluxadoline have same likelihood of having adequate relief as those staying on eluxadoline keep benefits of higher QALYs, but have fewer costs of treatment claim stopping is not due lack of efficacy ERG: Should model discontinuation but need extensive work Instead assume that patients who stop eluxadoline have the same health outcomes and costs as those on placebo arm What health benefits and costs should apply to people who stop eluxadoline? 22

23 Utility values used by the company Adequately Relieved (Responder) Adequately Relieved (Non- Responder) Inadequately Relieved Company collected IBS-QoL scores, adequate relief status and EQ-5D scores at weeks 4, 8, 12 and end of treatment from IBS-2001 trial Used to derive EQ-5D utilities for each health state Dead Scenario analysis was conducted splitting adequate relief at 10 points and using utility values in Fisher et al Are the source and validity of utility values appropriate? 23

24 Resource use and costs Used by the company Small differences in costs and QALYS resource use and unit costs can have a big impact on the ICER Company approach: A survey of UK GPs (50 responses) estimating average resource use in IBS-D patients Fisher et al. used in scenario analysis ERG comments: Akehurst et al. (2002) not used by the company because it didn t meet its inclusion criteria But, it reports lower annual cost for IBS patients GP survey overestimates the number of endoscopies undertaken Once IBS is diagnosed, are endoscopies likely to be performed? 24

25 Resources use Comparison of GP survey, Fisher, and Akehurst GP survey Company basecase Fisher (2016) Company scenario Akehurst et al (2002) Identified by ERG Study Survey of 50 GPs Cost effectiveness Survey of IBS patients in UK primary care Population Intervention Patients with IBS-D Best supportive care Moderate to severe IBS-C who have not responded adequately or cannot tolerate antispasmodics and/or laxatives Linaclotide 172 patients with IBS Best supportive care Comparator - Antidepressants Control cohort Resource data GP survey of estimated resource use Interviews with 6 clinicians Review of GP records for 12 month period (6 mo prior, and 6 mo after recruitment 25

26 Annual resource use and costs GP survey Fisher (2016) Akehurst et al Resource use per AR + AR + Nonpatient per year AR IAR IBS RE NRE IAR IBS GP visit Out patient visit In patient visit A&E visit CT scan Ultrasound Colonosc Sigmoid Endoscopy X-ray Annual costs estimates per patient Company unit costs 2,646 4, ,336 2, ERG unit costs 2,113 3, , Which resource use estimates are appropriate? GP Survey or Fisher et al or other? Abbreviations: AR, adequately relieved, CT, computed tomography; IAR, inadequately relieved; NRE, non responder, RE, responder 26

27 ERG s comments Other comments Issue Downsteam costs and saving Stopping rule Compliance Adverse events ERG comment Noted that treatment cost of 624 is offset by 421 health state costs, resulting in a net cost of 203 for eluxadoline May not be reasonable to assume that the average placebo effectiveness applies to everyone stopping too optimistic? Compliance of treatment costs does not factor wastage The model does not include adverse events (e.g. pancreatitis, cardiac events) Should the cost of adverse events be included in the model? 27

28 Company s base case results ICER driven by small differences Total costs Total QALYs Incremental costs Incremental QALYs ICER ( /QALY) Deterministic No pharmacological therapy 17, Eluxadoline 18, ,213 Probabilistic No pharmacological therapy 17, Eluxadoline 18, ,129 Abbreviations: ICER, incremental cost-effectiveness ratio; Inc, incremental; QALYs, quality-adjusted life years; 28

29 Company s scenario analysis Selected scenarios Δ Cost Δ QALY ICER ( /QALY) Base case ,213 6 month time horizon , year time horizon ,213 Average transition probabilities used for extrapolation ,162 No stopping rule applied after week 28 1, ,842 GP survey subset used to estimate resource use Dominant Fisher et al scenario used to estimate resource use ,387 Utility average from trial arms ,673 Utility values for Fisher et al ,155 Abbreviations: Δ, the change in, QoL, quality of life; TPM, transition probability matrices 29

30 Issue ERG s revised base case ERG revision Discontining ERG: people who stop eluxadoline have the same health state distribution as placebo. Discontinuation rates from trial only Company: people who discontinue eluxadoline have the same health state distribution as those that continue eluxadoline Mortality ERG and company: Eluxadoline does not extent life Utility ERG and company: Values from IBS-2001 Compliance + wastage Resource use ERG: all patients get 100% of drugs in 1st 4 weeks wastage Company: assumes that NHS not charged for drugs not taken ERG: sensitivity analysis of Fisher et al. Company: a survey of 50 GPs Costs ERG corrected costs for: pancreatitis; NHS reference cost for outpatient follow-up visit; remove ½ cycle correction from drug costs; additional pharmacy cost; end of cycle discontinuation estimates to drug costs Company: see section of the company submission Inflation ERG: 4% for inpatient and outpatient costs Company: 10% for inpatient and outpatient costs Which assumptions should the model include? 30

31 ERG revised base case Total costs Total QALYs Δ costs Δ QALYs ICER ( /QALY) Company base case No pharmacological treament 17, Eluxadoline 18, ,213 ERG base case No pharmacological treatment 4, Eluxadoline 5, ,779 Abbreviations: ICER, incremental cost-effectiveness ratio; QALYs, quality-adjusted life years; Δ, change in 31

32 ERG sensitivity analysis (1) Δ Cost Δ QALY ICER Base ,779 SA00 Using company discontinuation ,897 SA01 Secondary care initiation ,149 SA02 No GP liver function test ,215 Adverse events discontinuations GP SA03 visit ,869 SA04 ERG discontinuation calcs 28 weeks ,733 SA05 No stopping rule 2, ,747 SA06 Exclude IBS-2001 data ,625 SA07 100% compliance ,610 SA08 No adequate relief split by IBS-QoL ,066 SA09 Treatment specific QoL values ,501 SA10 Clinical guideline 61 QoL gain ,066 SA = sensitivity analysis 32

33 ERG sensitivity analysis (2) Cont. Δ Cost Δ QALY ICER Base ,779 SA11 Average transition probabilities extrapolation ,969 SA12a 6 month time horizon ,587 SA12b 1 year time horizon ,382 SA12c 3 year time horizon ,819 SA13a GP survey resource use ,312 SA13b GP survey subset resource use ,457 SA13c Fisher base case resource use ,406 SA14 No downstream cost offsets ,905 SA15 Company unit costs ,408 SA13a+SA ,631 SA13b+SA ,796 33

34 Innovation and equality Innovation Company considers eluxadoline innovative because: 1 st -in-class treatment 1 st product developed specifically to treat symptoms associated with IBS-D addresses multiple symptoms simultaneously Different mechanism of action from previous treatments Addresses unmet need of medications licensed for IBS, usually managed by off-label medication Equality considerations None identified Is eluxadoline an innovative therapy? Have all the potential equality considerations been considered? 34

35 Issues for discussion for Part 2 Is eluxadoline for treating irritable bowel syndrome with diarrhoea Effective compared with treatments currently offered in the NHS Good value for money given limited NHS resources? 35