Prucalopride for the treatment of chronic constipation in women

1. Appraisal Committee’s preliminary recommendations

1.1 Prucalopride is recommended as an option for the treatment of chronic constipation in women for whom laxatives fail to provide adequate relief.

1.2 Prucalopride should only be considered in women who have been managed by a clinician with experience of treating chronic constipation. The women should have tried at least two different types of laxative, and lifestyle modification, for at least 6 months, but have not had relief from constipation.

2 The technology

2.1 Prucalopride (Resolor, Movetis) is a selective serotonin (5-HT4) receptor agonist that predominantly stimulates colonic motility. Prucalopride has a UK marketing authorisation for the ‘symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief’.

2.2 Prucalopride is administered orally. The summary of product characteristics (SPC) states that the recommended dose of prucalopride is 2 mg once daily for adult women (up to 65 years old) and 1 mg once daily for older women (over 65 years old). The dose for older women can be increased to 2 mg once daily if needed. If once-daily prucalopride is not effective after 4 weeks, the patient should be re-examined and the benefit of continuing treatment reconsidered.

2.3 The SPC reports that the most common undesirable effects that may be associated with prucalopride treatment include headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhoea). For full details of side effects and contraindications, see the SPC.

2.4 Prucalopride is available in 1-mg and 2-mg tablets. The acquisition cost of prucalopride 1 mg is £38.69 for a pack of 28 tablets. The acquisition cost of prucalopride 2 mg is £59.52 for a pack of 28 tablets (excluding VAT; ‘The Monthly Index to Medical Specialties Monthly’ [MIMS], June 2010 edition). The manufacturer estimated that the annual cost of treatment with prucalopride is £622 for adult women and £403 for older women, excluding any monitoring costs, assuming that each patient receives treatment for an average of 220 days each year. Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer’s submission

3.1 The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of prucalopride and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.2 The manufacturer described nine trials that provided evidence on the clinical effectiveness of prucalopride in women with chronic constipation. There were three pivotal phase III randomised, double-blind, placebo-controlled trials in adults (aged 18­65 years) with chronic constipation (PRU-INT-6, PRU-USA-11 and PRU-USA-13), one phase III, randomised, double-blind, placebo-controlled trial in older patients (65 years or older, PRU-INT-12), one trial in patients with opioid-induced constipation (PRU-INT-8), one retreatment study (PRU-USA-28) and three extended, open-label, single-arm, observational studies (PRU-INT-10, PRU-USA-22 and PRU-INT-17). The key clinical evidence presented by the manufacturer was derived from the three pivotal trials, which reported the efficacy of prucalopride compared with placebo in adults, and the PRU-INT-12 trial that reported the efficacy of prucalopride compared with placebo in older patients. The number of patients randomised to the PRU-INT-6, PRU-USA-11, PRU-USA-13 and PRU-INT-12 trials was 720, 628, 651 and 305 respectively. Approximately 90% of patients in the pivotal trials were women. The manufacturer also presented other trials that reported additional safety considerations and response rates (see section 3.9). The manufacturer’s submission stated that patients were enrolled into the pivotal trials and PRU-INT-12 if they had a history of chronic constipation (defined as no more than 2 spontaneous complete bowel movements per week) and one or more of the following for at least 6 months before the screening visit:

• straining during at least 25% of bowel movements
• very hard or hard stools in at least 25% of bowel movements
• sensation of incomplete evacuation for at least 25% of bowel movements.

3.3 There was a 2-week run-in period for each pivotal trial (PRU-INT-6, PRU-USA-11, PRU-USA-13) and PRU-INT-12, in which no laxative medication (except for rescue medication) was allowed. Patients were then randomised 1:1:1 to either prucalopride 2 mg, prucalopride 4 mg or placebo. Patients in PRU-INT-12 were also randomised to prucalopride 1 mg. If patients had not had a bowel movement for 3 days or more, they could receive a single dose of 15 mg bisacodyl as rescue medication. If there was no bowel movement the dose of bisacodyl could be increased, and if there was still no bowel movement after an increase in the dose of bisacodyl, an enema could be administered. In the pivotal trials patients were treated for 12 weeks and in PRU-INT-12 patients were treated for 4 weeks. Data were collected at 4- and 12-week time points.

3.4 The primary outcome measure in the pivotal trials was three or more spontaneous complete bowel movements per week. The proportion of patients treated with prucalopride 2 mg in the pivotal trials who had three or more spontaneous complete bowel movements per week during weeks 1–4 ranged from 23.7% to 32.1%, compared with 9.8% to 11.5% for placebo (all p ≤ 0.001). During weeks 1–12, the proportion of patients treated with prucalopride 2 mg who had three or more spontaneous complete bowel movements per week ranged from 19.5% to 28.9% compared with 9.6% to 13.0% for placebo (all p ≤ 0.01).

3.5 The proportion of patients treated with prucalopride 2 mg in the pivotal trials who had an average increase of one or more spontaneous complete bowel movements per week (the secondary outcome measure) during weeks 1– 4 ranged from 41.0% to 56.5% compared with 20.9% to 25.5% for placebo (all p ≤ 0.001). During weeks 1–12 of treatment, the proportion of patients who had an average increase of one or more spontaneous complete bowel movements per week ranged from 38.1% to 50.3% for prucalopride 2 mg compared with 20.9% to 27.5% for placebo (all p ≤ 0.001).

3.6 In PRU-INT-12 the proportion of patients treated with prucalopride 1 mg and 2 mg who had a mean of three or more spontaneous complete bowel movements per week during weeks 1­4 was 39.5% and 32.0% respectively compared with 20.0% for placebo (p ≤ 0.05). In addition, the proportions of patients treated with prucalopride 1 mg and 2 mg who had an average increase of one or more spontaneous complete bowel movements per week during weeks 1­4 were 61.1% and 56.9% respectively compared with 33.8% for placebo (p ≤ 0.05).

3.7 The manufacturer’s submission reported quality-of-life data from the pivotal trials, which were derived from Patient Assessment of Constipation – Symptoms (PAC-SYM) and Patient Assessment of Constipation – Quality of Life (PAC-QOL) scores. All pivotal trials showed a significantly greater improvement in PAC-QOL scores for patients treated with prucalopride compared with placebo at weeks 1­4 and weeks 1­12 (both p < 0.001 compared with placebo). Statistically significant improvements in PAC-SYM scores were also seen in all trials at weeks 1­4 (p ≤ 0.001 compared with placebo) and in all trials except PRU-INT-6 at weeks 1­12 (p ≤ 0.05). The PRU-INT-12 trial also reported quality-of-life data derived from PAC-SYM and PAC-QOL scores. It was reported that the overall mean PAC-SYM scores for prucalopride 1 mg and 2 mg were 0.88 and 1.10 respectively compared with 1.22 for placebo. The overall mean PAC-QOL scores for prucalopride 1 mg and 2 mg at 4 weeks were 0.95 and 1.12 respectively compared with 1.26 for placebo (both p ≤ 0.05).

3.8 Surveys of the SF-36 mental component summary and the SF-36 physical component summary were taken during the run-in period and at weeks 4 and 12. No trials showed statistically significant greater improvements in SF-36 scores for prucalopride compared with placebo at week 12. The results were not used further in subsequent sections of the manufacturer’s submission.

3.9 The following three single-arm studies were designed to assess the long-term tolerability and safety of prucalopride:

• PRU-INT-10: included patients from PRU-INT-6 (pivotal trial) and PRU-INT-12 (trial in older patients).
• PRU-USA-22: included patients from PRU-USA-3 (phase II, dose-response trial), PRU-USA-11 and PRU-USA-13 (pivotal trials), PRU-USA-21 (phase II dose-response trial), PRU-USA-25 (phase III, dose-titration trial), PRU-USA-27 (opioid-induced chronic constipation trial) and PRU-USA-28 (phase III retreatment trial).
• PRU-INT-17: included patients from PRU-INT-8 and PRU-INT-14 (both opioid-induced chronic constipation trials).

Studies PRU-INT-10, PRU-USA-22 and PRU-INT-17 had a duration of 24, 36 and 12 months respectively. All patients received prucalopride doses ranging from 0 to 4 mg. Results from these studies reported that prucalopride treatment was associated with an improvement in constipation from baseline at all time points (this was statistically significant in PRU-INT-10 and PRU-USA-22) and a decrease in the use of laxatives. At 12 months, on average, less than 50% of patients remained in these trials. Reasons for stopping treatment included insufficient treatment response (18%), withdrawal of consent (15%) and adverse events (9%). However for the three trials, most patients (approximately 45%) discontinued treatment because the previous trial sponsor decided to stop the prucalopride developmental programme worldwide.

3.10 The manufacturer reported that prucalopride was generally well tolerated and that the majority of adverse events were mild or moderate in the clinical trials. In PRU-INT-6, 80.8% of patients in the prucalopride 2-mg arm reported at least one adverse event, compared with 66.0% in the placebo arm. The incidence of serious adverse events was 2.1% in both the prucalopride and placebo arms. The most frequently reported adverse events included headache, nausea and abdominal pain. The incidence of diarrhoea in the prucalopride 2-mg arm (13.0%) was more than twice that of the placebo arm (5.4%). The adverse-event profiles in the PRU-USA-11 and PRU-USA-13 trials were similar to those in the PRU-INT-6 trial. The onset of these adverse events was most frequently reported on the day after the start of treatment (‘day one’) and the duration was short. The manufacturer reported that when day one was excluded from the analysis, the incidence of adverse events was comparable between the treatment groups.

3.11 The manufacturer developed a decision analytic model based on patient-level data for women only (data for men from the trials were excluded). The model compared prucalopride with placebo. In both arms, bisacodyl as rescue medication was allowed. In the base case, results were presented for adult women aged younger than 65 years who received prucalopride 2 mg daily and women aged 65 years and above (older women) who received prucalopride 1 mg daily. Treatment duration was 4 weeks, after which patients could only continue treatment if they had three or more spontaneous complete bowel movements per week.

3.12 Two additional analyses were presented. One incorporated data for adult women only and one incorporated data for older women only. For the first 12 weeks, the model for adult women included randomised controlled trial data for all women treated with prucalopride 2 mg. Additional observational trial data were incorporated up to a further 40 weeks beyond the initial trial period. The model in older women incorporated randomised controlled trial data for women treated with prucalopride 1 mg in the first 4 weeks followed by observational data for up to 1 year.

3.13 No discounting was applied in the model because both costs and utility values were modelled for 1 year. The only costs incorporated into the economic model were the list prices of prucalopride 2 mg (£2.13 per tablet) and prucalopride 1 mg (£1.38 per tablet). No cost was assumed for the placebo arm. The manufacturer assumed that patients would take their medication for only part of the year (220 days). Treatment compliance was included in the economic model. Costs and utility values for placebo plus rescue therapy were not included in the model. Adverse events and their associated costs were not included in the model. The manufacturer acknowledged that the rates of adverse events were comparable between prucalopride and placebo and therefore it was considered that including these events would not affect the outcome of the analysis.

3.14 Clinical data incorporated into the model were derived from the three pivotal trials, the trial for older women, the extension studies and other trials not fully described in the manufacturer’s submission. Three additional dose-response trials (PRU-INT-1, PRU-INT-2 and PRU-USA-3), one trial in older patients (PRU-USA-26) and two phase II trials (PRU-FRA-1 and PRU-GBR-4) were used to inform the model but no methods or results for these trials were included in the submission. PAC-SYM and PAC-QOL data from the clinical trials were mapped into EQ-5D using the generalised least squares regression method. People who had chronic constipation that did not respond to prucalopride were assumed to have no quality-adjusted life year (QALY) gain. PAC-QOL is a measure from 1 (mild symptoms) to 4 (severe symptoms), and the PAC-QOL score of a patient who has severe chronic constipation (PAC-QOL 4) was estimated to map onto an EQ-5D score of 0.585 (on the 0 to 1 EQ-5D scale).

3.15 The manufacturer’s base case presented an average cost-effectiveness ratio because no cost for the comparator was included in the model. The average cost of prucalopride for all women was £498 with an average QALY gain of 0.0316, resulting in an average incremental cost-effectiveness ratio (ICER) of £15,700 per QALY gained. The average cost of prucalopride for adult women was £622 with an average QALY gain of 0.0369, resulting in an ICER of £16,800 per QALY gained. The average cost of prucalopride for older women was £403 with an average QALY gain of 0.0342, resulting in an ICER of £11,700 per QALY gained.

3.16 The manufacturer also presented an analysis that included all patients who had an additional bowel movement per week. The manufacturer estimated that for all women, the annual cost per patient to reach the secondary outcome would be £498 with an average QALY gain of 0.0277, resulting in an ICER of £18,000 per QALY gained. For the adult population, the cost would be £622 with an average QALY gain of 0.0342, resulting in an ICER of £18,000 per QALY gained. The cost for the older women was £403 with a QALY gain of 0.0255, resulting in an ICER of £15,815 per QALY gained.

3.17 The manufacturer presented probabilistic sensitivity analysesfor the following groups: all women; adult women (18–64 years); and older women (65 years or older), with and without adjusting for baseline severity of constipation. The probabilistic sensitivity analysis results showed that the probabilities of the ICERs for prucalopride exceeding £30,000 per QALY gained were approximately 45%, 44% and 47% respectively for all women, adult women and older women. The probabilities of the ICERs for prucalopride exceeding £20,000 per QALY gained were approximately 40%, 36% and 45% respectively for all women, adult women and older women. The manufacturer reported that the key drivers of cost effectiveness were:

• the effect of constipation severity at baseline on treatment effectiveness (that is, if the treatment effect is assumed to be the same regardless of baseline severity, the probability of prucalopride being cost effective at £20,000 per QALY gained is increased)
• the ability to identify people whose constipation did not respond to prucalopride at a very early stage of treatment
• the acquisition cost of prucalopride
• the utility values derived from mapping PAC-QOL to EQ-5D scores.

3.18 The ERG reviewed the evidence submitted by the manufacturer on the clinical and cost effectiveness of prucalopride. It noted that three trials (PRU-INT-6, PRU-USA-11 and PRU-USA-13) formed the basis of the manufacturer’s assessment of clinical effectiveness. However, the rationale for the focus on these three trials was not given. The ERG was unclear how patients from the original trials were selected for follow-up studies as no baseline data for these patients were provided in the manufacturer’s submission. The ERG considered it possible that the patients had constipation which was not necessarily refractory to laxative treatment. The ERG further noted that patients in the extension studies included a mixture of older patients and patients with opioid-induced chronic constipation and that the results were not separated. The ERG was further concerned that the high rate of withdrawal of patients from the long-term studies (more than 50% at 12 months) was likely to have resulted in patients who were relatively more satisfied with their treatment continuing with treatment compared with those dropping out.

3.19 Overall, the ERG noted that there was a considerable quantity of clinical-effectiveness evidence in adults that suggested an improvement in constipation for patients treated with prucalopride compared with placebo. The ERG calculated the weighted average of the effect of prucalopride across the pivotal trials and estimated that 28% of patients reached the primary outcome of three or more spontaneous complete bowel movements per week after treatment with prucalopride compared with 10.6% of people treated with placebo after 1­4 weeks. After 1­12 weeks, 23.8% of patients treated with prucalopride reached the primary outcome compared with 11.4% of patients treated with placebo.

3.20 The ERG was uncertain whether the patient population in the trials reflected the patient population in the marketing authorisation for prucalopride. It noted that in the three pivotal trials, 17% of patients at baseline answered that they had found their previous laxative treatment adequate. The ERG further considered that patients having one or two bowel movements per week while on laxative treatment were likely to be having beneficial effects from laxatives and therefore their constipation may not have been refractory to laxatives. It also considered that just any two of the criteria used by the manufacturer to describe chronic constipation alone would be unlikely to be sufficient evidence of treatment failure with laxatives.

3.21 The ERG noted that satisfaction scores at 12 months from three extension trials were used to justify the assumption of the sustained effectiveness of prucalopride from 12 to 52 weeks for the economic model. The ERG noted that many patients dropped out because of insufficient response (18%), withdrawal of consent (15%) and adverse events (9%). It also noted that on average, at 12 months, less than half of patients remained in these trials. The ERG therefore considered that this assumption was unjustified and that without a placebo arm in the trials, the true effectiveness of prucalopride was uncertain.

3.22 The ERG considered that the comparator used in the pivotal trials (placebo plus rescue medication with bisacodyl) did not represent standard clinical practice for chronic constipation. It suggested that a more appropriate comparator may have been a variety of oral laxative treatments, at the discretion of the treating clinician.

3.23 The ERG assessed the manufacturer’s cost-effectiveness analysis and considered their methodological approach acceptable. It noted that the manufacturer’s decision to exclude the cost of the comparator from the analysis was conservative. However, the ERG was concerned that precise details of patients and trials used to inform the economic model were not given or did not fully correspond with those described in the manufacturer’s submission.. It noted that five trials used for the economic model (PRU-INT-1, PRU-INT-2, PRU-USA-3, PRU-FRA-1 and PRU-GBR-4) were not fully described in the submission.

3.24 The ERG noted that data from PAC-QOL and PAC-SYM scores were used to elicit quality of life and were then mapped to the EQ-5D using SF-36 scores obtained from the trials. The ERG was concerned that the SF-36 data did not directly contribute to EQ-5D scores, even though these results were available from the trials, and no sensitivity analysis was undertaken by the manufacturer to test the impact of using SF-36 results.

3.25 The ERG noted that the manufacturer’s model only allowed for variation in the response rate and mean treatment rates to be analysed. It also noted that no explicit allowance was made for withdrawal from treatment at any time after 4 weeks and that the assumption that the last measured QALY gain was sustained for the rest of the year was not tested in the model.

3.26 The ERG noted there were more adverse events in the prucalopride arms than in the placebo arms of the trials. It was concerned that adverse events, including rare events, were not included in the model. The ERG considered that adverse event costs could be higher with prucalopride treatment, but noted that these were not included in the model.

3.27 The ERG ran the manufacturer’s model using alternative scenarios and assumptions including the following:

• Assuming that people who responded to treatment with prucalopride would receive treatment for a mean of 220 days or 365 days.
• Using response rates taken from pooled trial estimates at week 4 at the appropriate dose calculated in the effectiveness review.
• Allowing for the possibility that adverse events may be higher in the prucalopride arm than the placebo arm by increasing costs by 5% and reducing QALY gain by 5% in the prucalopride arm.
• Reducing the effectiveness (QALY) of prucalopride and placebo uniformly by 25%, 50% and 75% to allow for possible variation in the regression method used to calculate the QALYs.

The ERG concluded that the results from its sensitivity analysis were not significantly different from those provided by the manufacturer.

3.28 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available on the prucalopride guidance page.

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of prucalopride, having considered evidence on the nature of chronic constipation and the value placed on the benefits of prucalopride by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

Clinical effectiveness

4.2 The Committee discussed current treatments for chronic constipation and the position of prucalopride in the chronic constipation treatment pathway. The Committee considered the clinical specialists’ advice that patients who have had an inadequate response to an oral laxative often try many types of laxatives before considering invasive options such as suppositories, enemas, rectal irrigation or manual disimpaction. In severe cases of chronic constipation, pharmacological treatments for other conditions are used outside their licensed indications because they have diarrhoea as a side effect. The Committee heard from clinical specialists that many patients’ lives are impaired by laxative treatments with unpredictable and uncontrollable bowel movements The Committee also heard that the primary aim of treatment is to enable patients to have predictable bowel movements rather than sporadic relief in response to rescue medication. The clinical specialists stated that patients with intractable constipation can have a very low quality of life and feelings of hopelessness. The Committee heard that there have not been any new laxative treatments available in the UK for over 25 years. It considered that prucalopride would be a useful treatment for people who have tried at least two different types of laxatives, and lifestyle modification, for at least 6 months without gaining adequate relief from their constipation.

4.3 The Committee then considered the patient selection and the conduct of the clinical trials. The Committee noted that the inclusion criteria in the trials had been patients with chronic constipation in whom laxatives failed to provide adequate relief. The Committee also noted that it was unclear how inadequate relief had been defined in the trials. The Committee heard from the ERG that up to 30% of the patients in the trials responded to laxatives and their constipation may not have been refractory to laxatives. The Committee heard from the clinical specialists that it is often difficult to differentiate between people in whom laxatives do not provide adequate relief from those who no longer want to use laxatives, despite any benefit they may achieve, because of the side effects of treatment. The Committee concluded that adequate relief had not been properly defined by the manufacturer.

4.4 The Committee noted from the ERG’s pooled results that approximately 30% of patients’ constipation in the pivotal trials responded to placebo. The clinical specialists stated that it was not unusual for patients with gastrointestinal conditions to respond to placebo in high numbers, and that they were not surprised by the high response to placebo in the trials. The Committee was assured that in clinical practice, any treatment that provides at least a 10% improvement in response over placebo is considered to be clinically meaningful. The Committee also noted that a high proportion of patients stopped treatment in the extension studies. The Committee heard from the manufacturer that most of the patients whose constipation did not respond to treatment in the extension studies (18% out of the 20% who were non-responders) also did not respond in the randomised trial period. The Committee also noted that patients whose constipation responds to treatment with prucalopride are likely to demonstrate a response within 28 days of treatment, and that patients whose constipation does not respond in that period are unlikely to respond with prolonged treatment.

4.5 The Committee considered the comparator, placebo plus rescue medication with bisacodyl, used in the clinical trials. The Committee noted the concern of NHS representatives that the use of placebo as a comparator did not reflect current practice for chronic constipation in the NHS. The Committee heard from the clinical specialists that clinical trial protocols for studies of chronic constipation stipulate that placebo should be the comparator. The Committee heard that more intrusive interventions such as rectal irrigation or even surgery (as proposed in the decision problem for this appraisal) have risks and provide only temporary relief, and are not appropriate comparators to prucalopride. The Committee noted that bisacodyl was used as a rescue laxative in the clinical trials and could have been a comparator. The Committee heard from the clinical specialists that usually patients whose constipation has not responded adequately to laxatives would be encouraged to stop all current treatments, then restart their laxative regimen in a stepwise manner. The Committee agreed that it would be difficult to define a standard laxative regimen as a comparator for patients with chronic constipation.

4.6 The Committee discussed the clinical effectiveness of prucalopride. The Committee was aware of the data presented by the manufacturer that showed prucalopride to be more effective than placebo in women with chronic constipation during the trial periods of 4 weeks for older women and 12 weeks for women aged 18–64 years. The Committee questioned how well the trial extensions proved that clinical effectiveness is sustained. The Committee heard from the clinical specialists that prucalopride’s mechanism of action is on the gut muscle rather than the mucosa and that this mechanism of action means that efficacy could be sustained in the long term. The Committee was also aware of the stopping rule in the SPC for prucalopride, which restricts treatment beyond 28 days to patients who gained normal bowel movements while on treatment. It heard from the clinical specialists that if a patient did not have an adequate response to prucalopride after 28 days, treatment would be stopped and other options considered for the management of their condition. The Committee considered that the available data demonstrated that prucalopride was clinically effective in providing relief to patients with chronic constipation.

4.7 The Committee considered the adverse effects of prucalopride. It noted that diarrhoea and headaches were common in the clinical trials but that most side effects were mild to moderate in severity. The Committee heard from the clinical specialists that these side effects are often symptoms of chronic constipation and may not always be caused by prucalopride. It also heard that patients regularly have their medication reviewed by their clinicians to make sure that their constipation is not a side effect of any treatments (prescription and non-prescription) they are receiving. The Committee was also aware that prucalopride belongs to the same class of drugs as cisapride, which is associated with serious cardiovascular side effects. The Committee heard from clinical specialists that prucalopride has a selective mechanism of action and may not have the same cardiovascular side effects as cisapride. However, the Committee was concerned that the long-term side effects of prucalopride, such as effects on people with cardiovascular conditions, may need to await long term treatment and were not observed in the clinical trials conducted.

Cost effectiveness

4.8 The Committee considered the quality-of-life data presented in the manufacturer’s submission. The Committee noted that disease specific measures (PAC-QOL and PAC-SYM) were used to elicit quality of life and were then mapped to EQ-5D using SF-36 scores obtained from the trials. The Committee heard from the clinical specialists that patients with a PAC-QOL score of 4 (equating to an EQ-5D of 0.585) are substantially limited in their quality of life. Although PAC-QOL and therefore EQ-5D improved with prucalopride treatment, the Committee noted that this was not reflected in the SF-36 data directly measured in the trials. The manufacturer stated that further SF-36 data (not in the submission) for people whose constipation responded to treatment showed statistically significant improvement for prucalopride compared with placebo.

4.9 The Committee considered the cost of possible comparators in the treatment of chronic constipation. The Committee heard from the clinical specialists that interventions used after inadequate response to laxatives such as bowel irrigation or colonoscopy would incur higher costs than prucalopride. The Committee concluded that other costs of managing chronic constipation in secondary care, such as consultation time, could conceivably be reduced by the use of prucalopride.

4.10 The Committee discussed the manufacturer’s ICER calculations and the ERG’s exploratory analysis, in which the ERG ran the manufacturer’s model using different alternative scenarios and assumptions. The Committee noted that in the base case presented by the manufacturer, the average cost of prucalopride for all women was given as £498 with a QALY gain of 0.0316, resulting in an ICER of £15,700 per QALY gained. The average cost of prucalopride for adult women was given as £622 with a QALY gain of 0.0369, resulting in an ICER of £16,800 per QALY gained. The average cost of prucalopride for older women was given as £403 with a QALY gain of 0.0342, resulting in an ICER of £11,700 per QALY gained. Although the Committee had concerns about patient selection in the clinical trials and about the extrapolation of benefits beyond the trials, the ERG had shown the manufacturer’s cost-effectiveness estimates to be reasonably stable under varied assumptions. The Committee also agreed that the costs of chronic constipation presented by the manufacturer in its economic model were probably conservative and if the true resource costs associated with treating chronic constipation were included, it was likely that the ICERs presented by the manufacturer would be reduced.

4.11 The Committee was therefore persuaded that the most plausible ICER for prucalopride compared with placebo plus rescue medication was likely to be below £20,000 per QALY gained. Therefore, the Committee recommended prucalopride as an option for the treatment of chronic constipation in women for whom laxatives fail to provide adequate relief. The Committee agreed with the clinical specialists that women who would be suitable for treatment with prucalopride should be treated by a clinician with experience in the management of chronic constipation, and that these women should have tried at least two different types of laxatives, and lifestyle modification, for at least 6 months, without having adequate relief to their constipation.

Summary of Appraisal Committee’s key conclusions

TAXXX (STA)	Appraisal Title: Prucalopride for the treatment of chronic constipation in women	ACD section(s)
Key conclusion
Prucalopride is recommended as an option for the treatment of chronic constipation in women for whom laxatives fail to provide adequate relief. The Committee concluded that prucalopride should only be considered in women who have been managed by a clinician with experience of treating chronic constipation. The women should have tried at least two different types of laxative, and lifestyle modification, for at least 6 months, but have not had relief from constipation.
Current practice
Clinical need of patients, including the availability of alternative treatments	The Committee considered the clinical specialists’ advice that invasive interventions such as rectal irrigation or manual disimpaction may be used in patients for whom laxatives fail to provide adequate relief, however these measures are associated with risks and only provide temporary relief. In severe cases, pharmacological agents may be used outside their licensed indications because they have diarrhoea as a side effect.	4.2, 4.5
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?	The Committee heard from the clinical specialists that there have not been any new laxative treatments available in the UK for over 25 years. The Committee heard from the clinical specialists that prucalopride’s mechanism of action is on the gut muscle rather than the mucosa and that this mechanism of action means that efficacy could be sustained in the long term.	4.2
What is the position of the treatment in the pathway of care for the condition?	The Committee considered that prucalopride would be used by patients who had received at least two different types of laxative, and lifestyle modification, for at least 6 months without having adequate relief from their constipation.	4.11
Adverse effects	The Committee noted that diarrhoea and headaches were common in people who were treated with prucalopride. They noted that most side effects were mild to moderate in severity. The Committee noted that prucalopride belongs to the same class of drugs as cisapride which is associated with serious cardiovascular side effects. The Committee was concerned that some of the long-term side effects of prucalopride may not have been observed yet in the clinical trials conducted.	4.7
Evidence for clinical effectiveness
Availability, nature and quality of evidence	The Committee considered that the available data demonstrated that prucalopride was clinically effective in providing relief to some patients with chronic constipation.	4.6
Relevance to general clinical practice in the NHS	The Committee noted that the comparator used in clinical trials was placebo plus rescue medication with bisacodyl, which did not reflect current practice for chronic constipation in the NHS. The Committee heard that more intrusive interventions such as rectal irrigation or even surgery (as proposed in the decision problem for this appraisal) have risks and provide only temporary relief, and are not appropriate comparators to prucalopride. The Committee heard from the clinical specialists that generally patients whose constipation has not responded adequately to laxatives would usually be encouraged to stop all current treatments, then restart their laxative regimen in a stepwise manner. The Committee agreed that it would be difficult to define a standard laxative regimen as a comparator for patients with chronic constipation. The Committee considered that other costs of managing chronic constipation in secondary care such as consultation time could conceivably be reduced by the use of prucalopride.	4.5 4.9
Uncertainties generated by the evidence	The Committee noted that it was unclear how inadequate relief had been defined in the trials. The Committee also noted that up to 30% of the patients’ constipation in the trials responded to laxatives and their constipation may not have been laxative refractory. The Committee questioned how well the trial extensions proved that the effectiveness of prucalopride is sustained.	4.4 4.6
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?	The manufacturer provided separate analyses of adult women (18–64yrs), older women (65 years or older) and all women combined.	-
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee considered that the available data demonstrated that prucalopride was clinically effective in providing relief to some patients with chronic constipation.	4.6
Evidence for cost effectiveness
Availability and nature of evidence	The Committee considered evidence on the cost effectiveness of prucalopride compared with placebo, including quality-of-life estimates, costs and ICERs presented by the manufacturer.	4.8-4.11
Uncertainties around and plausibility of assumptions and inputs in the economic model	The Committee noted that disease specific measures (PAC-QOL and PAC-SYM) were used to elicit quality of life and then mapped to EQ-5D using SF-36 scores obtained from the trial. The Committee was also aware of the concerns the ERG had raised about the mapping process. The Committee noted that the sensitivity analysis undertaken by the ERG did not result in significantly different results from those of the manufacturer. Although the Committee had concerns about patient selection in the clinical trials and about the extrapolation of benefits beyond the trials, the ERG had shown the manufacturer’s cost-effectiveness estimates to be reasonably stable under varied assumptions.	4.8 4.10
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?	The Committee was aware that the SF-36 data presented in the manufacturer’s submission were not used in the model and were not tested in a sensitivity analysis. The Committee heard from the manufacturer that further SF-36 data that was not in their submission showed statistically significant improvement for prucalopride compared with placebo in women whose constipation responded to prucalopride.	4.8
Are there specific groups of people for whom the technology is particularly cost effective?	For adult women in the ICER was £16,800 per QALY gained. For older women, the ICER was £11,700 per QALY gained.	4.10
What are the key drivers of cost effectiveness?	The Committee agreed that the costs of chronic constipation presented by the manufacturer in its economic model were probably conservative and if the true resource costs associated with treating chronic constipation were included, it was likely that the ICERs presented by the manufacturer would be reduced.	4.10
Most likely cost-effectiveness estimate (given as an ICER)	The Committee was persuaded that the most plausible ICER for prucalopride compared with placebo plus rescue medication was likely to be below £20,000 per QALY gained.	4.11
Additional factors taken into account
Patient Access Schemes (PPRS)	Not applicable to this appraisal.	-
End-of-life considerations	Not applicable to this appraisal.	-
Equalities considerations	No equality issues were raised during the scoping exercise or through the course of this appraisal.	-

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing report and costing template to estimate the savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Related NICE guidance

Published

• Irritable bowel syndrome in adults: diagnosis and management of irritable bowel syndrome in primary care. NICE clinical guideline 61(2008).
• Constipation in children and young people: diagnosis and management of idiopathic childhood constipation in primary and secondary care. NICE clinical guideline 99 (2010).

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in October 2012. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Andrew Stevens
Chair, Appraisal Committee C
July 2010

Appendix A: Appraisal Committee members and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Kathryn Abel

Reader and Consultant Psychiatrist/Director of Centre for Women's Mental Health, University of Manchester

Dr David Black
Director of Public Health, Derbyshire County Primary Care Trust

Dr Daniele Bryden
Consultant in Intensive Care Medicine/Anaesthesia Sheffield Teaching Hospitals NHS Trust

Professor Mike Campbell
Statistician, Institute of Primary Care and General Practice, University of Sheffield

David Chandler
Lay Member

Dr Mary Cooke
Lecturer School of Nursing, Midwifery & Social Work, University of Manchester

Dr Chris Cooper
General Practitioner, St John’s Way Medical Centre, London

Richard Devereaux-Phillips
Public Affairs and Reimbursement Manager UK & Ireland, Medtronic

Dr Wasim Hanif MD FRCP
Consultant Physician & Honorary Senior Lecturer University Hospital Birmingham

Professor Catherine Jackson
Professor of Primary Care Medicine, University of St Andrews

Henry Marsh
Consultant Neurosurgeon, St George's Hospital

Professor Gary McVeigh
Cardiovascular Medicine, Queens University Belfast and Consultant Physician Belfast City Hospital

Dr Neil Myers
General Practitioner

Dr Richard Nakielny
Consultant Radiologist, Sheffield Teaching Hospitals Foundation Trust

Dr Danielle Preedy
Lay Member

Dr Peter Selby
Consultant Physician, Central Manchester University Hospitals NHS Foundation Trust

Professor Andrew Stevens
Chair of Appraisal Committee C, Professor of Public Health, University of Birmingham

Dr Matt Stevenson
Technical Director, School of Health and Related Research, University of Sheffield

Professor Paul Trueman
Health Economics Research Group, Brunel University

Dr Judith Wardle
Lay Member

C NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Raphael Yugi
Technical Lead

Fiona Rinaldi
Technical Adviser

Lori Farrar
Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by West Midlands Health Technology Assessment Collaboration (WMHTAC):

• Pennant M, Orlando R, Barton P et al. Prucalopride for the treatment of women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief, June 2010

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Movetis Pharmaceuticals

II Professional/specialist and patient/carer groups:

• PromoCon
• Association of Continence Advice
• British Society of Gastroenterology
• Royal College of Nursing
• Royal College of Physicians

III Other consultees:

• Department of Health
• NHS Greenwich
• Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• NHS Quality Improvement Scotland
• Napp Pharmaceuticals (dantron)
• Norgine Pharmaceuticals (sterculia/frangula, macrogol, docusate sodium enema)
• National Institute for Health Research Health Technology Assessment Programme
• West Midlands Health Technology Assessment Collaboration (WMHTAC)

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on Prucalopride for the treatment of chronic constipation in women by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Anton Emmanuel, Senior Lecturer and Hon Consultant Gastroenterologist, nominated by British society of Gastroenterology – clinical specialist
• Professor Peter Whorwell, Professor of Medicine and Gastroenterology, nominated by Movetis Pharmaceuticals – clinical specialist
• June Rogers MBE, Team Director, nominated by PromoCon – patient expert

D The following individuals were nominated as NHS Commissioning experts by the selected NHS Trust allocated to this appraisal. They gave their NHS commissioning personal view on prucalopride for the treatment of chronic constipation in women by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Rena Amin, Joint Head of Medicines Management selected by NHS Greenwich – NHS Commissioning expert

E Representatives from the following manufacturer/sponsor attended Committee Meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Movetis Pharmaceuticals