Prucalopride for the treatment of chronic constipation in women

The Committee discussed the nature of chronic constipation and current clinical practice for the treatment of people with laxative-refractory chronic constipation. The clinical specialists stated that chronic constipation has a wide spectrum of severity and that for a minority of people with intractable constipation there can be very low quality of life and feelings of hopelessness. The Committee understood that current practice is a stepped approach to management starting with lifestyle and dietary changes. If these changes provide inadequate relief, different classes of oral laxatives are available. For some people chronic constipation can become intractable, and relatively invasive procedures (such as suppositories, enemas, rectal irrigation and manual disimpaction) may be tried. The Committee heard from the manufacturer that the intended position of prucalopride in the treatment pathway for chronic constipation is after failure of oral laxatives because of inadequate efficacy or intolerance. The Committee noted the clinical specialists' advice that people who have had an inadequate response to an oral laxative often try many different types before considering invasive options. The Committee was aware that the scope for this appraisal was to consider the use of prucalopride in women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief, and for whom invasive procedures are being considered.

The Committee discussed patient selection and the conduct of the clinical trials. The Committee noted that the inclusion criteria in the trials were people 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. In addition, the Committee heard from the ERG that up to 30% of the people in the trials responded to laxatives, so their constipation may not have fitted these inclusion criteria. The Committee was also aware of concerns raised during consultation that because adequate relief had not been properly defined by the manufacturer, this could contribute to widespread use of prucalopride in people in whom laxatives had not necessarily failed. However, the Committee heard from the clinical specialists that it is often difficult to differentiate between people for whom laxatives do not provide adequate relief and those who no longer want to use laxatives because of the side effects, despite any treatment benefit they may achieve. Based on advice from the clinical specialists, the Committee concluded that inadequate relief from previous laxative treatments could be defined by duration of follow-up and by the number of laxatives previously used.

The Committee considered the comparator, placebo plus rescue medication with bisacodyl, used in the clinical trials. The Committee noted the concerns of the NHS representatives that the use of placebo as a comparator did not reflect current clinical practice for chronic constipation and that prucalopride had not been compared with some of the less expensive oral laxatives commonly used in the NHS. It was aware that similar concerns had been raised during consultation. The Committee also noted that bisacodyl was used as rescue medication in the clinical trials and it could have been a comparator. However, it heard from the manufacturer that in clinical practice, people for whom laxatives fail to provide adequate relief sometimes adopt a 'do nothing' approach and later present with faecal impaction. At this stage, invasive procedures (such as rectal irrigation and faecal disimpaction) and occasionally surgery are used to resolve the constipation. The Committee also heard from the clinical specialists that people whose constipation has not responded adequately to laxatives would usually be encouraged to stop all current treatments and then restart their laxative regimen in a stepwise manner. The clinical specialists further stated that in clinical trials for studies of chronic constipation, placebo is often the comparator. The clinical specialists noted that invasive procedures have risks and provide only temporary relief, and are therefore not appropriate comparators to prucalopride. In view of the different classes of laxatives used in clinical practice and the fact that many of these are often used in rotation to avoid tolerance, the Committee agreed that it would be difficult to define a standard laxative regimen as a comparator for people with laxative-refractory chronic constipation.

The Committee discussed the clinical effectiveness of prucalopride. It 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 (65 years and older) and 12 weeks for adult women (18 to 64 years). The Committee was aware of concerns from consultees that the short duration of the clinical trials may not adequately reflect the efficacy of a drug that treats a long-term condition. It was also aware of the open-label extension studies that showed that prucalopride was efficacious in the long term. The Committee questioned how well the extension studies proved that the clinical effectiveness of prucalopride is sustained, given the high drop-out rate. However, it heard from the manufacturer that 90% of the people whose constipation did not respond to treatment in the extension studies also had no response in the randomised trial period (that is, were already non-responders), which suggests that for people whose constipation does not respond early with prucalopride, their condition will not respond with continued treatment. The Committee heard from the manufacturer that people whose constipation responds to treatment with prucalopride are likely to have a response within 28 days of treatment, and that people whose constipation does not respond in that period are unlikely to have a response with treatment longer than 28 days. The Committee also 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. Although some consultees argued that the mechanism of action of prucalopride is not unique and that it did not prove that tolerance to prucalopride (and subsequent dose increases) did not occur, the Committee was persuaded that some people may benefit from continued use of prucalopride. The Committee was persuaded that the stopping rule in the SPC for prucalopride, which restricts treatment after 4 weeks in women who gained normal bowel movements while on treatment, would be followed by prescribing clinicians and limit use in people who do not respond early to treatment with prucalopride.

The Committee noted from the ERG's analysis that a substantial proportion of people with chronic constipation in the pivotal trials responded to placebo (see section 3.18). The clinical specialists stated that it was not unusual for people with gastrointestinal conditions to respond to placebo, 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 considered that the available data demonstrated that prucalopride was clinically effective in providing relief to women with laxative-refractory chronic constipation.

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 people regularly have their medication reviewed by their clinicians to make sure that their constipation is not a side effect of any treatments they are receiving (prescription and non-prescription). The Committee was 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 some side effects of prucalopride, such as possible cardiovascular effects, may only be apparent after long-term treatment and were not observed in the clinical trials conducted.

The Committee considered the quality-of-life data presented in the manufacturer's submission. The Committee noted that disease specific quality-of-life measures (PAC-QOL and PAC-SYM) were mapped to EQ-5D using SF-36 scores obtained from the trials. The Committee heard from the clinical specialists that people with a PAC-QOL score of 4 (equating to an EQ-5D of 0.585), as observed in the clinical trials, have substantially limited 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 Committee was aware of the concerns raised by the ERG that the assumptions used in the mapping equation could not be tested and may therefore not be robust. It questioned if SF-36 data from the trials would give similar EQ-5D improvement had they been used in the model; and why this had not been tested in a sensitivity analysis. 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. Sensitivity analyses of these outcomes were conducted by the manufacturer and were considered to be consistent with results from the ERG's analyses when assumptions about the acquisition cost of prucalopride and the number of days on treatment were varied. The Committee concluded that changing the mapping equation to include SF-36 instead of PAC-QOL would be unlikely to alter the results of the model substantially.

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 £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 £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 £403 with a QALY gain of 0.0342, resulting in an ICER of £11,700 per QALY gained. Although the Committee had concerns about the generalisability of the populations selected for the clinical trials to the decision problem and about the extrapolation of benefits beyond the trials, the Committee concluded that the ERG had shown the manufacturer's cost-effectiveness estimates to be reasonably stable under varied assumptions.

The Committee considered the true resource costs of treating chronic constipation when laxatives fail to provide adequate relief, such as referrals to secondary care, rectal irrigation and surgery. It agreed that these costs could be reduced by using prucalopride. Based on these considerations, 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 were included, it was likely that the ICERs presented by the manufacturer would be reduced.

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. Therefore, the Committee agreed that prucalopride would be an appropriate use of NHS resources and recommended that prucalopride should be considered as an option for the treatment of chronic constipation in women only when they have used the highest tolerated recommended doses of at least 2 laxatives from different classes for at least 6 months, without having adequate relief of their constipation, and invasive treatment is being considered. The Committee acknowledged that if treatment with prucalopride is not effective after 4 weeks, the woman should be re-examined and the benefit of continuing treatment reconsidered, in line with current advice in the marketing authorisation. The Committee agreed with the clinical specialists that women suitable for treatment with prucalopride should be treated by a clinician with experience in managing chronic constipation who has carefully reviewed the woman's previous courses of laxative treatments.