Pentosan polysulfate sodium for treating bladder pain syndrome

3.1 The clinical experts explained that bladder pain syndrome is a chronic bladder condition characterised by pain, urinary urgency, frequency and getting up at night to pass urine. The patient expert explained that people with bladder pain syndrome need the toilet up to 60 times a day and that some people had considered suicide because of the pain. Treatments generally aim to control the symptoms because there is no cure for the condition. The committee concluded that bladder pain syndrome is incurable, very challenging to manage and causes extreme pain, which severely affects quality of life.

3.2 The clinical experts explained that bladder pain syndrome may affect approximately 400,000 people in the UK but only around 10% of these will present for treatment. The committee acknowledged that within the broader bladder pain syndrome population are people who also have glomerulations or Hunner's lesions. The marketing authorisation for pentosan polysulfate sodium is for treating 'bladder pain syndrome characterised by either glomerulations or Hunner's lesions in adults with moderate to severe pain, urgency and frequency of micturition'. The committee considered that this was the relevant population for the appraisal.

3.3 Treatment options for people with bladder pain syndrome and either glomerulations or Hunner's lesions include:

3.4 The clinical experts explained that the treatment pathway for bladder pain syndrome can vary substantially between services across the country. They added that the condition is difficult to diagnose and the presence of glomerulations is not specific to bladder pain syndrome. Services use international guidelines to guide clinical management and the recommendations for treating the condition vary. The company noted that bladder pain syndrome is initially treated with oral medication (see section 3.3). If glomerulations or Hunner's lesions are found, then people can continue to have oral treatments as best supportive care or be offered bladder instillations. The patient experts explained that not all treatments are available in all areas of the country. Treatments typically depend on where a person lives and what is offered at their local hospital rather than what is best for their condition. The company and clinical experts stated that pentosan polysulfate sodium would only be used in secondary care. The committee recognised that there is substantial variability in the clinical management of bladder pain syndrome and the treatment pathway is poorly defined. However, the committee agreed that pentosan polysulfate sodium would only be available as a treatment option in secondary care.

3.5 The company submitted analyses comparing pentosan polysulfate sodium with bladder instillations. At the second committee meeting, the company said that it was positioning pentosan polysulfate sodium as an alternative to bladder instillations. Bladder instillations are offered to people who can tolerate them. The clinical experts explained that other treatment options for the condition are available. They noted that laser surgery for Hunner's lesions can be considered at any point in the treatment pathway. Also, botulinum toxin type A and sacral neuromodulation are generally used in research and not routine clinical practice. The clinical experts explained that, if available, pentosan polysulfate sodium would be tried before bladder instillations. The committee recognised that pentosan polysulfate sodium could be offered at different points in the treatment pathway but would tend to be used before bladder instillations. Considering the information from the clinical experts, the committee agreed that bladder instillations were a standard clinical management option for this condition and were a relevant comparator.

3.6 The company's submission included analyses comparing pentosan polysulfate sodium with best supportive care (which is the continuation of oral medication). However, after consultation the company stated that it did not consider pentosan polysulfate sodium to be an alternative to best supportive care. At the first committee meeting, the clinical experts advised that best supportive care is offered to people who can't tolerate bladder instillations, or if bladder instillations are unsuitable for them. They highlighted that some people would choose best supportive care because bladder instillations are invasive. The clinical experts estimated that bladder instillations would not be suitable for less than 5% of patients. The committee recognised that the proportion of people who would have best supportive care instead of bladder instillations was low. However, it considered that pentosan polysulfate sodium would be an alternative treatment option for this group of people. Because of this, the committee concluded that best supportive care was still a relevant comparator for this limited population.

3.7 The company's clinical effectiveness evidence came from 4 randomised controlled trials comparing pentosan polysulfate sodium with placebo in people with bladder pain syndrome and either glomerulations or Hunner's lesions. The trials were published between 1987 and 2003. The ERG noted that:

3.8 To compare pentosan polysulfate sodium with bladder instillations, the company used an indirect treatment comparison. Both the company and the ERG acknowledged that this was necessary, but agreed it was challenging because of:

3.9 The ERG did a Bayesian network meta-analysis, which showed response rates of 33% for pentosan polysulfate sodium compared with 24% for bladder instillations. After the technical engagement stage, the company also did a Bayesian network meta-analysis comparing pentosan polysulfate sodium with bladder instillations as a scenario analysis. This showed response rates of 38% for pentosan polysulfate sodium compared with 28% for bladder instillations. The ERG advised that the company's network meta-analysis had methodological limitations because it did not use separate baseline and treatment effects models to estimate absolute response rates. The committee understood that although both the company's and the ERG's approaches had their limitations, the best possible methods should be used for an indirect treatment comparison. At the first meeting, the committee concluded that the ERG's Bayesian network meta-analysis was acceptable because it better characterised the uncertainty in comparing active treatments. After consultation, the company argued that neither method was ideal and so kept the Bucher method in its base-case analysis. The committee agreed that all the indirect treatment comparisons it had seen had limitations. But it considered that it had not heard anything to change its original decision that the ERG's Bayesian network meta-analysis was more acceptable than the company's Bucher method.

3.10 The company noted that the high response rates (16%) in the placebo arms of the pentosan polysulfate sodium trials did not reflect clinical practice. It considered these high response rates would underestimate the effectiveness of pentosan polysulfate sodium. The ERG noted that the high response rates could be explained by regression to the mean, which would also be present in the intervention arms. The ERG also noted that in the company's model, the absolute difference in treatment effect becomes greater with increasing best supportive care response. This would result in the high response rate in the placebo arm favouring pentosan polysulfate sodium because the company's analysis used relative risks. The company's base-case analysis modelled a 15.8% placebo response rate. The company's Bayesian scenario analysis included the placebo arms of the bladder instillation trials, which gave an 18.9% estimated response rate. The clinical experts explained that real-world evidence may suggest even higher placebo response rates. This is expected because patients with the condition initially have benefit, but this is not sustained beyond 3 months. The committee acknowledged that the clinical experts' views and the ERG's analysis results (15.5%) were broadly in line with the placebo response rates from the pentosan polysulfate sodium trials (16%). The committee concluded that a 16% response rate to placebo was acceptable to use in the cost-effectiveness analysis, and that the company's base-case analysis was in line with this.

3.11 In its base-case model, the company applied a utility decrement associated with bladder instillations. The company mapped patient survey data collected in the Sant et al. (2003) trial to EQ‑5D data. The company used responses to a question in the survey on the use of bladder instillations in the previous 6 months. The ERG noted that the wording of this survey question was vague. This could have meant that patients who had never had bladder instillations did not answer the question and this was recorded incorrectly as missing data. The ERG's preferred method to account for the missing data was to use multiple imputation (a statistical method used to reduce bias arising from missing data). After consultation, the company outlined that multiple imputation was not appropriate because the missing data were not missing at random. The company also highlighted methodological challenges because the data predicted by the imputation would depend on the data that informed the imputation. The committee understood that there were very few responses from the patient survey about quality of life associated with pentosan polysulfate sodium treatment. The committee concluded that missing data from the patient survey was not adequately accounted for in the company's model.

3.12 After the technical engagement stage, the company provided clinical expert evidence and a systematic review to support its assumption that bladder instillations are associated with an increase in urinary tract infections (UTIs). The company explained that the evidence showed that people with UTIs have substantially lower quality of life than those without UTIs. It also proposed that UTIs in people with bladder pain syndrome have a bigger impact on quality of life than UTIs in the general population. The ERG noted that the company's model assumed that everyone having bladder instillations would have a UTI and that the associated decrement was modelled for a lifetime. The clinical experts explained that not all people having bladder instillations would get a UTI and although the symptoms may last longer than for the general population these would not continue indefinitely. They also noted that people would have the choice of continuing bladder instillation treatment if they did get a UTI. The company noted that UTIs are only 1 aspect of the decrement associated with bladder instillations. After consultation, the company emphasised the evidence relating to the impact of UTIs on quality of life including the quality of life data reported by Cervigni et al. (2017). The committee considered that the Cervigni study was not generalisable to the population covered by the pentosan polysulfate sodium marketing authorisation. This was because the study included a trial population who were not covered by the marketing authorisation (pentosan polysulfate sodium was used as initial treatment for some patients and for others, pentosan polysulfate sodium treatment had already failed before), which introduced some uncertainty into the analyses. The study was based on Italian EQ‑5D valuation and the values in the study didn't correspond with response to treatment. The committee considered that it had not seen any new information about the duration of UTIs or the proportion of patients who had UTIs. The committee concluded that there was insufficient evidence to assume a direct link between bladder instillations and UTIs and that any associated decrement was likely to be short-lived.

3.13 The company justified modelling a utility decrement for bladder instillations because it considered them to be invasive and associated with adverse effects. The committee noted that the utility decrement was applied for all patients who had bladder instillations for the lifetime of the company's model. It also noted that the utility score for patients having subsequent bladder instillations was counterintuitive when compared with the utility score for people whose condition did not respond to treatment and who moved onto best supportive care (these results are academic in confidence and cannot be reported here). The ERG noted that the difference in utility score in the survey between people who had and people who had not recently had bladder instillations may have reflected baseline patient characteristics rather than treatment. The clinical experts also added that any decrement associated with bladder instillations was likely to be short-lived because the treatment would be stopped if there were any adverse events. The committee concluded that applying a utility decrement for bladder instillations was not appropriate.

3.14 The company modelled weekly administration of first-time bladder instillations for the first 4 weeks, and 4‑weekly administration after this point. This frequency also applied to all subsequent bladder instillations. The clinical experts explained that initial treatment with bladder instillations would be weekly for 4 weeks followed by maintenance treatment once every 4 weeks for 4 to 6 months. Continuation would be based on response to treatment. They also noted that it was reasonable to administer maintenance treatment at 6‑weekly intervals for subsequent bladder instillations if this achieved the same response in patients as 4‑weekly administration. The patient expert explained that maintenance treatment intervals vary according to the person and can be either monthly or when symptoms return. If maintenance treatment is led by the patient based on their symptoms, this would lengthen the interval between instillations beyond 4 weeks. The ERG's model accounted for this variation. It included 6‑weekly maintenance intervals for subsequent bladder instillations and for first-time bladder instillations after a year of treatment. The committee acknowledged the variation in clinical practice and recognised that administration would be different for first-time and subsequent bladder instillations. The committee considered the company's response to consultation. This outlined that 4‑weekly administration is in line with the manufacturer's recommendations, treatment is tailored to individual patient needs, and variability in dosing frequency results in some intervals being shorter than 4‑weekly whereas others are longer. However, based on the evidence from the ERG and clinical experts, the committee concluded that it was acceptable to assume 6‑weekly administration for subsequent bladder instillations and for first-time bladder instillations after the first year (in line with the ERG's model).

3.15 Both the company's and the ERG's models assumed that bladder instillations were administered indefinitely. The clinical experts explained that bladder instillations would not continue for a lifetime and estimated that only 5% of patients would continue with them after 5 years. The committee acknowledged that in clinical practice bladder instillations would not continue indefinitely and most patients would stop within 5 years. It also recognised that best supportive care becomes a more relevant comparator if more patients stop treatment with bladder instillations.

3.16 The company's model included a proportion of patients who would have inpatient care for bladder instillations. The ERG noted that the disease-related costs in the company's model had been overestimated because not all of the resource use was a result of bladder pain syndrome with glomerulations or Hunner's lesions. The clinical experts explained that most people having bladder instillations are seen in outpatient care; the number having inpatient care is negligible. The committee considered that the company had overestimated the disease-related costs by modelling a proportion of patients to have inpatient care. The committee concluded that inpatient resource use would be minimal in a population having bladder instillations. However, it was aware that the incremental cost-effectiveness ratio (ICER) was not sensitive to this parameter in the model.

3.17 The committee noted the substantial uncertainty in the model inputs, specifically:

3.18 The company's base case included the following assumptions:

3.19 The company's base case included the following assumptions:

3.20 The committee acknowledged that the treatment pathway for bladder pain syndrome was complex and varied between services. The clinical experts advised that pentosan polysulfate sodium would generally be used before bladder instillations or for people who could not have bladder instillations. However, the experts and responses to consultation indicated that pentosan polysulfate sodium may be used after bladder instillations have been tried. The committee accepted that the complex pathway made it difficult to separate populations based on comparators.

3.21 In the company's and the ERG's models, patients having bladder instillations were assumed to stay on them indefinitely. The models did not capture the cost effectiveness of pentosan polysulfate sodium when it was taken after a lack of response to treatment with bladder instillations. The models also did not capture the cost effectiveness of pentosan polysulfate sodium when it was taken in combination with bladder instillations. The committee concluded that it could not assess the cost effectiveness of pentosan polysulfate sodium for these populations.

3.22 The clinical experts stated that there are many different types of oral treatments for bladder pain syndrome and that these have to be tried repeatedly. The committee was aware that best supportive care consisted of less expensive oral treatments than pentosan polysulfate sodium. It was also aware that some people get good disease control from standard oral treatments. The company and clinical experts agreed that pentosan polysulfate sodium would be used after inadequate response to standard oral treatments. The committee concluded that standard oral treatments should be tried first (see section 3.3) and that pentosan polysulfate sodium should only be used for people who have stopped these treatments because of a lack of response.

3.23 The clinical experts explained that bladder instillations would be unsuitable for less than 5% of people. The committee acknowledged that because this is likely to be a small population, the estimated impact on NHS resources is also likely to be small (see section 6.2.14 in NICE's guide to the methods of technology appraisal).

3.24 The ICER for the comparison with best supportive care was higher than what is considered to be cost effective. But the ICER for the comparison with bladder instillations was considered to be a cost-effective use of NHS resources, taking into account:

3.25 The company and a clinical expert highlighted that bladder pain syndrome affects more women than men. However, issues related to differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal.