Pentosan polysulfate sodium for treating bladder pain syndrome

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 bladder pain syndrome can lead to people needing 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 disrupts normal living.

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.

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

The clinical experts explained that the treatment pathway for bladder pain syndrome can vary substantially between services across the country. They explained that the condition is difficult to diagnose and that the presence of glomerulations is not specific to bladder pain syndrome. The clinical guideline recommendations for treating the condition vary and services use a variety of international guidelines to guide clinical management. 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, or be offered bladder instillations. The patient experts explained that not all treatments are available in all areas of the country; treatments depend on where a person lives and what is offered at their local hospital rather than what is suitable for their condition. The committee recognised that there is substantial variability in the clinical management of bladder pain syndrome and the treatment pathway is poorly defined.

The company submitted analyses comparing pentosan polysulfate sodium with bladder instillations and with best supportive care. Bladder instillations are offered to people who can tolerate them. Best supportive care continues to be offered to people who can't tolerate bladder instillations, or if bladder instillations are unsuitable for them. The clinical experts highlighted that some people would choose not to have bladder instillations because of their invasive nature and would instead choose best supportive care. The company noted that best supportive care is the continuation of oral treatments (see section 3.3). The clinical experts explained that, if available, pentosan polysulfate sodium would be tried before bladder instillations. The clinical experts explained that other treatment options for the condition are available. But they noted that laser surgery for Hunner's lesions can be considered at any point in the treatment pathway and that botulinum toxin type A and sacral neuromodulation are generally used in research and not routine clinical practice. The committee acknowledged the variation in clinical practice. It recognised that pentosan polysulfate sodium could be given at different points in the treatment pathway but it would tend to be used before bladder instillations. However, considering the information from clinical experts, the committee agreed that bladder instillations and best supportive care were the standard clinical management options for this condition and were the most relevant comparators.

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:

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:

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 for an indirect treatment comparison should be used. The committee concluded that the ERG's Bayesian network meta-analysis was acceptable because it better characterised the uncertainty in comparing active treatments.

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. In the company's updated analysis, it 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 derive 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.

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 the question in the survey about previous bladder instillation use was vague. This could have meant that patients who never used bladder instillation 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). It also highlighted that the patient survey did not collect data on utilities associated with pentosan polysulfate treatment. The committee concluded that missing data from the patient survey was not adequately accounted for in the company's model.

After the technical engagement stage, the company provided clinical expert evidence and a systematic review to support their 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 be given 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. It provided an alternative sensitivity analysis based on a paper by Cervigni et al. (2017). The committee noted that this analysis did not include a utility decrement for UTIs and resulted in incremental cost-effectiveness ratios (ICERs) that are similar to the company's base case. However, the committee also noted that this analysis included a trial population who were not covered by the marketing authorisation, which introduced some uncertainty into the analyses. The committee concluded that there was insufficient evidence to assume a direct link between bladder instillations and UTIs and that any associated decrement is likely to be short-lived.

The company justified modelling a utility decrement for bladder instillations because it considered bladder instillations 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 counter-intuitive when compared against the utility score for people whose condition did not respond to treatment having best supportive care. This was unlikely to be the case. The ERG noted that the difference in utility in the patient survey between people who had and people who had not recently used bladder instillations may reflect baseline patient characteristics rather than being treatment specific. The patient and clinical experts explained that both bladder instillations and pentosan polysulfate sodium may be associated with decrements. 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.

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 monthly for 4 to 6 months, and continuation would be based on response to treatment. They also noted that it is reasonable to administer maintenance treatment at 6-weekly intervals for subsequent bladder instillations if this achieved the same response in patients as a 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 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).

The company's model assumed that bladder instillations are 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.

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 is a result of bladder pain syndrome with glomerulations or Hunner's lesions. The clinical experts explained that most people having bladder instillation 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.

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

The company's updated base case included the following committee-preferred assumptions:

The company's updated base case included the following committee-preferred assumptions:

The company's base-case ICER compared with best supportive care (including a confidential commercial arrangement) was £76,213 per QALY gained. The committee's preferred modelling assumptions were reflected in the ERG's analyses:

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.

Pentosan polysulfate sodium is not recommended for use in the NHS, within its marketing authorisation, for treating bladder pain syndrome. Despite taking into account the unmet need for effective treatment options for this population and the committee's most plausible assumptions, the ICERs for the comparisons with bladder instillations and with best supportive care were much higher than what is considered to be a cost-effective use of NHS resources. Therefore, the committee could not recommend pentosan polysulfate sodium for treating bladder pain syndrome with glomerulations or Hunner's lesions in adults with moderate to severe pain, urgency and frequency of urination.