4 Committee discussion

The appraisal committee reviewed the data available on the clinical and cost effectiveness of abiraterone, having considered evidence on the nature of metastatic hormone-relapsed prostate cancer and the value placed on the benefits of abiraterone by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.

4.1 The committee considered current treatment options in England for people with metastatic hormone-relapsed prostate cancer who have no or only mild symptoms. The committee heard from clinical experts that, when cytotoxic chemotherapy is indicated, most people have docetaxel. The clinical experts stated that docetaxel is normally offered to people with rapidly progressing disease who are fit enough for chemotherapy and who have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. They added that deferring docetaxel in this group would not be appropriate because the disease rapidly progresses, and patients may not be fit enough to have it at a later date. However, when people have no or mild symptoms, clinicians may instead offer best supportive care including corticosteroids such as prednisolone or dexamethasone. The committee heard from the clinical experts that some patients chose not to have docetaxel. The committee noted that abiraterone, which is taken with prednisolone, has a marketing authorisation for use before chemotherapy. It understood that patients can currently get abiraterone at this point in the treatment pathway through the Cancer Drugs Fund. It heard from the clinical experts that there is no consensus on how to decide whether to offer abiraterone to patients, but that clinicians would generally offer it, in addition to best supportive care, to people with few symptoms to delay chemotherapy, or to treat people who are unable or do not wish to have chemotherapy. The committee also understood from the clinical experts that they switch patients from abiraterone to docetaxel within a week of disease progression if the patients are fit enough for docetaxel. The committee was aware that, during the course of this appraisal, enzalutamide had been recommended by NICE for use before chemotherapy. The committee accepted that, when deciding whether to offer abiraterone, enzalutamide, corticosteroids or docetaxel, clinicians would take into account a person's fitness for chemotherapy, performance status, symptom severity and the patient's views on taking chemotherapy. The committee was aware of responses to consultation, highlighting that it is important to patients and clinicians to have a choice of treatments. It concluded that both patients and clinicians would like to have the option of using abiraterone.

4.2 The committee discussed the relevant comparators for abiraterone, noting that the scope issued by NICE in 2012 included docetaxel and best supportive care. It understood that the company did not present a comparison of abiraterone with docetaxel because the marketing authorisation states that abiraterone should be used for people for whom chemotherapy is not yet indicated. The committee agreed that this was appropriate. The committee noted that enzalutamide was now available for the same indication as abiraterone, but was not included in the final scope issued by NICE for the appraisal of abiraterone because, at that time, enzalutamide was not licensed for this indication. The committee agreed that enzalutamide should not be included as a comparator in its decision-making for abiraterone. The committee concluded that the key comparison in this appraisal was between a sequence of:

  • abiraterone followed by docetaxel and subsequent treatments, and

  • watchful waiting (including best supportive care) followed by docetaxel and subsequent treatments.

    The committee noted that, in current clinical practice in England, the 'subsequent treatments' in the second sequence may include abiraterone. It acknowledged that some patients may not have docetaxel at any stage.

4.3 The committee heard from the patient experts that it is important to have the option of delaying chemotherapy because chemotherapy has adverse effects that reduce people's quality of life. The patient experts advised that chemotherapy may be particularly poorly tolerated by older people or those who lack support from a partner or carer. The patient experts stated that some people may choose not to have, or to delay, chemotherapy to avoid its debilitating effects and to maximise their quality of life, even if it may mean dying sooner. However, the committee also noted responses to consultation suggesting that disease and performance status may worsen, and that this may lead to some people becoming unable to tolerate the side effects associated with chemotherapy later on or unable to gain the full survival advantage from the sequence of treatments now available. The committee appreciated that abiraterone delayed the time to treatment with chemotherapy in COU‑AA‑302. It also understood that patients taking abiraterone switch to docetaxel when clinically indicated, so that chemotherapy is not delayed once needed. The committee concluded that there is some uncertainty about the benefits or consequences of delaying chemotherapy in terms of survival and quality of life, but accepted the view of patients that delaying chemotherapy is of value to them.

4.4 The committee discussed using abiraterone in people who are not fit enough for chemotherapy. It heard from clinical experts, commentators during consultation and the company that these patients currently get abiraterone through the Cancer Drugs Fund. The committee noted, however, that COU‑AA‑302 included only people with a good performance status (ECOG 0 or 1) and few comorbidities (see section 3.4), and so did not include people unfit for chemotherapy. The committee therefore considered that there was no clinical evidence available to allow it to appraise the cost effectiveness of abiraterone in this population. The committee was also aware that the marketing authorisation for abiraterone does not include people for whom chemotherapy is indicated (that is, people with more than mild symptoms) but who are unfit for chemotherapy. The committee was therefore unable to make a separate recommendation for people who are not fit for chemotherapy.

Clinical effectiveness

4.5 The committee considered whether the randomised placebo-controlled trial COU‑AA‑302 was generalisable to clinical practice in England. It noted that the trial recruited 9% of its patients from the UK and that people in both arms had prednisolone/prednisone. In line with advice from the clinical experts, the committee considered that the placebo arm reflected best supportive care in England before treatment with chemotherapy. The committee heard from the clinical experts that the average age of people in COU‑AA‑302 was similar to that of the people who would be offered abiraterone in clinical practice in England. It heard that the reasons for stopping abiraterone treatment in the trial broadly reflect clinical practice in England. The committee noted that patients in the study stopped treatment with abiraterone when their disease progressed radiographically or clinically, at which point they could have other treatments including docetaxel. The clinical experts stated that, in clinical practice in England, people would get abiraterone or best supportive care until clinical progression rather than radiographic progression. The clinical experts advised that people switch to docetaxel within a week of clinical progression if they are fit enough to tolerate chemotherapy. Despite the difference in defining progression-free survival, the committee concluded that COU‑AA‑302 generally reflected clinical practice in the UK and was relevant to address the decision problem.

4.6 The committee discussed the clinical-effectiveness results from COU‑AA‑302, noting that abiraterone delayed the progression of disease (diagnosed radiographically) compared with placebo. The committee was aware that the survival benefit of abiraterone compared with placebo was not statistically significant at the second and third interim analyses, but was statistically significant at the final analysis. The committee was aware that the company unblinded COU‑AA‑302 early, between the second and third interim analyses, based on advice from the Independent Data Monitoring committee (see section 3.3). It also heard that, after unblinding, people in the trial having placebo could cross over to have abiraterone. Following a request from the committee, the company provided data on treatment switching and subsequent treatments in COU‑AA‑302, to clarify the impact of these factors on the final survival estimates.

4.7 The committee discussed the company's additional evidence about treatment switching and subsequent treatments in COU‑AA‑302. It noted that patients had treatments that prolong survival but are not routinely available in the NHS, specifically:

  • About 42% of patients in the placebo group had cabazitaxel, sipuleucel‑T or abiraterone before docetaxel. The committee noted that, although currently offered via the Cancer Drugs Fund, cabazitaxel is not recommended for prostate cancer in NICE's technology appraisal on cabazitaxel for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. Sipuleucel‑T no longer has a UK marketing authorisation.

  • About 27% of patients in the abiraterone group had cabazitaxel or sipuleucel T.

    In the abiraterone group, about 29% of patients had subsequent abiraterone or enzalutamide which would not be offered in the NHS. The committee noted that the company provided evidence about selected additional therapies including docetaxel (which is part of established NHS treatment) and ketoconazole (which has not been proven to extend life); the committee concluded it was not necessary to control for the effects of docetaxel and ketoconazole in analyses. The committee agreed that treatment switching and subsequent treatments that are not available in the NHS probably extended survival in both groups of COU‑AA‑302, but the effect was probably greater for the placebo group because more people took these treatments. It was aware that the company's analysis controlling for treatment switching improved the hazard ratio for overall survival from 0.81 (unadjusted estimate) to 0.74, although it recognised that hazard ratios were not used in the modelling. Overall, the committee concluded that abiraterone delayed disease progression and improved overall survival compared with placebo, but that there was uncertainty about the extent of the survival benefit.

Cost effectiveness

4.8 The committee understood that the company had developed a discrete event simulation model, rather than the more commonly used Markov model, because it allowed more flexibility to reflect a sequence of treatments, and to model response to treatments that depend on previous treatments. The committee agreed that using a discrete event simulation model was not unreasonable, but that the company's model was particularly complex. In particular, for each of the model's 17 equations predicting time to events or disease status, the committee noted that the company made a large number of judgements when determining which covariates to include and which parametric distribution to choose for extrapolation (see section 3.14). The committee noted that, for 2 equations, the company had not followed its own statistical plan when choosing covariates, and the committee agreed that this could introduce bias to the model. The committee concluded that the company's model was complex and lacked transparency, which made it difficult for the evidence review group (ERG) to validate and critique, and for the committee to determine the plausibility of the model outcomes.

4.9 The committee discussed the clinical data used to inform the company's model. It noted that the company preferred to use data from the third interim analysis of COU‑AA‑302 rather than the final analysis because the interim data needed less adjustment for patients who crossed over from the placebo group to the abiraterone group. The committee concluded that it was reasonable to use data from the third interim analysis, but it requested that the company provide further evidence comparing the modelled estimates with the final trial data for time on first treatment and overall survival (see sections 4.12–4.14).

4.10 The committee discussed the company's choice of parametric distribution for each of the 10 equations in the model that needed extrapolating. The committee was aware that the company considered several functions and selected the best fitting distribution using statistical criteria and visual inspection. The committee noted that:

  • A log-logistic curve had been used to extrapolate the equations to predict:

    • time from starting to stopping first treatment with abiraterone or best supportive care

    • time from starting docetaxel to death (if patient died while taking docetaxel).

  • A log-normal distribution had been used to extrapolate the equation to predict:

    • time from stopping abiraterone or best supportive care to starting docetaxel.

  • All other prediction equations had been extrapolated with a Weibull distribution.

    The committee heard from the ERG that using the log-logistic distribution for extrapolating is sometimes criticised because it has a 'long tail', unlike the Weibull distribution. A 'long tail' means that some patients continue for a long time without having the relevant event (such as stopping treatment). The committee, noting NICE's Guide to the methods of technology appraisal 2013, concluded that it was appropriate to explore the impact of using different parametric distributions on the model results.

4.11 The committee discussed the sensitivity analyses that used different parametric distributions. Using a Weibull instead of a log-logistic distribution for 1 equation (time from starting to stopping first treatment) increased the company's base-case incremental cost-effectiveness ratio (ICER) from £28,600 to £35,800 per quality-adjusted life year (QALY) gained. Similarly, using Weibull instead of log-logistic distributions for 2 equations (time from starting to stopping first treatment and time from starting docetaxel to death while taking docetaxel) increased the ERG's exploratory base-case ICER from £35,500 to £55,600 per QALY gained. The committee was also aware of the company's analysis, submitted in response to the second appraisal consultation document, using a piecewise curve for predicting time on first treatment (see section 3.22). Using the piecewise curve increased the company's base-case ICER from £28,600 to £32,800 per QALY gained. The committee heard from the company that it preferred to use the log-logistic distribution to predict time on first treatment because, if people's disease responds to abiraterone, they tend to stay on it for a long time. After the third committee meeting, the committee asked the company to submit additional data about treatment durations with abiraterone.

4.12 The committee discussed how long people take abiraterone, noting that the company had provided 3 sets of data: the final analysis of COU‑AA‑302; data from clinical practice in the UK; and data from clinical practice in the US. The UK data are commercial-in-confidence and cannot be presented here.

  • The committee inspected the final Kaplan–Meier curves from the COU‑AA‑302 trial and compared them with the extrapolation curves used in the company's model (that is, log-logistic in the base case and Weibull or piecewise in sensitivity analyses). For the abiraterone arm, for the time period for which data were available (the trial period), the committee agreed with the company that the log-logistic curve was the best fit to the trial data. However, it noted that the log-logistic curve predicted that some patients remained on abiraterone for a long time and about 4% took abiraterone for at least 8 years, but the trial data did not support this prediction because the maximum follow-up time in the trial was about 5 years. The committee noted that the Weibull curve predicted that fewer patients remain on abiraterone in the long term, and the piecewise curve gave predictions that were in-between the log-logistic and Weibull curves.

  • The committee discussed the UK data. It noted that the company had not presented the sample size, and the data included people treated with abiraterone both before and after chemotherapy. The committee concluded that the UK data could not be used to inform its decision.

  • The committee discussed the data from healthcare insurance claims made by 8,326 patients treated with abiraterone in the US; these patients had not had previous chemotherapy. It noted that 14% of people were still taking abiraterone after 4.4 years. While the committee had concerns about whether the results were generalisable to the UK, it concluded that some patients in the UK were likely to take abiraterone for long periods of time.

    Having considered all of the evidence, the committee concluded that its preferred analysis used either a log-logistic curve or a piecewise curve to predict time on abiraterone.

4.13 The committee discussed how long people remain on best supportive care before starting docetaxel, noting that the company had provided data from the final analysis of COU‑AA‑302. The committee was concerned that neither the log-logistic distribution (used in the base case) nor the Weibull distribution (used in sensitivity analyses) provided a good fit to the final trial data, and both distributions overestimated the time that patients would remain on best supportive care. The committee noted that the piecewise curve (used in sensitivity analyses) was a closer fit to the trial data, but in this analysis the company assumed that all patients stopped having best supportive care at about 1,000 days; the committee was concerned that this assumption may not be clinically plausible. The committee concluded that, for predicting time on best supportive care, it preferred to use the same distribution as was used for abiraterone (that is, log-logistic or piecewise, see section 4.12).

4.14 The committee discussed the predictions of overall survival in the company's model. It inspected the final Kaplan-Meier survival curves from the trial and compared them with the survival curves predicted by the company's base-case model, which extrapolated beyond the trial data. The committee noted that, beyond about 3 years of follow-up, for both treatment groups the trial data showed longer survival times than predicted by the model. The committee acknowledged that this may be because of treatment switching and the use of subsequent treatments in the trial that are not available on the NHS (see section 4.7). It was also aware that, because of these potential confounders, the company had used data from the third interim analysis for modelling rather than the final analysis. The committee was aware of the company's response to the second appraisal consultation document, which stated that the model over-estimated survival times with best supportive care when compared with the placebo group of the trial after adjusting for treatment switching. The committee concluded that the model predictions of overall survival were uncertain and it was unclear whether the model over- or under-estimated survival times.

4.15 The committee discussed the company's method for adjusting modelled survival times to remove the benefit of treatments that were used in the COU‑AA‑302 trial but are not used in the NHS. The committee understood that the survival times of patients in the abiraterone arm of the model were reduced to remove the benefit of cabazitaxel, enzalutamide and re-treatment with abiraterone. The committee accepted that it was appropriate to adjust for treatments that have a survival benefit and which are not available in the NHS. However, it noted that the company's method (see section 3.13) was an approach that neither the ERG nor the committee had seen before. The committee noted that adjusting for subsequent treatments had a modest impact on the ICER (the company's base case with adjustment was £28,600 per QALY gained; a scenario without adjustment was £27,700 per QALY gained). The committee also noted that the company did not adjust for treatment switching and subsequent treatments in the best supportive care arm of the model. Overall, the committee concluded that adjustment for subsequent treatments in the abiraterone arm should be included in the analyses used for decision-making, recognising that such an adjustment was included in the company's base-case and scenario analyses, and the ERG's exploratory base case.

4.16 The committee discussed the trial population used to inform the model. It noted that, for each prediction equation, the company used data from all the patients in the COU‑AA‑302 intention-to-treat (ITT) population who had complete data for the covariates in that equation. Consequently, the sample size varied between equations; the minimum sample was the 902 people for whom complete data were available (the 'full covariate subgroup'). The company's approach is subsequently referred to as 'using the full covariate subgroup'. The committee was aware that the ERG preferred to use the ITT population for modelling, which meant that the ERG's prediction equations did not include covariates. The committee heard that, in the company's opinion, it was appropriate to use the full covariate subgroup because:

  • Covariates were needed to predict patients' response to the 3 lines of treatment in the model.

  • There was no statistically significant difference in baseline characteristics between the ITT and full covariate subgroup.

  • The predicted survival times with abiraterone had a better fit to the trial data when using the full covariate subgroup than when using the ITT population.

    The committee heard that the ERG preferred to use the ITT population because:

  • The full covariate subgroup was a non-random subset of the ITT population, and using the subgroup could bias the results of the model. That is, the reasons patients did not have complete data may have been related to the clinical outcomes for those patients.

  • The incremental survival benefit seems overestimated when using the full covariate population.

    The ERG's analysis using the ITT population increased the company's base-case ICER from £28,600 to £35,200 per QALY gained. The committee agreed that, as a general principle, it preferred to use the ITT population for modelling because this reduces the risk of bias. However, in this specific case, the committee agreed with the company that using the full covariate subgroup provided a closer fit to the trial data. Accordingly, the committee concluded that, on this occasion, it was appropriate to use the full covariate subgroup rather than the ITT population.

4.17 The committee discussed the survival estimates for the post-docetaxel phase of the model. It noted that abiraterone taken after docetaxel had been appraised in abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen (hereafter referred to as TA259), but that the company had not used data from TA259 to check the validity of its model in the current appraisal. It also noted that the modelled post-docetaxel survival times were shorter in the current appraisal (based on data from COU‑AA‑302) than in TA259 (based on data from COU‑AA‑301). The committee was aware that the ERG carried out a scenario analysis in which it fixed post-docetaxel survival to be the same as in COU‑AA‑301, and this increased the ICER. The committee heard from the company that, although the estimates from COU‑AA‑301 came from a larger sample of patients, it did not consider these data to be relevant for the current appraisal because the population in COU‑AA‑301 was different from that in COU‑AA‑302. In particular, the company stated that people in COU‑AA‑301 started docetaxel earlier in their treatment pathway than in COU‑AA‑302 and therefore people in COU‑AA‑301 were also fitter at the point they started post-docetaxel treatments. During the committee meeting, the company stated that the model was designed to follow individual patients through several stages of treatment. In the company's opinion, it was not appropriate to use the COU‑AA‑301 data in the model because doing so would 'break randomisation' and it would not be possible to adjust the data to reflect differences in baseline characteristics between the COU‑AA‑301 trial and the modelled population. On balance, and because of the complex model chosen by the company, the committee agreed with the company and concluded that it was appropriate to use COU‑AA‑302 to estimate post-docetaxel survival times. Nonetheless, it concluded that uncertainty about the modelled survival times persisted because only a small number of patients from COU‑AA‑302 contributed data to this phase of the model.

4.18 The committee discussed the utility values in the company's model. It understood that the company derived utility values, by phase of treatment, from 3 sources:

  • a survey it carried out in patients in the UK with metastatic hormone-relapsed prostate cancer (4 values)

  • COU‑AA‑302 (1 value reflecting an increase in utility experienced by people taking abiraterone before or after docetaxel, using Functional Assessment of Cancer Therapy prostate cancer subscale [FACT-P] data mapped to EQ‑5D)

  • the literature (1 value for quality of life at the end of life).

    The committee had concerns about the study that the company used to map FACT‑P data from COU‑AA‑302 to EQ‑5D. Specifically, the committee was concerned about how the mapping function had been validated, whether uncertainty around the assumptions in the mapping function had been tested in sensitivity analyses, and how the company had chosen when to apply the mapped utility values rather than using values from other sources. The committee questioned whether it was appropriate for the company to include an increment in utility associated with taking abiraterone, given that patients on abiraterone have more adverse events than patients on best supportive care. However, it heard from clinical experts that the adverse events people had on abiraterone were mild and tolerable, and the committee noted that the utility increment associated with taking abiraterone came from trial data. It was also aware of the company's opinion that the adverse events that were more common with abiraterone did not impact on quality of life. The committee accepted that it was appropriate to include a utility increment associated with taking abiraterone in the model. Overall, the committee concluded that the company's modelled utility values were plausible.

4.19 The committee discussed the costs used in the model.

  • It understood that, in the COU‑AA‑302 trial, patients took 98% of the licensed dose on average and so the company's base-case model used 98% of the cost of the licensed dose of abiraterone. The committee considered that the cost of unused tablets was unlikely to be recovered by the NHS, so the full cost of the licensed dose of abiraterone should be included in the model.

  • The committee noted that the costs of administering the PAS, although low, had not been included in the modelling and considered that these costs should have been included. It noted that, in response to the second appraisal consultation document, the company submitted an analysis including these costs.

  • The committee noted that generic versions of docetaxel have become available during the course of the appraisal. To account for this, the company had reduced the cost of docetaxel by 20% from the British national formulary (BNF) cost (£856 for a 160‑mg vial), and the ERG presented a scenario using the electronic market information tool (eMIT) cost (£35 for a 160‑mg vial). The committee noted that, in response to the second appraisal consultation document, the company submitted an analysis using the eMIT cost for docetaxel; this increased the company's base-case ICER from £28,600 to £29,600 per QALY gained. However, the committee recognised that other costs (for drugs or NHS care), which may have also changed during the course of the appraisal, had not been amended and the impact on the ICER of amending these costs was unknown. The committee agreed that the cost of docetaxel may vary across the NHS, but it was likely to be closer to the eMIT cost than that modelled by the company.

    The committee noted that the company's assumptions relating to these costs favoured abiraterone, but that including the committee's preferred assumptions increased the ICER for abiraterone compared with best supportive care only slightly.

4.20 The committee discussed how the company incorporated the abiraterone PAS in its model. It was aware of an existing simple discount PAS for abiraterone, which was agreed as part of TA259 (the appraisal of abiraterone after docetaxel). The committee was also aware that:

  • if the current appraisal recommended abiraterone, then the new complex PAS would apply to abiraterone used either before or after docetaxel

  • if the current appraisal did not recommend abiraterone before docetaxel, then the old PAS would exist for abiraterone after docetaxel.

    The committee noted that the company's model applied the new complex PAS to abiraterone used before but also after docetaxel. The committee noted that an alternative approach was to apply the existing simple PAS to abiraterone used after docetaxel (in the best supportive care arm of the model); it agreed that this would represent the current cost to the NHS of providing abiraterone after docetaxel, but also the future cost of providing abiraterone after docetaxel if the current appraisal did not recommend abiraterone. It noted that the ERG's exploratory analyses applied the existing simple PAS to abiraterone used after docetaxel and that this increased the ICER. The committee heard that, although the company accepted that it was technically correct to apply the existing simple PAS to abiraterone used after docetaxel, it did not think that this approach was reasonable because the 2 PAS's would never exist at the same time. The committee acknowledged that the 2 PAS's would not and could not exist at the same time. Nonetheless it concluded that it was appropriate to include the existing PAS in the best supportive care arm of the model and the new complex PAS in the abiraterone arm for the purposes of decision-making, and it acknowledged that using this approach in a scenario analysis had a modest impact on the ICER.

4.21 The committee considered whether it should take into account the consequences of the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism, when appraising abiraterone. It noted that the company had not made a case for the relevance of the PPRS in this appraisal. The committee noted NICE's position statement in this regard, and accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. After asking the company, the committee heard nothing to suggest that there is any basis for taking a different view on the PPRS in this appraisal of abiraterone. It therefore concluded that the PPRS payment mechanism was not applicable when considering the cost effectiveness of abiraterone.

4.22 The committee discussed whether abiraterone could be considered a cost-effective use of NHS resources. It had concluded that its preferred approach was:

  • to use the full covariate subgroup (as per the company's base case)

  • to use either a log-logistic curve (as per the company's base case) or a piecewise curve (as per the company's sensitivity analysis provided after the second consultation) to predict time on first treatment.

    The committee noted that the company's base-case ICER was £28,600 per QALY gained and the company's ICER using a piecewise curve was £32,800 per QALY gained. The committee agreed that including its preferred assumptions for costs would increase these ICERs, but only slightly (see sections 4.19 and 4.20). The committee remained concerned that the company's model was complex and lacked transparency (see section 4.8). Nonetheless, the committee concluded that the ICER was likely to lie between £28,600 and £32,800 per QALY gained.

4.23 The committee considered supplementary advice from NICE that should be taken into account when appraising treatments that may extend the life of patients with short life expectancy and that are licensed for indications that affect small numbers of people with incurable illnesses. For this advice to be applied, all of the following criteria must be met:

  • The treatment is indicated for patients with a short life expectancy, normally less than 24 months.

  • There is sufficient evidence to indicate that the treatment offers an extension to life, normally of at least an additional 3 months, compared with current NHS treatment.

  • The treatment is licensed or otherwise indicated for small patient populations normally not exceeding a cumulative total of 7,000 for all licensed indications in England.

    In addition, when taking these criteria into account, the committee must be persuaded that the estimates of extension to life are robust, and the assumptions used in the reference case economic modelling are plausible, objective and robust.

4.24 To address whether metastatic hormone-resistant prostate cancer at this stage of therapy is associated with a mean life expectancy of less than 24 months, the committee considered the median overall survival in the control arm of COU‑AA‑302, noting that it was about 30 months. The committee heard from the company in the first meeting that it had estimated the mean survival for the best supportive care arm as 32 months. The committee considered the company's and stakeholder comments received during consultation suggesting that people treated in the NHS would have a lower life expectancy than people in the best supportive care arm of COU‑AA‑302. These comments included:

  • In the trial, people had active treatments after docetaxel that are not available in the NHS including 'sipuleucel‑T, cabazitaxel, ketoconazole and retreatment with abiraterone'. The committee agreed that it was appropriate to adjust survival estimates for active treatments that are not used in the NHS but the company had not done this for the survival estimate for people receiving best supportive care. The committee noted that ketoconazole has not been proven to improve survival in patients with metastatic hormone-resistant prostate cancer, and therefore would not affect survival outcomes.

  • COU‑AA‑302 excluded patients with significant comorbidities and a life expectancy of less than 6 months (see section 3.4), which would make the life expectancy in the control arm longer than in the real-world population. The committee noted that both the clinical experts and the company had stated that COU‑AA‑302 was generalisable to clinical practice in England and reflected patients who would be offered abiraterone in England.

    The committee concluded that COU‑AA‑302 provides a reasonable estimate of the median life expectancy for people with metastatic hormone-resistant prostate cancer for whom abiraterone is indicated, but the impact of active treatments used in the trial that are not used in the NHS was unclear. The committee further concluded that adjusting for these was unlikely to reduce the mean life expectancy from 32 months to below 24 months.

4.25 The committee considered carefully the company's review of the published literature on alternative estimates of survival for people with prostate cancer. Overall, the committee concluded that current mean life expectancy for people with metastatic hormone-relapsed prostate cancer for whom chemotherapy is not yet indicated was unlikely to be less than 24 months.

4.26 Having determined that abiraterone did not meet the 'end of life' criterion on life expectancy, the committee discussed the criteria of small patient population and whether abiraterone extended life by more than an average of 3 months. It noted that the company, in its response to the appraisal consultation document, estimated that 6,782 people would be eligible for the pre- and post-docetaxel marketing authorisations in England, but that a proportion of the population eligible for abiraterone after docetaxel would not have abiraterone if they had it before docetaxel. The committee concluded that the eligible population for England did not exceed 7,000 and that abiraterone therefore met the end-of-life criterion for a small patient population. The committee noted that the final analysis of COU‑AA‑302 showed a median survival benefit of 4.4 months and the modelled mean survival benefit was longer than this. It concluded that the extension-to-life criterion was met. However, because the 24 month life expectancy criterion had not been met, the committee concluded that the end-of-life criteria did not apply to abiraterone taken before docetaxel in the treatment pathway.

4.27 The committee considered whether abiraterone was innovative and whether it had substantial, demonstrable and distinctive benefits not adequately captured in the modelling of the QALYs. The committee noted that, although abiraterone is not a new technology, it was the first active treatment available for this position in the treatment pathway and, in this regard, was innovative. It then considered whether the model captured the benefits of either having abiraterone at an earlier point in the treatment pathway when people had higher quality of life, or delaying the need for cytotoxic chemotherapy, such as docetaxel. The committee noted that the model predicted that people in the abiraterone arm have more time with better utility before docetaxel than people on best supportive care. However, the committee agreed that the benefit of delaying chemotherapy perceived by patients may not have been fully captured by the utility values included in the modelling and that accounting for this would have reduced the ICER. The committee concluded that abiraterone was innovative and this should be considered in its decision-making.

4.28 The committee noted that NICE's Guide to the methods of technology appraisal states that, if a technology has a most plausible ICER above £30,000 per QALY gained, the committee will need to identify an increasingly stronger case for supporting the technology as an effective use of NHS resources. The committee noted that:

  • The most plausible ICER for abiraterone compared with best supportive care was between £28,600 and £32,800 per QALY gained.

  • Abiraterone was the first active treatment available for this position in the treatment pathway and, in this regard, was innovative.

  • The utility values in the model may not fully capture the benefit to patients of delaying cytotoxic chemotherapy.

    Taking all of these factors into account, the committee agreed that the ICER for abiraterone compared with best supportive care would likely fall below £30,000 per QALY gained, and it considered abiraterone to be a cost-effective use of NHS resources. The committee concluded that abiraterone in combination with prednisone or prednisolone should be recommended within its marketing authorisation, for treating metastatic hormone-relapsed prostate cancer in people who have no or mild symptoms after androgen deprivation therapy has failed and in whom chemotherapy is not yet clinically indicated.

Summary of appraisal committee's key conclusions

TA387

Appraisal title: Abiraterone for metastatic hormone-relapsed prostate cancer before chemotherapy is indicated

Section

Key conclusion

Abiraterone in combination with prednisone or prednisolone is recommended, within its marketing authorisation, as an option for treating metastatic hormone-relapsed prostate cancer:

  • in people who have no or mild symptoms after androgen deprivation therapy has failed, and before chemotherapy is indicated

  • only when the company provides abiraterone in accordance with the commercial access arrangement as agreed with NHS England.

1.1

The committee concluded that abiraterone delayed disease progression and improved overall survival compared with placebo.

4.7

The committee concluded that the incremental cost-effectiveness ratio (ICER) for abiraterone compared with best supportive care was likely to lie between £28,600 and £32,800 per quality-adjusted life year (QALY) gained. It noted that abiraterone was innovative and that the utility values in the model may not fully capture the benefit to patients of delaying cytotoxic chemotherapy.

4.22, 4.27

Current practice

Clinical need of patients, including the availability of alternative treatments

The committee understood that chemotherapy can reduce a person's quality of life and that treatments delaying the need for chemotherapy are highly valued by patients.

4.3

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?

Although abiraterone is not a new technology, it was the first active treatment available for this position in the treatment pathway and, in this regard, is innovative.

4.27

There is some uncertainty about the benefits and consequences of delaying chemotherapy, but patients value delaying chemotherapy.

4.3

What is the position of the treatment in the pathway of care for the condition?

There is no consensus on how to decide whether to offer abiraterone to patients, but clinicians generally offer it, in addition to best supportive care, to people with few symptoms to delay chemotherapy, or to treat people who are unable or do not wish to have chemotherapy.

4.1

Adverse reactions

Abiraterone plus prednisone or prednisolone increases the risk of adverse events compared with prednisone or prednisolone alone, but patients can tolerate the adverse events associated with abiraterone.

4.18

Evidence for clinical effectiveness

Availability, nature and quality of evidence

The clinical-effectiveness evidence came from a randomised placebo-controlled trial, COU‑AA‑302, that recruited 9% of its patients from the UK.

4.5

Relevance to general clinical practice in the NHS

The committee concluded that COU‑AA‑302 generally reflected clinical practice in the UK and was relevant to address the decision problem.

4.5

Uncertainties generated by the evidence

The survival benefit of abiraterone compared with placebo was not statistically significant at the third interim analyses of COU‑AA‑302 (the data cut-off used in the modelling), but was statistically significant at the final analysis.

There was uncertainty around the extent of benefit with abiraterone at the final analysis because the trial was unblinded and people could cross over to abiraterone from the placebo arm. Furthermore, people in both treatment arms could have subsequent treatments that are not available in the NHS.

4.6, 4.7

Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?

None were identified.

-

Estimate of the size of the clinical effectiveness including strength of supporting evidence

The committee concluded that abiraterone delayed disease progression and improved overall survival compared with placebo, but that there was uncertainty about the extent of the survival benefit.

4.7

Evidence for cost effectiveness

Availability and nature of evidence

The company developed a discrete event simulation model because it allowed the flexibility to include a sequence of treatments, and to model response to treatments that depend on previous treatments.

4.8

Uncertainties around and plausibility of assumptions and inputs in the economic model

The company's model was complex and lacked transparency, which made it difficult for the evidence review group (ERG) to validate and critique it.

4.8

In the model, data needed to be extrapolated beyond the period of the follow-up from COU‑AA‑302. The choice of extrapolation distribution affected the estimated duration of first treatment, which was a driver of the ICER. To support its choice of a log-logistic extrapolation, the company provided data from: the final trial analysis; UK clinical practice; and US clinical practice. The committee concluded that its preferred analysis used either a log-logistic curve or a piecewise curve to predict time on first treatment.

4.10–4.13

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 company's model used utility values from the trial (Functional Assessment of Cancer Therapy [prostate cancer subscale] mapped to EQ‑5D), a survey and the literature. The model included a utility increment associated with taking abiraterone. Overall, the committee concluded that the company's modelled utility values were plausible.

4.18

The committee agreed that the benefit of delaying chemotherapy perceived by patients may not have been fully captured by the utility values included in the modelling and that accounting for this would have reduced the ICER.

4.27

Are there specific groups of people for whom the technology is particularly cost effective?

None were identified.

-

What are the key drivers of cost effectiveness?

Using a Weibull or piecewise distribution instead of a log-logistic distribution for predicting time on first treatment increased the ICER.

4.11

The choice of trial population used to inform the model: the company's model used results from the subgroup of 902 people in COU‑AA‑302 for whom complete data were available on baseline characteristics. The ERG's exploratory base case used the intention-to-treat (ITT) population instead, and this increased the ICER. The committee agreed that, as a general principle, it preferred to use the ITT population for modelling because this reduces the risk of bias. However, in this specific case, the committee agreed with the company that using the full covariate subgroup provided a closer fit to the trial data. Accordingly, the committee preferred to use the full covariate subgroup.

4.16

Most likely cost-effectiveness estimate (given as an ICER)

The committee concluded that the ICER was likely to lie between £28,600 and £32,800 per QALY gained.

4.22

Additional factors taken into account

Patient access schemes (PPRS)

The company has agreed a confidential commercial access arrangement with NHS England.

A complex patient access scheme was agreed, and taken into account, during guidance development. This was replaced in July 2016 by the commercial access arrangement. The complex patient access scheme no longer applies.

2.3

End-of-life considerations

The committee concluded that abiraterone was licensed for a small patient population, and it is likely that abiraterone when given before docetaxel leads to a life extension of 3 months.

The committee concluded that current mean life expectancy for people with metastatic hormone-relapsed prostate cancer for whom chemotherapy is not yet indicated was unlikely to be less than 24 months, and abiraterone at this stage in the treatment pathway did not meet the end-of-life criterion for short life expectancy.

4.23–4.26

Equalities considerations and social value judgements

No equality issues were raised during the appraisal committee meetings.

n/a