Everolimus for preventing organ rejection in liver transplantation

Clinical effectiveness

4.4 The Committee considered the evidence presented by the company on the clinical effectiveness of everolimus in combination with reduced‑dose tacrolimus. It understood that the main source of evidence was the H2304 randomised controlled trial and that everolimus was statistically non‑inferior to standard‑dose tacrolimus given as monotherapy for the primary composite outcome of treated biopsy proven acute rejection (tBPAR), graft loss or death at both 12 and 24 months. The Committee heard from the clinical expert that very early episodes of acute rejection are rarely problematic and are usually successfully treated, but preventing episodes of acute rejection later was important because they may progress to steroid‑resistant rejection and rapid graft loss. Any treatment that reduced episodes of acute rejection would be clinically beneficial. The Committee also heard from a clinical expert that mild chronic rejection may sometimes be associated with poor compliance with medication. Although initially asymptomatic, it can have a slowly progressive course to graft loss. The Committee also noted that everolimus with reduced‑dose tacrolimus was associated with a smaller reduction in renal function compared with standard‑dose tacrolimus at 12 and 24 months after transplantation as measured by change in estimated glomerular filtration rate (eGFR). The Committee concluded that the results of H2304 suggested that everolimus with reduced‑dose tacrolimus was non‑inferior to standard‑dose tacrolimus alone for the composite hepatic outcome in the trial, and was an effective treatment for reducing the decline in renal function when compared with standard‑dose tacrolimus.

4.5 The Committee considered the generalisability of H2304 to clinical practice in England. It noted that only a small number of patients were recruited to the trial from UK centres and that the direct relevance of the trial to standard NHS practice in England was limited because the comparator, standard‑dose tacrolimus as monotherapy, is not used. The Committee heard from the clinical expert that people in the trial also had better baseline renal function than is typically seen for patients in England (81 ml/min/1.73 m² in H2304 compared with approximately 60 ml/min/1.73 m² in clinical practice). In addition, the Committee noted the ERG's comments that a reduced dose of tacrolimus was considered standard care in the UK and that the blood trough levels for reduced‑dose tacrolimus in the everolimus arm of H2304 (at around 5–6 ng/ml at 6 and 12 months) would be higher than expected in UK clinical practice. However, the Committee recalled the comments from the clinical expert that although the aim in clinical practice was to reduce the blood trough levels to below 5 ng/ml, an audit had shown that this did not seem to be consistently achieved (see section 4.2). The Committee appreciated that the audit provided only a single assessment of tacrolimus blood trough levels achieved in clinical practice in 2013, but that nevertheless it represented the best available evidence on current UK practice. It also noted that the company had stated in its response to the appraisal consultation document that most people in the everolimus with reduced‑dose‑tacrolimus arm of H2304 achieved tacrolimus blood trough levels below 5 ng/ml. Taking this into account, the Committee concluded that patients in the everolimus with reduced‑dose tacrolimus arm of H2304 probably had lower tacrolimus blood trough levels than generally achieved in current clinical practice, although the magnitude of the difference remained uncertain. The Committee agreed that H2304 was well conducted but noted the high drop‑out rates, the better renal function of participants than in clinical practice, and the limited long‑term follow‑up. It concluded that, although H2304 showed that everolimus with reduced‑dose tacrolimus was an effective treatment for preventing organ rejection and preserving renal function compared with standard‑dose tacrolimus, there was uncertainty about how any benefit demonstrated in the trial would translate into clinical practice.

4.6 The Committee considered the network meta‑analyses presented by the company to estimate the relative effectiveness of everolimus compared with the comparators specified in the scope. It was aware that the results of the network meta‑analyses suggested that everolimus was expected to be comparable to other treatments for the outcomes of overall survival and graft survival at 12 and 24 months after transplantation, and that everolimus was ranked as the best treatment for reducing the incidence of tBPAR at 3, 6 and 12 months. The Committee noted the ERG's comments that there was inconsistency across studies with respect to tacrolimus blood trough levels. It also noted the ERG's concerns that the data used for the tBPAR outcome could not be verified because of a lack of clarity and transparency in the company submission (see section 3.30). It was also aware that in response to the appraisal consultation document, the company had carried out an exploratory analysis of the network meta‑analysis, reclassifying some studies with respect to standard or reduced‑dose tacrolimus, but had used this to explore hepatic outcomes only. The Committee concluded that there was considerable uncertainty in the results of the network meta‑analyses because the dose of tacrolimus was so heterogeneous between the included studies and the company's approach lacked transparency because it was unclear which studies had been included for the analysis of specific outcomes.

4.7 The Committee considered the adverse events associated with everolimus in combination with reduced‑dose tacrolimus from H2304. It noted that lipid changes occurred more frequently in the everolimus group than in the standard‑dose tacrolimus group and that there was a higher incidence of new onset diabetes mellitus and biliary leaks in the everolimus group at 24 months after transplantation. The Committee noted the clinical expert's comments that in practice the side effects of everolimus were significant but manageable and that with patient engagement they would be better tolerated. It also noted the comments that treatment with everolimus reduced the known risks associated with tacrolimus. The Committee concluded that the side effects of treatment with everolimus were manageable for patients and that treatment with everolimus could reduce the dose and therefore the risks associated with tacrolimus.

Cost effectiveness

4.8 The Committee considered the company's economic model and the critique and exploratory analyses performed by the ERG. It noted that the company presented a patient‑simulation model consisting of a core hepatic rejection model and a renal sub‑model. The Committee accepted the ERG's concerns about the structure and complexity of the model and agreed that a patient‑simulation model may not have been the most appropriate design. It also questioned why the company had presented 2 discrete models instead of an integrated model, because hepatic and renal function are not entirely independent. It also accepted the ERG's comments that the 3‑month cycles in the model were too long to capture all the relevant events and that monthly cycles may have been more appropriate, and that the time horizon of 80 years was unnecessarily long. The Committee noted that following consultation on the appraisal consultation document, the company had submitted an updated model that incorporated 11 amendments (see section 3.70) including a shorter time horizon of 40 years. However, the Committee considered that the other 10 amendments to the model addressed only issues related to model inputs and did not address specific concerns raised by the ERG about structural issues. The Committee concluded that the choice of 2 separate models and the way in which they had been constructed was not necessarily the most appropriate approach to the economic evaluation and that these concerns applied to both the original and updated models supplied by the company.

4.9 The Committee discussed the original and updated model inputs, noting that the company had derived the efficacy estimates from the network meta‑analysis. The Committee agreed that there was considerable uncertainty in the results of the network meta‑analysis, related to the lack of clarity and transparency in the company's submission and inconsistency across studies with respect to tacrolimus blood trough levels (see section 4.6). The Committee noted that in its updated base‑case analysis the company had amended the renal‑efficacy inputs for the comparator arms, using the reduced‑dose‑tacrolimus arm of the network meta‑analysis rather than the standard‑dose arm as in the original submission (see section 3.70) because the company acknowledged that the studies informing the reduced‑dose‑tacrolimus arm would be considered standard dose in clinical practice (that is, trough levels were consistently more than 7.5 ng/ml). However, the Committee was aware that these changes had not been validated by the ERG. In an exploratory analysis the company had constructed an updated network meta‑analysis by reclassifying studies based on tacrolimus trough levels. The resulting data on hepatic outcomes had been used for the exploratory analysis, but were not incorporated into the updated base case. The Committee concluded that the changes made by the company in the new base case did not address the lack of clarity and transparency in the company's original submission, and did not address some fundamental concerns about the reliability of the model.

4.10 The Committee considered the utility values used in the core hepatic‑rejection model and the renal sub‑model. It noted the concerns of the ERG that the utility values used by the company for each of the health states in the core hepatic‑rejection model did not differ (utility value of 0.58) apart from graft loss (0.53) and death (0.00). The Committee heard from the clinical expert that the utility for people in states other than the stable post‑transplant state should be lower because of the deteriorating physical health, the need for more medical intervention and the associated anxiety. It noted that the company had submitted a scenario analysis following consultation on the appraisal consultation document that altered the assumption for the utility associated with the health states of acute rejection, acute steroid‑resistant rejection and mild‑chronic rejection (that is, it reduced the utility from 0.58 to 0.56 for each of these health states). However, the Committee did not accept that the evidence for the new values was robust and therefore their inclusion did not improve the validity or plausibility of the ICER. For the renal sub‑model, the Committee questioned the plausibility of the reduction in utility from 0.83 to 0.64 for patients moving from having no kidney disease to having chronic kidney disease stages 1 or 2 because many people will be asymptomatic and not be aware of the reduced renal function at these earlier stages. It noted that the utility values for the stages of chronic kidney disease were derived from a study of patients who had a renal transplant. However, it accepted the comments from the company that the best available literature sources were used for each of the health states and that, because the lower of the renal and hepatic model utility values was used to estimate joint state utility, no patient in the model would ever be assigned a utility score of 0.83.

4.11 The Committee discussed other limitations of the model. It heard from the clinical expert that non‑immunological conditions such as cardiovascular disease were major causes of death for patients in the years following a liver transplant. However, the Committee considered that it was unclear how the company had accounted for this in the model. The Committee also noted that the ERG had identified a logical error in the original model which meant that cycles were 'missing' from the renal sub‑model and that this reflected a problem in the model structure or formulae. It noted that the company reported that it had corrected this error in its updated model but was also aware that the ERG had not validated this. The Committee concluded that, despite the company's amendments to the model following the consultation on the appraisal consultation document, there remained significant limitations and a substantial lack of clarity associated with the model as described in sections 4.8 to 4.10.

4.12 The Committee discussed the cost‑effectiveness results for everolimus with reduced‑dose tacrolimus compared with the azathioprine and mycophenolate‑mofetil treatment regimens (both in combination with standard‑dose tacrolimus). It considered that the base‑case ICERs from the original and updated models presented by the company were very high: £187,800 and £104,800 per QALY gained respectively when compared with the azathioprine treatment regimen, and £110,800 and £176,600 per QALY gained respectively when compared with the mycophenolate mofetil regimen. The Committee queried the reason for the reversal in the results relative to the comparator in the original, compared with the updated model. It heard from the company that this reflected technical errors in the original model that had been corrected in the updated analysis. The Committee concluded that the company's base‑case ICERs from both the original and updated models were substantially outside the range that would normally be considered a cost‑effective use of NHS resources (£20,000–30,000 per QALY gained).

4.13 The Committee discussed the company's scenario analyses. It considered that the most relevant scenario analysis was the one in which the company changed the assumption of baseline eGFR from 81 ml/min/1.73 m² in the base case (the mean from the H2304 trial), to 60 ml/min/1.73 m², as this was more reflective of the baseline eGFRs seen in clinical practice (see section 4.4). The Committee noted that, when using the original model, this scenario resulted in ICERs for everolimus with reduced‑dose tacrolimus of £179,400 per QALY gained compared with the azathioprine treatment regimen and £184,400 per QALY gained compared with the mycophenolate mofetil regimen. When this scenario was used in the updated model, the ICERs increased from the base‑case estimate of £104,800 to £107,600 per QALY gained, when compared with the azathioprine regimen, and from £176,600 to £197,400 per QALY gained when compared with the mycophenolate mofetil regimen. It concluded that the ICERs for this scenario in both the original and updated models remained substantially outside the range that would normally be considered a cost‑effective use of NHS resources.

4.14 The Committee discussed the way in which the mild chronic‑rejection health state had been implemented in the model. It was aware that both the original and the updated model assumed that if people entered the mild chronic‑rejection health state they never recovered and remained in that state until death. The Committee noted the concerns of the ERG about the clinical validity of how this health state was implemented in the model and that it had a substantial impact on the cost‑effectiveness calculations in a scenario analysis where this health state was removed. The Committee took into account the clinical expert's comment that mild chronic rejection could have a slowly progressive course to graft loss and that it is associated with an increased number of interventions, visits to hospital and anxiety in patients about deterioration in their health. It concluded that the mild chronic‑rejection health state was clinically important, and would be associated with increased care costs so it was not necessary to exclude it from the model.

4.15 The Committee discussed the robustness of the ICERs presented by the company. It noted that the ERG lacked confidence in the original model results and had concerns regarding the stability of the model because it found considerable variation in the base‑case ICERs when the model was re‑run without any changes to the model inputs. The Committee acknowledged that the updated model results submitted by the company suggested greater stability (see section 3.73), although these had not been validated by the ERG. The Committee remained cautious about the robustness of the ICERs. However, it was unable to identify any factors that it believed would lower the company's estimates of cost‑effectiveness. It concluded that the ICERs for everolimus with reduced‑dose tacrolimus were unlikely to be lower than the company's estimates of £184,000 per QALY gained compared with the mycophenolate mofetil treatment regimen and £107,600 per QALY gained compared with the azathioprine treatment regimen. Therefore everolimus with reduced‑dose tacrolimus did not represent a cost‑effective use of NHS resources and could not be recommended for preventing organ rejection after liver transplantation.

4.16 The Committee considered whether everolimus with reduced‑dose tacrolimus was innovative. It noted the company's comments about the need to reduce the complications of treatment with calcineurin inhibitors, including nephrotoxicity, and the view of a clinical expert that there is currently no treatment other than everolimus that safely enables clinicians to rapidly reduce tacrolimus blood trough levels, thereby potentially preserving renal function. The Committee agreed that everolimus was innovative in its potential to preserve renal function but it could not identify any substantial health benefits that had not been captured in the QALY estimates. It concluded that everolimus had not been shown to be cost effective and could not be recommended for use in the NHS.

4.17 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 everolimus. 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'. The Committee heard nothing to suggest that there is any basis for taking a different view with regard to the relevance of the PPRS to this appraisal of everolimus. It therefore concluded that the PPRS payment mechanism was irrelevant for the consideration of the cost effectiveness of everolimus.

Summary of Appraisal Committee's key conclusions