Renal transplantation - immunosuppressive regimens for children and adolescents
Immunosuppressive therapy for renal transplantation in children and adolescents (TA99)
4. Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
4.1. Clinical effectiveness
Only a small amount of evidence on clinical effectiveness was identified from randomised controlled trials (RCTs) involving paediatric renal transplant recipients. Therefore, the assessment included results from RCTs in adult renal transplant recipients and results from non-randomised comparative studies in paediatric renal transplant recipients.
4.1.1. One unpublished randomised, placebo-controlled trial in paediatric renal transplant recipients was identified. Basiliximab induction therapy (10–20 mg) versus no induction therapy was added to concomitant triple therapy of tacrolimus, azathioprine and a corticosteroid in 197 children and adolescents up to 18 years of age. Efficacy and safety were assessed at 6 months. Details of the study were provided, but the results were marked ‘academic in confidence’.
4.1.2. Four randomised, placebo-controlled trials in adults were also identified (total n = 500). Basiliximab induction therapy (20 mg) versus placebo or no therapy was added to concomitant triple therapy of ciclosporin, azathioprine and a corticosteroid. Only one trial reported outcomes beyond 1 year.
4.1.3. A meta-analysis of the results from the RCTs showed a statistically significant advantage in favour of basiliximab in terms of fewer biopsy-proven acute rejection episodes at 6 months’ follow-up (relative risk [RR] 0.61, 95% confidence interval [CI] 0.46 to 0.80). However, the meta-analysis showed no statistically significant advantage of basiliximab in terms of graft or patient survival within the limited follow-up period.
4.1.4. There were no statistically significant differences between treatment arms in terms of the incidence of CMV infection (at 6 months), PTDM, liver disease or withdrawals (at 6 months). Drug switching because of adverse events was not reported.
4.1.5. Six retrospective, comparative non-randomised studies in paediatric renal transplant recipients were identified. However, only three of these studies compared basiliximab (10 or 20 mg) with no induction therapy.
4.1.6. None of the three studies (total n = 152) showed a statistically significant difference in the incidence of biopsy-proven acute rejection or graft loss between the basiliximab and control groups at 12 months. Mortality was zero for both treatment groups in all three studies. Little information on side effects was reported, although one of the studies reported that, at 12 months, a higher proportion of patients receiving basiliximab had withdrawn from treatment compared with patients not receiving induction therapy.
4.1.7. No RCTs that included children or adolescents were identified.
4.1.8. One placebo-controlled, randomised trial in adult renal transplant recipients was identified (n = 260). Daclizumab induction therapy (1 mg/kg) versus placebo was added to concomitant triple therapy of ciclosporin, azathioprine and a corticosteroid.
4.1.9. The results indicated a statistically significant advantage in favour of daclizumab in terms of fewer biopsy-proven acute rejection episodes at 6 months’ follow-up (RR 0.63, 95% CI 0.42 to 0.94). However, no statistically significant advantage of daclizumab in terms of graft or patient survival was shown.
4.1.10. There was no statistically significant difference in the incidence of CMV infection at 6 months between those receiving daclizumab and those receiving placebo. The rates of hyperlipidaemia, PTDM, lymphoproliferative disease and withdrawals because of adverse events were not reported.
4.1.11. No comparative non-randomised studies of daclizumab in paediatric renal transplant recipients could be identified. The manufacturer’s submission included one non-comparative, non-randomised study. Details of the study were provided, but the results were marked ‘academic in confidence’.
4.1.12. One paediatric RCT (n = 204) was identified. It compared a triple therapy combination of tacrolimus (0.3 mg/kg), azathioprine and a corticosteroid with a triple therapy combination of ciclosporin (microemulsion), azathioprine and a corticosteroid. One third of patients withdrew from the trial within 6 months.
4.1.13. The results showed a statistically significant advantage in favour of the tacrolimus-based regimen in terms of fewer biopsy-proven acute rejection episodes (RR 0.42, 95% CI 0.26 to 0.69) at 6 months. However, no statistically significant advantage of tacrolimus in terms of graft or patient survival was demonstrated at 6 months.
4.1.14. At 1 year, the proportions of graft losses in the tacrolimus and ciclosporin treatment groups were not statistically different (p = 0.08). However, statistically significant differences in favour of tacrolimus were reported at 4-year follow-up (11/103 [11%] graft losses with tacrolimus compared with 20/93 [22%] with ciclosporin; p = 0.03). An indicator of graft function, the glomerular filtration rate (GFR), was statistically significantly higher at 1 year in those receiving tacrolimus than in those receiving ciclosporin: the mean GFR with tacrolimus was 62.5 ml/min, whereas the mean GFR with ciclosporin was 56.4 ml/min (p = 0.003).
4.1.15. No statistically significant differences in side effects were recorded at 6 months between the tacrolimus- and ciclosporin-based regimens, as abstracted by the Assessment Group. However, the Assessment Group did not look specifically at cosmetic side effects, such as excessive hair growth. A statistically significantly smaller proportion of the tacrolimus-treated group than the ciclosporin-treated group withdrew from the trial because of adverse events (RR 0.61, 95% CI 0.39 to 0.96).
4.1.16. Nine RCTs in adult renal transplant recipients were identified (total n = 1664). These compared a triple therapy combination of tacrolimus, azathioprine and a corticosteroid with a triple therapy combination of ciclosporin, azathioprine and a corticosteroid. The dose of tacrolimus used across the studies ranged from 0.1 to 0.3 mg/kg. Follow-up ranged from 6 months to 6 years.
4.1.17. A meta-analysis of the results from the RCTs showed a statistically significant advantage in favour of the tacrolimus-based regimen in terms of fewer biopsy-proven acute rejection episodes at 1-year follow-up (RR 0.61, 95% CI 0.53 to 0.71). However, the meta-analysis showed no statistically significant advantage of tacrolimus in terms of graft or patient survival.
4.1.18. Two RCTs had follow-up periods of 3 years or more. However, no statistically significant differences in all-cause mortality, graft loss or graft function were reported in either trial at long-term follow-up.
4.1.19. The RCTs in adult renal transplant recipients showed that the incidence of treatment side effects (excluding data on cosmetic side effects, which were not available) and rates of withdrawal because of adverse events were similar for both treatment groups with the exception of PTDM, the incidence of which was statistically significantly higher with tacrolimus (RR 2.38, 95% CI 1.32 to 4.31), and hyperlipidaemia, which occurred at a lower incidence with tacrolimus (RR 0.47, 95% CI 0.24 to 0.93). A statistically significantly lower level of drug switching because of adverse events was associated with tacrolimus compared with ciclosporin (RR 0.10, 95% CI 0.04 to 0.27).
4.1.20. Two comparative, non-randomised studies of ciclosporin and tacrolimus were identified in paediatric renal transplant recipients (total n = 1010). One study reported a statistically significant advantage of tacrolimus over ciclosporin in terms of improved graft function at 1-year and 2-year follow-up (mean creatinine clearance rates at year 2 of 96.7 ml/min and 73.2 ml/min [per 1.73 m 2 body surface area] respectively; p < 0.0001). No other statistically significant differences were reported in either study for any other outcomes.
4.1.21. No RCTs comparing MMF-based treatment regimens with azathioprine-based regimens in paediatric renal transplant recipients were identified.
4.1.22. Seven RCTs in adult renal transplant recipients were identified (total n = 1273). These compared a triple therapy combination of MMF (2–3 g), ciclosporin and a corticosteroid with a triple therapy combination of azathioprine, ciclosporin and a corticosteroid.
4.1.23. A meta-analysis showed a statistically significant advantage in favour of MMF over azathioprine in terms of fewer biopsy-proven acute rejection episodes at 1-year follow-up (RR 0.60, 95% CI 0.47 to 0.76). However, the meta-analysis showed no statistically significant advantage of the MMF-based regimen in terms of graft or patient survival at the same point of follow-up.
4.1.24. No statistically significant differences between the MMF- and azathioprine-based regimens were observed at 1-year follow-up in terms of the rates of post-transplant lymphoproliferative disease and withdrawals because of adverse events. The incidence of PTDM and hyperlipidaemia was not reported, but CMV infection rates were higher with MMF treatment (RR 1.43, 95% CI 1.02 to 2.01).
4.1.25. Four comparative non-randomised studies in paediatric renal transplant recipients were available to the Appraisal Committee. These compared MMF-based with azathioprine-based regimens, but few results allowing direct comparison of the two treatment regimens were reported. Two of the studies did not report details of the rates of biopsy-proven acute rejection. One study reported that no patient receiving MMF (n = 7) had biopsy-proven acute rejection, while three patients in the azathioprine group (n=7) had biopsy-proven acute rejection. Another study, with historical control design, reported biopsy-proven acute rejection rates at 1 year of 39% in the MMF-treated group (n = 86) and 59% in the azathioprine-treated group (n = 54), with 3-year rates of 44% and 59% respectively.
4.1.26. The Appraisal Committee considered evidence from two non-randomised studies of MMF in corticosteroid-reduction/withdrawal strategies for paediatric patients. One was a retrospective case–control study in 40 paediatric patients receiving MMF and ciclosporin with a mean follow-up of 46 months. No episodes of biopsy-proven rejection occurred in the group in which corticosteroids were withdrawn, and the standardised body mass index decreased by 49% in this group. Another observational study reported results using a corticosteroid-avoidance immunosuppressive regimen that included daclizumab, tacrolimus and MMF in paediatric patients. Patient and graft survival rates were reported to be equivalent to those in historical controls. The corticosteroid-free group experienced anaemia, which was normalised by 6 months following treatment with erythropoietin.
4.1.27. No RCTs comparing MPS-based treatment regimens with azathioprine-based regimens in paediatric renal transplant recipients were identified.
4.1.28. Only one RCT in adult renal transplant recipients was identified (n = 423). This compared a triple therapy combination of MPS (1.4 g/day), ciclosporin and a corticosteroid with a regimen of MMF plus ciclosporin and a corticosteroid. The trial was powered to detect equivalence in outcomes. No statistically significant differences between the treatment groups were reported at 1-year follow-up in terms of biopsy-proven acute rejection episodes, graft loss, side effects, or rates of withdrawal because of adverse events. Rates of drug switching and changes in health-related quality of life were not reported.
4.1.29. No non-randomised comparative studies comparing MPS with azathioprine in paediatric renal transplant recipients were identified.
4.1.30. Two unpublished RCTs in paediatric renal transplant recipients were identified. One was ongoing and no data were available. Details of the other study were provided, but the results were marked ‘academic in confidence’. In addition, two published RCTs in adult renal transplant recipients were identified that also included some paediatric recipients (total n = 15/1295).
4.1.31. Four further RCTs of the use of sirolimus in adult renal transplant recipients were identified. Two trials compared sirolimus (2 or 5 mg/day) with azathioprine (in triple therapy regimens also containing ciclosporin and a corticosteroid). One trial compared sirolimus (16–24 mg/m 2 /day followed by 8–12 mg/m 2 /day) with ciclosporin (in triple therapy regimens that also contained azathioprine and a corticosteroid). The fourth RCT assessed the impact of a 3-month period of sirolimus treatment plus ciclosporin and a corticosteroid, and then randomised patients to continue sirolimus and a corticosteroid while either continuing or stopping ciclosporin. In a meta-analysis of the two studies comparing sirolimus with azathioprine, the number of biopsy-proven acute rejection episodes was statistically significantly lower in those receiving the sirolimus regimen at 1-year follow-up (RR 0.60, 95% CI 0.45 to 0.80). In another meta-analysis, serum creatinine was statistically significantly lower at 1-year follow-up in patients for whom ciclosporin had been removed from the regimen at 3 months compared with those in whom sirolimus and ciclosporin had been continued. No other statistically significant differences were reported in favour of ciclosporin withdrawal in any of the four RCTs in terms of biopsy-proven acute rejection, graft loss, patient survival or graft function.
4.1.32. No non-randomised comparative studies in paediatric renal transplant recipients were identified.
4.2. Cost effectiveness
4.2.1. No published economic evaluations of any of the drugs pertinent to this appraisal in paediatric or adolescent patients met the inclusion criteria for this review. Three economic evaluations were submitted by the manufacturers. All of these, as well as the evaluation performed by the Assessment Group, were based on an adaptation to the Birmingham Sensitivity Analysis (BSA) model that was constructed previously by the Assessment Group for the appraisal of immunosuppressive treatments in adult renal transplant recipients (see section 8). The Assessment Group’s paediatric version of the original adult model is referred to as the BSAp model.
4.2.2. Key features of the BSAp model include the following.
- It is a Markov model containing three health states: functioning graft; graft failed/dialysis; and death.
- An NHS perspective was adopted for costs and benefits.
- Costs and quality-adjusted life years (QALYs) were discounted at 6% and 1.5%, respectively.
- Patient and graft survival was predicted using acute rejection rates at 1-year follow-up and extrapolated over 10 years.
- If relevant child/adolescent RCTs were not available, acute rejection rates were based on RCTs in adults.
- The BSAp model used utility values of 0.5 for dialysis and 0.75 for a functioning graft.
- In the base case, the cost of dialysis was assumed to be just over £21,000/year (reflecting the costs of treating adult patients).
- The cost of treating each episode of acute rejection was put at £4600, based on amalgamating the various estimates given in the manufacturers’ submissions for the appraisal of these treatments in adults.
- The costs and disutility associated with side effects were linked to withdrawals because of adverse events from the trials, but were only included where evidence suggested that there was a difference in withdrawals between treatment regimens.
- A programming error in the original BSA model was corrected in this BSAp version.
4.2.3. Both the manufacturer and the Assessment Group estimated that triple therapy regimens that included basiliximab (induction therapy) were more effective and less costly compared with triple therapy regimens that did not include basiliximab. In the absence of paediatric trial data, acute rejection rates for ciclosporin-based regimens were estimated using adult RCTs. Cost-effectiveness estimates for tacrolimus-based regimens were based on a single relevant paediatric RCT (which was marked confidential).
4.2.4. Both the manufacturer and the Assessment Group estimated that triple therapy regimens that included daclizumab (induction therapy) were more effective and less costly compared with triple therapy regimens that did not include daclizumab. Both cost-effectiveness estimates were based on the acute rejection rates from adult RCTs in the absence of suitable paediatric RCT evidence.
4.2.5. Both the manufacturer’s and the Assessment Group’s economic evaluations compared tacrolimus-based with ciclosporin-based triple therapy regimens, and incorporated rejection rates reported by an RCT in paediatric patients.
4.2.6. The manufacturer estimated the cost effectiveness of a tacrolimus-based triple therapy regimen compared with a ciclosporin-based triple therapy regimen to be about £18,000 for an age group of below 13 years and about £31,000 for an age group of 13–18 years. These estimates include the costs and effects of switching treatments (because of side effects), but the probabilities of these events occurring were based on expert opinion. When no difference in switching rates between ciclosporin- and tacrolimus-based regimens was assumed, the cost effectiveness of tacrolimus decreased considerably.
4.2.7. The Assessment Group estimated the cost effectiveness of tacrolimus to be approximately £145,000 per QALY gained (excluding the consideration of the impact of side effects). However, changing the hazard ratio associated with acute rejection episodes and the risk of graft loss to 1.96 (from 1.41) and increasing the cost of dialysis to £50,000 (from £21,000) further reduced the cost per QALY gained to approximately £34,000.
4.2.8. The manufacturer’s economic evaluation suggested that MMF was less costly and more effective than azathioprine in a ciclosporin-based regimen. Rates of acute rejection (clinical as opposed to biopsy-confirmed) were based on a single non-randomised comparative study undertaken in children.
4.2.9. The Assessment Group estimated the cost effectiveness of MMF compared to azathioprine in a ciclosporin-based regimen to be approximately £195,000 per QALY gained. This estimate was based on acute rejection rates derived from the meta-analysis of MMF RCTs in adult patients and on a hazard ratio associated with acute rejection episodes and the risk of graft loss of 1.41. When this hazard ratio was increased to 1.96 (in line with the estimate used in the adult appraisal) and the cost of paediatric dialysis was increased to £50,000, the cost per QALY gained changed to approximately £60,000.
4.2.10. Neither the manufacturer nor the Assessment Group undertook a specific economic evaluation of MPS. However, the manufacturer claimed that because MPS and MMF are clinically equivalent, the cost effectiveness of the two treatments is also similar.
4.2.11. The manufacturer referred to an economic evaluation from the appraisal of immunosuppressive treatments in adult renal transplant recipients (NICE Technology Appraisal Guidance no. 85). The evaluation assessed the cost effectiveness of a sirolimus regimen that involved ciclosporin withdrawal and a corticosteroid compared with a standard calcineurin inhibitor-based treatment regimen. No RCT evidence was available for these treatment regimens; therefore treatment effects were estimated by incorporating the results from a number of other studies. The results from this analysis were used to suggest that sirolimus was a more effective and less costly treatment option.
4.2.12. The Assessment Group did not perform an economic evaluation of sirolimus because there was deemed to be insufficient clinical evidence.
4.3. Consideration of the evidence
4.3.1. The Committee reviewed the data available on the clinical and cost effectiveness of basiliximab, daclizumab, tacrolimus, MMF, MPS and sirolimus for renal transplantation in children and adolescents, having considered evidence on the nature of the condition and the value placed on the benefits of immunosuppressive therapy by people who have undergone renal transplantation, those who represent them, and clinical experts. It was also mindful of the need to take account of the effective use of NHS resources.
4.3.2. The Committee recognised the paucity of RCTs in children and adolescents undergoing renal transplantation. In addition, the Committee had been directed by NICE’s Guidance Executive (in accordance with the appeal determination following the appraisal of these agents in adults) to consider all the evidence available on the clinical and cost effectiveness of immunosuppressive regimens in children and adolescents. The Committee therefore took into account observational evidence on the use of immunosuppressive regimens in children and adolescent transplant recipients, and considered RCT and other evidence relating to adults wherever necessary.
4.3.3. The Committee was also aware that the Department of Health and the Welsh Assembly Government had indicated that the Institute should consider the use of immunosuppressant drugs in renal transplant recipients as they are used in current practice, which may include use outside the terms of the UK marketing authorisation.
4.3.4. The Committee was persuaded of important differences in the management of renal transplantation between adults and children/adolescents: in particular, that there were significant differences in the relative importance to the patient of treatment side effects. The Committee heard from the experts that the actual or perceived potential for cosmetic side effects was a major contributor to lack of concordance with the immunosuppressant regimen that was prescribed, and thus a major cause of renal graft failure. Therefore, this should be taken into consideration in assessing the balance of costs and benefits of the various drugs.
4.3.5. The Committee additionally heard from the experts that the annual cost of renal replacement therapy and support for children and adolescents was much higher than that for adults. This extra cost for younger patients was related to a number of reasons and specific requirements for this patient group, including:
- increased numbers of clinical staff and other personnel required to support particularly young patients (for example, higher ratio of nursing staff, reduced numbers of patients per nephrologist, need for other support staff such as play therapists for children and psychological support for adolescents)
- increased equipment costs for dialysers and other devices for young children
- higher costs associated with the treatment of acute rejection episodes.
- Further details of the costs of renal replacement therapy and support in children and adolescents were obtained from two paediatric centres in the UK, which showed that these costs are approximately £50,000–£60,000/year.
- The Committee also noted that all submitted economic evaluations were based on the model constructed by the Assessment Group for the appraisal of immunosuppressive regimens for adults. This model based the annual cost of dialysis for children and adolescents on the cost used in the adult model (approximately £21,000/year). The annual cost for children and adolescents is therefore likely to have been significantly underestimated.
4.3.6. On the basis of these considerations, the Committee carefully reviewed the economic model constructed for this appraisal by the Assessment Group. It noted that the Assessment Group had assumed a hazard ratio for the association between acute rejection episodes and long-term graft survival of 1.41 based on data from a single study in paediatric patients, compared with that used in the appraisal of immunosuppression in adult renal transplant recipients of 1.96. The Committee noted the concerns expressed by consultees regarding the paediatric study: in particular, that the study involved only transplants from living, related donors, and that the results may not be applicable to the paediatric population undergoing renal transplantation in the UK. The Committee also heard from the experts that there was no plausible clinical reason to believe that this hazard ratio should be different for children and adolescents compared with adults. For these reasons, the Committee accepted a hazard ratio of 1.96 as the appropriate value to be incorporated into the economic analysis for this appraisal.
4.3.7. Therefore, all incremental cost-effectiveness ratios (ICERs) reported by the Assessment Group and quoted in the remainder of this considerations section are based on a cost of dialysis of £50,000–£60,000/year and a hazard ratio associated with acute rejection episodes and graft loss of 1.96. The Committee also considered the higher costs of an acute rejection episode (other than those associated with the requirement for dialysis); however, these costs were not adjusted because insufficient evidence was available to the Committee to make any change.
4.3.8. The Committee noted the single RCT undertaken in paediatric patients and the confidential nature of this information. The Committee also noted that no RCTs had been undertaken of either basiliximab or daclizumab in combination with ciclosporin-based regimens in paediatric patients. In the absence of this information, the Committee considered the evidence relating to adults, which suggested that the use of induction therapies reduced acute rejection rates and costs to the NHS compared with no induction therapy. The Committee also heard from the experts that there was no evidence to suggest that acute rejection rates should be different for paediatric compared with adult populations. The Committee accepted the evidence of the treatments in combination with ciclosporin in adults, and concluded that there was no reason that this should be different in children and adolescents. It therefore considered the submitted estimates of cost effectiveness to be reasonable estimates.
4.3.9. The Committee noted that, as was the case for the appraisal of immunosuppressive regimens in adults, experts reported that basiliximab and daclizumab are more commonly used for patients with higher levels of immunological risk, although neither has UK marketing authorisation for patients at high immunological risk. The Committee was persuaded of a need for additional options for immunosuppression for this group, and the experts stated that there was no reason to anticipate that these agents would be less safe or less effective in the high-risk group.
4.3.10. The Committee noted the RCT evidence of basiliximab in combination with tacrolimus, and the confidential nature of this information. In light of this evidence, the Committee concluded that the use of basiliximab or daclizumab should be recommended as options for children and adolescents undergoing renal transplantation only as part of ciclosporin-based regimens, irrespective of the patient’s immunological risk.
4.3.11. The Committee considered that the evidence from the single RCT of tacrolimus-based immunosuppressive regimens in paediatric patients demonstrated that it reduced acute rejection rates compared with ciclosporin-based regimens.
4.3.12. The Committee also noted the discrepancies between the manufacturer’s and the Assessment Group’s estimates of cost effectiveness. It was persuaded that much of the difference could be explained by differing assumptions regarding the costs and effects of treatment side effects. The Committee heard from the experts that in younger patients (particularly adolescents), the relatively greater incidence of cosmetic side effects associated with the use of ciclosporin compared with tacrolimus was an important issue. The Committee noted that the Assessment Group’s cost-effectiveness estimate was approximately £34,000 per QALY gained, but this estimate is without any consideration of treatment side effects or the increased cost of an acute rejection episode. Taking these factors into consideration, the ICERs were likely to be less than those quoted in both the models reviewed.
4.3.13. The Committee also took note of the comments made by the clinical experts regarding the different side-effect profiles of the two calcineurin inhibitors and the importance of minimising the risk of cosmetic and clinical side effects in paediatric patients, because such effects were a common cause of non-concordance with medication and consequent graft rejection and loss. The Committee was therefore persuaded that both calcineurin inhibitors should be available as optional treatments, and the decision about which to use should be based, in part, on the relevance of the respective side effects to the patient. The Committee therefore concluded that tacrolimus should be recommended for children and adolescents as an optional alternative to ciclosporin.
4.3.14. The Committee noted that episodes of acute rejection are sometimes treated by switching the calcineurin inhibitor from ciclosporin to tacrolimus, and that this use of tacrolimus is specified separately in its licensed indications. However, because this essentially constitutes a change to the initial or maintenance therapy, the Committee understood that the recommendations already included its use for this indication (see section 1.2).
4.3.15. The Committee noted that there were no RCTs of MMF in paediatric or adolescent patients and discussed in detail the results of the review of non-randomised studies. The Committee considered that the meta-analysis of MMF in adult patients was likely to be important in informing their estimation of differential acute rejection rates in paediatric or adolescent patients.
4.3.16. The Committee noted that the meta-analysis of adult RCTs indicated that MMF reduced the number of acute rejection episodes compared with azathioprine. It also noted that the ICER produced by the Assessment Group that incorporated this value was approximately £60,000 per QALY for MMF compared with azathioprine. The Committee noted that the manufacturer’s economic evaluation suggested that MMF was less costly and more effective than azathioprine. It considered that this analysis included estimates of acute rejection rates taken from a single non-randomised, comparative study and that the historical control design of this study may have led to bias in the selection of patients. The Committee concluded that the meta-analysis of adult RCTs was the most acceptable evidence to inform the acute rejection rates used in the economic analysis. Therefore, the Committee concluded that the assessment of cost effectiveness conducted by the Assessment Group was the most appropriate analysis on which to base its recommendations.
4.3.17. The Committee was also persuaded that, as is the case for adults, MMF has a potentially clinically significant role in situations where there is a very high risk of calcineurin inhibitor nephrotoxicity, because it allows the use of these drugs to be minimised or avoided. Such situations include delayed graft function, or if kidneys are at particular risk of developing delayed graft function (for example, kidneys from non-heart-beating donors or if there is known prolonged warm or cold ischaemia time). The Committee considered that, in such circumstances, minimisation of exposure to nephrotoxic drugs was desirable, and the use of MMF therapy to cover this period of increased risk from calcineurin inhibitor nephrotoxicity was likely to be cost effective in terms of reducing the high risk of graft failure at this time. However, the Committee considered that this therapeutic approach should be maintained only until this period of high risk has passed.
4.3.18. The Committee further considered the evidence presented on MMF for the appraisal of immunosuppressive regimens in adults. In particular, it considered the situation where a patient’s renal function decreases gradually after transplantation, as indicated by progressively rising creatinine levels (that is, where chronic allograft dysfunction is evident), and reduction of the dose of calcineurin inhibitor is desirable to avoid further loss of kidney function. Under these circumstances, substitution of calcineurin inhibitors with MMF was likely to be both clinically and cost effective. The Committee considered that the same would be true for children and adolescents.
4.3.19. The Committee discussed with the clinical experts a possible additional role for MMF for children and adults in terms of preventing graft loss specifically when it is considered important to escalate immunosuppressive therapy (for example, after acute rejection episodes). However, the Committee was unable to provide specific guidance on this indication because of the lack of any direct evidence.
4.3.20. The Committee was persuaded that, in general, reducing or withdrawing corticosteroids given as part of immunosuppressive regimens was important because of the known potential contribution of these agents to poor growth and metabolic complications in children. The Committee considered the evidence from non-randomised studies provided by the manufacturer of MMF relating to the reduction of corticosteroids in immunosuppressive regimens (containing daclizumab, tacrolimus and MMF). The Committee considered the evidence available for the effect of MMF in the reduction/withdrawal of corticosteroids and noted that there were no RCTs supporting the use of MMF specifically in this indication. The Committee concluded that, on the basis of the evidence presented, there was insufficient evidence to recommend MMF as part of treatment regimens for the reduction/withdrawal of corticosteroids, except within well-designed randomised clinical trials.
4.3.21. In the absence of any RCT evidence to support the use of MPS in children and adolescents, the Committee paid particular attention to the claims from the manufacturer that MPS and MMF were equivalent products. However, the Committee concluded that the absence of information relating to appropriate dose size and frequency in paediatric patients meant that the clinical and cost effectiveness of MPS was, at best, highly uncertain. Moreover, the Committee understood that issues of drug absorption and appropriate dosing schedules are particularly important for children and adolescent patients. The Committee could not, therefore, conclude that MPS was clinically or cost effective on the evidence available.
4.3.22. As with the appraisal of the immunosuppressive regimens in adults, the Committee noted that there were no clinical studies directly comparing the sirolimus regimen that currently has UK marketing authorisation (sirolimus with corticosteroids in combination with ciclosporin tapered to discontinuation) with standard calcineurin-inhibitor-based therapies. Indeed, in the two studies of the licensed regimen, sirolimus was also used in the comparator arms. The Committee did not accept that this licensed regimen was clinically more effective than standard ciclosporin-based immunosuppression on the basis of the available evidence.
4.3.23. The Committee also concluded that, given the lack of other treatment options and the high risk and cost of returning to dialysis, in circumstances of proven intolerance to calcineurin inhibitors necessitating their complete withdrawal, sirolimus in combination with corticosteroids should be considered as an option.
