Aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years

1 Appraisal Committee's preliminary recommendations

1.1 The Committee is minded not to recommend aripiprazole as an option for the treatment of schizophrenia in people aged 15 to 17 years.

1.2 The Committee recommends that NICE requests further information on the clinical and cost effectiveness of aripiprazole from the manufacturer, as described in 1.3 to 1.6. This information should be made available for the next Appraisal Committee meeting.

1.3 The information should include evidence on the clinical effectiveness of aripiprazole compared with risperidone, olanzapine, quetiapine, amisulpride and clozapine. This evidence should examine the relative effectiveness of each agent compared with placebo and with each other. Outcomes should be reported using the following scores:

• total Positive and Negative Syndrome Scale (PANSS)
• positive and negative PANSS subscale scores
• Clinical Global Impression for severity (CGI-severity) and improvement (CGI-improvement)
• Children's Global Assessment Scale (CGAS)
• Paediatric Quality of Life and Enjoyment and Satisfaction Questionnaire (P-QLES-Q).

1.4 Information about how the clinical and cost-effectiveness of aripiprazole may differ for people aged 15 to 17 years with schizophrenia who also have learning difficulties is required.

1.5 The information should include an economic analysis of aripiprazole incorporating the following comparators: risperidone; olanzapine; quetiapine; and clozapine (as rescue treatment). An analysis is required for the following four treatment sequences:

• aripiprazole followed by risperidone then olanzapine then clozapine
• risperidone followed by aripiprazole then olanzapine then clozapine
• risperidone followed by olanzapine then aripiprazole then clozapine
• risperidone followed by olanzapine then quetiapine then clozapine.

1.6 For each of the four treatment sequences in 1.5 the following factors should be considered:

• A range of doses for each comparator, including low doses (which are commonly prescribed for adolescents)
• Observed differences (and standard errors) in PANSS scores
• The sensitivity of the incremental cost-effectiveness ratio (ICER) to rates of relapse informed by PANSS scores
• Data on all adverse treatment effects, including weight gain, extrapyramidal symptoms such as akathisia, sexual dysfunction (modelled if necessary from the incidence of hyperprolactinaemia), somnolence, and aggression
• Inclusion of lay utility values (rather than patient values) from Briggs et al.

2 The technology

2.1 Aripiprazole (Abilify, Bristol-Myers Squibb and Otsuka Pharmaceuticals) has a UK marketing authorisation for the treatment of schizophrenia in people aged 15 years and older.

2.2 Aripiprazole is administered orally. The summary of product characteristics (SPC) states that the recommended dose for aripiprazole is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using aripiprazole oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg.

2.3 The SPC states that the most commonly reported adverse reactions associated with aripiprazole treatment include akathisia and nausea. For full details of adverse reactions, contraindications, special warnings and precautions for use, see the SPC.

2.4 Aripiprazole is available in 5-mg, 10-mg, 15-mg and 30-mg tablets. The acquisition cost of aripiprazole 5 mg, 10 mg and 15 mg is £97.67 for 28 tablets. The acquisition cost of aripiprazole 30 mg is £195.33 for 28 tablets. The acquisition cost of aripiprazole oral solution 1 mg/ml is £104.64 for 150 ml. Costs exclude VAT and are from the British national formulary [BNF] 59^th edition. Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of aripiprazole and a review of this submission by the Evidence Review Group (ERG; appendix B).

Clinical effectiveness

3.1 The manufacturer performed a systematic review to identify randomised controlled trials (RCTs) comparing aripiprazole with antipsychotic drugs (olanzapine, risperidone, quetiapine, haloperidol, and amisulpride) or placebo. Clozapine was listed as a comparator in the final scope but was excluded from the systematic review as the manufacturer did not consider it to be used in routine clinical practice for the treatment of schizophrenia in adolescents. All the other treatments included in the systematic review are listed in the final scope, with the exception of haloperidol.

3.2 Six RCTs were identified, none of which compared aripiprazole with another antipsychotic drug. Of the six RCTs, only one on the use of aripiprazole in adolescents (study 31-03-239) compared with placebo was identified. Study 31-03-239 was a phase III, multicentre, randomised, double-blind, placebo-controlled trial that enrolled 302 people aged between 13 and 17 years with schizophrenia (diagnosed using the 'Diagnostic and statistical manual of mental disorders, 4th edition' ['DSM-IV'] and confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version [K-SADS-PL]). Participants were randomly assigned to one of three study arms: a once-daily fixed dose of either 10 mg or 30 mg of aripiprazole, or matching placebo. Supporting data on adverse events were from two open-label single-arm extension studies.

3.3 The primary outcome in the RCT was mean change from baseline in PANSS score at 6-week follow-up, with reductions in score indicating an improvement in symptoms. Secondary outcomes included: Positive and Negative Syndrome Scale (PANSS), Children's Global Assessment Scale (CGAS), Clinical Global Impression for Severity (CGI-severity) and Improvement (CGI-improvement), and time to discontinuation (for all reasons). The number of hospitalisations was also included. Health-related quality of life was assessed using the paediatric quality of life and enjoyment and satisfaction questionnaire (P-QLES-Q) total and overall scores at baseline and at 6-week follow-up.

3.4 The results from the RCT showed that at 6-week follow-up all three groups showed reductions in PANSS score (that is, an improvement in symptoms). Compared with the group who received placebo, statistically significant differences in the degree of improvement were observed in the group who received aripiprazole 10 mg (5.5 difference; p = 0.05) and the group who received aripiprazole 30 mg (7.4 difference; p = 0.007). At 6-week follow-up all three groups showed reductions in PANSS positive subscale scores, and, compared with placebo, these reductions were statistically significant in the two groups who received aripiprazole. All three groups also showed reductions in PANSS negative subscale scores at 6-week follow-up; compared with placebo this reduction was statistically significant only in the group who received 10 mg aripiprazole.

3.5 At 6-week follow-up mean change in CGAS scores showed statistically significant increases (improvements) from baseline in the groups who received 10 mg and 30 mg aripiprazole compared with the group who received placebo. Mean CGI-severity and CGI-improvement scores at 6-week follow-up showed statistically significant decreases (improvements) from baseline in the groups who received 10 mg or 30 mg aripiprazole compared with the group who received placebo. Health-related quality of life as assessed by P-QLES-Q total and overall scores at baseline and at 6-week follow-up showed statistically significant changes in both the group receiving 10 mg aripiprazole and the group who received 30 mg aripiprazole compared with the group who received placebo.

3.6 The manufacturer presented a post-hoc subgroup analysis of the RCT to assess the similarity between the trial participants aged 15 to 17 years and adults with schizophrenia. The manufacturer used a cut-off age of 15 years to separate participants aged 15 to 17 years from those who were aged 13 to 14 years. The manufacturer stated that efficacy improvements in the subgroup aged 15 to 17 years were comparable to those in the overall dataset. The manufacturer also stated that a maintenance effect was observed in participants aged 15 to 17 years, and that tolerability and safety profiles were similar in the trial participants and in adult patients with schizophrenia.

3.7 Data on adverse events were taken from the RCT comparing aripiprazole with placebo and from two open-label single-arm extension studies (31-03-241 and 31-05-243). Participants who completed the RCT were eligible to enter an open-label extension study of aripiprazole for 6 months (31-03-241). The second open-label extension study (31-05-243) included participants who completed the first extension study (31-03-241).

3.8 The most common treatment-related adverse events observed in the RCT comparing aripiprazole with placebo were extrapyramidal disorder, somnolence and tremor. Overall, a higher percentage of participants in the groups who received aripiprazole experienced treatment-related adverse events (71% of those who received 10 mg aripiprazole and 72.5% of those who received 30 mg aripiprazole) compared with the placebo group (57%). The majority of treatment-related adverse events were mild or moderate in severity. The rates of serious treatment-emergent adverse events were low for all groups; with an incidence of 3% in the placebo group and 4% in the groups who received 10 mg and 30 mg aripiprazole. Mean weight and body mass index (BMI) z-scores at each visit were within 0.5 standard deviations of the general population for all three groups. A 'significant' weight gain at 6-week follow-up (defined as a weight gain of 7% or more from baseline) was seen in 4% of the participants who received 10 mg aripiprazole, 5.2% of those who received 30 mg aripiprazole and 1% of those in the placebo group. A 'significant' weight loss at 6-week follow-up (defined as a weight loss of 7% or more from baseline) was seen in 3% of the participants who received 10 mg aripiprazole, 2.1% of those who received 30 mg aripiprazole and 6.1% of those in the placebo group.

3.9 Changes from baseline in extrapyramidal symptoms as shown by the Simpson-Angus scale showed a statistically significant difference between the aripiprazole groups and the placebo group (0.5 in the group who received aripiprazole 10 mg [p < 0.007], 0.3 in the group who received aripiprazole 30 mg [p < 0.05] and -0.3 in the placebo group). In this study, the Barnes scale and the Abnormal Involuntary Movement Scale were also analysed and showed no statistically significant differences (data not reported). Mean serum prolactin levels at 6-week follow-up relative to baseline were -8.45 ng/ml for the group who received placebo, 11.93 ng/ml for the group who received10 mg aripiprazole and 15.14 ng/ml for the group who received 30 mg aripiprazole. The aripiprazole groups showed statistically significant greater changes in prolactin levels compared with the placebo groups (10 mg aripiprazole group, p = 0.003; 30 mg aripiprazole group, p < 0.0001). The manufacturer's submission stated that overall, aripiprazole has no impact on cardiac conduction, and the impact on metabolic parameters and prolactin levels appears to be less than for other atypical antipsychotics.

3.10 The results of the first of the two open-label extension studies (study 31-05-243) showed that the majority of treatment-related adverse events were mild or moderate in severity. At least one treatment-related adverse event was reported by 48.2% of participants receiving long-term treatment with aripiprazole. Influenza, vomiting and headache were the only treatment-related adverse events reported by 5% or more of the participants. Serious adverse events occurred in 5.9% of participants. The manufacturer's submission stated that data were insufficient to draw conclusions about the impact of aripiprazole treatment on clinical chemistry parameters such as prolactin levels. At 6-week follow-up 12.7% of participants had a weight gain from baseline of 7% or more and 7% had a weight loss from baseline of 7% or more. No clinically meaningful changes in mean QT or QTc intervals or other ECG abnormalities were observed.

3.11 The results of the second open-label study (31-03-241) showed that the majority of treatment-related adverse events were mild or moderate in severity. In the subgroup of participants with schizophrenia, 69% had at least one treatment-related adverse event and 5.9% had a serious adverse event. At 6-week follow-up, 24.5% of participants had a weight gain from baseline of 7% or more and 4.6% had a weight loss from baseline of 7% or more. There were no clinically meaningful changes reported in mean QT or QTc intervals or other ECG abnormalities.

3.12 The manufacturer's systematic review also attempted to identify studies that could be included in an adjusted indirect comparison to provide data comparing aripiprazole with olanzapine, the chosen comparator in the manufacturer's submission. Of the six trials identified, two were deemed eligible for inclusion in an indirect comparison: study 31-03-239 that compared aripiprazole with placebo, and a study by Kryzhanovskaya et al. (2009) that compared olanzapine with placebo in adolescents with schizophrenia. All the other studies were deemed by the manufacturer to be unsuitable for inclusion in the indirect comparison as they either did not include a placebo group or did not contain sufficient data for comparison. The olanzapine RCT was a phase III, multi-centre, randomised, double-blind, placebo-controlled trial that enrolled 107 participants aged between 13 and 17 years with schizophrenia (diagnosed using the 'Diagnostic and statistical manual of mental disorders, 4th edition text revision' ['DSM-IV-TR']. Participants were randomly assigned to either flexible doses of olanzapine (2.5-20 mg/day) or placebo.

3.13 Data on clinical efficacy (withdrawals because of adverse events, lack of efficacy or other reasons, weight gain of 7% or more, somnolence and treatment with benzodiazepines [used as a surrogate for extrapyramidal symptoms]) were extracted from the RCTs and analysed for use in the economic evaluation. Data from the study of olanzapine were compared with data from the study of aripiprazole using the placebo arms of each trial as a common comparator. Data were also extracted from the clinical study reports for aripiprazole. No further details on the methodological approach taken to data extraction for the indirect comparison were provided in the manufacturer's submission.

3.14 The results of the adjusted indirect comparison were reported as an odds ratio (OR) and relative risk (RR), each with 95% confidence intervals (CI). The manufacturer's submission did not provide further details on how these results were generated from the ORs and RRs of the individual RCTs. The estimates of the effectiveness of aripiprazole relative to olanzapine were used primarily to inform the economic model.

Cost effectiveness

3.15 The manufacturer carried out a systematic review of the literature to identify cost-effectiveness studies of aripiprazole for the treatment of schizophrenia in adolescents. No studies were identified that assessed the cost effectiveness of aripiprazole in adolescents with schizophrenia; however four economic evaluations that included aripiprazole in adults with schizophrenia were identified and reviewed.

3.16 The manufacturer presented a decision tree followed by a Markov model to estimate the cost effectiveness of first-line aripiprazole compared with first-line olanzapine for the treatment of schizophrenia in adolescents. The model incorporates first-line, second-line and third-line treatments and allows people to switch to the next treatment when one treatment is discontinued or their condition relapses. In the first two cycles of the model, people undergoing treatment may discontinue and switch to another antipsychotic drug (from aripiprazole to olanzapine or vice versa). These cycles are represented as two health states in the decision tree: stable schizophrenia and withdrawal (because of lack of efficacy, adverse events or other reasons). In the second cycle, people's condition may also relapse, which is reflected as an additional health state in this cycle. People whose condition does not relapse or who discontinue treatment are assumed to continue on treatment in the stable schizophrenia state. Discontinuation is assumed to occur only in the first two cycles. From the third treatment cycle onwards, people are assumed to either continue in a stable condition or their condition may relapse and they may subsequently switch antipsychotic treatment. This is reflected by using a Markov process that involves only two states - maintenance on treatment and relapse. People who discontinue treatment or whose condition relapses on the second treatment are assumed to receive clozapine as a last-resort treatment and to continue receiving clozapine after their condition has relapsed. The model adopted a 3-year time horizon on the basis that this was the maximum duration an individual would remain in this patient group before being considered an adult (at which point other treatment options may be available). Death was not modelled because of the short time horizon and a lack of efficacy data on death rates.

3.17 The manufacturer's base-case analysis compared first-line aripiprazole with first-line olanzapine in people aged 13-17 years with schizophrenia, which is broader than the UK marketing authorisation for aripiprazole (adolescents aged 15-17 years with schizophrenia). Results were presented in terms of total and incremental costs and quality-adjusted life years (QALYs) and ICERs for the two strategies.

3.18 The model used withdrawal and adverse event data, but not primary outcome data, from published RCTs and the indirect comparison. The probabilities of withdrawals and adverse events were calculated directly from the aripiprazole RCT and from the manufacturer's adjusted indirect comparison. The manufacturer stated that no long-term data on treatment effects, including rates of relapse with aripiprazole and olanzapine, were identified in the literature for the adolescent population. Data on rates of relapse were therefore taken from a study of adults with schizophrenia that compared aripiprazole with other atypical antipsychotics. The study reported a relative risk of relapse with aripiprazole of 0.92 (95% CI 0.67 to 1.26) compared with other atypical antipsychotics. However, the manufacturer stated that this value was an error, as it did not equal the ratio of the proportion of people whose condition had relapsed after using other atypical antipsychotics divided by the proportion of people whose condition had relapsed after using aripiprazole. The manufacturer adjusted the value and used this higher adjusted relative risk of relapse (that is, the patient's condition is more likely to relapse) in the economic model.

3.19 The manufacturer also found limited or no adolescent data for utility values and resource use. Utilities for the health states were taken from a study of adults with schizophrenia in the UK. The study reported separate utilities for patients and non-patients. The manufacturer used the utilities derived from patients in its economic model.

3.20 The model included four types of resource use and costs: drug acquisition, on-treatment monitoring and switching of medication, management of adverse events, and health state costs. Treatment costs were calculated using daily drug dosages from the SPCs supported by the mean/median dosages in study 31-03-239 and the trial reported by Kryzhanovskaya et al. (2009). Resource use associated with switching medication was based on three 20-minute visits to a psychiatrist. Resource use associated with adverse treatment effects adopted in the model was based on assumptions made in NICE clinical guideline 82 (CG82), 'Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care' (2009) about weight gain and extrapyramidal symptoms, and clinical opinion for somnolence. Resource use associated with relapse which was applied in the model was also based on CG82.

3.21 In the manufacturer's deterministic base case and probabilistic base-case analyses, first-line treatment with aripiprazole is estimated to dominate first-line treatment with olanzapine. The manufacturer conducted a number of one-way deterministic sensitivity analyses which showed that varying the relative risk of relapse and the daily cost of aripiprazole had the greatest effect on the ICERs. The ICERs varied between -£123,663 and £628,706 per QALY gained for a relative risk of relapse of 0.679 to 1.261 and from -£64,755 and £130,723 per QALY gained for a daily cost of aripiprazole of £2.28 to £6.84. The probabilistic sensitivity analysis suggested that first-line aripiprazole had a 96% probability of being cost effective at £20,000 per QALY gained when compared with first-line olanzapine.

3.22 The manufacturer's submission also presented four scenario analyses, of which three intended to test structural assumptions of the model concerning the use of adult relative risk of relapse, the exclusion of extrapyramidal symptoms and the disutility from treatment with clozapine. The remaining scenario analyses addressed the methodological decision of electing to use odds ratios from the trial outcomes instead of relative risks. The analyses that had the greatest effect were those in which the relative risk of relapse was changed and in which people receiving benzodiazepines (used as a proxy for extrapyramidal symptoms) were included.

3.23 The ERG commented that there were no RCTs comparing aripiprazole with any other atypical antipsychotic in adolescents. The ERG noted that the evidence of clinical effectiveness was based on only one RCT (study 31-03-239). The ERG considered that the RCT was relevant to the decision problem and provided evidence that is generalisable to the UK population. However, the trial included adolescents aged 13 to 17 years which is broader than the population defined in the final scope and in the UK marketing authorisation for aripiprazole (which is for 15 years and older). The ERG also noted that there were differences in the three treatment arms of the trial, with a greater proportion of white people, people who had previously received antipsychotic treatment and females in the 10 mg aripiprazole group compared with the 30 mg aripiprazole group. The ERG noted that the two open-label extension studies included adolescents and adults with schizophrenia and with bipolar I disorder.

3.24 The ERG commented on the clinical outcomes presented in the manufacturer's submission. The ERG noted that there are no agreed parameters by which clinically meaningful changes or differences in PANSS, CGI, CGAS, and P-QLES-Q can be pre-defined. The ERG noted that the clinical significance of the differences observed in PANSS scores, which was the manufacture's chosen primary outcome, was not provided by the manufacturer. The ERG also commented that no explanation was given by the manufacturer for the apparent placebo effect observed in the trial. The ERG also noted that data from three scales used to assess the clinical effects of aripiprazole were reported in the 31-03-239 study and clinical study report, but were not included in the manufacturer's submission.

3.25 The ERG noted that only a subset of the relevant outcomes reported in the RCTs were used in the indirect comparison. The ERG also commented that no formal assessment of heterogeneity was carried out on the indirect comparison by the manufacturer. The ERG noted differences between the two trials in previous use of antipsychotics and the number of countries included. The ERG commented that there were a large number of withdrawals because of lack of efficacy in adolescents in the placebo group of the olanzapine study (51%), and that the overall proportions of adolescents withdrawing from the study were higher in the olanzapine study (32% olanzapine compared with 57% placebo) than in the aripiprazole study. The ERG also noted that the manufacturer's submission did not provide an interpretation of the results of the adjusted indirect comparison or any critical assessment of the results of the analysis. It was noted that a trial reported by Hass and colleagues comparing standard and subtherapeutic doses of risperidone in adolescents with schizophrenia was not identified in the systematic review or included in the indirect comparison because it was published after the manufacturer's systematic review of the literature was carried out.

3.26 The ERG considered that in general the manufacturer's approach to the economic evaluation was appropriate. However, the ERG noted a number of concerns about the cost-effectiveness analysis, including the approach used to compare sequential treatment strategies. These concerns included:

• the major contribution to the total costs for both treatment strategies of the costs of managing relapses
• the exclusion of risperidone, which is currently the most common first-line treatment for schizophrenia in adolescent populations in the UK
• the exclusion of potentially relevant adverse events such as extrapyramidal symptoms and sexual dysfunction, in the model
• the appropriateness of applying data derived from adult populations, such as relative risk values, to adolescents, and the uncertainty that this generates in the model
• the appropriateness of using a re-derived relative risk value based on crude relative risk reported in the published paper.

3.27 The ERG made revisions to the manufacturer's model to correct errors (relating to the cost of relapse in cycle 2 and the Health Resource Group [HRG] cost code that was applied). When the cost of relapse in cycle 2 was revised it resulted in a higher ICER than was reported in the manufacturer's base case for the comparison of first-line aripiprazole with first-line olanzapine (£6231 per QALY gained). Revising the HRG cost code had no effect on the result (aripiprazole dominated olanzapine in the revised result and the base case). The ERG also noted there was an error in the presentation of all the probabilistic sensitivity results relating to the inclusion of total undiscounted cost for first-line olanzapine. Revising this error resulted in considerably higher ICERs than those reported in the manufacturer's base case (ranging from £22,182 per QALY gained in the ERG analysis after correcting for this error to £47,103 per QALY gained after correcting for this error and applying a relative risk of relapse of 0.92).

3.28 The ERG performed a number of analyses on the corrected model to apply alternative estimates for parameter inputs and explore the impact of alternative structural assumptions and the methods used in the adjusted indirect comparison. These included:

• removing an apparent double-counting in which patients whose condition relapsed accrue the full cycle cost of medication in the cycle in which their condition relapses and the full cycle cost of their next available line of medication in the following cycle, while also attracting the full cycle cost for management of relapse
• assuming that fewer adolescents whose condition relapses would be admitted as inpatients
• assuming that the disutility associated with weight gain continues while people remain on a given treatment
• assuming that utility for people discontinuing treatment in the first cycle is 20% lower than for people with stable schizophrenia
• assuming that the length of stay for people whose condition has relapsed and are admitted as inpatients is increased to 107.7 days
• applying the relative risk of relapse of 0.92 reported by Moeller and colleagues rather than the assumed higher value (that is, more likely to relapse) derived by the manufacturer

3.29 The cumulative results presented by the ERG showed that adjusting medication costs for people with schizophrenia whose condition relapses approximately doubles the incremental costs without affecting the incremental QALYs, increasing the ICER from £6231 to £13,763 per QALY gained. The ICER increases from £13,763 to £23,144 per QALY gained when the disutility for people discontinuing treatment because of adverse events is reduced and the disutility associated with weight gain is continued while people remain on a given treatment. When the proportion of people whose condition has relapsed and who are admitted as inpatients is increased to 50% and applied to the assumptions already considered, it results in aripiprazole dominating olanzapine (that is, aripiprazole is more effective and less expensive than olanzapine). However, when the length of stay for admitted patients is increased to 107.7 days, the ICER increases to £69,638 per QALY gained, and increases further to £232,981 per QALY gained when the relative risk of relapse of 0.92 reported by Moeller and colleagues is used.

3.30 The ERG also presented exploratory analyses in which the unit costs of risperidone for the treatment of adolescents with schizophrenia and the odds ratios relating to early discontinuations with risperidone (based on an adjusted indirect comparison) were applied to the manufacturer's economic model. In the first analysis, the cost of first-line treatment with risperidone was substituted for the cost of first-line treatment with olanzapine in the manufacturer's model, which caused the ICERs for aripiprazole as a first-line treatment to increase significantly, ranging from £89,114 to £112,012 per QALY gained compared with risperidone. The ERG noted that this analysis did not use any clinical data specific to risperidone, and implicitly assumed that the odds ratios derived for olanzapine (relative to aripiprazole) could be applied to risperidone. To examine the impact of applying odds ratios derived from an alternative data source, an adjusted indirect comparison was conducted using data from an RCT on the use of risperidone in adolescents aged 13 to 17 years, reported by Haas and colleagues (2009) to estimate the odds ratios for discontinuation (due to adverse events, lack of efficacy and other reasons) and for treatment-related adverse effects (weight gain, somnolence and extrapyramidal symptoms). The ERG noted that the risperidone RCT compared standard dose (1.5 - 6.0 mg/day) risperidone with a 'sub-therapeutic' (but not proven ineffective) dose, which was ten-fold lower than the dose in the active arm of the study (that is, 0.15 - 0.6 mg/day risperidone). Therefore they cautioned that the occurrence of treatment discontinuations associated with risperidone may be underestimated in the study, and hence the odds ratios derived in the adjusted indirect comparison may be biased against aripiprazole. Using this data in the manufacturer's economic model, the ERG's analysis suggested that first-line risperidone dominated first-line aripiprazole (that is, first-line aripiprazole is a less cost-effective option compared with first-line risperidone).

3.31 Full details of all the evidence are in the manufacturer's submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of aripiprazole, having considered evidence on the nature of schizophrenia in people aged 15 years and older and the value placed on the benefits of aripiprazole by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Appraisal Committee discussed current standard clinical management of schizophrenia in adolescents. It heard from clinical specialists and patient experts that antipsychotics are prescribed only after a psychological assessment and a discussion with the person with schizophrenia. The choice of treatment depends on a number of factors, including adverse events associated with the treatment, previous treatments the person has received and the responses to them, and adverse events experienced while on those treatments. Adolescents with schizophrenia are usually treated with atypical antipsychotics at a low dose and are closely monitored.

4.3 The clinical specialists noted that the main aim of treatment is to maximise the control of schizophrenia and minimise the adverse events that are the most troublesome for each individual. The Committee heard from the patient experts that effective control of schizophrenia with aripiprazole would allow adolescents to return to normal functioning in terms of work or schooling. The Committee understood from the clinical specialists that no single atypical antipsychotic drug is considered to be more clinically effective than the others; however risperidone is the most widely used first-line atypical antipsychotic in UK clinical practice because clinicians have extensive experience of using it to treat schizophrenia, and often achieve control with low doses and without troublesome adverse events. The clinical specialists also stated that when an atypical antipsychotic medication is prescribed, control of schizophrenia and adverse events are assessed over a period of 6 weeks or more and an alternative atypical antipsychotic can be considered if the first antipsychotic proves unsatisfactory. Other atypical antipsychotics such as aripiprazole, olanzapine, quetiapine or amisulpride may be used if control of schizophrenia is not achieved with risperidone. The clinical specialists also explained that clozapine is sometimes also prescribed, however because it needs careful monitoring for particular side effects, it is prescribed only if the schizophrenia is refractory to at least three other antipsychotic treatments, as rescue therapy. The Committee noted that some of the atypical antipsychotics described by the clinical specialists do not have a marketing authorisation for the treatment of adolescents with schizophrenia, but acknowledged that licensing is not a prerequisite to prescribing. The Committee agreed with the clinical specialists that it is important for adolescents with schizophrenia to have a range of treatment options before considering rescue therapy with clozapine, and therefore concluded that aripiprazole may be a suitable alternative first- or second-line treatment option compared with risperidone, olanzapine, quetiapine or amisulpride for people aged 15 years and older with schizophrenia.

4.4 The Committee heard from the clinical specialists and patient experts that there are a number of dose-related adverse events associated with atypical antipsychotic treatments, including weight gain, sexual dysfunction, hyperprolactinaemia, aggression, and extrapyramidal symptoms including akathisia. Adolescents are often less tolerant of adverse events than adults, leading to problems with adherence to medication. The Committee heard from the clinical specialists that some treatments are associated with particular adverse events: olanzapine can lead to weight gain, risperidone can be associated with akathisia, amisulpride can increase prolactin levels, and aripiprazole can be associated with akathisia and a subjective feeling of aggression (for which benzodiazepine co-treatment may be used). The clinical specialists stated that these adverse events are dose related and therefore it is preferable to start prescribing any atypical antipsychotic at a low dose. The Committee accepted that all atypical antipsychotics are associated with adverse events and that accounts of the use of aripiprazole suggest that it may be as safe and well tolerated as the other treatments.

Clinical effectiveness

4.5 The Committee noted that the clinical effectiveness evidence presented in the manufacturer's submission was derived mainly from one RCT (study 31-03-241) that studied treatment with aripiprazole at two different doses compared with placebo, with supporting data on adverse events from two open-label single-arm extension studies. The Committee noted that the 31-03-241 study was placebo-controlled and did not provide a head-to-head comparison of aripiprazole against any atypical antipsychotics.

4.6 The Committee noted that the 31-03-241 study showed a reduction in PANSS score (that is, an improvement in symptoms) at week 6 in all three study arms. Statistically significant differences in the degree of improvement were observed in the aripiprazole groups compared with the placebo group (p = 0.05 for either dose compared with placebo). The Committee heard from the clinical specialists that the PANSS score is a well-recognised tool used in clinical trials for the measurement of positive, negative and general psychopathology symptoms in schizophrenia. However, the results are often difficult to relate to UK clinical practice as the tool is not routinely used by clinicians. The Committee accepted that the PANSS score is a valid tool for the measurement of positive, negative and general psychopathology symptoms and that evidence from the 31-03-241 study demonstrates a reduction in schizophrenic symptoms in the aripiprazole groups.

4.7 The Committee was aware that the manufacturer's submission included a very limited evidence base and did not present clinical-effectiveness evidence on the primary outcome for olanzapine (the manufacturer's chosen comparator). Nor did the manufacturer present clinical-effectiveness evidence on both the primary and secondary outcomes for all comparators routinely used in UK clinical practice. The Committee was aware that two clinical trials (examining olanzapine compared with placebo, and risperidone compared with placebo) were available. The Committee noted that both trials appear to show greater relative reductions in PANSS positive and negative scores in their treatment arms compared with placebo than were seen in the aripiprazole trial. The Committee noted that there also appeared to be a large placebo effect in the aripiprazole trial, but heard from the manufacturer that the precise cause of this effect was unknown. The Committee agreed that it had not been presented with sufficient information to fully assess the relative clinical effectiveness of aripiprazole and concluded that more evidence for each of the atypical antipsychotics routinely used in UK clinical practice (risperidone, olanzapine, quetiapine, amisulpride and clozapine (only as rescue therapy)) should be requested and analysed by the manufacturer.

Cost effectiveness

4.8 The Committee considered the manufacturer's economic model, and the critique and exploratory analyses performed by the ERG. It noted that the manufacturer used a decision tree, followed by a Markov model, to estimate the cost effectiveness of first-line aripiprazole compared with first-line olanzapine for the treatment of schizophrenia in adolescents. Data were derived from the manufacturer's adjusted indirect comparison using secondary outcome data for aripiprazole and olanzapine.

4.9 The Committee considered the ERG's concerns about a number of aspects of the economic model, such as the omission of comparators specified in the final scope, the omission of primary outcome data, the omission of data on relevant adverse events (such as extrapyramidal symptoms and sexual dysfunction), and the appropriateness of data sources used to populate the model (given that there was no evidence from systematic targeted searches). The Committee was also aware that the ERG had identified a number of technical errors in the manufacturer's model. The Committee heard from the ERG that data on relapse health state utility, disutility associated with treatment-related adverse events and resource use assumptions were all derived from studies of adults rather than adolescent populations in the absence of data specific to the population in the scope of the appraisal. The Committee concluded that while this approach can be justified, it needs to be acknowledged as a limitation and source of uncertainty when interpreting the results of the economic evaluation.

4.10 The Committee considered the ERG's concern that the manufacturer's economic analysis was based on a more limited comparison than outlined in the final scope (that is, a comparison of only first-line aripiprazole compared with first-line olanzapine). The Committee agreed that an economic analysis of aripiprazole incorporating the following comparators: risperidone; olanzapine; quetiapine; and clozapine (as rescue treatment) should be sought from the manufacturer. The Committee agreed that this analysis should include the following treatment sequences: aripiprazole, risperidone, olanzapine, clozapine; risperidone, aripiprazole, olanzapine, clozapine; risperidone, olanzapine, aripiprazole, clozapine; risperidone, olanzapine, quetiapine, clozapine. The Committee was mindful of the testimony from the clinical specialists that atypical antipsychotics are generally administered at low doses for adolescents, and therefore requested that the manufacturer provide analyses examining a range of doses (including low doses) for each comparator to reflect UK clinical practice.

4.11 The Committee was mindful of the ERG's concern that the manufacturer's economic model only included a subset of data on the outcomes reported in the RCTs, used in the indirect comparison. The Committee considered that rates of relapse might be inferred from the primary outcome results of the included trials. The Committee concluded that clarification on the link between relapse rates and the primary outcomes listed in the trials should be sought from the manufacturer, and analyses incorporating PANSS data should be run in the economic model. The Committee requests that sensitivity analyses also be undertaken to explore the sensitivity of the ICER to the rate of relapse informed by different PANSS scores.

4.12 The Committee discussed the manufacturer's omission of data on some clinically-important adverse events (such as extrapyramidal symptoms and sexual dysfunction) from the economic model and concluded that the manufacturer should incorporate data on all adverse events associated with atypical antipsychotics in the economic model, acknowledging that there are differences between the comparator drugs. Adverse events that should be included in the model include: weight gain, extrapyramidal symptoms including akathisia, sexual dysfunction (modelled if necessary from hyperprolactinaemia), somnolence, and aggression.

4.13 The Committee discussed the utility data used in the economic model. It considered that the data from Briggs et al., although obtained from an adult population, had been derived appropriately however it is unclear whether the utility values accurately reflect the impact of disease or treatment-related side effects on adolescents with schizophrenia. The Committee acknowledged that values from lay people rather than patients should have been used in the economic model and requested that the manufacturer consider adopting this approach in any revised analyses.

4.14 The Committee noted that the base-case ICER, following revisions from the ERG, for first-line aripiprazole compared with first-line olanzapine was £6200 per QALY gained. However, the Committee also noted that the economic model contained a number of assumptions that were inappropriate, and that sensitivity analyses conducted by the ERG suggested the ICER could be as high as £233,000 per QALY gained if certain assumptions were varied. Furthermore, it noted that aripiprazole was dominated by risperidone in the ERG's exploratory analyses. It concluded that the ICERs presented by the manufacturer could not be accepted without revision. Therefore the Committee was minded not to recommend aripiprazole for the treatment of schizophrenia in adolescents aged 15 to 17 years as a cost-effective use of NHS resources. The Committee requested further clarification from the manufacturer, which should be made available for a second Appraisal Committee meeting (see sections 1.2 to 1.6).

4.15 The Committee considered whether its recommendations were associated with any potential issues related to equality. The Committee was aware that consultees and commentators suggested that one area of potential discrimination was that the diagnosis of schizophrenia requires a definitive methodological approach using precise diagnostic criteria detailed in a number of tools, including DSM-IV and K-SADS-PL. The Committee noted that while some people with learning difficulties may exhibit psychoses, unless they fulfil the DSM-IV and K-SADS-PL criteria for schizophrenia they do not (by definition) have schizophrenia, and therefore are not appropriate for inclusion in this appraisal. It noted that both the DSM-IV and K-SADS-PL are used in clinical practice, as well as in studies of schizophrenia. The Committee concluded that the manufacturer should consider how the clinical and cost-effectiveness of aripiprazole may differ for people with schizophrenia who have learning difficulties (see section 1.4).

Summary of Appraisal Committee's key conclusions

TAXXX (STA)	6 Appraisal title: Aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years	ACD section
Key conclusion
The Committee is minded not to recommend aripiprazole, within its licensed indication, for the treatment of schizophrenia in people aged 15-17 years. The Committee recommends that NICE requests further clarification from the manufacturer, which should be made available for a second Appraisal Committee meeting.		4.14 and section 1
Current practice
Clinical need of patients including the availability of alternative treatments	The Committee concluded that it is important for adolescents with schizophrenia to have a range of treatment options before considering rescue therapy with clozapine, and therefore concluded that aripiprazole may be a suitable alternative first- or second-line treatment option compared with risperidone, olanzapine, quetiapine or amisulpride for people aged 15 years and older with schizophrenia.	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?	The Committee heard from the patient experts that effective control of schizophrenia with aripiprazole would allow adolescents to return to normal functioning in terms of work or schooling. The Committee understood from the clinical specialists that no single atypical antipsychotic drug is considered to be more clinically effective than the others.	4.3 4.3
What is the position of the treatment in the pathway of care for the condition?	The Committee heard from the clinical specialists that risperidone is the most widely used first-line atypical antipsychotic in UK clinical practice for adolescents with schizophrenia. Other atypical antipsychotics, such as aripiprazole, olanzapine, quetiapine or amisulpride may be used if control of schizophrenia is not achieved with risperidone. It was noted that clozapine can be prescribed as a rescue therapy only if the schizophrenia is refractory to at least 3 other antipsychotic treatments.	4.3
Adverse events	The Committee heard from the clinical specialists and patient experts that there are a number of dose-related adverse events associated with atypical antipsychotic treatments, including weight gain, sexual dysfunction, hyperprolactinaemia, aggression and extrapyramidal symptoms including akathisia. The Committee accepted that accounts of the use of aripiprazole suggest that it may be as safe and well tolerated as the other treatments.	4.4
Evidence for clinical effectiveness
Availability, nature and quality of the evidence	The clinical evidence presented in the manufacturer's submission was derived mainly from one RCT that studied treatment with aripiprazole at two different doses compared with placebo. Supporting data on adverse events was obtained from two open-label single-arm extension studies. An indirect comparison was also conducted to compare aripiprazole first-line with olanzapine first-line. No head-to-head data were available to compare aripiprazole against any atypical antipsychotic treatments. The Committee was aware that the manufacturer's submission included a very limited evidence base and did not present clinical-effectiveness evidence on the primary or secondary outcomes for all comparators routinely used in UK clinical practice.	4.5 4.5 4.7
Relevance to general clinical practice in the NHS	The Committee heard from the clinical specialists that choice of treatment depends on a number of factors. Adolescents with schizophrenia are usually treated with atypical antipsychotics at a low dose and are closely monitored.	4.2
Uncertainties generated by the evidence	The Committee heard from the clinical specialists that the PANSS score (primary outcome) is a well-recognised tool used in clinical trials, however the results are often difficult to relate to UK clinical practice as the tool is not routinely used by clinicians. The Committee noted that there appeared to be a large placebo effect in the aripiprazole trial, but heard from the manufacturer that the precise cause of this effect was unknown. The Committee agreed that it had not been presented with sufficient information to fully assess the relative clinical effectiveness of aripiprazole and concluded that evidence for each of the atypical antipsychotics routinely used in UK clinical practice (risperidone, olanzapine, quetiapine, amisulpride and clozapine (as rescue therapy only)) should be requested and analysed by the manufacturer.	4.6 4.7 4.7
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?	Not applicable.	-
Estimate of the size of the clinical effectiveness including strength of supporting evidence	The Committee accepted that PANSS score is a valid tool for the measurement of positive, negative and general psychopathology symptoms and that available evidence demonstrated a reduction in schizophrenic symptoms in the aripiprazole groups.	4.6
Evidence for cost effectiveness
Availability and nature of evidence	The Committee considered the manufacturer's economic model and the critique and exploratory analyses performed by the ERG. The Committee heard from the ERG that some data used in the model were derived from adults rather than adolescent populations in the absence of data specific to adolescents. The Committee concluded that while this approach can be justified, it needs to be acknowledged as a limitation and source of uncertainty.	4.8 4.9
Uncertainties around and plausibility of assumptions and inputs in the economic model	The Committee considered the ERG's concerns about a number of aspects of the economic model, such as the omission of comparators specified in the final scope, the omission of primary outcome data, the omission of data on relevant adverse events and the appropriateness of data sources used to populate the model. The Committee considered the ERG's concern that the manufacturer's economic analysis was based on a more limited comparison than outlined in the final scope (that is, a comparison of only first-line aripiprazole compared with first-line olanzapine). The Committee agreed that an analysis of aripiprazole incorporating the following comparators: risperidone, olanzapine, quetiapine and clozapine (as rescue therapy) should be requested from the manufacturer. The Committee also requested that the manufacturer provide analyses examining a range of doses (including low doses) for each comparator to reflect UK clinical practice. The Committee concluded that clarification on the link between relapse rates and the primary outcomes in the trials should be sought from the manufacturer, and analyses incorporating PANSS data should be run in the economic model. The Committee also requested that sensitivity analyses be undertaken to explore the sensitivity of the ICER to the rate of relapse informed by different PANSS scores. The Committee concluded that the manufacturer should incorporate data on all adverse events associated with atypical antipsychotics in the economic model, acknowledging that there are differences between the comparator drugs.	4.9 4.10 4.11 4.12
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 Committee discussed the utility data used in the economic model and considered that given that it had been obtained from an adult population, it was unclear whether the utility values accurately reflect the impact of disease or treatment-related side effects on adolescents with schizophrenia. The Committee acknowledged that values from lay people rather than patients should have been used in the economic model and requested that the manufacturer consider adopting this approach in any revised analyses.	4.13
Are there specific groups of people for whom the technology is particularly cost-effective?	Not applicable.	-
Most likely cost-effectiveness estimate (given as an ICER)	The Committee noted that the base case ICER following revisions from the ERG for first-line aripiprazole compared with first-line olanzapine was £6200 per QALY gained. However it was concerned that due to a number of uncertainties in the model that the ICER could be as high as £233,000 per QALY gained (in line with sensitivity analyses conducted by the ERG). Furthermore it noted that aripiprazole was dominated by risperidone in the ERG's exploratory analyses. The Committee concluded that the ICERs presented could not be accepted without revision.	4.14
Additional factors taken into account
Patient Access Schemes (PPRS)	Not applicable to this appraisal.	-
End-of-life considerations	Not applicable to this appraisal.	-
Equalities considerations, social value judgements	The Committee was aware that consultees and commentators suggested that one area of potential discrimination was that the diagnosis of schizophrenia requires a definitive methodological approach using precise diagnostic criteria which may not be met by people with learning difficulties. The Committee concluded that the manufacturer should consider how the clinical and cost-effectiveness of aripiprazole may differ for people with schizophrenia who have learning difficulties.	4.15

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX).

• Slides highlighting key messages for local discussion.
• Costing report and costing template to estimate the savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Related NICE guidance

Published

• Schizophrenia: core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. NICE clinical guideline 82 (2009). Available from www.nice.org.uk/guidance/CG82
• Guidance on the use of electroconvulsive therapy. NICE technology appraisal guidance 59 (2003). Available from www.nice.org.uk/guidance/TA59

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in September 2013. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Andrew Stevens
Chair, Appraisal Committee
August 2010

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered that there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr David Black

Director of Public Health, Derbyshire County Primary Care Trust

Dr Daniele Bryden

Consultant in Intensive Care Medicine / Anaesthesia Sheffield Teaching Hospitals NHS Trust

David Chandler

Lay Member

Dr Chris Cooper

General Practitioner, St John's Way Medical Centre, London

Professor Peter Crome

Consultant Physician, Bucknall Hospital

Dr Christine Davey

Senior Researcher, North Yorkshire Alliance R & D Unit

Richard Devereaux-Phillips

Public Affairs and Reimbursement Manager UK & Ireland, Medtronic

Dr Rachel A Elliott

Lord Trent Professor of Medicines and Health, University of Nottingham

Dr Alan Haycox

Reader in Health Economics, University of Liverpool Management School

Dr Peter Jackson

Clinical Pharmacologist, University of Sheffield

Henry Marsh

Consultant Neurosurgeon, St George's Hospital

Professor Gary McVeigh

Cardiovascular Medicine, Queens University Belfast and Consultant Physician Belfast City Hospital

Dr Eugene Milne

Deputy Medical Director, North East Strategic Health Authority

Dr Neil Myers

General Practitioner

Dr Richard Nakielny

Consultant Radiologist, Sheffield Teaching Hospitals Foundation Trust

Dr Katherine Payne

Health Economics Research Fellow, University of Manchester

Dr Danielle Preedy

Lay Member

Dr Peter Selby

Consultant Physician, Central Manchester University Hospitals NHS Foundation Trust

Dr Surinder Sethi

Consultant in Public Health Medicine, North West Specialised Services Commissioning Team

Professor Andrew Stevens

Chair of Appraisal Committee C, Professor of Public Health, University of Birmingham

Dr Matt Stevenson

Technical Director, School of Health and Related Research, University of Sheffield

Professor Paul Trueman

Health Economics Research Group, Brunel University

Dr Judith Wardle

Lay Member

B Guideline representatives

The following individuals, representing the Guideline Development Group responsible for developing NICE's clinical guideline related to this topic, were invited to attend the meeting to observe and to contribute as advisers to the Committee.

• Peter Pratt, Sheffield Health and Social Care NHS Foundation Trust

C NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Fay McCracken / Scott Goulden

Technical Leads

Fiona Rinaldi

Technical Adviser

Lori Farrar

Project Manager

Appendix B: Sources of evidence considered by the Committee

A The Evidence Review Group (ERG) report for this appraisal was prepared by Southampton Health Technology Assessments Centre:

• Jones J, Mendes D, Frampton GK, Harris P, Loveman, E. Aripiprazole for the treatment of schizophrenia in adolescents (aged 15-17 years), July 2010.

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Bristol-Myers Squibb / Otsuka Pharmaceuticals

II Professional/specialist and patient/carer groups:

• British Association for Psychopharmacology
• Royal College of Nursing
• Royal College of Paediatrics and Child Health
• Royal College of Pathologists
• Royal College of Psychiatrists

III Other consultees:

• Betsi Cadwaladr University Health Board
• Department of Health
• Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Hafal
• Medicines and Healthcare products Regulatory Agency
• NHS Quality Improvement Scotland
• AstraZeneca UK
• Eli Lilly and Company
• Cochrane Schizophrenia Group
• National Institute for Health Research Health Technology Assessment Programme
• Southampton Health Technology Assessments Centre
• National Collaborating Centre for Mental Health

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on Aripiprazole for the treatment of schizophrenia in people aged 15 to17 years by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Clare Lamb, Consultant Psychiatrist, nominated by Welsh Assembly Government - clinical specialist
• Tim McDougall, Nurse Consultant, Nominated by Royal College of Nursing - clinical specialist
• Clive Travis- patient expert
• Janey Antoniou (written statement only) - patient expert

D Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.