Addendum to the Evidence Review Group Report on Aripiprazole for the treatment of schizophrenia in adolescents (aged years)

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1 Addendum to the Evidence Review Group Report on Aripiprzole for the tretment of schizophreni in dolescents (ged yers) Produced by Authors Correspondence to Southmpton Helth Technology Assessments Centre (SHTAC) Jeremy Jones Din Mendes Geoff Frmpton Petr Hrris Emm Lovemn Emm Lovemn Senior Reserch Fellow Southmpton Helth Technology Assessments Centre (SHTAC) University of Southmpton Epsilon House, Enterprise Rod Southmpton Science Prk Chilworth, Southmpton SO16 7NS 3 rd August 2010 Pge 1 of 16

2 Introduction SHTAC were requested to provide dditionl nlyses for the STA of ripiprzole for the tretment of schizophreni in dolescents (ged yers). This ddendum sets out to ddress the following questions: 1. Wht re the unit costs for nd wht re the likely dily costs for prescribing for dolescent schizophreni? 2. Cn n indiction of the cost effectiveness of the first-line ripiprzole strtegy compred with first-line strtegy be provided using the estimted costs for (for dolescent schizophreni) nd the mnufcturer s economic model? These issues were identified s importnt by NICE s is generlly reported s the current stndrd first line tretment in dolescent schizophreni, while the mnufcturer s economic model includes olnzpine s the min comprtor (due to indequcies in the evidence bse, discussed in the MS nd the ERG report). Other comprtors in the NICE scope were not modelled here. A limittion of this modelling is tht dt on is from one RCT only, not bsed on evidence from systemtic review. 1. To nswer the first question, cost nd pckging informtion from the BNF were used, long with the reported dosge from published RCT using in dolescent schizophreni (by Hs nd collegues 1 ). 2. Two nlyses were conducted to provide n indiction of the cost effectiveness of first-line ripiprzole, reltive to first-line. In both nlyses the first-line ripiprzole strtegy consisted of ripiprzole followed [on tretment discontinution in the first cycle (due to dverse events, lck of efficcy or due to other cuses) or on relpse in subsequent cycles] by, with clozpine reserved s rescue mediction. The first-line strtegy consisted of followed [on tretment discontinution in the first cycle (due to dverse events, lck of efficcy or due to other cuses) or on relpse in subsequent cycles] by ripiprzole, with clozpine reserved s rescue mediction. - 2) In the first nlysis, costs for olnzpine (in the mnufcturer s economic model) were replced with costs for. No other chnges were mde to the input dt in the mnufcturer s economic model. - 2b) In the second nlysis, odds rtios (ORs) for reltive to ripiprzole, were estimted using n djusted indirect comprison nd included in the mnufcturer s model. As noted, no dditionl serches were conducted. The nlyses were performed using the limited dt tht hd lredy been identified in the MS nd therefore need to be interpreted with cution. Pge 2 of 16

3 Key cvets on the djusted indirect comprison nd nlyses presented in this ddendum re: - The evidence bse for is very limited. It is not bsed on systemtic review, but on single RCT. - The RCT reported by Hs nd collegues 1 (for ) is not plcebo-controlled tril, but compres the stndrd dose of with sub-therpeutic (but not proven ineffective) dose. - The durtion of the tril reported by Hs nd collegues 1 is longer (8 weeks) thn the tril for ripiprzole (6 weeks). - There hs been no ssessment of similrities between studies. Question 1 - Estimting the cost per dy nd cost per cycle for Costs for were tken from the current BNF (No. 59, Mrch ) nd were confirmed using the current BNF for children. 3 BNF for Children gives dose rnge of 4-6mg per dy for cute nd chronic psychoses in children ged 12 to 18 yers (stting dditionlly tht is not licensed for use in children under 15 yers for psychoses). However there is no dosing dvice specific to dolescent schizophreni. The medin dose in the RCT reported by Hs nd collegues 1 ws 4mg per dy, using orl solution. Risperidone (generic) is vilble in 0.5mg, 1mg, 2mg, 3mg, 4mg nd 6mg tblets, s 0.5mg, 1mg nd 2mg orodispersible tblets nd lso liquid (t concentrtion of 1mg/mL). Tble 1 reports unit costs of (dosge, pcket size, cost per pcket nd cost per milligrm) nd estimtes of dily nd cycle costs (ssuming dose of 4mg per dy nd 42-dy cycle, s in the mnufcturer s model). There is wide rnge in cycle costs depending on the preferred mode of dministrtion (from 3.17 to for tblets, to for orodispersible tblets nd for liquid). Tble 2 reports the equivlent costs for proprietry preprtion of. All drugs included in tretment strtegies in the MS were costed on the bsis of being dministered s tblets for consistency the bse cse nlysis including will be costed on the bsis of being dministered s tblets nd will only consider options tht will deliver the required dily dose exctly (1mg, 2mg nd 4mg for tblets or 1mg nd 2mg for orodispersible tblets). In the bse cse reported in the following section we dopt dily cost of for (non-proprietry, delivered s 4mg tblet). A rnge of potentil dily costs (from low of for 2 x 2mg tblets of [non-proprietry] dily to high of for brnded orl solution) will be considered in scenrio nlysis. Pge 3 of 16

4 Tble 1 Risperidone unit costs, cost per dy nd cost per cycle (non-proprietry) Mode of dministrtion Tblet Orodispersible tblet Dose Pck size Cost ( ) Cost per mg ( ) Cost per dy ( ) Cost per cycle b ( ) 0.5mg 20 tblets mg 20 tblets mg 60 tblets mg 60 tblets mg 60 tblets mg 60 tblets mg 28 tblets mg 28 tblets mg 28 tblets mg 28 tblets Liquid 1 mg/ml 100 ml Dily dosge estimted t 4mg b Assuming dily dosge of 4mg nd cycle length of 42 dys (s in MS) Tble 2 Risperidone unit costs, cost per dy nd cost per cycle (brnded) Mode of dministrtion Dose Pck size Cost ( ) Cost per mg ( ) Cost per dy ( ) Cost per cycle b ( ) Tblet Orodispersible tblet 0.5mg 20 tblets mg 20 tblets mg 60 tblets mg 60 tblets mg 60 tblets mg 60 tblets mg 28 tblets mg 28 tblets mg 28 tblets mg 28 tblets mg 28 tblets mg 28 tblets Liquid 1 mg/ml 100 ml Dily dosge estimted t 4mg b Assuming dily dosge of 4mg nd cycle length of 42 dys (s in MS) Pge 4 of 16

5 Question 2 replce olnzpine costs with costs in first-line ripiprzole nd first-line olnzpine strtegies To provide n indiction of the cost effectiveness of first-line ripiprzole compred with firstline, the unit costs of were substituted in plce of olnzpine in the mnufcturer s economic model. This chnge only pplies to the min lines of tretment ptients who relpse still receive olnzpine t the higher dose of 15mg per dy for the durtion of their relpse, s ssumed in the mnufcturer s bse cse. Cvets to be borne in mind with this nlysis re tht: o Clinicl dt pplied for [discontinution in first cycle of tretment (due to intolerble dverse effects, lck of efficcy nd ll other cuses) nd tretment-relted dverse effects (weight gin, somnolence nd use of benzodizepines (s proxy for EPS))] were bsed on olnzpine; o This nlysis does not ccount for dverse effects tht might be relevnt for the comprison of ripiprzole with, such s dystoni, crdic rrhythmis, prolctin nd cholesterol increse (which re less frequent with ripiprzole), or tremor (more frequent with ). 4 Tble 3 reports results of nlyses replicting those in the MS nd in the ERG report for firstline ripiprzole compred with first-line olnzpine, nd new nlyses compring first-line ripiprzole with first-line. Tble 3 Comprison of cost effectiveness results for first-line ripiprzole compred with firstline olnzpine nd compred with first-line, bsed on the MS bse cse nd on ERG corrections to the MS bse cse. Inptient cost per dy = 534 (s in originl submission) MS bse cse ERG corrected compred with firstline olnzpine compred with firstline compred with firstline olnzpine compred with firstline Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs ripiprzole 23, , , , comprtor 23, , , , Difference ICER ( per QALY gined) Dominnt 89,899 6, ,012 in the originl submission, while utility effect of relpsing ptients on first-line mediction (in the second model cycle) ws pplied, no cost of mnging these relpses ws included. The ERG included these costs in their corrected nlysis. There ws n error in the MS relting to estimted inptient cost per dy (clrifiction ws requested from mnufcturer). Tble 4 reports results of nlysis replicting those in the Pge 5 of 16

6 mnufcturer s response to our request for clrifiction nd updting the ERG corrected results for the MS error in inptient cost per dy. Tble 4 Comprison of cost effectiveness results for first-line ripiprzole compred with firstline olnzpine nd compred with first-line, bsed on the MS bse cse nd on ERG corrections to the MS bse cse. Inptient cost per dy = 513 (s in clrifiction) MS bse cse ERG corrected ripiprzole comprtor compred with firstline olnzpine compred with firstline compred with firstline olnzpine compred with firstline Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs 22, , , , , , , , Difference ICER( per QALY gined) Dominnt 89,114 4, ,388 in the originl submission, while utility effect of relpsing ptients on first-line mediction (in the second model cycle) ws pplied no cost of mnging these relpses ws included. The ERG included these costs in their corrected nlysis. There re no substntive differences between results in Tble 3 nd Tble 4 in ll comprisons the cost difference is pproximtely 100 greter in the ERG corrected nlyses compred with the results from the MS bse cse. In both Tble 3 nd Tble 4 the MS bse cse reports first-line ripiprzole s dominting first line olnzpine, wheres the ERG corrected bse cse shows slightly higher costs for first-line ripiprzole compred with first line olnzpine. In contrst results bsed on both the MS bse cse ssumptions nd the ERG corrected nlysis show first-line ripiprzole s more costly thn first-line (with cost difference between pproximtely 390 nd 490). In ll the nlyses reported in Tble 3 nd Tble 4 first-line ripiprzole is ssocited with high vlue ICERs compred with first-line (pproximtely 90,000 to 112,000 per QALY gined). Tble 5 reports totl nd incrementl costs nd QALYs long with ICERs for first-line ripiprzole compred with first-line, dopting low nd high cost ssumptions for s described erlier (see Tble 1 nd Tble 2). Pge 6 of 16

7 Tble 5 Cost effectiveness of first-line ripiprzole compred with first-line. Adopting low nd high cost ssumptions for ERG corrected cost per dy = cost per dy = Cost ( ) QALYs Cost ( ) QALYs ripiprzole 22, , , , Difference ICER ( per QALY 133,779 56,708 gined) includes cost of mnging relpses on first-line mediction (in the second model cycle) nd corrected inptient cost per dy Tble 6 nd Tble 7 report selected scenrio nlyses included in the ERG report, pplied to the comprison of first-line ripiprzole with first-line. The mnufcturer s bse cse ssumed tht the length of inptient sty for relpsed ptients ws 42 dys (1 cycle) without justifying this ssumption. We did not identify ny routine dt sources for inptient sty for relpsed dolescent ptients with schizophreni. However, clinicl dvice to the ERG suggested the length of sty ssumed in the MS my be too low. For the scenrio nlysis we used n verge length of sty from current HES dt (107.7 dys, note tht these dt re not reported for the dolescent ge group lone). In the second scenrio we pplied the RR of relpse reported by Moeller nd collegues 5 rther thn the vlue *********ssumed by the mnufcturer, derived s the rtio of the crude risks. In the third scenrio we ssumed tht fewer dolescents who experience relpse would be dmitted s in-ptients. Clinicl dvice to the ERG suggested tht this proportion my be lower in children nd dolescents, thn in dults (the bse cse vlue in the MS ws bsed on vlue dopted for the NICE guideline on dult schizophreni 6 ). For the finl scenrio we ttempted to remove possible double-counting of tretment costs, where relpsed ptients ccrue the full cycle cost of mediction in the cycle in which they relpse nd the full cycle costs of their next vilble line of mediction in the following cycle, while lso ttrcting the full cycle cost for mngement of relpse. The potentil impct of this ws explored by subtrcting hlf the cycle cost for ptients current mediction in the cycle in which they experience relpse, nd lso hlf the cycle cost of their next vilble line of mediction in the cycle following relpse. In the first nd second scenrios (longer inptient length of sty for relpsed ptients nd using the reported RR of relpse) the difference in cost between first-line ripiprzole nd first-line incresed by round hlf, while the QALY gin reduced very slightly in the second scenrio (from to ), resulting in ICERs round 170,000 per Pge 7 of 16

8 QALY gined. Reducing the proportion of relpsed ptients who were expected to be treted s inptients resulted in slight reduction in the cost between first-line ripiprzole nd first-line, however the ICER remined high (pproximtely 97,000 per QALY gined) see Tble 6. Tble 7 reports the cumultive effect of these chnges, with the ICER rising from 110,388 to 244,035 per QALY gined. Pge 8 of 16

9 Tble 6 Selected scenrio nlyses pplied to comprison with first-line ripiprzole ERG corrected LOS = RR relpse = 0.92 % IP = 50 Adjust drug cost for relpse Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs 22, , , , , , , , , , Difference ICER ( per QALY gined) 110, , ,864 96, ,091 includes cost of mnging relpses on first-line mediction (in the second model cycle) nd corrected inptient cost per dy Tble 7 Repet bove but cumultive ripiprzole ERG corrected LOS = RR relpse = 0.92 % IP = 50 Adjust drug cost for relpse Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs 22, , , , , , , , , , Difference , ICER ( per QALY gined) 110, , , , ,035 includes cost of mnging relpses on first-line mediction (in the second model cycle) nd corrected inptient cost per dy Pge 9 of 16

10 Question 2b replce olnzpine costs with costs nd updte odds rtios for discontinutions nd dverse effects using vilble (less vlid) dt The previous nlysis did not use ny clinicl dt specific to, nd implicitly ssumes tht ORs derived for olnzpine (reltive to ripiprzole) cn be pplied to. To exmine the impct of pplying ORs derived from n lterntive dt source, n djusted indirect comprison ws conducted using dt from the RCT reported by Hs nd collegues 1 to estimte the ORs for discontinution (due to dverse events, lck of efficcy nd other resons) nd for tretment-relted dverse effects (weight gin, somnolence nd EPS). Cvets to be borne in mind with this nlysis re tht: o The RCT reported by Hs nd collegues 1 (for ) is not plcebo-controlled tril, but compres the stndrd dose of with subtherpeutic (but not proven ineffective) dose; o The durtion of the tril reported by Hs nd collegues 1 is longer (8 weeks) thn the tril for ripiprzole (6 weeks); o The nlysis does not ccount for dverse effects tht might be relevnt for the comprison of ripiprzole with, such s dystoni, crdic rrhythmis, prolctin nd cholesterol increse, or tremor; 4 o Assumptions hve been mde from the vilble evidence round vlues for weight gin nd EPS. Tble 8 reports the input dt for ripiprzole used in the djusted indirect comprison (tken from MS). The mjority of these dt were tken from the MS (Tble 21, pge 53). Dt on EPS were tken from Findling nd collegues. 7 Tble 8 Input dt for ripiprzole in djusted indirect comprison Aripiprzole Plcebo Events Non Non OR SE 95%CI N Events N Events Events Withdrwl (AE) , Withdrwl (LoE) **** **** 100 **** **** , Withdrwl (other) **** **** 100 **** **** , 1.95 Weight gin **** **** 84 **** **** , Somnolence , 5.46 EPS , 8.29 EPS events were bsed on symptoms not on use of benzodizepines (used s proxy for EPS in the MS) Pge 10 of 16

11 Tble 9 reports the input dt for used in the djusted indirect comprison (tken from the RCT reported by Hs nd collegues 1 ). Note tht the comprtor group in this tril ws low-dose, not plcebo. Tble 9 Input dt for in djusted indirect comprison Risperidone (stndrd) Risperidone (low dose) Withdrwl (AE) Withdrwl (LoE) Withdrwl (other) Events Non Events N Events Non Events N OR SE 95%CI , , , 1.35 Weight gin , 9.28 Somnolence , 8.22 EPS b , 8.85 the OR clculted for weight gin is bsed on figures reported in the tril publiction for ptients [who] experienced weight gin s n dverse event. No further detils of this ctegoristion re given. This contrsts with the nlysis presented in the MS, for ripiprzole, which defined significnt weight gin s being n increse of greter thn or equl to 7% over bseline. b EPS events were bsed on symptoms not on the use of benzodizepines (used s proxy for EPS in the MS) Tble 10 reports the ORs for compred with ripiprzole, estimted in the djusted indirect comprison, which suggest tht is fvoured over ripiprzole in terms of withdrwl (due to dverse events nd lck of efficcy) though this is not sttisticlly significnt t 5% level. The ORs lso suggest tht is fvoured over ripiprzole in terms of weight gin s tretment-relted dverse effect. In contrst, ripiprzole is fvoured over for somnolence nd EPS. Tble 10 Odds rtios of versus ripiprzole estimted in the djusted indirect comprison OR SE 95%CI Withdrwl (AE) , Withdrwl (LoE) , Withdrwl (other) , Weight gin , Somnolence , EPS , Tble 11 reports results of nlyses replicting those in the MS nd in the ERG report for first-line ripiprzole compred with first-line olnzpine nd compred with first-line, including the ORs estimted in the djusted indirect comprison (reported in Tble 10). The overll effect of the updted ssumptions for the ORs for discontinution nd Pge 11 of 16

12 dverse effects hs mde the first-line ripiprzole strtegy less effective thn the first-line strtegy. Tking this in conjunction with the lower cost of the first-line strtegy mens tht the first-line ripiprzole strtegy is dominted. Tble 11 Comprison of cost effectiveness results for first-line ripiprzole compred with first-line olnzpine nd compred with first-line, bsed on the MS bse cse nd on ERG corrections to the MS bse cse. Inptient cost per dy = 534 (s in originl submission) MS bse cse ERG corrected compred with firstline olnzpine compred with firstline compred with firstline olnzpine compred with firstline Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs ripiprzole 23, , , , comprtor 23, , , , Difference ICER ( per QALY gined) Dominnt Dominted 6,231 Dominted includes cost of mnging relpses on first-line mediction There ws n error in the MS relting to estimted inptient cost per dy (clrifiction ws requested from mnufcturer). Tble 12 reports results of nlysis replicting those in the mnufcturer s response to our request for clrifiction nd updting the ERG corrected results for the MS error in inptient cost per dy. Tble 12 Comprison of cost effectiveness results for first-line ripiprzole compred with first-line olnzpine nd compred with first-line, bsed on the MS bse cse nd on ERG corrections to the MS bse cse. Inptient cost per dy = 513 (s in clrifiction) MS bse cse ERG corrected compred with firstline olnzpine compred with firstline compred with firstline olnzpine compred with firstline Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs ripiprzole 22, , , , comprtor 23, , , , Difference ICER ( per QALY gined) Dominnt Dominted 4,607 Dominted includes cost of mnging relpses on first-line mediction Pge 12 of 16

13 Tble 13 reports totl nd incrementl costs nd QALYs long with ICERs for first-line ripiprzole compred with first-line, dopting low nd high cost ssumptions for s described erlier (see Tble 1 nd Tble 2). Tble 13 Cost effectiveness of first-line ripiprzole compred with first-line. Adopting low nd high cost ssumptions for ERG corrected cost per dy = cost per dy = Cost ( ) QALYs Cost ( ) QALYs ripiprzole 22, , , , Difference ICER ( per QALY Dominted Dominted gined) includes cost of mnging relpses on first-line mediction (in the second model cycle) nd corrected inptient cost per dy Tble 14 nd Tble 15 report selected scenrio nlyses included in the ERG report, pplied to the comprison of first-line ripiprzole with first-line. ripiprzole is dominted by first-line in ech of the scenrio nlyses. Pge 13 of 16

14 Tble 14 Selected scenrio nlyses pplied to comprison with first-line ripiprzole ERG corrected LOS = RR relpse = 0.92 % IP = 50 Adjust drug cost for relpse Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs 22, , , , , , , , , , Difference ICER ( per QALY gined) Dominted Dominted Dominted Dominted Dominted includes cost of mnging relpses on first-line mediction Tble 15 Repet bove but cumultive ripiprzole ERG corrected LOS = RR relpse = 0.92 % IP = 50 Adjust drug cost for relpse Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs Cost ( ) QALYs 22, , , , , , , , , , Difference , , , ICER ( per QALY gined) Dominted Dominted Dominted Dominted Dominted includes cost of mnging relpses on first-line mediction Pge 14 of 16

15 Summry ripiprzole is less cost effective option when compred with first-line, rther thn with first-line olnzpine. However the nlyses presented here need to be interpreted with cution. The first pproch to estimting the cost effectiveness of first-line ripiprzole, compred with first-line, ws bsed solely on replcing olnzpine costs in the mnufcturer s economic model with costs for. The clinicl dt relting to erly discontinutions with first-line were bsed on ORs estimted for olnzpine reltive to ripiprzole. In the second pproch to estimting the cost effectiveness of nlysis first-line ripiprzole, compred with first-line, ORs relting to erly discontinutions with (bsed on n djusted indirect comprison) were pplied in the model. It should be noted tht, while the RCT of ripiprzole (reported by Findling nd collegues 7 ) ws plcebocontrolled, the RCT of (reported by Hs nd collegues 1 ) compred stndrddose with sub-therpeutic (but not proven ineffective) dose. The occurrence of tretment discontinution ssocited with my be under-estimted, by compring stndrd-dose with n ctive (if sub-therpeutic ) comprtor. Hence the ORs derived in the djusted indirect comprison my be bised ginst ripiprzole. Pge 15 of 16

16 Reference List 1. Hs M, Eerdekens M, Kushner S, Singer J, Augustyns I, Quiroz J et l. Efficcy, sfety nd tolerbility of two dosing regimens in dolescent schizophreni: double-blind study. British Journl of Psychitry 2009;194: Joint Formulry Committee. British Ntionl Formulry 59. London: British Medicl Assocition nd Royl Phrmceuticl Society of Gret Britin, Peditric Formulry Commitee. BNF for Children Komoss K, Rummel-Kluge C, Schmid F, Hunger H, Schwrz S, El-Syeh HGG et l. Aripiprzole versus other typicl ntipsychotics for schizophreni. Cochrne Dtbse of Systemtic Reviews Issue 4 Art No.CD DOI / CD pub3. 5. Moeller KE, Shiremn TI, Liskow BI. Relpse rtes in ptients with schizophreni receiving ripiprzole in comprison with other typicl ntipsychotics. J Clin Psychitry 2006;67: Ntionl Collborting Centre for Mentl Helth. Schizophreni: core interventions in the tretment nd mngement of schizophreni in dults in primry nd secondry cre (updted edition). London: British Psychologicl Society nd the Royl College of Psychitrists; Findling RL, Robb A, Nyils M, Forbes RA, Jin N, Ivnov S et l. A multi-center, rndomized, double-blind, plcebo-controlled study of orl ripiprzole for tretment of dolescents with schizophreni. Am J Psychitry 2008;165: Pge 16 of 16