A comparison of the cost-effectiveness of treatment of prolonged acute convulsive epileptic seizures in children across Europe

Lee, Dawn C. et al. Article A comparison of the cost-effectiveness of treatment of prolonged acute convulsive epileptic seizures in children across Europe Health Economics Review Provided in Cooperation with: Springer Nature Suggested Citation: Lee, Dawn C. et al. (2014) : A comparison of the cost-effectiveness of treatment of prolonged acute convulsive epileptic seizures in children across Europe, Health Economics Review, ISSN 2191-1991, Springer, Heidelberg, Vol. 4, Iss. 6, pp. 1-15, https://doi.org/10.1186/s13561-014-0006-6 This Version is available at: https://hdl.handle.net/10419/150462 Standard-Nutzungsbedingungen: Die Dokumente auf EconStor dürfen zu eigenen wissenschaftlichen Zwecken und zum Privatgebrauch gespeichert und kopiert werden. Sie dürfen die Dokumente nicht für öffentliche oder kommerzielle Zwecke vervielfältigen, öffentlich ausstellen, öffentlich zugänglich machen, vertreiben oder anderweitig nutzen. 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If the documents have been made available under an Open Content Licence (especially Creative Commons Licences), you may exercise further usage rights as specified in the indicated licence. http://creativecommons.org/licenses/by/2.0/ RESEARCH Open Access A comparison of the cost-effectiveness of treatment of prolonged acute convulsive epileptic seizures in children across Europe Dawn C Lee 1* , Daniel Gladwell 1 , Anthony J Hatswell 1 , Joshua Porter 1 , Nic Brereton 1 , Elaine Tate 1 and Alison L Saunders 2 Abstract In the majority of children and adolescents with epilepsy, optimal drug therapy adequately controls their condition. However, among the remaining patients who are still uncontrolled despite mono-, bior tri-therapy with chronic anti-epileptic treatment, a rescue medication is required. In Western Europe, the licensed medications available for first-line treatment of prolonged acute convulsive seizures (PACS) vary widely, and so comparators for clinical and economic evaluation are not consistent. No European guidelines currently exist for the treatment of PACS in children and adolescents and limited evidence is available for the effectiveness of treatments in the community setting. The authors present cost-effectiveness data for BUCCOLAM® (midazolam oromucosal solution) for the treatment of PACS in children and adolescents in the context of the treatment pathway in seven European countries in patients from 6 months to 18 years. For each country, the health economic model consisted of a decision tree, with decision nodes informed by clinical data and expert opinion obtained via a Delphi methodology. The events modelled are those associated with a patient experiencing a seizure in the community setting. The model assessed the likelihood of medication being administered successfully and of seizure cessation. The associated resource use was also modelled, and ambulance call-outs and hospitalisations were considered. The patient’s quality of life was estimated by clinicians, who completed a five-level EuroQol five dimensions questionnaire from the perspective of a child or adolescent suffering a seizure. Despite differences in current therapy, treatment patterns and healthcare costs in all countries assessed, BUCCOLAM was shown to be cost saving and offered increased health-related benefits for patients in the treatment of PACS compared with the current local standard of care. Keywords: Epilepsy; Cost–utility modelling; BUCCOLAM; Health technology assessment Background Even in a relatively homogeneous region such as Western Europe, with similar population demographics and state-provided healthcare systems, differences in culture, legislation and financial incentives can mean that the treatment of patients with the same condition varies between countries. In some disease areas, the pathway of care (even the healthcare setting; that is, primary versus secondary care) may, therefore, differ between countries, and some drugs may be used routinely in one country but not be available in another. A consequence of these variations is that pharmaceutical companies are faced with different challenges in persuading health technology assessment (HTA) agencies in each country of the value of their product. In this paper, we consider the example of BUCCOLAM (midazolam oromucosal solution; available from ViroPharma SPRL –BVBA, Belgium) in the treatment of prolonged, acute, convulsive seizures (PACS) in children and adolescents [1]. Across Europe, 130,000 new cases of epilepsy are recorded each year among children and adolescents (an incidence rate of 70–80 per 100,000) [2,3]. The incidence is particularly high during the first year of life, and the likelihood of developing the condition then decreases during childhood [3]. Anti-epileptic drug therapy is the primary treatment for children with epilepsy, with the aim of preventing seizures [4], and approximately 70% of * Correspondence: [email protected] 1 BresMed, North Church House, 84 Queen Street, Sheffield S1 2DW, UK Full list of author information is available at the end of the article © 2014 Lee et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lee et al. Health Economics Review 2014, 4:6 http://www.healtheconomicsreview.com/content/4/1/6 patients become seizure-free with optimal drug therapy [3,5]. However, patients do not always receive optimal drug therapy and approximately 50–60% of patients with epilepsy experience breakthrough seizures during the course of a year, some of whom will require a prescription for rescue medication [2]. Children who have severe, symptomatic epilepsy are those who are most commonly prescribed rescue medication [6]. The longer a seizure continues, the greater the likelihood of pharmacoresistance to termination and a worse health outcome for the patient, including increased risks of subsequent prolonged seizure activity, memory deficits and learning difficulties [7,8]. In addition, the impact on health resources is greater because these patients require more intensive medical assistance [6,9-11]. The costs of direct medical care for children with epilepsy can be very high –a recent study in Germany, for example, showed that the mean direct medical cost over three months was €1,940 for children with non-drugresistant seizures and €3,464 for those with drugresistant seizures [12]. Prompt treatment with rescue medication is an important aspect of care for children experiencing PACS; however, such treatment provides a particular challenge because these seizures occur predominantly in the community setting where rescue medication and trained carers may not always be available. A recent study by Anderson et al. noted that the ideal drug for the treatment of convulsive seizures in paediatric patients would have the following characteristics [8]: A rapid onset of action. A broad spectrum of efficacy; that is, not restricted to a particular seizure type or underlying cause. A prolonged duration of action. Minimal adverse effects. A simple and socially acceptable administration route for both patient and caregiver. Easy storage and portability. In most European countries, no clear guidance is available for the treatment of PACS outside of the hospital setting and no clear guidance is provided for caregivers [13,14]. In Western Europe, the treatment pathways for the use of rescue medication in the management of PACS can be broadly categorised into two groups: many continental European countries primarily advocate the use of licensed treatments, whereas a number of other countries primarily employ unlicensed treatments. More specifically, in Denmark, France, Germany, Italy and Spain the mainstay of rescue treatment is rectal diazepam, which was the only licensed treatment for PACS in children until recently. In Switzerland and Germany, there is frequent off-label buccal use of fast dissolving lorazepam tablets (as well as rectal diazepam). Countries that most commonly use unlicensed buccal midazolam include the UK, Sweden and Norway [13]. A significant body of evidence now supports buccal midazolam as an effective and safe first-line therapy for prolonged seizures [8], which avoids the social stigma of rectal administration. In September 2011, BUCCOLAM was granted a Paediatric-Use Marketing Authorisation (PUMA) by the European Medicines Agency (EMA) [1]. The PUMA initiative aims to ensure that medicines used to treat children are subject to high-quality, ethical research and are appropriately authorised without subjecting the paediatric population to unnecessary clinical trials [15]. In most European countries, BUCCOLAM is indicated for the treatment of PACS in infants, toddlers, children and adolescents (from three months to <18 years). For infants between three and six months of age, treatment should be in a hospital setting where monitoring is possible and resuscitation equipment is available. In Switzerland, BUCCOLAM is indicated for emergency treatment of PACS lasting more than five minutes in children from six months to 18 years. In all European countries, BUCCOLAM must only be used by parents/ carers where the patient has been diagnosed to have epilepsy. This case study of BUCCOLAM provides an informative illustration of how variation in a treatment pathway can lead to different HTA considerations for the same innovative technology. Methods Modelling the local treatment pathway Decision analytic models were constructed to assess the cost-effectiveness of BUCCOLAM in seven European countries. The original model was built for an HTA submission in Scotland [16], and was subsequently adapted for use in Wales, Germany, France, Spain, Italy and Switzerland. In the Republic of Ireland, a full decision analytic model was not required for reimbursement purposes, as BUCCOLAM was accepted following a rapid review. Treatment pathway In the absence of coherent European guidance on the treatment of PACS in the community, the use of rescue medication is determined locally and is subject to substantial variation. In addition to this, information on the effectiveness of the various rescue medications is not available, with only limited information available on their efficacy. This is the result of many products being used unlicensed or off-label, which is a relatively common practice in paediatric medicine throughout Europe [17]. Lee et al. Health Economics Review 2014, 4:6 Page 2 of 15 http://www.healtheconomicsreview.com/content/4/1/6 Clinical opinion was derived from Delphi panel surveys and interviews with clinical experts. The numbers and backgrounds of the participating experts for each country are shown in Additional file 1: Table S1. Expert responses were used to determine the local pattern of care in each jurisdiction and to derive model parameter estimates. In general, experts were consistent in their estimates for parameters used to model hospitalisation and healthcare resource use. A greater variation was seen in estimates for events in the community setting, both between clinicians and by country. This was attributed to the fact that clinicians rarely directly observe treatment in the community, resulting in greater uncertainty in their responses. In Scotland, Wales and Spain, expert opinion was supplemented with parent surveys to address this limitation. Variation was observed in the treatment pathways of different countries, particularly concerning the rescue medication administered by parents and carers following a seizure in the community setting. The established treatment practice involved the use of an unlicensed buccal midazolam preparation in Scotland and Wales, rectal diazepam in Spain and Italy, and a combination of rectal diazepam with other licensed and/or off-label or unlicensed rescue medications in Germany, France and Switzerland. Differences in paramedic and hospital drug use were also seen between countries. The established current pattern of treatment formed the comparator arm of the model for each country and is shown in Table 1. Variation was also observed in the treatment practices used by parents and carers (Table 2). In Wales, Germany, France and Switzerland, some parents and carers had instructions from their clinician to administer a second dose of rescue medication if the first dose did not stop the seizure. In Germany, France and Switzerland, patients were not necessarily taken to hospital after an ambulance call-out, with paramedics administering medication and often awaiting results before taking the child to hospital. These differences were incorporated into the models to better define the decision problem for the relevant healthcare system. Efficacy No data that specifically evaluate the efficacy of buccal midazolam in prefilled syringes are currently available. Five studies comparing the efficacy of buccal midazolam with that of rectal diazepam have been conducted [8]. The source of efficacy data used within the models was the study by McIntyre et al. [18]. This is the only published controlled trial comparing buccal midazolam (the intravenous preparation of midazolam hydrochloride, administered into the buccal cavity) with rectal diazepam that was conducted in a European context with a Table 1 Medications currently administered in the community, by ambulance paramedics and in hospital Country Carer administration Paramedic administration Hospital administration Source Scotland Buccal midazolam 100% Rectal diazepam 100% Buccal midazolam 100% Delphi panel and patient surveys Wales Buccal midazolam 95% Rectal diazepam 100% Buccal midazolam 38% Delphi panel and patient surveys Rectal diazepam 5% Rectal diazepam 62% Germany Rectal diazepam 81% Rectal diazepam 82% Rectal diazepam 82% Delphi panel Buccal use of lorazepam tablets 19% Lorazepam 6% Lorazepam 6% Clonazepam 6% Clonazepam 6% Phenytoin 6% Phenytoin 6% Spain Rectal diazepam 100% Rectal diazepam 100% Rectal diazepam 100% Delphi panel and patient surveys France Rectal diazepam 92% Rectal diazepam 84% Rectal diazepam 84% Delphi panel IV clonazepam 10% IV clonazepam 10%Oral clonazepam 8% Phenytoin 6% Phenytoin 6% Italy Rectal diazepam 100% Rectal diazepam 10% Rectal diazepam 65% Delphi panel IV midazolam 90% IV midazolam 35% Switzerland Rectal diazepam 45% Rectal diazepam 50% Rectal diazepam 50% Clinician interviews Buccal lorazepam 54% IV diazepam 6% IV diazepam 6% Intranasal midazolam <2% IV lorazepam 43% IV lorazepam 43% Intranasal midazolam 1% Intranasal midazolam 1% IV clonazepam <1% IV clonazepam <1% Phenobarbital <1% Phenobarbital <1% IV = intravenous. ‘Buccal midazolam’in this table refers to the unlicensed preparation. Lee et al. Health Economics Review 2014, 4:6 Page 3 of 15 http://www.healtheconomicsreview.com/content/4/1/6 large sample size (n = 219 seizure episodes). This study also reported outcomes directly related to resource use associated with seizures, which is a key contributor to the expected incremental benefit of BUCCOLAM. Although the trial observed a UK cohort, the comparative efficacy of buccal midazolam in reducing the duration of seizures and the probability of repeat seizures is assumed to be applicable to all the countries considered in this article. The following assumptions were made in order to use the outcomes of the McIntyre publication within the economic model and estimate the chance of a seizure lasting more than ten minutes, the chance of a repeat seizure and the duration of seizures: BUCCOLAM (midazolam oromucosal solution) has equal efficacy to IV midazolam as hydrochloride 5 mg/ml administered by the oromucosal route. All other formulations of buccal midazolam and intranasal midazolam have equal efficacy to IV midazolam as hydrochloride 5 mg/ml administered by the oromucosal route. Model comparators other than buccal and intranasal midazolam share the same efficacy outcomes as rectal diazepam. These assumptions were based on the advice of clinical experts in several countries. In the case of off-label medications, the assumption of equal efficacy with rectal diazepam was a conservative estimate as clinical experts in several countries suggested that other off-label medications, such as lorazepam tablets administered by the buccal route, were less efficacious than rectal diazepam. This conclusion is supported by pharmacokinetic evidence indicating that midazolam is more likely to achieve therapeutic plasma concentrations than lorazepam [8]. Effectiveness The primary source of effectiveness data used in the models was clinical expert opinion, which was obtained through Delphi panel research conducted in a number of European countries as part of the cost-effectiveness assessment of BUCCOLAM. The Delphi process involved three rounds: the first consisted of a questionnaire and the second consisted of either a second questionnaire or a group face-to-face meeting at which the initial questionnaire results were presented back to all participants and amended or validated; the final round provided an opportunity for comment or revision on the consensus gained in the second round [19]. The Delphi panels reported a number of different expected advantages for BUCCOLAM compared with each of the main treatment alternatives used in the community. They estimated that BUCCOLAM had both an efficacy and an effectiveness advantage over rectal diazepam Table 2 Key structural characteristics and major treatment pathway differences a of European cost-effectiveness model adaptations Country Model features Scotland ●Patient simulation for buccal midazolam comparison ●Parents/carers only give a single dose ●Taken to hospital if ambulance called Wales ●Patient simulation for buccal midazolam comparison ●Allows for second doses of treatment under emergency care plans ●Taken to hospital if ambulance called ●Chance of inpatient admission is 100% for patients suffering multiple seizures ●Additional chance of admission to intensive care for patients suffering multiple seizures Germany ●Allows for second doses to be administered ●Patient may not necessarily be taken to hospital after ambulance call-out Spain ●Parents/carers only give a single dose ●Taken to hospital if ambulance called France ●Allows for second doses to be administered ●Patient may not necessarily be taken to hospital after ambulance call-out Italy ●Parents/carers only give a single dose ●Taken to hospital if ambulance called Switzerland ●Allows for second doses to be administered ●Patient may not necessarily be taken to hospital after ambulance call-out a According to clinician consultation. Lee et al. Health Economics Review 2014, 4:6 Page 4 of 15 http://www.healtheconomicsreview.com/content/4/1/6 and off-label buccal use of lorazepam tablets and, in many cases, that it had an effectiveness advantage compared with unlicensed buccal midazolam. This advantage in effectiveness could be attributed to BUCCOLAM being presented in prefilled syringes and, in some countries, to the additional willingness or ability of carers (such as teachers) to administer a licensed product via the oromucosal route, leading to a reduction in ambulance call-outs. The Delphi panels also estimated a reduction in wastage costs with BUCCOLAM, due to its convenient and efficient mode of packaging (BUCCOLAM in four prefilled unit-dose syringes versus unlicensed buccal midazolam for which the most widely used presentation is a single 10 ml bottle with four syringes). These results are supported by a recent survey completed by a total of 129 healthcare professionals in six European countries, which indicates that the biggest barrier to administering rescue medication to children suffering PACS in the community is fear of legal consequences, either due to the use of unlicensed medication or due to the lack of social acceptability of rectal administration [13]. Core model structure Decision tree model A decision tree approach was used to reflect the events during and immediately following PACS. The structure of this model, which was built in Microsoft Excel, is shown in Figure 1 [16]. A number of events can trigger an ambulance call-out in the decision tree; a carer not administering treatment in the community, failed delivery of treatment by the carer, a seizure that lasts more than ten minutes or a repeat seizure within one hour of the first. Once an ambulance has arrived, paramedics may administer further treatment, and a patient may be taken to hospital. If a patient is taken to hospital, patients may receive further treatment, and may be admitted for a hospital stay. The decision node probabilities are tailored to accurately represent the pattern of care in each country. The probabilities of seizure cessation, repeat seizures and the duration of seizures are based on the relative efficacy of buccal midazolam compared with rectal diazepam, as reported by McIntyre et al. [18]. The parameterisation of these decision nodes for each country is shown in Table 3. Medication failure can occur in the model for various reasons, including: no treatment being available at the location of the seizure; poor absorption from the site of administration; or incorrect dose measurement. Delphi panel members and local clinicians were asked to estimate how the availability of a licensed preparation might affect the likelihood of treatment administration in the community setting. Experts in all countries agreed that administration of treatment in the event of a seizure would be more likely with BUCCOLAM (Table 3). Similarly, it was expected that the risk of administration errors resulting in underor overdosing would be reduced with BUCCOLAM compared with many of the treatments comprising current care. Patient simulation In the UK, a different amount of wastage is expected for licensed and unlicensed buccal midazolam supplied in four-dose bottles. A patient simulation model was, Figure 1 Structure of decision tree included in all country adaptations [16]. * 2nd dose must only be given according to prior medical advice. Lee et al. Health Economics Review 2014, 4:6 Page 5 of 15 http://www.healtheconomicsreview.com/content/4/1/6 therefore, incorporated into the UK model to predict the pattern of patients’seizures and whether or not rescue medication is available at the time of seizure, allowing the calculation of the cost of expected drug wastage over the time horizon of the model. Further details on the simulation model used in the UK cost-effectiveness analysis can be found in Lee et al. [16]. Costs and resource use Cost data were typically acquired from national reference price lists for each country, and expert opinion on the expected resource use following PACS was also obtained. The key resource use and drug costs included in the models are shown in Table 4. These are all shown in euros, for ease of comparison. The price of BUCCOLAM included in each adaptation of the model was current at the time it was developed. UK costs have been updated to the most recent cost data and so differ from those quoted in the HTA submissions in Scotland and Wales. As the price for BUCCOLAM in Switzerland has not yet been determined, the price used in the model is the maximum price allowable under the price referencing rules in Switzerland and is based on the agreed prices in the reference countries. Health-related quality of life The quality-adjusted life-year (QALY) decrement associated with PACS was calculated as the product of the duration of a seizure event and the estimated healthrelated utility value during this time. The former was broken down to represent three phases of a seizure episode: During the seizure Postictal period –the period during which the brain recovers immediately following the seizure Recovery period –the time taken for the patient to recover back to baseline utility. Due to a paucity of published utility data pertaining to a child’s health status during a seizure episode, healthrelated quality of life (HRQoL) estimates were elicited from clinical experts The utility values used in the Table 3 Node probabilities from the different country adaptations of the model Country Chance of carer not administering treatment Chance of failed administration resulting in ambulance call-out Chance of parent/carer administering 2nd dose Chance of inpatient admission after ambulance call-out Chance of ICU admission if admitted to hospital Chance of ambulance taking patient to hospital a Chance seizure lasts more than 10 minutes Chance of repeat seizure Average number of seizures per month Scotland BUCCOLAM 10%; Current care 16% BUCCOLAM 6%; Current care 8% BUCCOLAM 0%; Current care 0% BUCCOLAM 20%; Current care 20% BUCCOLAM 20%; Current care 20% –BUCCOLAM 35%; Current care 35% BUCCOLAM 14%; Current care 14% 1.26 Wales BUCCOLAM 5%; Current care 6.2% BUCCOLAM 3.5%; Current care 4.1% BUCCOLAM 30%; Current care 30% BUCCOLAM 10%; Current care 10% b BUCCOLAM 2%; Current care 2% –BUCCOLAM 35%; Current care 36% BUCCOLAM 14%; Current care 33% 1.17 Germany BUCCOLAM 24%; Current care 37% BUCCOLAM 10%; Current care 18% BUCCOLAM 10%; Current care 10% BUCCOLAM 90%; Current care 90% BUCCOLAM 10%; Current care 10% BUCCOLAM 90%; Current care 90% BUCCOLAM 35%; Current care 59% BUCCOLAM 14%; Current care 33% 1.27 Spain BUCCOLAM 10%; Current Care 70% BUCCOLAM 5%; Current care 10% BUCCOLAM 0%; Current care 0% BUCCOLAM 20%; Current care 66% BUCCOLAM 20%; Current care 10% –BUCCOLAM 35%; Current care 59% BUCCOLAM 14%; Current care 33% 0.75 France BUCCOLAM 30%; Current Care 50% BUCCOLAM 10%; Current care 50% BUCCOLAM 10%; Current care 10% BUCCOLAM 51%; Current care 51% BUCCOLAM 23.58%; Current care 23.58% BUCCOLAM 80%; Current care 80% BUCCOLAM 35%; Current care 59% BUCCOLAM 14%; Current care 33% 0.27 Italy BUCCOLAM 30%; Current Care 39% BUCCOLAM 15%; Current care 40% BUCCOLAM 0%; Current care 0% BUCCOLAM 70%; Current care 70% BUCCOLAM 14%; Current care 14% –BUCCOLAM 35%; Current care 59% BUCCOLAM 14%; Current care 33% 0.37 Switzerland BUCCOLAM 16%; Current care 24% BUCCOLAM 3%; Current care 14% BUCCOLAM 20%; Current care 20% BUCCOLAM 70%; Current care 70% BUCCOLAM 22.22%; Current care 22.22% BUCCOLAM 98%; Current care 98% BUCCOLAM 35%; Current care 59% BUCCOLAM 14%; Current care 33% 0.32 a Germany, France and Switzerland only; b In the Welsh model, patient who suffered repeat seizures had a 100% probability of hospital admission. Lee et al. Health Economics Review 2014, 4:6 Page 6 of 15 http://www.healtheconomicsreview.com/content/4/1/6 analyses were initially measured for the construction of the Scottish model. These values were based on the estimates of four UK clinicians, who had been asked to complete a five-level EuroQol five dimensions (EQ-5D5L) questionnaire from the perspective of a child suffering a seizure. It is neither feasible nor ethical to administer a patient reported outcome measure to a child during or shortly after a seizure. Therefore the methods established as best practice for capturing HRQoL for chronic conditions would have been unsuitable for estimating the effect of acute episodes on HRQoL. Repeating the measurement and valuation exercises for each country was not feasible; especially as EQ-5D5L tariffs were not available for all the countries considered. To include the appropriate perspective in valuing the health impact of the intervention for each country, the UK values were distributed to the local Delphi panel members and key opinion leaders (KOLs) to adjust and validate based on their own expertise (Table 5). The average time taken to recover to baseline HRQoL differed according to the events that followed the seizure. Post-seizure events were categorised into the following four scenarios: There was no need for an ambulance to be called An ambulance was called, but the patient was not admitted to hospital The patient was admitted to hospital, but not into an intensive care unit (ICU) The patient was admitted to an ICU. Following the end of a seizure, it is assumed that the recovery of utility at the start of the postictal period is instant, and the recovery back to baseline utility is linear over the duration of the recovery period. The duration of the seizure itself was determined within the model by the treatment received and was based on the publication by McIntyre et al. [18]: eight Table 4 Drug and resource costs by country Scotland Wales Germany Spain France Italy Switzerland Reference year 2012–2013 2012–2013 2012–2013 2012–2013 2011–2012 2012 2012 Cost elements Ambulance cost €317.23 €284.68 €0.00 a €309.36 €1,120.76 €113.27 €1,217.06 A&E: admitted patients €141.35 €141.35 €542.87 €129.23 –€335.12 – A&E: non-admitted patients €113.41 €113.41 €542.87 €111.10 €25.32 €335.12 €6,194.85 Inpatient admission €680.16 €680.16 €403.00 €1,616.89 €1,436.21 €1,147.75 €6,194.85 ICU admission €1,574.28 €1,574.28 €1,115.00 €2,254.91 €8,980.05 €4,322.30 €15,157.31 Drug costs (per dose) BUCCOLAM b €26.97 c €26.97 c €28.54 €17.38 €17.17 €22.65 €39.93 d Rectal diazepam €2.24 €2.24 €5.08 €0.94 €0.53 €0.00 e €5.27 Unlicensed buccal midazolam €30.38 f €30.66 g ––––– Phenytoin ––€6.60 –€0.06 –– Oral clonazepam ––––€0.08 –– IV clonazepam ––€1.70 –€0.79 –€5.29 Lorazepam tablets ––€0.39 –––€0.55 IV midazolam –––––€4.18 – Intranasal midazolam ––––––€36.51 Chloral hydrate ––––––€1.40 Phenobarbital ––––––€82.78 IV diazepam ––––––€7.20 IV lorazepam ––––––€2.40 A&E = accident and emergency; ICU = intensive care unit; IV = intravenous. a Ambulance costs for Germany set to zero as they are included in aggregated A&E costs; b The drug costs used for BUCCOLAM were defined by local HTA body requirements (e.g. ex factory, public price) and include VAT as appropriate, therefore are not comparable between countries; c The drug cost used represents an average of each of the four strengths available; d At the time of publication, the approved price for BUCCOLAM in this country has not been agreed –the price shown is the maximum price allowable under the price referencing rules in Switzerland. e Italian cost of rectal diazepam is zero as this drug is not reimbursed by the Italian national health service; f Based on May 2013 Drug Tariff [20]; g Based on May 2013 Drug Tariff price plus a sourcing fee for medicines classed as ‘specials’[21,22]. All costs are presented in Euros, converted on 30/10/12, using the following rates from xe.com currency converter: 1 Euro (EUR) = 0.806579 British Pound (GBP), 0.82165 Swiss Francs (CHF). Lee et al. Health Economics Review 2014, 4:6 Page 7 of 15 http://www.healtheconomicsreview.com/content/4/1/6 minutes for seizures treated with BUCCOLAM, or buccal or intranasal midazolam, and 15 minutes for rectal diazepam or other rescue medications. The duration of the postictal and recovery periods in each of these scenarios was estimated by the Delphi panel members and clinicians in each country, to accurately represent the expected HRQoL impact on the patient. Both the HRQoL estimates and the expected duration of seizure events are summarised by country in Table 5. An additional consideration highlighted by clinical experts was a subpopulation of children who suffer from a severe disability as a result of their epilepsy; for these children, the QALY loss due to a seizure was expected to be much lower because of their lower baseline HRQoL. The proportion of patients estimated to have a severe disability in each country is reported in Table 5, together with the reduced baseline and event utility implemented for these patients. Model outputs The primary outputs of the models were the incremental costs and QALYs associated with implementation of the licensed BUCCOLAM preparation. All country models featured an estimate of the expected annual budget impact associated with adopting BUCCOLAM as standard care. These analyses were informed by national registry data and estimates provided by local Delphi panel members and KOLs. Results presented within this manuscript are for an average year, with no discounting being applied. Deterministic sensitivity analyses Deterministic sensitivity analyses were performed to assess the robustness of the models to changes in key parameter values. The upper and lower bounds of each parameter were modelled to calculate the maximum and minimum incremental cost-effectiveness ratios (ICERs) Table 5 Utility values and event durations used to calculate QALYs lost to seizures Utility values Scotland Wales Germany Spain France Italy Switzerland Proportion of patients with severe disability 10% 20% 20% 10% 46% 50% 17.5% Quality of life for patients without severe disabilities Baseline 0.879 0.920 0.920 0.879 0.879 0.920 0.864 During seizure −0.204 −0.334 −0.334 −0.204 −0.436 −0.334 −0.436 Following seizure –no ambulance 0.722 0.722 0.722 0.722 0.507 0.722 0.358 Following seizure – ambulance called 0.100 0.100 0.100 0.100 0.413 0.100 0.336 Quality of life for patients with severe disabilities Baseline −0.127 −0.127 −0.127 −0.127 −0.001 −0.127 −0.127 During seizure −0.359 −0.359 −0.359 −0.359 −0.516 −0.359 −0.594 Following seizure –no ambulance −0.313 −0.313 −0.313 −0.313 −0.230 −0.313 −0.313 Following seizure – ambulance called −0.313 −0.313 −0.313 −0.313 −0.216 −0.313 −0.313 Event timings Average duration of seizure (minutes) BUCCOLAM 8; Current care 8 BUCCOLAM 8; Current care 8.35 BUCCOLAM 8; Current care 15 BUCCOLAM 8; Current care 15 BUCCOLAM 8; Current care 15 BUCCOLAM 8; Current care 15 BUCCOLAM 8; Current care 15 Time to recovery (hours) –where available, the duration of the postictal phase is shown in parentheses No ambulance 21.0 24.0 (4.0) 0.9 (0.6) 21.0 1.25 (0.2) 21.0 BUCCOLAM 1.25; Current care 1.24 (0.2) Ambulance but no hospitalisation 40.5 30.0 (4.0) 3.0 (1.0) 40.5 2.0 (0.6) 40.5 BUCCOLAM 2.00; Current care 1.98 (0.6) Ambulance and hospitalisation 64.5 96.0 (14.0) 6.0 (2.5) 64.5 12.5 (0.6) 112.5 BUCCOLAM 12.50; Current care 12.48 (0.6) Ambulance and hospitalisation in intensive care unit 88.5 120.0 (24.0) 6.0 (2.5) 88.5 12.5 (0.6) 136.5 BUCCOLAM 12.50; Current care 12.48 (0.6) QALYs = quality-adjusted life-years. 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Submit your manuscript to a journal and benefi t from: 7 Convenient online submission 7 Rigorous peer review 7 Immediate publication on acceptance 7 Open access: articles freely available online 7 High visibility within the fi eld 7 Retaining the copyright to your article Submit your next manuscript at 7 springeropen.com Lee et al. Health Economics Review 2014, 4:6 Page 15 of 15 http://www.healtheconomicsreview.com/content/4/1/6