Clin Drug Investig

https://doi.org/10.1007/s40261-017-0615-z

ORIGINAL RESEARCH ARTICLE

Budget Impact Analysis of Brivaracetam Adjunctive Therapy

for Partial-Onset Epileptic Seizures in Valencia Community,
Spain
Isabel Barrachina-Martı́nez1 • David Vivas-Consuelo1 • Anna Piera-Balbastre2

Ó Springer International Publishing AG, part of Springer Nature 2017

Abstract antiepileptics is approximately €3.6 million. The number of

Background and Objective More than 30% of patients with patients eligible for treatment with brivaracetam would
epilepsy have inadequate control of seizures with drug increase from 42 to 179 and annual savings of 0.09–0.37%
therapy. The goal of this study is to determine the budget would be created, representing €41,873 over 5 years
impact (BI) of the introduction of brivaracetam to the port- (0.23% of the total budget). The sensitivity analysis cor-
folio of approved drugs in Spain as adjunctive therapy for the roborates that the probability of achieving savings with
treatment of partial-onset epilepsy in patients over 16 years brivaracetam is around 84%.
old with a 5-year time horizon in the Valencia Community, a Conclusions Brivaracetam is a therapeutic alternative that
Spanish region with a population of 5 million. allows savings for the health system in patients with non-con-
Methods The BI model compares the pharmaceutical trolled epilepsy when used as monotherapy, having a fixed,
expenditure on antiepileptics in two scenarios: with and predictable annual cost (independent of dose) from the first day
without brivaracetam. It assumes that the introduction and of treatment as the lack of need for titration means the patient is
increased use of brivaracetam will lead to a proportional within a range of therapeutic doses from the first dose.
decrease in consumption of coexisting adjunctive antiepilep-
tics and calculates the evolution of the consumption of bri-
varacetam over 5 years (2016–2020). The model was Key Points
designed from the perspective of the Spanish National Health
System. Data on the candidate population, consumption of Brivaracetam is a new third-generation antiepileptic
antiepileptics, market share and pharmaceutical expenditure drug offering a therapeutic alternative for
were obtained from real-world data. Finally, a sensitivity concomitant therapy in the treatment of partial-onset
analysis was carried out on the set of variables involved in the epileptic seizures, with or without secondary
evolution of costs using a Monte-Carlo simulation. generalisation, in adults and adolescents above
Results The model estimates that the target population 16 years of age.
eligible for adjunctive antiepileptics will hold at around
The results from this budget impact analysis suggest
2352 between 2016 and 2020. Annual expenditure on
that brivaracetam is a cost-saving therapeutic
strategy for adjunctive therapy for epilepsy in Spain.

& Isabel Barrachina-Martı́nez

ibarrach@upvnet.upv.es
1 Introduction
1
Departament of Economics and Social Sciences. Research
Centre for Health Economics and Management, INECO,
Epilepsy is one of the most common chronic neurological
Universitat Politècnica de València, Edificio 7 J, Camino de
Vera s/n, 46022 Valencia, Spain diseases in the world, with the World Health Organization
2 estimating that it affects around 50 million people [1].
Department of Neurology, Hospital Clı́nico Universitario de
Valencia, Valencia, Spain According a recent systematic review, the prevalence of
 I. B. Martı́nez et al.

active epilepsy was 6.38 per 1000 persons, while the life- (retigabine, eslicarbazepine, lacosamide, perampanel and
time prevalence was 7.60 per 1000 persons. The annual zonisamide) AEDs have been added. Nevertheless, 30% of
cumulative incidence of epilepsy was 67.77 per 100,000 patients do not have entirely controlled epilepsy [6, 11].
persons, while the incidence rate was 61.44 per 100,000 The choice of the most suitable AED depends principally
person-years [2]. on the patient’s type of epilepsy, its effectiveness and the
There are two types of epileptic seizure: generalised individual profile for tolerability and adverse effects. Gen-
seizures, in which the entire surface of the brain is affected erally, the new drugs are better tolerated, though not always
at the same time, and partial-onset or focal seizures, which more effective [12]. When comparing treatments, it is
begin by affecting one part of the brain [3, 4]. In Spain it is important to compare (1) drugs with the same indication [in
estimated that around 400,000 people are affected by epi- this case, adjunctive drugs for partial-onset epileptic sei-
lepsy, with nearly 60% of patients having partial-onset or zures (POS)]; (2) the need for titration and duration of it
focal seizures [4]. (speed in stabilising the patient); (3) available pharmaceu-
Antiepileptic treatment centres on achieving the greatest tical forms for different clinical situations; (4) dosage
reduction in the number of epileptic seizures while min- (which will influence long-term compliance); (5) cost per
imising adverse effects and long-term toxicity as far as treatment per day (affordable for the health service); (6)
possible. Clinical evidence shows that monotherapy with efficiency and effectiveness in real life; and (7) safety and
antiepileptic drugs (AEDs) is effective in 70% of patients interactions profile (associated with being a first-, second-
[5]. The remaining 30% need adjunctive treatment to or third-generation drug).
control the seizures [6] and, of these, approximately 25% Brivaracetam is a new third-generation AED offering a
have epilepsy that is difficult to control, refractory or therapeutic alternative for concomitant therapy in the
resistant to AEDs. This implies difficulty for the neurolo- treatment of POS, with or without secondary generalisa-
gist in its management and the need to study other treat- tion, in adults and adolescents above 16 years of age. This
ment strategies or optimise available pharmacological drug was approved by the European Medicines Agency in
treatments. The importance of refractory epilepsy is in the January 2016 [13]. Unlike other AEDs, it has a fixed cost
significant decrease in quality of life with, moreover, the independent of dosage, having no need for titration and
presence of associated morbidities (depression being the ensuring the patient is within a therapeutic dosage range
most frequent) and an increased probability of early death from the first day. It has a good tolerability profile and is
compared with patients with controlled epilepsy [7, 8]. commercialised in all pharmaceutical forms to deal with
The annual direct cost of epilepsy in Spain is estimated different patient profiles (out-patients and hospitalised
to be €2978/patient in the case of controlled epilepsy and patients) [14, 15].
between €4964 [9] and €6935 [4] per patient for non- When introducing a new medicine to the existing port-
controlled epilepsy, that is, the cost is between 1.7 and 2.3 folio for a disease, the budget impact (BI) analysis (BIA)
times greater for non-controlled than controlled patients. for the new medicine is an important tool in helping make
This proportion reaches 2.7 times greater in infantile epi- decisions. A BIA is implemented to assess the sustain-
lepsy [3]. Furthermore, non-controlled epilepsy is associ- ability of the use of a new technology, in this case a new
ated with a greater consumption of healthcare resources, drug. As such, the goal of this study was to determine the
lower quality of life and a greater incidence of severe BI of the introduction of brivaracetam to the portfolio of
depression. Therefore, it places a considerable burden on approved drugs in Spain as adjunctive therapy for the
the National Health Service and society, as severe levels of treatment of POS in patients over 16 years of age with a
anxiety and depression are associated with very high costs 5-year time horizon in the Valencia Community (VC), a
for the health system [10]. Spanish region with a population of 5 million.
The neurologist has more than 20 AEDs available for the
treatment of epilepsy, some of which have numerous
adverse effects and interactions that can complicate patient
treatment and management, especially for those with 2 Materials and Methods
refractory epilepsy [5]. Since 1993, more than 12 new
AEDs have been approved that have an effect on seizure 2.1 Design
control and a better tolerability profile, as well as a lower
risk of drug interactions. To the four classic or first-gener- The BIA model was based on the latest methodological
ation AEDs (phenobarbital, phenytoin, carbamazepine and recommendations proposed by the International Society for
sodium valproate), eight second-generation (gabapentin, Pharmacoeconomics and Outcomes Research (ISPOR)
oxcarbazepine, topiramate, lamotrigine, vigabatrin, prega- principles on good practice for BIA [16]. The model esti-
balin, tiagabine and levetiracetam) and five third-generation mates the incremental BI of adopting brivaracetam as a
Budget Impact Analysis of Brivaracetam for Partial-Onset Epileptic Seizures

treatment for POS, and is structured in six basic steps for [19], retigabine [20] and zonisamide [21] (Table 1). Reti-
estimating BI: (1) estimating the target population; (2) gabine was withdrawn from the market in June 2017, but is
selecting a time horizon; (3) identifying the current and nevertheless included as it was commercially available at
projected treatment mix; (4) estimating current and future the time of the study (January 2016).
drug costs; (5) estimating the change in disease-related costs; The model was constructed using Microsoft ExcelÒ
and (6) estimating and presenting changes in annual BI. (Microsoft Corp., Redmond, WA, USA) and is based on
The starting point is the current market share of other the international recommendations for evaluations of this
AEDs in VC, obtained from real-word data from the kind [16].
regional electronic prescribing system. The model simu-
lates brivaracetam entering the market and drawing a 2.2 Estimating the Target Population
market share in pre-defined proportions from the other
available therapies. Therefore, if in year 1 brivaracetam is The target population was patients over 16 years of age
assumed to reach 1.77% market share, the model simulates diagnosed with epilepsy and taking AEDs, both in
what proportion of this 1.77% is drawn from each of the monotherapy and as adjunctive treatment. This was
other replacement therapies. This is due to the particular extracted from the database of the Valencian Health
difficulty of establishing a market share in indications such Department (Generalitat Valenciana), which registers all
as POS, given how many drugs are used in combination holders of a health card for 2013. These data were anon-
and the difficulty in obtaining market share data for the ymised and we selected the following variables per patient:
specific patient population (Fig. 1). age, sex, International Classification of Diseases, 9th
The assumptions and choices for the model are as fol- Revision, Clinical Modification (ICD-9-CM) diagnosis
lows: (1) all patients in year 1 are assumed to be a mix of codes, drug dosage by Anatomical Therapeutic Chemical
incidental and prevalent patients; (2) the model does not (ATC) code and pharmaceutical expenditure.
take into account any treatment switches for any reason; (3) To avoid selecting any patient who was being treated with
patients are assumed to be 100% compliant to each regimen AEDs for diseases other than epilepsy, the diagnoses related to
they receive; (4) for all adjunctive lines it is envisaged that epilepsy selected were ICD-9-CM 345.90, 345.10 and 345.50,
when brivaracetam is introduced, its market share may and these were cross-checked with the data for drug con-
grow over time, and therefore the treatment mixes including sumption corresponding to AEDs with ATC codes N03AA,
brivaracetam can be adjusted from year 1 to year 5; and (5) N03AB, N03AD, N03AE, N03AF, N03AG and N03AX.
the safety profile of AEDs is considered to be similar. The number of patients with POS, with or without
The growth rate was calculated assuming an annual secondary generalisation, were estimated from existing
population increase of 0.05%, in accordance with 2016 epidemiological data in the literature, as were the data on
data from the National Statistics Institute (INE), and a incidence and prevalence [4].
mortality of 1.9% [4], taken from available data for 2013.
The third-generation drugs included in this comparison 2.3 Perspective and Time Horizon
are those that, according to their summary of product
characteristics (SmPC), have the same indications as The BI is determined from the perspective of the health
adjunctive for POS, with or without secondary generali- service of the VC with a time horizon of 5 years, from
sation: lacosamide [17], eslicarbazepine [18], perampanel 2016 to 2020.

t=0 Titraon and response assessment Year 1 Year 2 – 4 Year 5

Brivaracetam Brivaracetam

Brivaracetam Brivaracetam
Other AEDS Other AEDS

Response rate Response rate

Brivaracetam

Brivaracetam Brivaracetam Brivaracetam Brivaracetam Brivaracetam

Other AEDS Other AEDS Other AEDS Other AEDS Other AEDS

Response rate
Growth rate Growth rate
Starng point

Fig. 1 Model structure of the budget impact analysis. AED antiepileptic drug, t time
 I. B. Martı́nez et al.

Table 1 List of selected comparators according to indication

Antiepileptic Indication Dosage No. of Main action/ Pharmaceutical Approved dosage range Dosage applied
days of mechanism form according to datasheet in model
titration (mg/day) (mg/day)

Retigabinea Drug-resistant 3/day 56 K? channel Tablets 600–1200 900

partial onset activation
(adjunctive)
Perampanel Generalised and 1/day 33 Glutamatergic Tablets 2–12 8
partial inhibition
(adjunctive)
Eslicarbazepine Partial onset 1/day 14 Na? channel Tablets 400–1200 800
(adjunctive) inhibition
Lacosamide Partial onset 2/day 11 Na? channel Tablets, 200–400 300
(adjunctive) inhibition intravenousb
Zonisamide Partial onset 1–2/day 14/28 Calcium Capsules 200–500 400
(monotherapy or T-type
adjunctive) thalamic
channel
Brivaracetam Partial onset 2/day 0 Binding to Tablets, oral 50–200 100
(adjunctive) SV2A solution,
intravenousb
Compiled from data published in authorised summary of product characteristics. European Medicines Agency (EMA) and Spanish Agency of
Medicines and Medical Devices (AEMPS)
SV2A synaptic vesicle glycoprotein 2A
a
Withdrawn from market in June 2017
b
Lacosamide and brivaracetam may be used intravenously in special hospital clinical situations, such as status epilepticus or surgical operations.
Dosage is variable

2.4 Estimating Antiepileptic Drug Market Share share that is proportionally extracted from the other
and Treatment Mix available therapies. This approach was adopted in order to
reduce the work of compiling data on the present market
To obtain the market shares, the consumption data for AEDs share of all the relevant substitute therapies. Table 3 shows
was crossed-checked with the diagnoses of epilepsy in order the number of patients that would be taking each therapy
to extract drug consumption for uses other than epilepsy. for each of the 5 years in the model.
Table 2 shows the total market share of each AED for
treating epilepsy, including the total market share for each 2.5 Estimate of Costs
AED, the percentage of each AED used as monotherapy,
the percentage of each AED used as adjunctive treatment The base year for the costs considered in the model is 2016.
and the total annual pharmaceutical expenditure. To calculate the average daily costs for each drug, data were
The total pharmaceutical expenditure on AEDs was used from the Ministry of Health, Social Services and
€15,342,650, with the AEDs included in the model Equality (Ministerio de Sanidad Servicios Sociales e Igual-
accounting for 32.33% of the total (€4,960,118) with a dad) [22] and BOT-PLUS [23], using the ex-factory price.
market share of 9.78%. The percentage of patients receiving All AEDs except brivaracetam have a titration phase on
monotherapy was 3.25% (447 patients) and 14.10% (2395 initiating the treatment, varying between several days and
patients) were treated with adjunctive therapy. several weeks. During this phase treatment is not effective,
Market share change as each AED is introduced into the as the dose is gradually increased daily until it reaches the
model as adjunctive therapy for the treatment of POS. effective dose. The costs associated with this titration
Simulation of how market share varies on the introduction period for each drug must be reflected in the model and
of brivaracetam is shown in Table 3. were calculated from the dosage scale given in the
To estimate the initial market share of brivaracetam, the approved SmPC for each over the time period established
patients considered eligible for treatment with brivarac- to reach the effective treatment dose [24]. These titration
etam were those who epilepsy was not controlled by the costs have been distributed over the 5 years of the study.
other therapies (Table 2). The model simulates the entry of The average daily costs of the maintenance phase for
brivaracetam onto the market with a predefined market each AED were calculated according to the average daily
Budget Impact Analysis of Brivaracetam for Partial-Onset Epileptic Seizures

Table 2 Market share of antiepileptic drugs and pharmaceutical expenditure in the Valencia Community
AED (Antiepileptic drugs) Market Patients in Patients in add-on Pharmaceutical
share (%)a monotherapy (%) treatment (%)b expenditure (€)

Classic AEDs
Carbamazepine 8.3 9.3 7.6 132,667
Clonazepam 6.4 2.1 9.2 46,449
Ethosuximide 0.1 0.0 0.2 7332
Phenobarbital 4.2 2.1 5.6 34,542
Phenytoin 5.8 5.3 6.1 49,476
Primidone 0.5 0.4 0.6 13,466
Valproic acid 16.3 20.2 13.8 641,081
Valpromide 0.1 0.1 0.1 1816
Total: classic AEDs 41.7 39.5 43.2 926,829
Second-generation AEDs
Gabapentin 3.1 3,0 3.2 132,421
Lamotrigine 10.1 11.4 9.3 1,105,525
Levetiracetam 24.3 34.0 18.0 6,639,228
Oxcarbazepine 3.5 4.1 3.1 286,374
Pregabalin 3.5 1.8 4.7 686,281
Rufinamide 0.1 0.0 0.1 83,987
Tiagabine 0.1 0.0 0.2 24,159
Topiramate 3.8 3,0 4.3 521,887
Vigabatrin 0.1 0.0 0.2 26,620
Total: second-generation AEDs 48.6 57.3 43.1 9,506,482
Third-generation AEDs
Eslicarbazepine 2.5 1.3 3.3 1,408,626
Lacosamide 3.6 0.9 5.5 1,937,087
Perampanel 1.0 0.0 1.6 399,520
Retigabine 0.1 0.0 0.2 32,825
Zonisamide 2.3 0.9 3.2 1,131,281
Total: third-generation AEDs 9.5 3.1 13.8 4,909,339
Total 100 100 100 15,342,650
AEDs antiepileptic drugs
a
Valencian Health Authority, Electronic Prescription System, 2014. Prescriptions for epilepsy diagnoses only
b
Patient with two or more add-on AEDs combined

dosage; all drugs included in the model had the same of the therapies studied is tied to the delivered dose. The
indications as brivaracetam. The dose considered was that number of days of treatment considered is 365 days per
stated in the SmPC. In accordance with the ISPOR year.
guidelines [16], costs were considered to have a discount Costs not related to the drugs, such as medical visits,
rate of 0% for the base case. Table 4 shows the cost per hospital admissions and emergencies, have not been
treatment per day for each AED for the average dose included in the BIA, which is limited only to the costs of
considered and the additional cost of the initial titration the adjunctive AEDs.
phase.
The average daily cost of monotherapy treatment must 2.6 Sensitivity Analysis
also be added to the adjunctive treatment cost for each
patient. This cost is calculated as an average of that for the In order to analyse the robustness of the results, a sensi-
most common therapies (carbamazepine, lamotrigine, tivity analysis was carried out with regard to those
oxcarbazepine, topiramate and valproate). parameters of the model considered to have greater
The dosage and frequency of administration is based on uncertainty associated with the values used in the base case
the SmPC for each product [13]. The pharmacological cost [25].
 I. B. Martı́nez et al.

Table 3 Initial market share and estimated variation in the following years
AED (antiepileptic Market Adjusted 2016 2017 2018 2019 2020
drug) share: to 100%
third- (%) Patients % Patients % Patients % Patients % Patients %
generation (n) (n) (n) (n) (n)
AEDs (%)

Eslicarbazepine 3.28 23.91 553 23.50 544 23.1 536 22.8 528 22.41 521 22.1
Lacosamide 5.46 39.80 919 39.08 905 38.4 891 37.8 878 37.26 867 36.8
Perampanel 1.59 11.59 267 11.36% 263 11.2 259 11.0 255 10.84 252 10.7
Retigabine 0.20 1.46 34 1.45 34 1.4 33 1.4 33 1.38 32 1.4
Zonisamide 3.19 23.25 537 22.83 528 22.5 520 22.1 513 21.77 506 21.5
Brivaracetam 42 1.77 80 3.4 116 4.9 149 6.34 179 7.59
Total 13.72 100 2352 100 2353 100 2354 100 2355 100 2357 100
AED antiepileptic drug

A one-way sensitivity analysis of the BI was performed 3 Results

for the cost variation of the daily dosage of brivaracetam
(alternative 1), and for increasing the brivaracetam market 3.1 Market Size
share by 10% (alternative 2), keeping the other variables
constant. In 2013 there were 4,714,840 people registered with a
Additionally, a probabilistic sensitivity analysis (PSA) health card out of a VC population of 4,931,281, of whom
was performed. In a Monte-Carlo simulation, 1000 inter- 82.58% (3,893,421) were over 16 years old. A diagnosis of
actions were carried out in which multiple variables epilepsy had been given in 26,972 (50.8% men), with an
introduced into the BIA varied simultaneously. The cost of average age of 51.32 years. Therefore, the percentage of
the daily dose behaved as a random variable of normal patients with epilepsy among those over 16 years old in the
distribution with an average price of €4 and a typical VC for that year was 0.69%.
deviation of 5% of the average (€0.2), being able to adopt Given the prevalence of partial-onset epilepsy is 60%
any value belonging to the distribution. Effectiveness [3], the approximate number of patients with partial-onset
randomly varied between 50 and 100%. Market share fol- epilepsy, calculated from the total number of patients
lowed the random values of normal distribution with an diagnosed with epilepsy, will be 16,183, and of these a
average obtained from initial values and a typical deviation total of 15,015 will be prevalent and 1168 incidental.
of 5% of the average. The discount rate varied randomly Only 22,676 (84%) of the patients diagnosed with epi-
between 0 and 3%. lepsy in the database took AEDs for treatment and, as such,
From the Monte-Carlo simulation we obtain the average this study is centred on them. Of this 84% of patients,
BI and standard deviation and the cumulative probability 61.9% are treated with monotherapy (14,035) and 38.1%
distribution to establish the probability of a negative with adjunctive treatments (8641).
(savings) or positive (increased cost) BI. The potential population for treatment with brivarac-
etam are those patients using adjunctive treatments. Of the

Table 4 Cost of drugs and AED (average daily dose) Cost/treatment/day (€)a Total titration phase cost (€)
titration
Zonisamide (400 mg/day) 3.55 51.72
Perampanel (8 mg/day) 3.78 186.48
Retigabine (900 mg/day) 3.80 106.56
Brivaracetam (independent of dose) 4.00 NA
Lacosamide (300 mg/day) 4.48 31.38
Eslicarbazepine (800 mg/day) 4.48 31.36
Average cost of concomitant monotherapy 0.60
NA not applicable—no titration is required
a
Ex-factory price
Budget Impact Analysis of Brivaracetam for Partial-Onset Epileptic Seizures

Table 5 Daily cost according Adjunctive Daily cost/unit (€) during Total cost
to market penetration therapies (maintenance) maintenance dose
2016 2017 2018 2019 2020
(€) (€) (€) (€) (€)

Eslicarbazepine acetate 4.48 2476 2437 2400 2365 2334

Lacosamide 4.48 4118 4052 3990 3932 3882
Perampanel 3.78 1010 994 979 965 952
Retigabine 3.8 130 128 126 124 122
Zonisamide 3.55 1906 1876 1847 1820 1797
Adjunctive therapies Total costs during titration 2016 2017 2018 2019 2020
(titration) (€) (€) (€) (€) (€) (€)

Eslicarbazepine acetate 31.36 3467 3412 3360 3311 3268

Lacosamide 31.38 5769 5677 5590 5509 5438
Perampanel 186.48 9968 9809 9659 9518 9396
Retigabine 106.56 727 715 704 694 685
Zonisamide 51.72 5554 5465 5382 5303 5235

Table 6 Summary of results 2016 2017 2018 2019 2020

Budget forecast without brivaracetam

Acquisition costs (€) 3,582,066 3,583,857 3,585,649 3,587,442 3,589,235
On initiation of AED (titration) (€) 25,943 25,956 25,969 25,982 25,995
Total without brivaracetam (€) 3,608,009 3,609,813 3,611,618 3,613,424 3,615,231
Budget forecast with brivaracetam
Acquisition costs (€) 3,579,440 3,578,839 3,578,356 3,578,021 3,577,951
On initiation of AED (titration) (€) 25,484 25,079 24,694 24,335 24,022
Total with brivaracetam (€) 3,604,924 3,603,918 3,603,051 3,602,356 3,601,974
Budget impact
Acquisition costs (€) - 2626 - 5017 - 7292 - 9421 - 11,284
On initiation of AED (titration) (€) - 459 - 877 - 1275 - 1647 - 1973
Total (€) - 3085 - 5895 - 8567 - 11,068 - 13,257
AED antiepileptic drug

8641 patients being treated with adjunctive therapy, for each year is calculated according to the daily unit cost
14.10% (2395) take one of the AEDs considered in the BIA and the number of patients on each treatment (Table 3).
model. Brivaracetam has no titration costs as it can be initiated
For the first year studied (2016), the model is based on a at an effective dosage, while the other AEDs have the
population of 2352 patients, the result of extrapolation of additional costs of titration, as shown in Table 5.
the 2013 population to 2016, according to the population Supposing for the base case that the share of brivarac-
growth and mortality data considered. etam increases from 1.77 to 7.59% in 5 years (Table 3), the
drug with the greatest displacement would be lacosamide,
3.2 Pharmaceutical Expenditure which would lose a market share of 2.32% due to the way
in which the calculations of drug displacement were made
The model presents results for the annual cost per patient, according to the initial market share of each drug.
calculated from both the titration phase (only attributable to
the first year) and maintenance (average dose for the fol- 3.3 Budget Impact
lowing years).
Table 5 shows the evolution of the total daily costs of The population of the VC with POS and eligible to take
the medicines according to the evolution of the patients and brivaracetam was 2352 patients in 2016 and is expected to
the market share of each of the treatments. The total cost stay more or less constant until 2020, assuming that the
market share will increase linearly with time. Table 6
 I. B. Martı́nez et al.

shows the total medication cost in the reference scenario corroborates the robustness of the analysis with the prob-
(without brivaracetam) and the new scenario (with ability obtained in these results (Fig. 3).
brivaracetam).
In the reference scenario, the total cost of the medication
is estimated to be €3.608 million in the first year, 4 Discussion
increasing to €3.615 million in the fifth year (up 0.20%),
while in the new scenario the total cost would hardly vary The BIA compares the scenario with and without bri-
over the 5 years (Fig. 2). varacetam, taking into account the population eligible for
It can be seen in Table 6 that the BI, estimated as the treatment with brivaracetam, the market shares of other
difference between both scenarios, is negative, thus rep- adjunctive treatments and their variation on linearly
resenting a saving, and the absolute value increases from introducing brivaracetam.
€3085 to €13,257. Over the total of the 5 years of the study, The BI is conditioned by the displacement power of
the introduction of brivaracetam on the market entails brivaracetam, which may be different to that considered
savings of €41,873, that is, 0.23% of the total budget. and reflects an increasingly large budget saving from
Savings from lower acquisition costs represents 85.12% of 0.09% in 2016 to 0.37% in 2020, an annual increasing
the total and savings for reduced titration costs are 14.9%. average of 0.07%. Furthermore, the displacement of the
other existing AEDs takes place as a function of their initial
3.4 Sensitivity Analysis market share, as a result of which the most used drug will
also be the most displaced in the model.
Table 7 shows the result of a one-way sensitivity analysis. The data source for this model is a real-life database of
A 1% decrease in the daily dosage cost of brivaracetam AED consumption for epilepsy in the VC, including the
implies an increase in budget savings of 19.7%, with the correct figures for the adult population with health cards
percentage of savings on the initial budget being 0.28% for and the prevalence of epilepsy, as well as present con-
a 5-year time horizon; that is, 0.05% greater than in the sumption of different drugs on the market. The prevalence
base case. An increase in cost of 1% would produce the of epilepsy obtained was 0.69% of the adult population.
opposite effect. The percentage of patients being treated with monotherapy
A variation of 10% greater than in the base case in the is 61.89%, which is different to that stated in other inter-
introductory market share of brivaracetam would result in national data of 70% [26].
10% budget savings, with the percentage in savings on the The results obtained for the VC can be extrapolated for
initial budget being 0.26%; that is, 0.02% greater than in the national population, in which there were 47,155 adult
the base case. patients with partial-onset epilepsy in 2016, to give savings
In the PSA we obtained a pattern of normal distribution of €824,431 over 5 years. This estimate of the target
of BI, with an average of - €33,719 and a standard devi- population for the whole of Spain was estimated based on
ation of €33,844. The probability that the BI entails a 80% of the national population being over 16 years and
saving for the National Health Service is 84%, which epidemiological data from the literature, and not from real
data on disease burden.

Fig. 2 Budget impact TOTAL BUDGETS

estimation
€ 3,615,231
€ 3,613,424
€ 3,611,618
€ 3,609,813
€ 3,608,009

€ 3,604,924

€ 3,603,918

€ 3,603,051

€ 3,602,356

€ 3,601,974

2016 2017 2018 2019 2020

Budget in Market without brivaracetam Budget in Market with brivaracetam

Budget Impact Analysis of Brivaracetam for Partial-Onset Epileptic Seizures

Table 7 Brivaracetam budget impact, base-case, and alternative analyses (in €)

Budget impact Base case (€) Alternative scenario 1: daily cost of Alternative scenario 2: market
brivaracetam 1% lower (€) shares rises 10% (€)

Without brivaracetam 18,058,095 18,058,095 18,058,095

With brivaracetam 18,016,222 18,007,974 18,012,035
Total 41,873 50,121 46,060

Fig. 3 Cumulative probability

that the budget impact entails a
saving for the National Health
Service

Therefore, this BIA shows that the gradual introduction would cost the health system the same and it would help
of brivaracetam in the VC creates a saving in the health control very refractory patients. Any increase in dose of the
service budget, with the amount depending fundamentally other co-adjunctive AEDs considered would, by contrast,
on the estimates used concerning the brivaracetam market bring with it an increase in the treatment cost per day. This
share, costs and market penetration throughout a 5-year effect helps decision-making regarding health manage-
time horizon. ment, as the BI would not be affected by a change in bri-
In the base case, average global savings are estimated to varacetam dosage for a specific situation.
be €41,873 over 5 years, which is 0.23% of the cost The majority of the limitations ascribable to the use of
attributable in this period to antiepileptic therapies in assumptions in this model have been dealt with by the
patients with POS in adjunctive treatment. sensitivity analysis carried out to test the robustness of the
The savings in titration costs become increasingly rel- model and to determine the impact on the final result of
evant in the period considered, as the titration costs of changes in the most sensitive variables. Nevertheless, there
brivaracetam are zero, while the other AED therapies it are other kinds of limitations in the model where uncer-
would replace always have positive titration costs. tainty could not be reduced and these must be taken into
In the first year of the analysis, therapy using brivarac- account.
etam can create a positive BI, though these additional costs First, it is a future projection model of the use of a drug
are compensated for by the savings in titration costs over based on multiple assumptions and on the attitude of
the following years. Effectively, this lack of need for clinicians to the introduction of brivaracetam to the AED
titration together with its fixed treatment cost per day (in- market. If this attitude is different to that expected, the
dependent of dosage) are two of the reasons that would brivaracetam market share could be different to that anal-
justify the potential savings associated with use of ysed in this study. Nevertheless, the sensitivity analysis
brivaracetam. shows that even with significant variation in the expected
The budget savings obtained could be even greater, due market share, the savings for the health service remain
to the treatment cost per day of brivaracetam being important.
established at €4.00, independent of the dose used. Second, only the costs of the medication were included,
Therefore, patients who need to increase their dose per day which implies that the analysis does not take into account
 I. B. Martı́nez et al.

other associated health costs, such as medical visits, etc. suitable response to conventional AEDs could produce net
The results of the BIA presuppose, therefore, that these savings of €41,873 over 5 years.
other costs are similar for any other scenario, and nor does Regional and national health services should promote
it incorporate other supposed savings regarding costs of the choice of rational and cost-effective therapeutic
admissions or emergencies [27]. Nevertheless, these sav- strategies, especially in chronic conditions such as epi-
ings would be shared between all AEDs proportionally to lepsy, which ensure long-term compliance with treatment
their market share. and favour control of the pathologies.
Third, the dosages considered in the base model could
underestimate the average real dosages being used by the Acknowledgements The opinions expressed in this paper are those
of the authors and do not necessary reflect those of the afore-named.
patients. In this case, the BIA obtained in the base case Any errors are the authors’ responsibility. We would also like to thank
corresponds to a conservative scenario and the savings John Wright for the English editing.
could be greater.
Fourth, the assumptions that the effectiveness of bri- Funding This work was supported partially by the Instituto de Salud
varacetam is 100%, the discontinuation rate is 0%, com- Carlos III-Ministerio de Economı́a y Competitividad and the Euro-
pean Union (FEDER [Fonds Européen de Développement Écono-
pliance is 100% and that all patients remain compliant to mique et Régional (European Fund for Economic and Regional
the end of the treatment imply a certain removal from Development)] funds)—FIS PI12/00037.
clinical reality. Nevertheless, for the purpose of the BIA,
this supposition is neutral, as it applies equally to all drugs Compliance with Ethical Standards
considered.
Conflict of interest David Vivas Consuelo has received a grant from
Last, the assumption that there will be no dosage UCB Pharma. Isabel Barrachina Martı́nez and Anna Piera Balbastre
increase for any drug throughout the 5 years of the analysis have no conflicts of interest to declare.
is unrealistic in clinical practice, especially with certain
drugs. This would, however, contribute to greater savings
in the BIA.
We believe that these effects compensate each other and References
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