Cost Effectiveness of Guanfacine Extended-Release versus Atomoxetine for the Treatment of...

Cost Effectiveness of GuanfacineExtended-Release versusAtomoxetine for the Treatment ofAttention-Deficit/Hyperactivity DisorderApplication of a Matching-Adjusted Indirect Comparison

M. Haim Erder,1 Jipan Xie,2 James E. Signorovitch,2 Kristina S. Chen,2 Paul Hodgkins,1

Mei Lu,2 Eric Q. Wu2 and Vanja Sikirica1

1 Shire Development LLC, Wayne, PA, USA

2 Analysis Group, Inc., Boston, MA, USA

Abstract Background: About 7% of children and adolescents are diagnosed with at-

tention-deficit/hyperactivity disorder (ADHD) in the US. Patients with

ADHD who are intolerant of or do not have an optimal response to stimu-

lants often use non-stimulants as alternative therapies. Guanfacine extended-

release (GXR) and atomoxetine (ATX) are the only non-stimulants approved

by the US Food and Drug Administration for once-daily use in the treatment

of children and adolescents withADHD in theUS. ATXhas been on themarket

since 2002 while GXR was recently approved in 2009. To date, there is no

comparative effectiveness or cost-effectiveness study comparing the two drugs.

Objectives: The aim of this study was to assess the cost effectiveness of GXR

versus ATX for the treatment of ADHD in children and adolescents, using

the comparative efficacy results from a matching-adjusted indirect compar-

ison (MAIC).

Methods: TheMAICmethod was used to compare the efficacy between GXR

(target dose and lower doses) and ATX (target dose) in the absence of head-

to-head clinical trials. Individual patients in the GXR trials were weighted

such that the summary baseline characteristics and the efficacy of the placebo

arm of the GXR trials matched exactly with those from published ATX trials.

After weighting, the efficacy (i.e. change in the ADHD rating scale, fourth

edition [ADHD-RS-IV] total score from baseline) was compared between

each GXR dosing group and the ATX group. The results from the MAIC

analyses were used to populate a 1-year Markov model that is used to com-

pare the cost effectiveness of GXR versus ATX from a US third-party payer

perspective. Effectiveness outcomes for each treatment group were estimated

as the proportion of responders, defined as patients with ‡25% reduction in

ADHD-RS-IV total score from baseline, and average quality-adjusted life

ORIGINAL RESEARCH ARTICLEAppl Health Econ Health Policy 2012; 10 (6): 381-395

1175-5652/12/0006-0381/$49.95/0

Adis ª 2012 Springer International Publishing AG. All rights reserved.

years (QALYs). Utilities associated with response/non-response and dis-

utilities due to adverse events were applied in the model. Costs included drug

and medical service costs and were inflated to 2011 US dollars ($US). In-

cremental cost/QALY and incremental cost/responder were estimated. Uni-

variate sensitivity analyses were conducted by varying all model parameters,

including costs, utilities, and response rate.

Results: The target dose of GXR was 0.12mg/kg/day. In match-adjusted

populations with balanced baseline characteristics, patients receiving GXR at

the dose of 0.09–0.12 (p= 0.0009) and 0.075–0.09mg/kg/day (p = 0.0248) hadbetter efficacy, while those receiving GXR at the dose of 0.046–0.075mg/kg/dayhad comparable efficacy (p= 0.0699), compared with patients receiving ATX at

the target dose of 1.2mg/kg/day. In the base case of the cost-effectiveness analysis(CEA), GXR had incremental cost-effectiveness ratios of $US10637/QALY and

$US853/responder, compared with ATX (incremental costs: $US74; incremental

effectiveness: 0.007 QALYs and 86 responders per 1000 patients treated). Results

of all univariate sensitivity analyses showed that the model results were robust to

changes in model inputs.

Conclusions: To our knowledge, this is the first application of the novel com-

parative efficacy method of MAIC to a CEAmodel. TheMAIC results indicate

thatGXR (0.075–0.12mg/kg/day) wasmore effective thanATX (1.2mg/kg/day)in the trial population. The CEA results indicate that GXR is cost effective

compared with ATX for the treatment of ADHD in children and adolescents.

Key points for decision makers

� Using a novel comparative effectiveness method, matching-adjusted indirect comparison(MAIC), the study showed guanfacine extended-release (GXR) 0.09–0.12mg/kg/day and0.075–0.090mg/kg/day were associated with better efficacy compared with atomoxetine(ATX) 1.2mg/kg in the trial population

� Using the efficacy inputs obtained from the MAIC, the study estimated incremental cost-effectiveness ratios at $US10637 per QALY and $US853 per responder comparing GXR withATX for the treatment of children and adolescents with attention-deficit/hyperactivity disorderin the base case, indicating that GXR is cost effective compared with ATX

Introduction

Attention-deficit/hyperactivity disorder (ADHD)is a common psychiatric disorder in children, af-fecting up to 7.2% of the population aged 4–17years in the US in 2007.[1] It presents a substantialeconomic burden with estimated incrementalcosts of $US143–$US266 billion (year 2010 val-ues).[2] ADHD treatment options approved by theUS Food and Drug Administration (FDA) in-

clude stimulants and non-stimulants. Stimulantsare the recommended first-line treatments forADHD; however, one study showed that approxi-mately 30% of children age 6–12 years with ADHDdid not have adequate response to the stimulantmethylphenidate,[3] and may need alternative treat-ments to control their symptoms. Non-stimulantsare not controlled substances and pose less risk ofdrug abuse or dependence.[4] Atomoxetine (ATX)and guanfacine extended-release (GXR) are the

382 Erder et al.

Adis ª 2012 Springer International Publishing AG. All rights reserved. Appl Health Econ Health Policy 2012; 10 (6)

only two FDA-approved once-daily non-stimulantsfor the treatment of children and adolescents withADHD.[5,6] Clinical trials have shown that bothdrugs had superior efficacy compared with pla-cebo;[7-10] however, to date, there is no head-to-head clinical trial comparing their relativeefficacy, nor is there any study evaluating the costeffectiveness of GXR compared with ATX.[11]

Comparative effectiveness research (CER) canhelp clinicians and policy makers make inform-ed decisions about alternative treatments. TheAmericanRecovery andReinvestmentAct (ARRA)passed in 2009 allocated $US1.1 billion to fundCER. Because direct comparisons between treat-ments in head-to-head trials are often unavail-able, indirect comparisons are the only remainingoption to obtain CER data in a timely fashion forpayers, physicians and patients to evaluate thevalue of a new treatment compared with alterna-tives. This study applies the comparative efficacydata of GXR and ATX from a newly developedmethod called matching-adjusted indirect com-parison (MAIC)[12] to evaluate the cost effective-ness of GXR versus ATX for the treatment ofADHD in children and adolescents from a USthird-party payer’s perspective.

Methods

Comparative Efficacy of GuanfacineExtended-Release (GXR) versus Atomoxetine(ATX) Using Matching-Adjusted IndirectComparison

The MAIC method has been used in severalpublished studies to estimate comparative effi-cacy of treatments for which head-to-head trialswere not available,[12-16] including in a recent studythat examined GXR versus ATX in children withADHD and comorbid oppositional defiant dis-order.[15] The MAIC method was applied in thisstudy to compare GXR versus ATX in childrenand adolescents with ADHD.A systematic reviewof double-blind, randomized, placebo-controlledtrials including GXR or ATX was conducted. Itidentified two GXR trials and one ATX trial thatmet the following selection criteria: (i) all patientswithin the age range of 6–18 years old (inclusive);(ii) trials not focusing on a subgroup of ADHD

patients, (e.g. patients with certain comorbiditiesor those who meet a specific severity threshold);(iii) GXR or ATX used as monotherapy; (iv) pres-ence of a common efficacy outcome with baselinescore reported, (in this case, ADHD rating scale,fourth edition [ADHD-RS-IV] total score); and(v) inclusion of the target weight-based dose(0.12mg/kg/day for GXR and 1.2mg/kg/day forATX) in a treatment group. These target doseswere selected based on the dosing levels, beyondwhich the package inserts state there is no addi-tional benefit demonstrated.[5,6] Detailed informa-tion on trial selection is included in Appendix 1 inthe Supplemental Digital Content, http://links.adisonline.com/APZ/A65. Summary results forpatients randomized to ATX 1.2mg/kg/day andplacebo arms were obtained from the publishedATX trial.[7] Individual patient data (IPD) wereavailable for GXR patients.[9,10] GXR patientswho met the inclusion/exclusion criteria used inthe ATX trial were included in the analysis. Inparticular, they were required to have an ADHD-RS-IV score ‡1.5 standard deviations above theage and gender norms at baseline.

GXR Patient Selection by Expected Dosing

Patients were selected based on their expectedweight-based dosing using the IPD from the twoGXR trials.[9,10] For patients randomized to theGXR arms, the expected weight-based dosing wascalculated as weight-based GXR dose= random-ized GXR dose (1, 2, 3 or 4mg/day)/body weight.Based on the expected weight-based dosing, pa-tients were classified into the following categories:0.09–0.12mg/kg/day, 0.075–0.09mg/kg/day and0.046–0.075mg/kg/day. Dosing ranges were usedto evaluate the efficacy of GXR because focusingon a particular dose (e.g. the target dose of0.12mg/kg/day) would have resulted in a smallsample size. Because some patients would neverachieve certain weight-based dose, even with thehighest fixed dose (4mg/kg), each placebo patientwas weighted according to his/her probability offalling into a weight-based dose category, assum-ing that the placebo patient had equal probabil-ity to be randomized into 1, 2, 3 or 4mg/day ofGXR. This would provide a comparable placebogroup for each weight-based GXR dose category.

Cost Effectiveness of GXR vs ATX 383


Matching-Adjusted Indirect Comparison toEstimate the Comparative Efficacy

Baseline characteristics were matched if theywere reported in the ATX trial and were alsoavailable in the GXR trials. Trial populationswere matched by assigning weights to individualpatients in the GXR trials such that (i) theirweighted mean (and standard deviations for con-tinuous variables) baseline characteristics (age,gender, baseline ADHD-RS-IV, inattentive and hy-peractivity/impulsivity subscale scores, and ADHDsubtypes) and mean placebo group efficacy (changein ADHD-RS-IV total score from baseline) match-ed those reported for the ATX trial; (ii) weightswere a linear function of the baseline character-istics; and (iii) weights were required to be as‘close’ as possible to equal weighting across all pa-tients. This last condition was imposed by mini-mizing the Euclidian distance between the newweights and equal weighting. It also had the effectof preserving the largest effective sample size forthe re-weighted GXR data (i.e. it minimized thesum of the squared weights). This would avoidextreme outlying weights that would allow undueinfluence by a small number of data points. Theweights depended only on baseline characteristicsand not on the treatment to which patients wereassigned.

The purpose of the re-weighting was to bal-ance baseline characteristics and placebo effectbetween trial populations. Mean changes in theADHD-RS-IV total score from baseline to end-point were then compared between the balancedtrial populations. Statistical significance was as-sessed using the bootstrap method with 1000 itera-tions.[17] The comparisons were conducted betweeneach GXR dosing group and the ATX group.

Response Rate Estimation

Because the ATX trial included in the MAICdid not report response rate as an endpoint (anecessary model input for the cost-effectivenessanalysis [CEA]), a prediction model was devel-oped based on other published ATX trials in orderto translate the change in ADHD-RS-IV totalscore into response rate. This model was devel-oped using data from all treatment groups in theATX trials[8,18-22] that reported baseline ADHD-

RS-IV total score, change in ADHD-RS-IV totalscore and rate of treatment response defined as‡25% reduction in ADHD-RS-IV total score frombaseline to endpoint. Using data from these trials, ameta-regression analysis established the followingmodel to estimate treatment response rate based onchange in ADHD-RS-IV total score: predicted re-sponse rate= 0.52659 - 0.00979*(baseline ADHD-RS-IV total score) - 0.03206*(change in ADHD-RS-IV total score).

The model was further tested using IPD fromthe pooled GXR trials. The observed and pre-dicted response rates were compared for differentGXR dosing categories; the prediction errorswere generally small, ranging from 1.5% to 2.3%.The prediction model was then applied to esti-mate treatment response rate for the three GXRdosing groups and the ATX group based on theestimated mean change in ADHD-RS-IV totalscore from the MAIC.

Cost-Effectiveness Analysis

A Markov model was developed to assess thecost effectiveness of GXR compared with ATXfrom aUS third-party payer’s perspective (figure 1).Themodelled time horizon was 1 year, which con-sisted of a 4-week drug titration period[9,23] and a48-week maintenance period. The model includedthe following health states: response (to ADHDtreatment), no response, and treatment discontin-uation. The cycle length was 1 week for the entiremodel period. The time horizon and health statesused in the current study were consistent with priorpublished cost-effectiveness studies in ADHD.[11,24]

The target population in the model had the samecharacteristics as the trial population included inthe MAIC study. Only direct costs (drug costs anddirect medical costs) borne by a third-party payerwere considered in the model.

Model Assumptions

� At the end of the 4-week titration period, GXRpatients received the maximum weight-baseddosing allowed by their body weight and ATXpatients received 1.2mg/kg/day.

� At the end of each cycle during the 4-week titra-tion period in the model, patients transitionedfrom non-response to response at a constant rate.

384 Erder et al.


� At the end of the 4-week titration period, non-responders discontinued the treatment; re-sponders remained in the response state andreceived treatment until the end of the modelperiod or when they discontinued treatment.

� To account for treatment persistence, themodel assumed that all patients on treatmentdiscontinued at a constant treatment-specificrate, which was applied for all patients duringthe first 4 weeks and for responders during therest of the model period.

� All non-responders incurred incremental med-ical costs associated with non-response (i.e. thecost difference between non-responders andresponders).

� Patients who discontinued treatment had thesame utility andmedical costs as non-responders.

� Adverse events (AEs) reduced the patients’health utilities during the titration period.

Model Parameter Inputs

Transition Probabilities

Transition probability from non-response toresponse in each cycle during the titration periodwas estimated using the predicted response ratesfor GXR and ATX (table I). The estimation as-sumed that response rates were achieved at the

end of the titration period (4 weeks) and that thetransition occurred at a constant rate. The con-stant discontinuation rate was estimated for eachtreatment based on the 2-year rate observed intheir respective long-term open-label trials.[32,35,36]

Costs

Unit drug costs (cost/pill) were obtained usingthe wholesale acquisition cost (WAC) for GXRand ATX, respectively (table I).[33] GXR had auniformWAC for different dosing strengths. Theunit cost for ATX was estimated as a weightedaverage of WACs for all dosing forms, weightedby the market share of each dosing form.[37] Dailyaverage consumption (DACON) was measuredas the number of pills consumed per day, and aDACON of 1.00 was used for both drugs in thebase-case scenario. This number was conservativefor ATXbecause the FDA-approved ATXdosingregimens include once-daily and twice-daily ad-ministration.[5] The CEA assumed that pharmacycosts consisted of only the treatment drug (i.e.GXR or ATX) costs.

Incremental medical cost associated with non-response was obtained from a study by Guevaraet al.[34] This study was selected because it esti-mated direct costs incurred by children and ado-lescents with ADHD from a third-party payer

Children and adolescentswith ADHD

Guanfacine extended-release

M

Response

Non-response (on treatment)

Titration(4 weeks)

Discontinuation

Response

Non-response (off treatment)

Discontinuation

Maintenance(48 weeks)

Response

Non-response (off treatment)

DiscontinuationResponse

Non-response (on treatment)

Discontinuation

Atomoxetine

M

M

M

Fig. 1. Model structure. ADHD =attention-deficit/hyperactivity disorder.



Table I. Model inputs for base case

Parameter Input

value

95% Confidence

interval

Source

Patient characteristics

Weight distribution Biederman et al.,[9] 2008: 96.0 lbs (54.0–271.0 lbs) [N =345]Sallee et al.,[10] 2009: 44 (SD =16) kg (25–108 kg) [N = 322]Lower bound: as observed in the GXR trial: 25 kg

Upper bound: for ATX to achieve 1.2mg/kg with maximum

labelled dose of 100mg (100/1.2 = 83 kg)

25–44 kg (could receive

0.09–0.12mg/kg/day)44.95%


0.075–0.090mg/kg/day)23.88%


0.046–0.075mg/kg/day)31.17%

Titration period (weeks)

GXR and ATX 4 Biederman et al.,[9] 2008;

Titration period supported by findings in Newcorn et al.[23]

2009: week 4 response was the best predictor of ultimate

clinical response

Utility

Utility for responder 0.837 Coghill et al.,[25] 2004

Utility for non-responder 0.773

ADHD-RS-IV score change and response rate

Change in ADHD-RS-IV score from baseline

GXR 0.09–0.12mg/kg/day -20.6 -23.7, -17.5 Results from MAIC

GXR 0.075–0.09mg/kg/day -19.6 -23.9, -15.3

GXR 0.046–0.075mg/kg/day -17.3 -19.9, -14.7

ATX 1.2mg/kg/day -13.6 -16.6, -10.6

Response rate

GXR 0.09–0.12mg/kg/day 80.3% 70.4, 90.3 Derived based on the change in ADHD-RS-IV score from

baselineGXR 0.075–0.09mg/kg/day 77.1% 63.3, 90.3

GXR 0.046–0.075mg/kg/day 69.7% 61.4, 78.1

ATX 1.2mg/kg/day 57.9% 48.3, 67.5

AEs

Duration (week) 4 The mean and median durations of sedative TEAEs in the

4mg/day group were 22.4 and 23.0 days, respectively.

Biederman et al.,[9] 2008

Disutilities associated AEs

Somnolence 0.10 Siddique et al.,[26] 2005

Headache 0.10 Evans[27] 1997

Fatigue 0.12 Butler et al.,[28] 2006; Lloyd et al.,[29] 2006

Abdominal pain 0.01 Anderson and Moser,[30] 1985

Vomiting 0.09 Selai et al.,[31] 2002

Nausea 0.09 Selai et al.,[31] 2002

Decreased appetite 0.09 Assumed to be the same as nausea

AEs associated with GXR GXR package insert[6]

Somnolence 38%

Headache 24%

Fatigue 14%

Abdominal pain 10%

Continued next page

386 Erder et al.


perspective in the US. Only medical costs re-ported in the study were used to derive the modelinput. Specifically, the incremental medical costincurred by children and adolescents with ADHD,estimated as the difference in medical costs betweenthose with and without ADHD. This difference wasused as the input for incremental medical costsassociated with non-response compared with re-sponse. All costs were inflation-adjusted to 2011USdollars using the medical care component of theConsumer Price Index.[38]

Utilities

Utilities associated with response and non-response were obtained from a study by Coghillet al.,[25] which estimated utilities in a group ofpatients with ADHD in theUKusing EQ-5D.Dis-utility of AEs was also considered in the model.Each AE affecting >5% of patients receiving GXRor ATXwas obtained from the package inserts.[5,6]

Disutility associated with each AE was obtainedfrom the literature.[26-31] Disutility for each treat-ment group was estimated as an average of the

Table I. Contd

Parameter Input

value

95% Confidence

interval

Source

Vomiting 2%

Nausea 6%

Decreased appetite 5%

AEs associated with ATX ATX package insert[5]

Somnolence 11%

Headache 19%

Fatigue 8%

Abdominal pain 18%

Vomiting 11%

Nausea 10%

Decreased appetite 16%

Weighted average of disutilities

GXR AEs (weighted) -0.090 Weighted average of disutility of each AE using proportion

of patients with that AE as the weight

ATX AEs (weighted) -0.076

Weekly rate of treatment discontinuation during maintenance (assuming constant hazard)

GXR 1.65% Biederman et al.,[9] 2008; Sallee et al.,[10] 2009

Discontinuation rates at 2 years were used to estimate the

weekly discontinuation rate, assuming the ratewas constant

ATX 1.72% Spencer et al.,[32] 2005

Drug cost

GXR

DACON 1.00 GXR package insert[6]

Unit cost (cost per pill) $US5.39 Medi-Span�[33], 2011

ATX

DACON 1.00 ATX package insert[5]

Unit cost (cost per pill) $US5.68 Weighted average of cost per pill for each dosing form

(Medi-Span�,[33] 2011) using market share as the weight

(data on file, Shire Pharmaceuticals, Inc.[33])

Incremental medical cost among non-responders compared with responders

Weekly cost $US16.60 Guevara et al.,[34] 2001

ADHD-RS-IV = attention-deficit/hyperactivity disorder rating scale, fourth edition; AE(s) =adverse event(s); ATX = atomoxetine; DACON =daily average consumption; GXR =guanfacine extended-release; MAIC =matching-adjusted indirect comparison; TEAEs = treatment-

emergent adverse events.



disutilities of the individual AEs weighted by theAE rates reported for each treatment group.[5,6]

Model Outputs

Model outputs included incremental cost perquality-adjusted life year (QALY) and incrementalcost per responder at 1 year. The cost effectivenessof GXR versus ATX was evaluated based on theestablished willingness-to-pay (WTP) threshold of$US50 000/QALY, which has been viewed as agenerally acceptable WTP threshold in the US.[39]

Univariate Sensitivity Analysis

To evaluate the uncertainty of model assump-tions and inputs, a univariate sensitivity analysiswas performed. The ranges for the response rates ofGXR and ATX were varied based on the 95% con-fidence intervals (CIs) of change in ADHD-RS-IVtotal score from the MAIC. Additionally, the GXRresponse rate was also varied, assuming that allpatients were in the lowest (0.046–0.075mg/kg/day)and highest dose (0.09–0.12mg/kg/day) categories,respectively. The utility associated with responsewas varied by –25% of the difference in utility be-tween response and non-response states in the basecase. Disutilities associated with AEs andGXR andATX drug unit costs were all varied by –25% of thecorresponding base-case values. In addition, thereal-world DACONs of 1.08 for GXR and 1.27 forATX, obtained from a largeUS pharmacy databaseanalysis, were used in the sensitivity analysis insteadof the base case of 1.00 for both treatments.[40]

Lastly, treatment discontinuation rates were variedin the sensitivity analyses in the following ways:(i) no discontinuation except for non-responders atthe end of the titration period, (ii) applying the base-case discontinuation rate forGXR to both treatmentgroups, and (iii) applying the base-case discontinua-tion rate for ATX to both treatment groups.

Results

Matching-Adjusted Indirect Comparison andResponse Rate Estimation

Three trials were included in the MAIC: twoGXR trials for which IPD were available and oneATX trial with published summary data. Detailedinformation on the three trials is presented in

table II. Before matching, baseline characteristicswere different between the GXR and ATX pop-ulations (table III). After matching, means andstandard deviations of continuous variables andpercentages of categorical variables for the ob-served baseline characteristics as well as the pla-cebo group efficacy were matched exactly betweenthe GXR and ATX trials. Within balanced trialpopulations, GXR 0.09–0.12mg/kg/daywas asso-ciated with a significantly greater reduction inADHD symptoms as measured by the ADHD-RS-IV total score (-20.6; [95%CI -23.7, -17.5] vs-13.6 [95% CI -16.6, -10.6], p < 0.01), comparedwith the ATX target dose of 1.2mg/kg/day. GXR0.075–0.090mg/kg/day was also associated witha significantly greater reduction in the ADHD-RS-IV total score (-19.6 [95% CI -23.9, -15.3]vs -13.6 [95% CI -16.6, -10.6], p= 0.02) com-pared with the ATX target dose. Finally, GXR0.046–0.075mg/kg/day was associated with anon-significant reduction in the ADHD-RS-IVtotal score (-17.3 [95% CI -19.9, -14.7] vs -13.6[95% CI -16.6, -10.6], p = 0.07). The predictedresponse rates for GXR 0.09–0.12, 0.075–0.09and 0.046–0.075mg/kg/day were 80.3%, 77.1%and 69.7%, respectively; for ATX 1.2mg/kg/day,it was 57.9%.

Cost-Effectiveness Analysis

Base Case (1 Year)

In the base case, the total costs per patient in-curred over 1 year were estimated at $US1482($US1043 drug costs and $US439 medical costs)for GXR, and $US1408 ($US861 drug costs and$US547 medical costs) for ATX. GXR was asso-ciated with an incremental total cost of $US74per patient for 0.007 more QALYs and 86 moreresponders/1000 treated patients compared withATX, yielding incremental cost-effectiveness ra-tios (ICERs) of $US10 637 per QALY gained and$US853 per responder (table IV).

Univariate Sensitivity Analyses

Results of the univariate sensitivity analysisshowed that the model results were robust tovariations in model inputs (table V). The resultswere most sensitive to changes in the unit costs ofGXR and ATX. The worst-case scenario resulted

388 Erder et al.


Table

II.ComparisonofselectedGXRandATXtrials

Trial

GXR

ATX

Differencebetweentrials

Biederm

anetal.,[9

]2008

Salleeetal.,[10]

Michelsonetal.,[7

]2001

Keyinclusion

criteria

ADHDbasedontheDSM-IV

criteria


criteria


criteria

Atleast1.5

standard

deviations

abovetheageandgendernorm

s

fortotalA

DHD-R

S-IVscore

orits

subscale

ofinattentivescore

or

hyperactivity/im

pulsivityscore

GXRtrialsdid

notrequirecertain

baselineADHD-R

S-IVscore

level.

Suchdifferencewasaddressedby

selectingGXRpatients

basedon

thecriteriareportedin

theATXtrial

Age(years)

6–17

6–17

8–18

Inclusionof6–7yearoldsand

exclusionof18yearoldsin

the

GXRtrials.Suchdifferencemay

potentially

biasin

favourofGXR,

butmeanandSDofagewere

exactlymatched

Gender

(%female)

25.5

28.1

28.6

aThedifferencein

genderwassmall

andwasexactlymatchedin

MAIC

Dose

Randomizedto

fixeddoseof

2–4mg/day

Randomizedto

fixeddoseof

1–4mg/day

Randomizedto

aweight-based

doseof0.5,1.2

and1.8

mg/kg/day

GXRusedfixeddoseswhile

ATX

usedweight-baseddose.Weight-

baseddoseswere

compared

betweenGXRandATXin

MAIC

Followup

8weeks:5weeksofdose

escalation/m

aintenanceand

3weeksdownward

tapering

Patients’efficacywere

evaluated

weeklyin

thefirst5weeks

9weeks:3weeksofdose

escalation,3weeksofstable

dose

and3weeksofdosetapering

Patients’efficacywere

evaluated

weeklyin

thefirst6weeks

8weeksoftreatm

ent

Patients

were

evaluatedweeklyfor

thefirst4weeksandbiweekly

thereafter

ATXpatients

were

treatedlonger

withstable

dose(nodosetapering)

thanGXRpatients.Thedifference

maypotentially

biastheresultsin

favourofATX

Titration

Startingat1mg/w

eekandincrease

by1mg/w

eekuntiltherandomized

doseisreached

Startingat1mg/w

eekandincrease

by1mg/w

eekuntiltherandomized

doseisreached

Startingat0.5

mg/kg/dayforthe

firstweekandincreaseto

0.8

mg/kg/dayfor1weekandthen

1.2

mg/kg/day

Titratedonceaweekin

alltrials

Primary

outcome

measures

ADHD-R

S-IVtotalscore

ADHD-R

S-IVtotalscore

ADHD-R

S-IVtotalscore

Primary

efficacyoutcomewas

comparable

aPercentagepresentedforthetreatm

entgroupof1.2

mg/kg/day,whichwasincludedin

theMAIC.

ADHD=attention-deficit/hyperactivity-disorder;

ADHD-R

S-IV=ADHD

rating

scale,fourth

edition;ATX=atomoxetine;DSM-IV=Diagnostic

and

StatisticalManualofMental

Disorders,fourthedition;GXR=guanfacineextended-release;MAIC

=matching-adjustedindirectcomparison.



from increasing the unit cost of GXR to 125%of the base-case value, and yielded an ICER of$US48 340. When the ATX unit cost was at 75%of its base-case value, the ICER was $US41 776.GXR was dominant in three scenarios: (i) theDACON for GXR was 1.08 and for ATX was1.27 based on the real-world drug utilizationdata, (ii) ATX unit cost was at 125% of its base-case value, and (iii) GXR unit cost was at 75% ofits base-case value. GXR unit cost at 75% of thebase-case value was the best-case scenario withGXR associated with $US187 lower cost and0.007 more QALYs than ATX.

Discussion

Although head-to-head randomized clinical trialsare considered to be the gold standard in CER,[41]

such data are not always available because thesetrials are costly and time-consuming. Withouthead-to-head trials that directly compare two treat-ments, conventional CEA often relies on compara-tive effectiveness data from indirect comparisonswithout adjusting for baseline differences across

trials. Without a head-to-head direct comparison,this study applied the MAIC, a novel method inCER,[12] to compare the efficacy ofGXRandATX

Table III. Baseline characteristics before and after matching

Baseline characteristics GXR ATX

Low dose

(0.046–0.075mg/kg/day)[N =147]a

Mid dose

(0.075–0.09mg/kg/day)[N= 46]a

High dose

(0.09–0.12mg/kg/day)[N =82]a

As reportedb

(N =84)

Pre-match Post-match Pre-match Post-match Pre-match Post-match

Mean age, y (SD) 10.9 (2.5) 11.5 (2.4) 10.1 (2.0)* 11.5 (2.4) 9.0 (1.8)* 11.5 (2.4) 11.5 (2.4)

Female, % (SD) 26.5 (44.1) 28.6 (45.2) 19.6 (39.7) 28.6 (45.2) 24.4 (42.9) 28.6 (45.2) 28.6 (45.2)

ADHD subtype, % (SD)

Inattentive 26.5 (44.1) 27.4 (44.6) 23.9 (42.7) 27.4 (44.6) 18.3 (38.7) 27.4 (44.6) 27.4 (44.6)

Hyperactive-impulsive 3.4 (18.1) 1.2 (10.8) 2.2 (14.6) 1.2 (10.8) 2.4 (15.4) 1.2 (10.8) 1.2 (10.8)

Combined 70.1 (45.8) 71.4 (45.2) 73.9 (43.9) 71.4 (45.2) 79.3 (40.5) 71.4 (45.2) 71.4 (45.2)

Baseline outcomes, mean (SD)

ADHD-RS-IV total score 38.9 (8.7) 39.2 (9.2) 39.5 (8.6) 39.2 (9.2) 40.1 (7.7) 39.2 (9.2) 39.2 (9.2)

Inattention subscale score 22.1 (4.0)* 16.9 (4.0) 21.7 (4.4)* 16.9 (4.0) 21.9 (3.8)* 16.9 (4.0) 16.9 (4.0)

Hyperactivity/impulsivity

subscale score

16.8 (6.7)* 22.2 (7.1) 17.8 (6.1)* 22.2 (7.1) 18.2 (5.7)* 22.2 (7.1) 22.2 (7.1)

a The effective sample sizes of GXR dosing groups after matching were 49, 16 and 38 in 0.046–0.075mg/kg/day, 0.075–0.090mg/kg/dayand 0.09–0.12mg/kg/day, respectively.

b The GXR group was matched with the ATX group; therefore the baseline characteristics of the ATX group remained the same before and

after matching.

ADHD =attention-deficit/hyperactivity disorder; ADHD-RS-IV=ADHD rating scale, fourth edition; ATX =atomoxetine; GXR = guanfacineextended-release; SD = standard deviation. * p< 0.05.

Table IV. Results for base case

GXR ATX Incremental

(GXR – ATX)

Effectiveness

QALY 0.798 0.791 0.007

Number of responders

(per 1000 patients)a326 240 86

Costs ($US)

Drug 1043 861 182

Medical 439 547 -108

Total 1482 1408 74

ICER of GXR vs ATX

$US10 637/QALY

$US853/respondera Responders are defined as patients with ‡25% reduction in

ADHD-RS-IV total score from baseline to endpoint.

ADHD-RS-IV= attention-deficit/hyperactivity disorder rating scale,

fourth edition; ATX =atomoxetine; GXR =guanfacine extended-

release; ICER= incremental cost-effectiveness ratio; QALY= quality-adjusted life-years.

390 Erder et al.


for the treatment of ADHD. This method utilizesIPD from trials of one treatment to match thepublished summary baseline characteristics fortrials of the other treatment. After matching thebaseline characteristics, the efficacy outcomes arecompared between balanced trial populations.

There are several advantages of the MAICmethod. First of all, this method fills a gap in CERmethodology by providing timely comparativeevidence for treatments with any number of trials(especially practical for new treatments, whichoften only have one pivotal trial). In addition, this

Table V. Results of univariate sensitivity analysis for GXR versus ATX

Parameter Lower bounda Upper bound

D Cost [$US] D QALY ICER (D Cost/D QALY) [$US]

D Cost

[$US]

D QALY ICER (D Cost/D QALY) [$US]

Patients

GXR weight-based dosing distribution

(Lower: 100% in 0.046–0.075mg/kg/day; Upper:100% in 0.09–0.12mg/kg/day)

35 0.0042 8249 97.78 0.0086 11 352

Utility

Utility associated with response

(–25% of difference in utility between response and

non-response)

74 0.0049 14 970 74 0.0089 8249

Response rateb

GXR (based on 95% CIs of change in ADHD-RS-IV

total score)

11 0.0026 4340 134 0.0113 11 873

ATX (based on 95% CIs of change in

ADHD-RS-IV total score)

138 0.0108 12 712 10 0.0030 3362

Disutility

AE disutility (–25% of the base-case values) 74 0.0072 10 233 74 0.0066 11 074

Rate of treatment discontinuation during maintenance

No discontinuation 113 0.0104 10 799

Applying the rate in the ATX long-term trial to

GXR group

65 0.0064 10 129

Applying the rate in the GXR long-term trials to

ATX group

67 0.0066 10 159

Drug cost

GXR unit price -187 0.0069 GXR dominant 334 0.0069 48 340

ATX average unit price 289 0.0069 41 776 -142 0.0069 GXR dominant

DACON from real world analysis (1.08 for GXR and

1.27 for ATX)

-76 0.0069 GXR dominant

Incremental medical cost in non-responders compared to responders

Weekly cost (–25%) 101 0.0069 14 541 47 0.0069 6733

No medical cost difference between responders and

non-responders

182 0.0069 26 254

a Sensitivity analyses for the three scenarios under ‘rate of treatment discontinuation’ and the scenario of ‘DACON’ were tests for alternative

scenarios; therefore, the lower and upper bounds did not apply.

b The upper limit of 95%CI corresponded to smaller reduction in the ADHD-RS-IV total score and thus represented lower bound of efficacy in

the table; the lower limit of 95% CI represented the upper bound of the efficacy in the table. A higher GXR response rate lead to a higher

ICER because more patients would be responders at the end of the titration period and thus stay on treatment; this would increase GXR

drug costs. For the same reason, a lower ATX response rate lead to a higher ICER because more patients discontinued ATX at the end of

titration period, which lowered ATX drug costs.

ADHD-RS-IV = attention-deficit/hyperactivity disorder rating scale, fourth edition; AE =adverse event; ATX = atomoxetine; CI = confidenceintervals; DACON= daily average consumption; GXR= guanfacine extended-release; ICER= incremental cost-effectiveness ratio; QALY=quality-adjusted life-years.



method allows for more extensive cross-trial ad-justment (by matching baseline characteristicsusing individual patient level data) compared withindirect comparison based only on aggregate data.

A recent publication by Signorovitch et al.[15]

also utilized the MAIC method to compare ATXand GXR in patients with ADHD and concomi-tant oppositional defiant disorder. The MAICmatching in that study was based on age, gender,height and weight and baseline ADHD-RS-IVtotal and subtype scores. Unfortunately, informa-tion on weight and height is not available in thepublished ATX trial[7] for our analysis. Thereforethe MAIC employed in this study could not matchon height and weight.

Another important difference is that the MAICmethod in the current study was adjusted forplacebo outcome during the matching whileSignorovitch et al.[15] did not adjust for placebo.When a small number of baseline characteristicsis available for matching, additional criteria, suchas balancing placebo outcomes, can help adjustfor differences between trial populations. Thisstudy incorporated the placebo arm data to im-prove the adjustment for potential unobservedcross-trial differences. That adjustment was un-necessary in Signorovitch et al.,[15] as the placebogroups were balanced between groups after theMAIC match was completed.

Lastly, other benefits of the MAIC approachinclude the fact that IPD have been a largely un-tapped resource for CER, due to prior lack ofappropriate methodology. MAIC requires IPDfrom trials of one treatment and not from theother(s) in the comparison; such IPD data are fre-quently available. Using these data, MAIC couldsubstantially increase the availability of reliablecomparative evidence for clinically and econom-ically relevant treatments.

After estimating the CER between the twodrugs, we assessed the cost effectiveness of GXRversus ATX using the comparative efficacy re-sults from MAIC. The base-case results showedthat GXR was cost effective compared with ATXat the end of the 1-year period with an ICER of$US10 637 per QALY gained. Despite the lowerWAC, GXR had an incremental drug cost of$US182 over ATX because more GXR patients

achieved response at the end of the titration periodand continued treatment. However, this incre-mental drug cost was partially offset by an averagemedical cost saving of $US108 among GXRpatients. Based on a WTP threshold of $US50000/QALY, which has been viewed as a generally ac-ceptableWTP threshold in the US,[39] GXR shouldbe considered cost effective compared with ATX inthis analysis.

Results of the univariate sensitivity analysissupported the robustness of the model as all sce-narios analysed in the current study yielded ICERsof less than $US50 000/QALY comparing GXRwith ATX. The scenario with the highest ICER($US48 340 per QALY) was when the unit costof GXR was 25% more than its base-case value.These results further support that GXR is costeffective compared with ATX for the treatment ofchildren and adolescents with ADHD.

In the current study, the results of the MAICwere applied as model inputs in the CEA model.To our knowledge, this is the first applicationof the MAIC to cost-effectiveness modelling. TheMAIC provides a more reliable comparison ofefficacy by adjusting for the differences in theobserved baseline characteristics, which results ina more reliable economic evaluation between thetwo treatments.

This is also the first CEA study comparing twonon-stimulants that are approved for once-dailydosing for the treatment of ADHD in the US. Inthe past decade, CEA has been increasingly usedto compare the values of different treatments inthe context of both clinical efficacy and economicvalues. The findings from this study could beinformative to payers as well as clinicians for as-sessing non-stimulant treatment options and se-lecting an effective and cost-effective option forchildren and adolescents with ADHD. Futureresearch should evaluate the findings from thisstudy by comparing them to the ones based onthe traditional direct and indirect comparisons.

Limitations

This study is subject to several limitations.First, as in any comparison of non-randomizedtreatment groups, MAIC assumes that there are

392 Erder et al.


no unobserved confounding factors between trials.Unobserved confounding may bias the results,which can only be addressed in a head-to-headrandomized trial.

In addition, the age range included in GXRand ATX trials was different, with a younger agegroup (6–7 years) present in the GXR trials butnot the ATX trial. Although this could lead topotential bias, we do not expect that this differ-ence would have substantial impact on the resultsfrom this analysis because we matched exactly onthe mean and standard deviation of age and com-pared weight-based doses instead of fixed doses.

Another limitation, inherent in clinical trials,is the issue of generalizability. Because the MAICwas based on a few selected trials, the results maynot be generalizable to the entire ADHD pop-ulation. However, it does not affect the internalvalidity of the study.

Also, as in any CEA, the study had to makesome assumptions when deriving the model in-puts and had to populate the model with inputsfrom the existing literature that may not applyto this study population. For example, withoutdata on real-world discontinuation rates, we de-rived a weekly discontinuation rate in this 1-yearmodel based on the 2-year observed discontinua-tion rate reported in the long-term GXR andATX trials,[32,35,36] assuming a constant hazardof discontinuation. This assumption may under-estimate the discontinuation rate if patients onboth treatments are equally more likely to discon-tinue at the beginning of the treatment. However,alternative assumptions were tested in the sensi-tivity analyses, including no discontinuation andapplication of identical discontinuation rates toboth groups (in the base case, ATX had a higherdiscontinuation rate). In each case, the results wereconsistent with the base-case scenario (ranging from$US10 129 to $US10 799 per QALY comparedwith the base case of $US10 637), suggesting thatthe results are not sensitive to the discontinuationrate assumption.

Similarly, one could argue that the calculation ofdrug costs should be based on patients’ body weightinstead of market share. Unfortunately, weight wasnot reported in the ATX[7] trial, thus weight couldnot be used to estimate the dose needed for ATX.

Since this may have affected ATX costs, sensitivityanalysis accounted for this by varying the ATXunit price and daily average consumption. Theweight has less impact on GXR costs because GXRhas a uniform price for all dosing forms. Resultsfrom other univariate sensitivity analyses alsoshowed that the base-case results were robust. Therobustness of the results could be further assessedusing probabilistic sensitivity analyses.

Furthermore, the study did not consider thefollowing issues due to lack of data: (i) the sub-sequent treatments for non-responders and (ii) costeffectiveness in separate subgroups (e.g. patientswho fail or are intolerant of stimulants). Themodelcould be further improved when more data areavailable.

Finally, the study was conducted from a USthird-party perspective and therefore did not in-clude indirect costs, which are a major compo-nent of ADHD costs.[2] Future studies, adoptinga social perspective, should include indirect costsin the model to comprehensively assess the eco-nomic value of ADHD treatments.

Conclusions

This study is the first to compare the cost ef-fectiveness of GXR versus ATX in the treatmentof ADHD. To our knowledge, this is also the firstapplication of the novel comparative effectivenessmethod of MAIC to CEA. The MAIC resultsindicate that, in the trial population, GXRwithinthe dosing range of 0.075–0.12mg/kg/day was moreefficacious than ATX 1.2mg/kg/day, the highesteffective dose of ATX approved by the US FDA.The CEA results indicate that compared withATX, GXR was cost effective in the treatment ofADHD in children and adolescents at the WTPthreshold of $US50 000 per QALY gained. TheCEA results were robust as all univariate sensi-tivity analyses in this study yielded ICERs thatwere less than $US50 000/QALY. The findingscould inform treatment decisions for patients withADHD. The MAIC method used in the studyenhances the armamentarium of available meth-ods for CER and could become a useful approachfor timely economic evaluations in the future.



Acknowledgements

This research and writing support was funded by ShireDevelopment LLC. Shire develops and markets drugs to treatvarious conditions, including ADHD, and is a manufacturerof guanfacine extended release in the US. M. Haim Erder,Paul Hodgkins, and Vanja Sikirica are employees of ShireDevelopment LLC and own stock/options in Shire Develop-ment LLC. Jipan Xie, James E. Signorovitch,Mei Lu and EricQ. Wu are employees of Analysis Group, Inc., which wascontracted and funded by Shire Development LLC to partneron this research. Kristina S. Chen was an employee of Anal-ysis Group, Inc. when the manuscript was developed. Theauthors independently conducted all analyses and developedthe manuscript. MHE, JX, EQW, and VS participated in thestudy design of the matching-adjusted indirect comparison(MAIC) and the cost-effectiveness analysis (CEA); JES andML participated in the study design, conducted the analysesof theMAIC and interpreted the results; MHE, JX, KSC, PH,EQW and VS participated in different phases of model de-velopment; all authors participated in the manuscript devel-opment and revision. VS will act as the guarantor of thecontent. The contents of this manuscript, the ultimate inter-pretation and the final decision to submit it for publication inApplied Health Economics and Health Policy were madejointly by the authors.

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Correspondence: Vanja Sikirica, PharmD, MPH, ShireDevelopment LLC, 725 Chesterbrook Boulevard, Wayne,PA 19087, USA.E-mail: [email protected]



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