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The economic analysis of the NICE TA on the use of methylphenidate, atomoxetine
and dexamfetamine for children and adolescents with ADHD (NICE, 2006b) incor-
porated a sub-analysis assessing the cost effectiveness of combination strategies rela-
tive to strategies involving only sequences of medications (King et al., 2006). Details
on the methodology adopted in the study analysis are provided in Chapter 10. The
sub-analysis including combination therapies assessed 37 strategies in total: 18 strate-
gies consisting of all possible three-line sequences of the medications reviewed, 18
respective strategies of three-line sequences of combined treatment, and a strategy of
no treatment. After excluding all strategies ruled out by dominance, two options
remained: a combination strategy consisting of behavioural therapy plus first-line
dexamfetamine, second-line atomoxetine and third-line MR methylphenidate admin-
istered every 8 hours, and a medication strategy consisting of first-line dexamfeta-
mine, second-line IR methylphenidate and third-line atomoxetine. The ICER of the
first versus the second strategy was £1,241,570/QALY; consequently, the authors
concluded that combination strategies were not cost effective from the perspective of
the NHS. However, the available clinical data for this analysis were very limited
(based on a single trial comparing IR methylphenidate alone versus in combination
with behavioural therapy) and no firm conclusions could be drawn.
Overall, the existing evidence reported in Zupancic and colleagues (1998) and
King and colleagues (2006) suggests that combination and psychological therapies
may not be cost-effective treatment options compared with medication for children
with ADHD. However, there were considerable limitations in the clinical-effectiveness
data used in the economic analyses, as described above. The study by Lord and Paisley
(2000) used resource use estimates representing UK routine clinical practice, and clini-
cal data from the MTA study, which evaluated intensive interventions in the US.
Considering also that the primary measure of outcome in the analysis was the SMD of
SNAP-IV scores rather than a dichotomous outcome, it is evident that no safe conclu-
sions can be made by this analysis either.
11.5.2 Economic modelling
Objective
The choice of treatment strategy among various types of interventions available to
children with ADHD was identified by the GDG and the health economist as an area
with potential major resource implications. The existing economic evidence in this
field was limited and was characterised by considerable uncertainty; therefore a
decision-analytic model was developed for this guideline to examine the relative
cost effectiveness of pharmacological, psychological and combination therapies for
children with ADHD.
Treatment strategies examined
The treatment strategies examined were medication versus behavioural therapy
versus combined therapy (that is, behavioural therapy provided concurrently with
medication). Medication was represented by use of methylphenidate in the economic
Combining and comparing psychological and pharmacological interventions
339
model, for three reasons: methylphenidate was the only drug examined in the clinical
trials comparing pharmacological with psychological and/or combined therapies that
were included in the guideline systematic literature review; it is the most commonly
used medication in clinical practice; finally, indirect clinical evidence suggests that it
is likely the most effective drug in improving core symptoms in children with ADHD.
Nevertheless, recommendations based on the results of the economic analysis refer to
medication as a treatment option, and are not intended to be specific to the use of
methylphenidate.
Medication was defined as use of IR methylphenidate at an average daily dose of
25 mg for 4 weeks (titration period), followed by use of MR methylphenidate at an
average daily dose of 36mg. Children taking medication had regular contacts with
healthcare professionals (psychiatrists or paediatricians and nurse specialists), with
higher intensity during the titration period. Behavioural therapy was defined as ten 1-
hour meetings of clinical psychologists with groups of ten parents of children with
ADHD. In addition, clinical psychologists provided telephone support to parents
when needed, and had two meetings with children’s teachers at school lasting 30
minutes each, in order to provide advice. Combined treatment consisted of both
medication and behavioural therapy.
Methods
Model structure An economic model in the form of a decision tree was developed to
estimate total costs and benefits associated with provision of medication, behavioural
therapy and combined treatment to children with ADHD. According to the model struc-
ture, hypothetical cohorts of children with ADHD were started on one of the three treat-
ment options under assessment. If children receiving behavioural therapy or medication
did not respond to treatment following completion of 8 weeks of therapy (in accordance
with the duration of clinical trials that provided efficacy data), they were switched to
medication or behavioural therapy, respectively, or to combined treatment. However,
children not responding to combined therapy after 8 weeks were not then offered
medication or behavioural therapy alone, as it was assumed that none of the ‘monother-
apy’ interventions would be effective following unsuccessful combination therapy. It
must be noted that the model assumed that non-response to a treatment option did not
affect effectiveness (that is, response rates) of subsequent treatments; this means that
response rates of any treatment option a child might have received were independent
from each other. Children on medication or combined intervention who stopped treat-
ment because of intolerable side effects were switched to behavioural therapy. Children
who switched to combined treatment because of non-responsiveness after 8 weeks of
medication were assumed not to experience intolerable side effects from combined
treatment, given that they had not experienced intolerable side effects from medication
alone. Children completing medication or combination therapy could also experience
(tolerable) side effects that did not affect continuation of therapy. Children not respond-
ing after two lines of treatment (or one, if they completed 8 weeks of combined treat-
ment and did not respond to it), were assumed to receive ‘other treatment’. This
consisted of further management of children with ADHD, including contacts with
healthcare professionals, unlicensed medications, inpatient care or no treatment.
Combining and comparing psychological and pharmacological interventions
340
Combining and comparing psychological and pharmacological interventions
341
The time horizon of the analysis was 1 year. Children responding to any of the
treatment options assessed were assumed to continue successful treatment beyond 8
weeks (with 100% compliance) and remain responsive (that is, retain improved symp-
toms) until the end of the analysis. Children non-responsive to treatment who moved
to ‘other treatment’ remained on it until the end of the analysis. It is acknowledged
that the time horizon of 1 year is rather limited and does not allow estimation of the
overall, long-term costs and benefits associated with treatment of children with
ADHD; however, there is no sufficient evidence to allow modelling for longer peri-
ods of time, as long-term harms and benefits of the examined interventions have not
been adequately explored. A schematic diagram of the decision tree is provided in
Figure 5.
Continue
Response
Continue
No response
Other
treatment
BT
Response
Cont inue
No response
Other
treatment
Combination
No response
Complete
Response
Continue
No response
Other treatment
BT
Stop
due to SE
Medication
Response
Continue
Response
Continue
No response
Complete
Stop
due to SE
Other treatment
Medication
Response
Continue
No response
Other
treatment
Complete
Stop
due to SE
Other treatment
Combination
No response
BT
Response
Continue
No response
Other treatment
Complete
Response
Continue
No response
Other treatment
BT
Stop
due to SE
Combination
Children
with ADHD
Response
Other treatment
Figure 5: Schematic diagram of the structure of the economic model
SE side effects; BT behavioural therapy
Costs and health benefit measures included in the analysis The analysis adopted the
perspective of the NHS. Health service costs consisted of intervention costs, costs
of monitoring children who responded to treatment and therefore remained in
receipt of any of the treatments assessed for the whole time horizon of the analysis,
as well as costs of ‘other treatment’ for children not responding to the treatment
options assessed.
Costs of treating side effects were not separately considered in the analysis
because the majority of side effects from medication (anorexia, nausea, insomnia,
headache, increased irritability, and so on) are routinely managed by healthcare
Combining and comparing psychological and pharmacological interventions
342
professionals responsible for the monitoring of children receiving medication and
were estimated not to incur extra costs.
Costs of personal social services and education services were not included in the
analysis owing to lack of relevant data, but it is unlikely that these differ significantly
across children receiving different types of treatment over the period of 1 year. Other
societal costs, such as social benefit payments and productivity losses of carers of
children with ADHD were not considered as they were beyond the scope of this
analysis. Benefits were expressed in the form of QALYs. Results are reported as
ICERs.
Effectiveness data and other clinical input parameters As already discussed in the
economic sections of Chapter 7, for the economic analyses undertaken in this guide-
line, it was decided to utilise data only from studies reporting outcomes as response
rates, with response defined in a way that the GDG found both clinically meaningful
and significant.
The guideline systematic review identified four studies that examined pharmaco-
logical versus psychological and/or combination therapies for children with ADHD and
reported outcomes as response rates (ABIKOFF2004B; GITTELMAN-KLEIN1976B;
KLEIN1997B; MTA1999B). GITTELMAN-KLEIN1976B and KLEIN1997B
compared methylphenidate with behavioural therapy and combined treatment.
ABIKOFF2004A compared methylphenidate with a combination of methylphenidate
and a multimodal psychosocial treatment that included parent training and counselling,
social skills training, psychotherapy and academic assistance. MTA1999B compared
intensive medication management with intensive behavioural therapy and a combina-
tion of the two. The definitions of the term ‘response’ established by the studies were
considered appropriate by the GDG. For the base-case analysis, it was decided to utilise
data from GITTELMAN-KLEIN1976B and KLEIN1997B, as the studies examined
the interventions of interest in this economic analysis; data from ABIKOFF2004A were
considered in a sensitivity analysis; data from MTA1999B were examined separately,
as the study involved interventions of high intensity.
The study population in GITTELMAN-KLEIN1976B and KLEIN1997B
consisted of school-age children with pervasive symptoms of ADHD and parent
reports for hyperactivity or behavioural problems at home. Both studies defined
response as a final score of 1 to 3 on the CGI-I scale (that is, completely well, much
improved, or improved). More details on the study characteristics can be found in
Appendix 17.
Analysis of efficacy data from the above trials was based on intention-to-treat
(that is, response rates were calculated taking into account the number of all children
participating in each arm at the start of the trials and not completers only); other
important input parameters for the economic model, such as rates of children drop-
ping out of treatment because of intolerable side effects as well as rates of side effects
in each treatment arm were not reported in these studies. For this reason, the propor-
tions of children who stopped medication or combined treatment because of intoler-
able side effects were derived from the guideline meta-analysis of studies comparing
methylphenidate with placebo, including comorbid and non-comorbid populations of
children with ADHD. The attributable risk of stopping methylphenidate because of
intolerable side effects was calculated by subtracting the overall rate of stopping
placebo because of side effects from the respective rate for methylphenidate. This
attributable risk estimate was applied to children who received medication or
combined treatment in the analysis, while children receiving behavioural therapy
were assumed not to experience intolerable side effects that would lead to discon-
tinuation of treatment.
Rates of side effects for children under medication or combined therapy were based
on the same dataset of studies (that is, placebo-controlled studies of methylphenidate
in children with ADHD including comorbid and non-comorbid populations) and were
estimated in a similar way. However, the existing studies did not report an overall
side-effect rate, but rather provided rates of specific side effects; it was not possible
to estimate an overall side-effect rate from these data as some children might have
experienced more than one side effect. In order to overcome this problem, it was
decided to proxy the overall rate of side effects for methylphenidate using data on the
rate of appetite loss; this was selected because it is a common, statistically significant
side effect of methylphenidate and also it is deemed to substantially reduce the
quality of life of children with ADHD. The attributable risk of side effects for
methylphenidate was therefore calculated as the difference between rate of appetite
loss for methylphenidate and rate of appetite loss for placebo; this estimate was
subsequently applied to children receiving medication or combined treatment; it was
assumed that, for the proportion of children experiencing side effects, these persisted
for the entirety of the time period when medication or combined treatment was
provided. Children receiving behavioural therapy or ‘other treatment’ did not experi-
ence side effects from treatment.
Discontinuation of treatment for reasons other than intolerable side effects was not
considered in the analysis owing to lack of data appropriate to inform the economic
model: GITTELMAN-KLEIN1976B and KLEIN1997B reported very small discon-
tinuation rates that were insignificant; moreover, it was not clearly reported from
which arms of the trials children dropped out. The only other available data came from
MTA1999B, which referred to intensive interventions, and therefore respective data
did not reflect discontinuation of treatment options assessed in this analysis. In addi-
tion, such data could only be applied to first-line treatment, as children completing
treatment without response, as well as their parents, were thought to demonstrate
different attitudes towards second-line treatment, which would not be reflected in
discontinuation rates characterising initiation of treatment.
The proportions of children moving to combined treatment following failure of
medication or behavioural therapy was based on a trial comparing medication with
behavioural therapy in which proportions of children not fully responding to the
interventions assessed were subsequently switched to combined treatment (Döpfner
et al., 2004).
Estimation of response rate of ‘other treatment’ was based on a published meta-
analysis of follow-up studies on children with ADHD; the study reported the annual
probability of continuation of residual ADHD symptoms in the population of people
with ADHD (Faraone et al., 2006), which was interpreted for the purposes of this
Combining and comparing psychological and pharmacological interventions
343
Combining and comparing psychological and pharmacological interventions
344
analysis as no response. From this annual rate, it was possible to estimate the response
rates of children that remained under ‘other treatment’ for varying time periods.
Effectiveness data and other clinical input parameters utilised in the base-case
economic analysis are presented in Table 37.
Input parameter Baseline Source/comments
value
Response rates
Medication 0.733 Meta-analysis of GITTELMAN-
KLEIN1976b and KLEIN1997b;
intention-to-treat analysis
Behavioural therapy 0.474
Combined treatment 0.976
Other treatment 0.040 Faraone et al., 2006; annual rate of
elimination of residual ADHD symp-
toms to the population of individuals
with ADHD
Stopping treatment because Guideline meta-analysis of
of intolerable side effects placebo-controlled trials of
Medication and 0.003 methylphenidate (including comorbid
combined treatment and non-comorbid populations of
children with ADHD). Attributable
risk (methylphenidate rate minus
placebo rate)
Side-effect rate Guideline meta-analysis of
Medication and 0.093 placebo-controlled trials of
combined treatment methylphenidate (including comorbid
and non-comorbid populations of
children with ADHD). Attributable
risk of appetite loss (methylphenidate
rate minus placebo rate)
Proportion of children
moving to combined
therapy following
unsuccessful treatment
Medication 0.884 Döpfner et al., 2004
Behavioural therapy 1.000
Table 37: Response rates and other clinical input parameters utilised in
the base-case economic analysis of pharmacological versus psychological
versus combined interventions for children with ADHD
Utility data and estimation of QALYs As already discussed in the economic section
of Chapter 7, two sets of utility scores were used for the economic analyses under-
taken in this guideline involving children with ADHD: base-case analyses utilised the
scores reported by Coghill and colleagues (2004), generated from EQ-5D; utility
scores provided by Secnik and colleagues (2005b), produced by SG technique using
vignettes of health states of children with ADHD in the UK, were used in a sensiti-
vity analysis.
One limitation of using Coghill and colleagues’ (2004) utility scores in the current
analysis was that they did not take into account any decrement in quality of life result-
ing from the presence of side effects. Nevertheless, this was an important parameter
to consider in this analysis, since children under medication or combined therapy
could experience side effects and a subsequent reduction in HRQoL, in contrast with
children under behavioural therapy, who did not experience side effects. For this
reason, a decrement in utility resulting from the presence of side effects was esti-
mated from Secnik and colleagues (2005b) and was applied to the base-case utility
scores to create additional scores for responders and non-responders experiencing
side effects. Regarding the sensitivity analysis that tested the data from Secnik and
colleagues (2005b), it was assumed that utility scores reflecting no medication/
untreated ADHD expressed utility of children receiving behavioural therapy.
Utility scores used in the economic analysis of pharmacological versus psycho-
logical versus combined treatment for children with ADHD are provided in Table 38.
It was assumed that HRQoL in children initially responding to treatment
improved linearly over 8 weeks starting from the utility score of non-responders and
reaching the utility score for responders (8 weeks was the duration of interventions in
the clinical trials considered in the economic analysis), and that it remained at this
value for the rest of the time of the analysis. Decrement in quality of life owing to the
presence of side effects was modelled from initiation of respective treatment. Once
side effects occurred, they were assumed to remain over the whole period over which
medication or combined therapy was provided. Children who stopped treatment
because of intolerable side effects faced a decrement in quality of life for 2 weeks,
after which the intolerable therapy was discontinued.
Resource utilisation and cost data
Owing to lack of patient-level cost data, deterministic costing of all treatment options
assessed was undertaken. Relevant healthcare resource use was estimated and subse-
quently combined with unit prices to provide total costs associated with medication,
behavioural therapy and combined treatment. Resource utilisation estimates reflected,
as closely as possible, resource use described in the clinical studies utilised in the
economic analysis (GITTELMAN-KLEIN1976B; KLEIN1997B). Where relevant
information on resource use was lacking (for example, resource use beyond the
duration of the trials) or was clearly unrepresentative of British routine practice, then
estimates were produced/modified based on the expert opinion of the GDG.
For children receiving medication, the GDG estimated the average optimal daily
dose of methylphenidate during titration and post-titration, which was, overall,
consistent with doses reported in the clinical studies that provided efficacy data.
Combining and comparing psychological and pharmacological interventions
345
Combining and comparing psychological and pharmacological interventions
346
Titration was estimated to last 4 weeks, over which time children received IR
methylphenidate. MR methylphenidate was administered post-titration, according to
routine clinical practice in the UK. Children were attended by a psychiatrist or a
paediatrician during titration. Those responding to medication were assumed to
continue receiving methylphenidate until the end of the analysis, being monitored by
a psychiatrist, paediatrician or a nurse at regular intervals. Children stopping medica-
tion because of intolerable side effects were assumed to receive methylphenidate for
2 weeks before discontinuing and to spend half of the total estimated time (during
titration) with a psychiatrist or paediatrician.
Health state Utility Source – comments
score
Base-case analysis
Responder – no side effects 0.837 Coghill et al., 2004; scores based
Responder – side effects 0.817 on EQ-5D; questionnaires
Non-responder – no side effects 0.773 completed by parents of children
Non-responder – side effects 0.753 with ADHD in the UK;
decrement in HRQoL owing to
presence of side effects estimated
based on Secnik et al., 2005b.
Sensitivity analysis
No medication – responder 0.95 Secnik et al., 2005b; scores
No medication – non-responder 0.90 generated using SG technique,
IR stimulant – responder – 0.91 asking parents of children with
no side effects ADHD in the UK to value ADHD
IR stimulant – responder – 0.90 health states described in side
effects vignettes.
IR stimulant – non-responder – 0.89
no side effects
IR stimulant – non-responder – 0.88
side effects
MR stimulant – responder – 0.93
no side effects
MR stimulant – responder – 0.91
side effects
MR stimulant – non-responder – 0.90
no side effects
MR stimulant – non-responder – 0.88
side effects
Table 38: Utility scores included in the economic model of pharmacological
versus psychological versus combined interventions for children with ADHD
Behavioural therapy in GITTELMAN-KLEIN1976B and KLEIN1997B was
provided to parents of children with ADHD on a one-to-one basis. However, existing
evidence indicated that clinical effectiveness of psychological interventions for chil-
dren with ADHD did not depend on the mode of delivery and was similar in individ-
ual and group-based therapies. Given that the intervention costs of group-based
therapies are spread to a number of families, group-based behavioural therapy domi-
nates individually delivered therapy because it produces the same clinical outcome at
a lower cost. For this reason, group-based behavioural therapy has been modelled in
the base-case analysis; the cost effectiveness of individual behavioural therapy versus
medication and combination therapy, indicated under special circumstances, has been
explored in a sensitivity analysis.
According to average resource use described in clinical trials of psychological
interventions for children and confirmed by GDG expert opinion, behavioural
therapy was modelled as ten meetings (lasting 1 hour each) of clinical psychologists
with groups of parents of children with ADHD. Every group comprised 10 families.
Clinical psychologists were assumed to spend an extra hour for training and prepara-
tion. In addition, based on resource use data reported in GITTELMAN-KLEIN1976B
and KLEIN1997B, these sessions were augmented by an average of 1 hour of tele-
phone contacts with each family. Clinical psychologists also visited the teachers of
the children at school and provided advice; two visits of 30 minutes each were
assumed. Following completion of the intervention, parents of children responding to
behavioural therapy attended three individual booster sessions with psychologists
lasting 30 minutes each, in order to maintain children’s response for the remaining
time of the analysis.
Resource use in combined treatment was the sum of resource use of medication
and behavioural therapy, given that the two interventions are led by different types of
healthcare professionals and no overlap in services provided occurs.
Regarding costs of ‘other treatment’, no data on average annual costs associated
with management of children with ADHD in the UK are available. King and
colleagues (2006) gave an overall estimate of £14 million spent on follow-up care of
children with ADHD by health, social and education services in England and Wales
(initial specialist assessment was excluded from these costs). Using this estimate, a
prevalence of ADHD equalling 3.62% in boys and 0.85% in girls (Ford et al., 2003),
and the population of boys and girls aged 5–18 in 2006 in England and Wales (Office
for National Statistics, 2007), it was estimated that a child with diagnosed ADHD
incurred on average a cost of £67 annually. This estimate may seem low, but it is
likely to reflect the fact that some children with ADHD may not receive any treatment
for this condition.
Unit prices were taken from the BNF 55 (Joint Formulary Committee, 2008), and
the Unit Costs for Health and Social Care 2006 (Curtis & Netten, 2006); 2006 prices
were used. The reported unit costs for clinical psychologists did not include qualifi-
cation costs, owing to lack of relevant data; it was therefore decided to exclude
qualification costs from the unit costs of all healthcare professions included in this
analysis, for consistency purposes. Discounting was not applied, as costs and benefits
were measured over a period of 1 year.
Combining and comparing psychological and pharmacological interventions
347
Combining and comparing psychological and pharmacological interventions
348
Resource use estimates and unit costs as well as total costs of interventions
assessed over the 1 year of the analysis are reported in Table 39.
Resource use estimate Cost Unit prices – sources and
comments
Medication
Methylphenidate BNF 55
Titration: 25mg/day IR – 4 weeks £12 Non-proprietary
Post-titration: 36 mg/day
MR – 4 weeks £38 Concerta
®
XL
– 44 weeks £415 Curtis & Netten, 2006; cost per
Contacts with healthcare hour of client contact excluding
professionals qualification costs:
Titration: 2 hours with £382 Consultant psychiatrist: £191
psychiatrist/paediatrician Nurse specialist (community): £63
Monitoring: 0.5 hour at months 4, £191 No unit costs specific to consultant
7 and 12; 50% with psychiatrist/ paediatricians were available; the
paediatrician and 50% with nurse GDG judged these should be
Total cost for 8 weeks £432 equal to unit costs of consultant
Total cost over 1 year for £1,038 psychiatrists
responders
Behavioural therapy
10 1 hour group sessions £660 Curtis & Netten, 2006; cost per
with parents hour of client contact excluding
1 extra hour training and £29 qualification costs:
preparation Clinical psychologist: £66
Total cost of group sessions £689
Total cost of group sessions £69
per family, assuming 10 families
in each group
1 hour telephone calls with £66
each family
2 0.5 hour with teachers £66
Travelling to school £3
3 0.5 hour individual £99
booster sessions
Table 39: Cost data utilised in the base-case economic analysis of
pharmacological versus psychological versus combined
interventions for children with ADHD
Continued
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