A systematic review and economic model of the effectiveness and ...

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Review of economic evaluations of ADHD drug interventions in children and adolescents
TABLE 81 Monthly response and relapse transition probabilities by subgroup used in the cost–utility model submitted by Eli Lilly
Parameter ATX MPH (instant or extended release) DEX No treatment
Subgroup 1
Response 0.7051 0.7727 NA NA
Relapse
Subgroup 2
0.0206 0.0206 NA NA
Response 0.6667 NA NA 0.4231
Relapse
Subgroup 3
0.0206 NA NA 0.0387
Response 0.6774 NA 0.6774 0.3983
Relapse
Subgroup 4
0.0257 NA 0.0257 0.0447
Response 0.5273 NA NA 0.3478
Relapse
Subgroup 5
0.0257 NA NA 0.0447
Response 0.6217 0.7003 NA NA
Relapse 0.0257 0.0257 NA NA
NA, not applicable.
It is not clear why the response and relapse rates
for DEX and no treatment are not applicable for
subgroups 1 and 5, as these patients are eligible
for these treatments, which both also feature in
the treatment strategy assigned to that subgroup.
It is also not made clear why the probability of
relapse differs for sub-groups 1 and 2, as
compared with 3, 4 and 5. These and other
unexplained variations in the reported figures
cannot be verified without examining the
electronic model. It was not possible to ascertain
whether the response rates extracted and
estimated were monthly response rates, or whether
an overall response rate from the trials was
applied as a monthly transition probability in the
model, which would overestimate response in the
model given that the average trial length was
> 1 month.
The probabilities of adverse events,
discontinuation due to adverse events,
discontinuations in non-responders due to
inefficacy, discontinuations due to other reasons
and the persistence of insomnia to the next cycle
are all assumed equal between active treatment
options. The probability of experiencing any
adverse event and the probability of
discontinuation are taken from a post hoc analysis
of data pooled from six trials comparing ATX with
placebo. 63,73,74,89,142,144 One of the trials 142 was a
subset analysis of another 89 and so to pool these
two trials was not appropriate. The pooled data
showed an adverse event rate of 49.2% on ATX
and 36.3% on placebo, and so the submission
employs the difference of 12.9% as the monthly
transition probability. Again, it is unclear whether
this rate was the monthly rate in the trials or, as is
more likely, the overall rate from the trials. The
average length of the six trials was just over
9 weeks, and so applying an overall rate as a
monthly transition probability would overestimate
the number of adverse events in the model. The
probability of discontinuation due to other reasons
(i.e. not inefficacy or adverse events) was estimated
to be 9.46% and may suffer from the same
problems as just detailed.
The probability of discontinuation due to
inefficacy does appear to have been calculated
correctly as a monthly probability of 9.89%;
although the assumptions used in this calculation
are not specified, we may infer that it was
calculated by assuming a constant transition rate
and hence an exponential distribution. The same
may be true of the monthly probability of
discontinuation due to adverse events, estimated
to be 12.09%.
An indirect meta-analysis of safety data (not
referenced) estimated an RR of insomnia of 0.428
for ATX compared with IR-MPH. This was applied
to an estimate of the risk of insomnia on ATX of
4.7% from the six pooled placebo-controlled
trials. 63,73,74,89,142,144 The subsequent rate of
insomnia on IR-MPH of 11.0% was then net of the
rate of insomnia on placebo from the same studies
(5.1%) as the model assumed that insomnia was
only experienced on medication. This net rate was