Atomoxetine Hydrochloride, capsules, 10 mg, 18 mg, 25 mg, 40 mg and 60 mg, Strattera®, July 2006
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Public Summary Document
Product: Atomoxetine Hydrochloride, capsules, 10 mg, 18 mg, 25 mg, 40 mg and 60 mg, Strattera®
Sponsor: Eli Lilly Australia Pty Ltd
Date of PBAC Consideration: July 2006
1. Purpose of Application
The re-submission requested the PBS listing of atomoxetine hydrochloride as an authority
required item for the treatment patients diagnosed with attention deficit hyperactivity
disorder (ADHD) between the ages of 6 and 18 years.
2. Background
This was the fourth submission to the PBAC for listing for the treatment of ADHD.
The first application was to the March 2004 meeting, a second was considered at March
2005.
A submission to list atomoxetine hydrochloride (‘atomoxetine’) capsules on the PBS
for attention deficit hyperactivity disorder (ADHD) was rejected by the PBAC at its
March 2004 meeting. The PBAC rejected the submission because the conclusion from the
trial evidence for atomoxetine was that it is non-inferior, rather than superior,
to the stimulants in terms of clinical benefits overall and thus atomoxetine is of
uncertain but unacceptable cost-effectiveness due to its increased costs.
The March 2005 submission was rejected because the conclusion from the trial evidence
for atomoxetine was that it was non-inferior, rather than superior, to the stimulants
in terms of clinical benefits overall and therefore atomoxetine was of uncertain but
unacceptable cost-effectiveness due to its increased costs.
The third was to the November 2005 meeting. The application was rejected on the basis
of unacceptable and uncertain cost-effectiveness. The PBAC’s principal concern about
the submission was reliability of the economic model and thus its results were considered
uncertain.
This re-submission presented the same positioning, supportive data and economic analyses
as presented in the previous submission (PBAC meeting November 2005) but focused specifically
on providing information to address concerns raised in the evaluation of that submission.
3. Registration Status
Atomoxetine is TGA registered for marketing in Australia for the ‘treatment of Attention
Deficit Hyperactivity Disorder (ADHD) as defined by DSM-IV criteria in children 6
years of age and older, adolescents and adults.’
The TGA approved Product Information has recently been amended to include a boxed
warning to highlight to physicians the importance of monitoring for the emergence
of suicidal related behaviours.
4. Listing requested and PBAC’s View
Authority Required
Initial treatment of patients with attention-deficit hyperactivity disorder (ADHD)
diagnosed between the ages of 6 and 18 years by a paediatrician or psychiatrist according
to the DSM-IV criteria where:
- Treatment with dexamphetamine sulfate or methylphenidate 10 mg poses an unacceptable medical risk due to the following contraindications to immediate-release stimulant treatment as specified in the TGA-approved product information:
- The patient has a history of substance abuse or misuse (other than alcohol); and/or
- The patient has comorbid motor tics or Tourette’s Syndrome; and/or
- The patient has comorbid severe anxiety diagnosed according to the DSM-IV.
OR
Treatment with dexamphetamine sulfate or methylphenidate 10 mg has resulted in the
development or worsening of a comorbid mood disorder (diagnosed according to the DSM-IV
criteria i.e. anxiety disorder, obsessive compulsive disorder, depressive disorder)
of a severity necessitating permanent stimulant treatment withdrawal; or where the
combination of stimulant treatment with another agent would pose an unacceptable medical
risk of a severity necessitating permanent stimulant treatment withdrawal.
OR
Treatment with dexamphetamine sulfate AND methylphenidate 10 mg has resulted in the
development of adverse reactions of a severity necessitating permanent treatment withdrawal:
- Adverse effects on growth and weight
- Adverse effects on sleep including insomnia
- Adverse effects on appetite including anorexia
Authority Required
Continuing treatment where the patient has previously been issued with an authority
prescription for this drug.
The PBAC’s view was that the requested restriction was appropriate and that most of
its previous concerns had been addressed in this submission.
5. Clinical Place for the Proposed Therapy
The sponsor proposed that atomoxetine had a clinical place where dexamphetamine sulfate
or methylphenidate were either contraindicated, resulted in a worsening of associated
conditions, or resulted in adverse events necessitating permanent treatment withdrawal.
6. Comparator
Placebo as previously agreed by the PBAC.
7. Clinical Trials
No changes had been made to the trial data presented in the previous submissions.
See Public Summary Document from November 2005 PBAC meeting.
8. Results of Trials
The key results were based on a meta-analysis of ten randomised placebo controlled
trials using the outcomes of the Attention Deficit Hyperactivity Disorder Rating Scale
4th Parent Version:Investigator administered and scored (ADHDRS-IV-Parent:Inv). The
ADHDRS-IV-Parent:Inv-Parent:Inv is an 18-item scale based on semi-structured interview
between a patient’s parent (or primary caretaker and a clinician experienced in working
with children with ADHD). According to the meta-analysis using this outcome measure,
atomoxetine was associated in the re-submission’s meta-analysis with a superior statistically
significant change from baseline to endpoint compared with placebo. The results of
this meta-analysis were derived from individual patient data (IPD). The results for
proportion of responders (?40% decrease from baseline to endpoint ADHDRS Total score)
were slightly changed from the previous re-submission in favour of atomoxetine.
The PBAC had previously noted that mean changes in ADHDRS-Parent: Inv were similar
between the overall meta-analysis and those individual trials in sub-types of patients
who are more representative of the populations for whom listing was requested. This
conclusion was addressed by comparing the proportions of patients with particular
co-morbidities recruited into certain trials with the ensuing results of these trials
against the results of the meta-analysis, with specific emphasis on anxiety (LYBP),
depression (LYAX), and tic disorders or Tourette’s syndrome (LYAS). This suggested
that there was no evidence of treatment effect modification across these different
patient groups. The PBAC thus considered it was reasonable to accept that the results
of the meta-analysis are generalisable to those populations for whom listing was sought.
No new toxicity data were presented in the re-submission because of its inclusion
in the previous submission. Since the previous re-submission, the TGA has implemented
the need to monitor all patients for suicidal ideation and behaviour by inclusion
of a boxed warning in the revised product information. Also included in this revised
product information was the need to exercise caution when prescribing atomoxetine
in patients who have a history of seizures and the rare cases of QT prolongation that
have occurred when atomoxetine has been given in conjunction with fluoxetine, paroxetine
or quinidine.
9. Clinical Claim
The submission claimed atomoxetine had significant advantages in effectiveness over
placebo but was more toxic. This claim of advantage over placebo had previously been
accepted by the PBAC.
10. Economic Analysis
The re-submission claimed that an updated preliminary economic evaluation was not
presented. However, the value assumed for a number of variables had changed from the
previous re-submission. These included a slight increase in the incremental effectiveness,
the average treatment duration which had decreased (reducing drug costs), the average
daily dose which had increased (increasing drug costs) and lower drug costs which
had been updated to reflect the new requested dispensed price from July 2006. Only
drug costs were included in the analysis.
The trial-based incremental cost per extra patient with ?40% reduction from baseline
in ADHD-RS total score over 56.21 days (mean daily dose 54.78mg/day) was < $1,000.
An updated modelled economic evaluation was presented. Although the structure of the
model remained the same, some of the values of variables were changed. The base case
modelled incremental discounted cost per extra discounted QALY was in the range of
$45,000 - $75,000 over 104 weeks.
As with the model presented in the previous re-submission, the model presented in
the current submission, on the basis of data from the LYBI trial, assumed that 50.4%
of non-responders to atomoxetine at 10 weeks will develop a delayed response after
up to 8 months of continued treatment and also assumed that 0% of non-responders to
atomoxetine at 10 weeks will develop a delayed response after up to 8 months of continued
treatment on the grounds that there is absence of evidence to suggest that patients
treated with placebo will experience a delayed response. The LYBI trial did not include
a placebo arm in the relevant phase of the trials used by the re-submission to permit
assessment of ‘delayed response’ in patients who continue therapy despite response
not being achieved at 8 weeks. Thus, the concern raised previously that the assumption
with respect to proportion of non-responders to placebo developing a delayed response
after up to 8 months of continued treatment being 0% (where it was assumed to be 50.4%
for non-responders to atomoxetine) was poorly supported remained unaddressed.
The PBAC noted that a key concern with the previous submission, the application of
the TTO methodology to elicit utilities remained. The ESC advised the key issue with
the elicitation of utilities is that a time trade off (TTO) approach in which a subject
is asked to trade off someone else’s life is not comparable with a standard time trade
off approach because it does not have the same basis in utility. A QALY weight is
a person’s individual preference ranking about health states for themselves. Even
if an adult is asked to imagine that she was a child, it is the adult who then has
to answer how much she wants to trade-off the child’s life whereas in standard TTO
the adult would be asked how much of her own life she would trade off. Implicitly
the utility function which has the adult’s survival, and the adult’s quality of life
is then taken as the child’s utility function.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was in the range of 10,000 – 50,000 in Year
4 under both treatment scenario 1 (where stimulant therapy is standard of care) and
under treatment scenario 2 (based on a treatment algorithm for patients with co-morbid
conditions).
The financial cost per year to the PBS (excluding co-payments) minus any savings in
use of other drugs was in the range of $10 – 30 million in Year 3 for treatment scenario
one and in the range of $30 – 60 million in Year 3 for treatment scenario two. As
previously, the submission proposed entering into price/volume agreement negotiations.
12. Recommendation and Reasons
The PBAC considered that the requested restriction was appropriate and that most of
its previous concerns had been addressed in this submission and by the Pre-Sub-Committee
and Pre-PBAC Responses. Further, it was reiterated at the hearing that the sponsor
is willing to enter into a risk-sharing arrangement to account for any doses greater
that 1.3 capsules per day. The outstanding issues about the economic model, which
led to uncertainty about the reliability of the base-case incremental cost-effectiveness
ratio, concerned the assumption about the delayed response at 8 months of non-responders
to atomoxetine at 10 weeks compared to non-responders to placebo at 10 weeks, the
assumption about a difference in relapse rates between the atomoxetine and placebo
arms of the model and utilities.
As with the model presented in the previous resubmission, this submission’s model,
on the basis of data from the LYBI trial, assumed that 50.4% of non-responders to
atomoxetine at 10 weeks will develop a delayed response after up to 8 months of continued
treatment. It also assumed that 0% of non-responders to placebo at 10 weeks will develop
a delayed response after up to 8 months of continued treatment on the grounds that
there is absence of evidence to suggest that patients treated with placebo will experience
a delayed response. The LYBI trial did not include a placebo arm after the initial
10 weeks period to permit assessment of ‘delayed response’ in patients who were initially
non-responders while on placebo. The PBAC agreed with the ESC that, in the absence
of evidence that non-responders in the atomoxetine arm have different subsequent response
rates in comparison with non-responders in the placebo arm, the most conservative
approach in the model would have been to assume no difference between the atomoxetine
and placebo arms of the model for this parameter. By assuming a differential effect
the model biases the results in atomoxetine’s favour.
The PBAC noted that the model was less sensitive to assumptions about the relapse
rates than those in relation to delayed response rates.
The PBAC accepted that it would be difficult to design a methodologically sound utility
study in ADHD and acknowledged the attempts made by the sponsor to address this problem.
However, the PBAC agreed with the ESC that the key issue with the elicitation of utilities
is that a time trade off approach in which a subject is asked to trade off someone
else’s life is not comparable with a standard time trade off approach because it does
not have the same basis in utility theory. The time trade off approach only provides
a QALY weight if specific assumptions are made about the form of the utility function
for the individual, which would exclude consideration of another individual’s survival
and quality of life. Thus, it is not appropriate to derive utility values by using
a method in which an individual (adult) is trading off the life of another individual
(child).
The PBAC recalled there were other issues raised by the ESC and PBAC in regard to
elicitation of utilities assumed in the model presented with the previous re-submission.
The utility values assumed in the model presented in the current re-submission are
the same as assumed in the model presented in the previous re-submission. These issues
include the use of a 70-year time horizon for the time trade off survey which is likely
to lead to lower utility weights because of respondents’ time preferences; derivation
of the final health states using visual analogue scales for health states, and asking
respondents to extrapolate from a child health state to the adult health state, particularly
for health states that relate to developmental/learning outcomes. The PBAC noted that
the model is most sensitive to assumed utility weights of the various health states
in the model. As noted above the model is also sensitive to the assumptions about
the delayed response by non-responders. Given the concerns about the assumptions about
these two factors in the model, there was uncertainty about the base-case modelled
incremental cost-effectiveness ratio, which between $45,000 and $75,000 was considered
high, and would likely be higher, given the above concerns. The PBAC therefore rejected
the submission because of uncertain cost-effectiveness.
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia.
It considers submissions in this context. A PBAC decision not to recommend listing
or not to recommend changing a listing does not represent a final PBAC view about
the merits of the medicine. A company can resubmit to the PBAC or seek independent
review of the PBAC decision.
14. Sponsor’s Comment
Eli Lilly Australia is disappointed with this outcome, but remains committed to finding a means to provide equitable access to Strattera® treatment for patients who need a treatment for ADHD that is not amphetamine-based. With regards to Utility analysis, we acknowledge that there are methodological issues, however, the results were not inconsistent with the outcomes of the trials. The new guidelines appear to have been taken some step to address this methodological issue.