Modafinil, tablet, 100 mg, Modavigil®, November 2008
Public summary document for Modafinil, tablet, 100 mg, Modavigil® November 2008
Page last updated: 19 March 2009
Public Summary Document
Product: Modafinil, tablet, 100 mg,
Sponsor: CSL Limited
Date of PBAC Consideration: November 2008
1. Purpose of Application
The Australasian Sleep Association (ASA) and the Australian New
Zealand Association of Neurologists (ANZAN) joint working party,
together with the sponsor requested an amendment to the PBS listing
of modafinil to allow use as first line therapy for the treatment
of narcolepsy. The Working Party also requested changes to the
diagnostic criteria for narcolepsy included in the current
restriction for modafinil.
A submission for modafinil was rejected by the PBAC at its June
2002 meeting, as was a re-submission to the March 2003 PBAC
meeting. The March 2003 application was rejected because of the
uncertain clinical benefit and uncertain cost-effectiveness.
At the November 2004 meeting, the PBAC recommended listing on the basis of acceptable cost-effectiveness in the patient group proposed. The PBAC considered that a continuation rule should not be required partly because patients would have to pay the full cost of the polysomnography test for continuing treatment, and that there may be problems with access to sleep laboratories in the time-frames specified for assessment of response. Modafinil was PBS listed 1 August 2005.
In March 2008 a joint working party between the ASA and ANZAN was established to review the current availability of modafinil for the treatment of narcolepsy in Australia. The stated impetus for the review was twofold: (i) increasing knowledge on the potential harms of dexamphetamine related to risk of sudden death, long term cardiovascular risk, psychiatric problems, potential for misuse and abuse which the submission noted has led to a detailed regulatory update in 2006 and 2007 and re-assessment of the implications for chronic lifetime therapy from early adulthood and (ii) clinical experience with the application of the diagnostic criteria for narcolepsy which finds they are too restrictive and are unnecessarily excluding patients from treatment.
3. Registration Status
Modafinil was TGA registered on 2 July 2002 for the improvement of
wakefulness in patients with excessive daytime sleepiness
associated with narcolepsy.
Two additional indications were TGA registered in April 2007:
- Treatment of excessive sleepiness associated with moderate to severe chronic shift work sleep disorder.
- Adjunct to continuous positive airways pressure in obstructive sleep apnoea/ hypopnoea syndrome in order to improve wakefulness.
4. Listing Requested and PBAC’s View
Initial treatment, by a qualified sleep medicine practitioner or neurologist, of patients with narcolepsy who meet the following definition:
i) Excessive daytime sleepiness, recurrent naps or lapses into sleep occurring almost daily for at least 3 months; and
ii) A definite history of cataplexy
A mean sleep latency less than or equal to 10 minutes on a Multiple Sleep Latency Test (MSLT). The MSLT must be preceded by nocturnal polysomnography. Sleep prior to
the MSLT must be at least 6 hours in duration
iii) An electroencephalographic (EEG) recording showing the pathologically rapid development of REM sleep; and
Absence of any medical or psychiatric disorder that could otherwise account for the hypersomnia.
Continuing treatment of narcolepsy, where the patient has previously been issued with an authority prescription for this drug.
For PBAC’s view see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Narcolepsy is a rare, chronic condition first affecting patients in
their late teens and early twenties and then remaining for life.
The defining and most debilitating symptom is excessive daytime
sleepiness manifested by both continuous sleepiness and
uncontrolled sleep attacks. This has a profound effect on the
individual’s social, academic and work performance and may
expose them to higher levels of risk from accidents.
Traditionally, stimulants such as methylphenidate and dexamphetamine have been the only treatment options for excessive daytime sleepiness in narcolepsy. The ASA/ANZAN Working Party claimed there is an argument for instatement of modafinil as first line therapy for narcolepsy due to its favourable benefit/risk profile to dexamphetamine, and lack of addictive potential.
The submission nominated “no treatment” as the main
comparator. The ASA/ANZAN working party believed that after recent
re-assessment of dexamphetamine safety, and considering narcolepsy
treatment was life-long, that from a legal and medical perspective
dexamphetamine could no longer be considered the standard of care
for narcolepsy, and as such was not an appropriate comparator for
For PBAC’s view see Recommendation and Reasons.
7. Clinical Trials
The basis of the submission is three direct randomised comparative
trials comparing modafinil and placebo (two of which have been
previously considered and Black (2006)) and four supplementary
studies – three cross-over studies comparing modafinil and
placebo and one non-comparative study in which patients switched
from stimulant to modafinil therapy for narcolepsy (all previously
considered by the PBAC). The trial by Black (2006) differed in
design to the trials previously considered by the PBAC as patient
eligibility criteria included that patients be on stable doses of
modafinil (i.e., a responder population) and the dose of modafinil
used ranged between 200 and 600 mg/day (the TGA approved doses were
The published trial changed from previous submissions was:
|Protocol title/ Publication title
|Direct randomised trial – modafinil versus placebo
|Black J et al
|Sodium oxybate improves excessive daytime sleepiness in narcolepsy.
|Black J et al. Sleep 2006; 29:939-946
8. Results of Trials
The key results of the trial reported by Black (2006) are
summarised in the table below. The primary outcome of the Black
(2006) trial was the 20 minute Maintenance of Wakefulness Test
(MWT), which was performed at visits 2, 3, 4 and 5 according to
Primary outcome: Maintenance of Wakefulness Test in the randomised trial Black (2006)
|Modafinil Mean minutes (SD)
|Placebo Mean minutes (SD)
|Visit 3 (randomisation)
|N=63, 10.48 (6.03)
|N=55, 9.74 (6.57)
|Visit 5 (8 weeks)
|N=62, 9.86 (5.89)
|N=53, 6.87 (6.14)
The re-submission presented new toxicity data as a summary of the
changes made to the modafinil and dexamphetamine product
information (PI) documents. The re-submission argued that due to
the safety concerns associated with the use of dexamphetamine that
dexamphetamine should no longer be considered as a first-line
option for the treatment of narcolepsy.
9. Clinical Claim
Although not explicitly stated, it was assumed that the
re-submission would describe modafinil as superior in terms of
comparative effectiveness but associated with greater toxicity than
placebo. Based on the supporting data, this description was
reasonable. However, as noted by the PBAC in its considerations of
the previous submissions, given the outcomes reported in the
trials, the patient relevance and magnitude of clinical benefit of
modafinil remained uncertain. The clinical importance of each
outcome measure was unclear and it was difficult to extrapolate
from the surrogate outcomes to clinically important endpoints.
Unambiguously patient relevant endpoints included being completely
free of drop attacks or achieving a level of reduction in sleep
attacks that would allow a patient to return to work and/or able to
10. Economic Analysis
The submission did not present an economic analysis. The PBAC
considered that the omission of economic analyses was
inappropriate. It was noted that modafinil and dexamphetamine have
drug costs of $3327 vs. $318 per year, respectively, for life long
therapy and uncertain relative net clinical effect, particularly in
the long term.
11. Estimated PBS Usage and Financial Implications
The likely number of patients/year were estimated to be <
10,000, while the financial cost/year to the PBS (excluding
co-payments) minus any savings in use of other drugs was estimated
to be < $ 10 million using the lower prevalence estimate and
> $10 million in Year 5 using a higher prevalence
12. Recommendation and Reasons
The PBAC welcomed the submission from the Australian Sleep
Association (ASA) and the Australian New Zealand Association of
Neurologists (ANZAN) joint working party and indicated its empathy
with the position put forward by this group. However, as noted
during the hearing the Committee must make its recommendations in
accordance with the National Health Act (1953) which requires it to
be satisfied that any new therapy (and by extension any change to
the PBS availability of an existing therapy) “where therapy
involving the use of a particular drug …is substantially
more costly than an alternative therapy …the Committee shall
not recommend to the Minister that the drug, preparation or class
be made available as pharmaceutical benefits …unless the
Committee is satisfied that the first-mentioned therapy, for some
patients, provides a significant improvement in efficacy or
reduction of toxicity over the alternative therapy or
The PBAC did not accept the premise of the submission that from a medical and legal view, dexamphetamine can no longer be considered the standard of care for treatment of this life-long condition, and was not an appropriate comparator for modafinil in the first-line setting. The Committee noted that the absence of a systematic review of the evidence in support of this statement was a significant impediment to its deliberations. Additionally, the comment made both in the Pre-Sub-Committee response and in the hearing that not all patients currently on dexamphetamine will switch to modafinil appeared to contradict the first statement. Although it was acknowledged that the decision to switch therapies in prevalent patients may be somewhat confounded by other factors (e.g. the “high” offered by dexamphetamine), and may differ from the decision on which therapy to initiate new patients, the Committee considered that overall there was insufficient basis for it to change its previous finding that dexamphetamine is the appropriate comparator (alternative therapy) for first-line modafinil.
The PBAC also recalled that the incremental benefit (efficacy and safety) of modafinil over dexamphetamine had not been previously established in the first-line setting. It was the large difference between the prices of the two drugs that forced the PBAC to consider the construct of the second-line indication and a comparison with placebo to be developed for modafinil in order for the product to be made available to patients. The PBAC further considered that the omission of economic analyses was inappropriate. It was noted that modafinil and dexamphetamine have drug costs of $3327 vs. $318 per year, respectively, for life long therapy and uncertain relative net clinical effect, particularly in the long term.
With respect to the requested changes to the current restriction’s diagnostic criteria for narcolepsy, the PBAC acknowledged the pre-Sub-Committee response argument that “the MSLT is neither perfectly sensitive nor specific for the diagnosis of narcolepsy”, and as such patients may be misdiagnosed and denied treatment, and that as the MSLT was only available in major centres it was an inappropriate requirement for the restriction. The Pre-Sub-Committee response also argued that the requirement for 2 or more sleep onset REM periods on MSLT was inappropriate as it would exclude up to 30 % of patients with narcolepsy. The pre-Sub-Committee response acknowledged that a mean sleep latency of 8 minutes was supported in the literature around narcolepsy diagnosis, but argued that this too could act to exclude excessively sleepy narcolepsy patients. The PBAC acknowledged the letter provided with the submission from the Australasian Sleep Association suggesting that there was a clinical need for the restriction to be broadened. However the criteria in the current restriction were based upon internationally accepted standards and no data or references were provided in support of the claims made in the pre-Sub-Committee response regarding the proportion of narcolepsy patients currently being denied modafinil treatment as a result of requirements related to the MSLT.
The PBAC therefore rejected the application because of insufficient evidence to support the claim that placebo rather than dexamphetamine is the appropriate comparator for modafinil in the first line setting and because of insufficient evidence to substantiate the claim that eligible patients are being denied treatment under the current restriction. The Committee indicated its willingness to hold further dialogue with the working party and other relevant stakeholders on the restriction’s diagnostic criteria.
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
The Australian Sleep Association (ASA) and the Australian New
Zealand Association of Neurologists (ANZAN) joint working party is
disappointed by the PBAC rejection. The working party will work
with the PBAC on the restriction’s diagnostic criteria to
ensure that they do not unnecessarily exclude narcolepsy patients