Botulinum toxin type A purified neurotoxin complex, lyophilised powder for IM injection, 100 units vial, Botox®, July 2008
Public summary document for Botulinum toxin type A purified neurotoxin complex, lyophilised powder for IM injection, 100 units vial, Botox®, July 2008
Page last updated: 31 October 2008
Public Summary Documents
Product:Botulinum toxin type A purified neurotoxin complex, lyophilised powder for IM injection, 100 units vial, Botox®
Sponsor: Allergan Australia Pty Ltd
Date of PBAC Consideration: July 2008
1. Purpose of Application
The submission sought to extend the current section 100 listing
(Botulinum Toxin Program) to include the treatment of moderate to
severe spasticity of the lower limb in ambulatory adults following
a stroke as a second line therapy when standard management has
failed or as an adjunct to physical therapy.
At the November 2005 PBAC meeting, the PBAC rejected an application
to extend the Section 100 listing for botulinum toxin type A
(Botox) to include the treatment of focal spasticity in adults
because of uncertainty with interpreting the extent of clinically
relevant benefits arising from the spasticity outcomes analysed by
the trials, uncertainty associated with the modelled physiotherapy
cost off-sets and the resulting unacceptable and uncertain
cost-effectiveness. (See PBAC Public Summary Document –
At the July 2006 PBAC meeting, the PBAC again rejected a submission seeking for the treatment of focal spasticity (upper and lower limbs) in adult patients who meet certain criteria because of uncertainty in extrapolation of response in terms of the Ashworth scale to a quality of life measure, and high and uncertain cost-effectiveness. (See PBAC Public Summary Document – July 2006)
3. Registration Status
Botulinum Toxin Type A Purified Neurotoxin Complex is indicated for:
- Treatment of blepharospasm associated with dystonia, including benign blepharospasm and VII nerve disorders (specifically hemifacial spasm) in patients twelve years and over;
- Treatment of cervical dystonia (spasmodic torticollis);
- Treatment of dynamic equinus foot deformity due to spasticity in juvenile cerebral palsy patients two years of age or older;
- Treatment of severe primary hyperhidrosis of the axillae;
- Treatment of glabellar lines associated with corrugator and/or procerus muscle activity;
- Treatment of focal spasticity in adults;
- Treatment of spasmodic dysphonia;
- Treatment of strabismus in children and adults.
4. Listing Requested and PBAC’s View
Section 100 (Botulinum Toxin Program)
Treatment of moderate to severe spasticity of the lower limb in ambulatory adults following a stroke as second line therapy when standard management has failed or as an adjunct to physical therapy.
To qualify for therapy patients must:
1. be ambulatory, with or without assistive devices/support
2. have no fixed muscle contracture in the targeted muscles for injection that would limit treatment efficacy
3. have spasticity which reduces walking speed
4. have a walking speed < 48 m/min over 10 metres, based on the standard 10 metre walk speed assessment.
To continue treatment after the first year:
Based on the standard 10 metre walk test, all patients must improve their walk distance by at least
15 m/min, relative to their baseline speed, in order to obtain continuing treatment.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Botulinum Toxin Type A (BTx-A) injection therapy treats spasticity
by allowing the muscle to relax. The effects of Botulinum Toxin
Type A are reversible and treatment provides a window of
opportunity in which other treatments, such as physical therapies,
can be used to regain muscle or joint function.
The submission nominated placebo as the main comparator, which was
previously accepted by the PBAC at the July 2006 meeting.
7. Clinical Trials
The submission provided new efficacy data from trial 702-8051. The
gait speed was measured and patients were allocated to one of four
functional walking categories. The change in categories after
treatment was analysed.
Only one supplementary randomised trial, which was presented in the previous submission, was published at the time of the submission, as follows:
|Trial/First author||Protocol title||Publication citation|
|Supplementary randomised trials|
|Verplancke et al (2005)||A randomised controlled trial of Botulinum toxin on lower limb spasticity following acute acquired severe brain injury||Clinical Rehabilitation (2005). 19(2):117-25|
8. Results of Trials
In terms of the distribution of patients into functional walking
categories in trial 702-8051, the submission reported that there
was no difference between the BTx-A and placebo treatment groups at
baseline, but after treatment there was a statistically significant
difference between the groups. The submission claimed that a larger
proportion of patients moved to a higher functional walking
category in the BTx-A treatment group compared to the placebo
The claim of superior efficacy was based on a difference in the distribution in walking categories between the groups post treatment only. The submission did not present the results in terms of change from baseline.
For PBAC’s comments on these results, see Recommendation and Reasons.
The submission presented new toxicity data: a) meta-analysis of discontinuation rates and adverse events in ten RCTs for the treatment of focal spasticity (upper or lower limb); b) data from post marketing surveillance.
The submission reported no significant differences in the incidence of adverse events between the two treatments. However, there are recent concerns regarding the safety profile of BTx-A from various drug regulatory agencies: FDA, Health Canada and Medicines and Healthcare products Regulatory Agency (MHRA) due to distant spread of BTx-A from the site of injection.
9. Clinical Claim
The submission claimed that BTx-A was therapeutically superior and
equivalent in terms of comparative safety to placebo.
The PBAC did not accept this claim, see Recommendation and Reasons.
10. Economic Analysis
The submission presented an updated modelled economic evaluation
(cost-utility). The utility values were obtained using the
assessment of quality of life (AQoL) questionnaire in 127 BTx-A
patients, using similar selection criteria employed in the key
trial. Patients in the trial and the utility studies were grouped
into one of the four functional walking categories based on gait
speed and each category was assigned a utility value. The
incremental cost effectiveness ratio (ICER) was estimated to be in
the range of
$15,000- $45,000 per quality adjusted life year (QALY).
Additional analyses were conducted during the evaluation. The model was sensitive to the utility values based on cause of the spasticity, number of walking speed categories and the number of vials per course of BTx-A treatment.
For PBAC’s view, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated to be less
than 10,000 in Year 5.
The financial cost per year to the PBS was estimated to be in the range of $10 – $30 million in Year 5.
12. Recommendation and Reasons
The PBAC noted that the requested listing was for lower limb
spasticity post stroke but that the evidence provided only included
patients suffering from post stroke equinovarus deformity and the
assumption that the results are applicable to the broader
population was not reasonable. The PBAC however noted that the
sponsor would accept the narrower listing of post stroke
equinovarus deformity if a positive recommendation was
The PBAC considered that there was considerable uncertainty in the clinical outcomes from the pivotal trial, 7028051. The efficacy results from this study provided in this submission were from a post-hoc analysis. The assignment of patients into walking categories was based purely on gait speed, and the relevance of the walking categories in determining change in overall patient functionality remains uncertain. Additionally, the placebo group had greater disability at baseline which favoured botulinum. The claim of superior efficacy is based on a difference in the distribution in walking categories between the groups post treatment only. The results of an analysis of change from baseline conducted during the evaluation suggest that there is no difference between the treatment groups in terms of change from baseline mobility (as defined by functional walking group) or responder rate (where a responder is defined as any patient who improves by at least one functional walking category from baseline). It is, however, acknowledged that the representativeness of these results is limited by the small size of the trial population.
Two supplementary studies, 138/139-8051 and 191622-501/502, also failed to show significant improvements in functionality. The PBAC further noted that duration of any response to botulinum toxin may be short (4-8 weeks) and that this may have implications if continuing treatment is limited to one per year.
Overall, the PBAC considered that the data provided failed to show either evidence for a sustained benefit with botulinum treatment, or evidence that a short term improvement allows a window in which, for example, additional physiotherapy may be undertaken to give longer term benefit.
The PBAC noted the participants in the utility study were different (healthier) than the patients in the trial, which may have resulted in the utility values being systematically overestimated. Additionally, the utility values were estimated in the absence of treatment with botulinum and therefore did not take into account any treatment related side-effects. The PBAC further noted that when the base case was reset to account for errors in the original analysis (utility adjusted for injection schedule, discounted utilities, and inclusion of physical therapy costs) the incremental cost/QALY was between $75,000 - $105,000, an increase of between $45,000 - $75,000 on the base case presented in the submission. The Committee considered that there was considerable residual uncertainty in this estimate due to significant overestimation of the benefit and underestimate of total cost.
Therefore, the PBAC rejected the submission because of uncertain clinical benefit and the resulting high and 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
The sponsor is disappointed with the PBAC’s decision but
acknowledges the limitations in the trial evidence. It will examine
whether additional clinical evidence can be made available to
support a re-submission.