Botulinum toxin type a purified neurotoxin complex, Lyophilised powder for I.M. injection 100 units vial, Botox®, July 2008
Public summary document for Botulinum toxin type a purified neurotoxin complex, Lyophilised powder for I.M. 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 I.M. injection 100 units
vial, Botox®
Sponsor: Allergan Australia Pty Ltd
Date of PBAC Consideration:July 2008
1. Purpose of Application
The re-submission sought to extend the Section 100 listing (under
the Botulinum Toxin Program) for botulinum toxin type A (BTx-A) to
include the treatment of moderate to severe spasticity of the upper
limb in adults following a stroke as an adjunct to physical
therapy.
2. Background
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 also PBAC Public Summary Document
November 2005)
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 also 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
The re-submission requested listing consistent with Clostridium botulinum type A toxin
(Dysport®) for upper limb spasticity.
Section 100 Botulinum Toxin Program
Note:
Arrangements to prescribe this item should be made by medical practitioners with Medicare
Australia, contact telephone number 1800 700 270.
Note:
The units used to express the potency of botulinum toxin preparations currently available
for PBS subsidy are not equivalent.
Treatment of moderate to severe spasticity [defined as MAS greater than or equal to
3 using modified Ashworth scale] of the upper limb in adults following a stroke, as
second line therapy when standard management has failed (e.g. physiotherapy and/or
oral spasticity agents) or as an adjunct to physical therapy.
Maximum number of treatments to be authorised is 4 per upper limb per lifetime. Treatment
should not be initiated until 3 to 6 months post-stroke in patients who do not have
established severe contracture. Treatment should be discontinued if the patient does
not respond (decrease of MAS greater than 1 in at least one joint) after two treatments.
Contraindications to treatment include established severe contracture, known sensitivity
to botulinum toxin.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Botox injection therapy treats spasticity by allowing the muscle to
relax. The effects of Botox are reversible and treatment provides a
window of opportunity in which other treatments such as
physiotherapy can be used to regain muscle or joint function.
6. Comparator
The submission nominated clostridium botulinum (Dysport®) as
the main comparator. The PBAC considered this was
appropriate.
7. Clinical Trials
The re-submission presented an indirect meta-analysis of five
direct randomised trials of BTx-A and six Dysport® trials in
upper limb with placebo as common comparator. The meta-analysis was
based on mean change in Ashworth score in wrist, elbow and finger
flexor muscles, although the Dysport® studies used Modified
Ashworth scale to measure spasticity.
The key trials and associated reports published at the time of the
re-submission are as follows:
| Trial ID/First Author | Protocol title / Publication title | Publication citation |
| BTx-A vs placebo | ||
| 008 Brashear A., et al,2002 | Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. | New England Journal of Medicine 347:395–400, 2002. |
| 130 Simpson D.M., et al Simpson 1996 | Double-blind, vehicle-controlled study to evaluate dosing, safety and efficacy of intramuscular botulinum toxin type A in upper limb spasticity post-stroke. | Neurology 46:1306–10, 1996. |
| 133/134 Childers M.K., et al 2004 | Multicenter, double-blind, placebo-controlled, parallel, dose-response clinical trial of intramuscular BTx-A in upper limb spasticity post-stroke | Archives of Physical Medicine and Rehabilitation 85:1063–9, 2004. |
| 418/422 De Beyl Z, et al 2000 | Multicenter, double-blind, vehicle -controlled, parallel study to evaluate dosing, safety and efficacy of intramuscular BTx-A in upper limb spasticity post-stroke | European Journal of Neurology 7(Suppl 3):23, 2000. |
| Dysport® vs placebo | ||
| Bakheit A.M., et al 2000 | A randomized, double-blind, placebo-controlled, dose-ranging study to compare the efficacy and safety of three doses of botulinum toxin type A (Dysport® ) with placebo in upper limb spasticity after stroke. | Stroke, 31:2402–6, 2000. |
| Bakheit A.M., et al 2001 | A randomized, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin type A in upper limb spasticity in patients with stroke. | European Journal of Neurology,1;8:559–65, 2001. |
| Bhakta B.B.,et al 2000 | Randomized double-blind placebo-controlled trial of botulinum toxin treatment on the disabling effects of severe arm spasticity in stroke. | Clinical Rehabilitation,14:213, 2000. |
| Hesse S., et al 1998 | Botulinum toxin type A and short-term electrical stimulation in the treatment of upper limb flexor spasticity after stroke: a randomized, double-blind, placebo-controlled trial. | Clinical Rehabilitation. 12:381–8, 1998. |
| Smith S.J., et al 2000 | A Botulinum toxin type A and short-term electrical stimulation in the treatment of upper limb flexor spasticity. | Clinical Rehabilitation, 14:5–13, 2000. |
| Suputtitada A., et al 2005 | The lowest effective dose of botulinum A toxin in adult patients with upper limb spasticity. | Disability and Rehabilitation, 27(4):176–184, 2005. |
8. Results of Trials
The key results of the meta-analyses of BTx-A or Dysport® vs. placebo trials are summarised in the table below.
| Outcome (Mean change in Ashworth score) | Assessment | BTx-A vs. placebo | Dysport® vs. placebo | ||
| Result | P value | Result | P value | ||
| Wrist flexor tone | WMD (95%CI) | - 0.74 (-1.05,-0.42) | <0.0001 | -0.80 (-1.37, -0.23) | <0.05 |
| Elbow flexor tone | WMD (95%CI) | - 0.30 (-0.52,-0.10) | 0.004 | -0.49 (-0.69, -0.28) | <0.05 |
| Finger flexor tone | WMD (95%CI) | -0.26 (-0.75,0.22) | 0.29 | -1.34 (-2.35,-0.33) | <0.05 |
| Responder * | RD (95%CI) | 0.36 (0.25,0.46) | <0.001 | 0.32 (0.15,0.49) | <0.001 |
* patient with a reduction in tone of
>
2 in Ashworth score in any
muscle
WMD weighted mean difference; RD risk difference; CI confidence
interval
The data indicated that both botulinum toxin type A and clostridium
botulinum treatment resulted in a statistically significant
difference in mean change in Ashworth score (Modified Ashworth
Score for clostridium botulinum) in wrist and elbow flexor muscles
and responder rate compared to placebo.
For PBAC’s comments on these results, see Recommendation
and Reasons.
The re-submission also presented the following new toxicity data:
a) comparison of discontinuations rates in the meta-analysis of five randomised control trials (RCTs) of BTx-A and six RCTs of Dysport®; and
b) data from post marketing surveillance.
The rate of discontinuations were similar across the BTx-A vs
placebo and Dysport vs placebo. 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 no worse in terms of
effectiveness and had similar toxicity to Dysport®. The PBAC
accepted this claim.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The re-submission presented a cost minimisation analysis. The
equi-effective doses were estimated as BTx-A 229U per treatment
course and Dysport® 989U per treatment course.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The re-submission estimated that the likely number of patients/year
to be less than 10,000 in Year 2 equating to a financial cost/year
to the PBS of between $10 – 30 million in Year 2. These costs
were based on a dose of 229U, the average dose across the key
trials.
12. Recommendation and Reasons
The PBAC recommended an extension to the Section 100 listing for
Botulinum toxin type A to include the treatment of moderate to
severe spasticity of the upper limb in adults following a stroke,
as second line therapy when standard management has failed or as an
adjunct to physical therapy, on a cost-minimisation basis compared
with clostridium botulinum. The equi-effective doses are botulinium
toxin type A 229U per treatment course and clostridium botulinum
989U based on the trial data. The PBAC noted that Botulinum toxin
type A Botox® would be required to join the current Risk
Sharing Arrangement that is in place for the Dysport®, and that
this agreement should include limits that do not allow patients to
have four treatments each per formulation.
The PBAC noted there is some uncertainty regarding the methods used
in the submission as there was no formal indirect comparison
between the meta-analysis results presented for the two agents.
Notwithstanding this, the data indicated that both botulinum toxin
type A and clostridium botulinum treatment resulted in a
statistically significant difference in mean change in Ashworth
score (Modified Ashworth Score for clostridium botulinum) in wrist
and elbow flexor muscles and responder rate compared to placebo.
The PBAC considered that the two products, although not
bioequivalent, can be expected to have similar clinical outcomes.
This is seen particularly in the responder rate (response was
defined as an Ashworth score change of greater than or equal to
two) notwithstanding the limited number of trials.
The PBAC considered the restriction should be the same as for the
currently listed clostridium botulinum for post-stroke upper limb
spacticity, however that the maximum total number of botulinum
treatments authorised be limited to 4 per upper limb, per lifetime.
The PBAC considered that the cost effectiveness would be
unacceptable if the number of treatments increased to 4 per each
formulation.
Recommendation
Add the following to the restriction under the BOTULINUM TOXIN
PROGRAM
To be finalised.
Section 100 (Botulinum Toxin Program)
Botulinum toxin type A purified neurotoxin complex
Treatment of moderate to severe spasticity [defined as MAS greater
than or equal to 3 using modified Ashworth scale] of the upper limb
in adults following a stroke, as second line therapy when standard
management has failed (e.g. physiotherapy and/or oral spasticity
agents) or as an adjunct to physical therapy.
Maximum number of treatments to be authorised is 4 (total Botox and
Dysport) per upper limb per lifetime. Treatment should not be
initiated until 3 to 6 months post-stroke in patients who do not
have established severe contracture. Treatment should be
discontinued if the patient does not respond (decrease of MAS
greater than 1 in at least one joint) after two treatments.
Contraindications to treatment include established severe
contracture, known sensitivity to botulinum toxin.
Note:
Arrangements to prescribe this item should be made by medical
practitioners with Medicare Australia, contact telephone number
1800 700 270.
Note:
The units used to express the potency of botulinum toxin
preparations currently available for PBS subsidy are not
equivalent.
Pack size: 1
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 believes botulinum toxin provides a valuable long-term
treatment option for patients following a stroke. The sponsor
acknowledges and supports the decision by the PBAC and it will
examine ways to demonstrate the longer-term benefits of treatment
to the committee.
