Botulinum toxin type A purified neurotoxin complex, lyophilised powder for I.M. injection, 100 units, Botox®, November 2009
Public Summary Document for Botulinum toxin type A purified neurotoxin complex, lyophilised powder for I.M. injection, 100 units, Botox®, November 2009
Page last updated: 19 March 2010
Public Summary Document
Product: Botulinum toxin type A purified
neurotoxin complex, lyophilised powder for I.M. injection, 100
units, Botox®
Sponsor: Allergan Australia Pty Ltd
Date of PBAC Consideration: November 2009
1. Purpose of Application
The submission sought to extend the current Section 100 (Botulinum
Toxin Program) listing for botulinum toxin type A to include the
treatment of severe hyperhidrosis of the axillae in adolescents and
adults following failure of topical treatments to reduce
sweating.
2. Background
Botulinum toxin type A had not been previously considered by the
PBAC for the treatment of severe hyperhidrosis of the
axillae.
3. Registration Status
Botulinum toxin type A for the treatment of severe primary
hyperhidrosis of the axillae was TGA registered on 17 January
2002.
Botulinum toxin type A is also TGA registered for the following:
- Blepharospasm associated with dystonia, including benign blepharospasm and VII nerve disorders (specifically hemifacial spasm) in patients twelve years and over;
- Cervical dystonia (spasmodic torticollis);
- Dynamic equinus foot deformity due to spasticity in juvenile cerebral palsy patients two years of age or older;
- Glabellar lines associated with corrugator and/or procerus muscle activity;
- Focal spasticity in adults;
- Spasmodic dysphonia;
- Strabismus in children and adults; and
- Focal spasticity of the upper and lower limbs, including dynamic equinas foot deformity, due to juvenile cerebral palsy in patients two years of age and older.
4. Listing Requested and PBAC’s View
Option 1
Section 100 (Botulinum Toxin Program)
For the treatment of severe primary axillary hyperhidrosis in adult
and adolescent patients (>12 years of age) that have been
diagnosed with focal, visible, excessive sweating of the axillae of
at least 6 months duration without apparent cause with at least two
of the following characteristics:
- Bilateral and relatively symmetric
- Impairs daily activities
- Frequency of at least one episode per week
- Age of onset less than 25 years
- Positive family history
- Cessation of focal sweating during sleep
AND
Have failed or are intolerant to treatment with topical Aluminium
chloride hexahydrate following a trial period of at least 1-2
months.
Maximum number of treatments per year is 2.
Option 2
Section 100 (Botulinum Toxin Program)
For the treatment of severe primary axillary hyperhidrosis in
patients:
- Diagnosed with severe primary hyperhidrosis of the axillae for at least six months.
- That have failed or are intolerant to treatment with topical Aluminium chloride hexahydrate following a trial period of at least 1-2 months, and
- where the baseline gravimetric measure exceeds the following:
- Adults (>18 years of age): Women: 100 mg of spontaneous resting axillary sweat production in each axilla measured gravimetrically at room temperature over a period of 5 minutes. Men: 150 mg of spontaneous resting axillary sweat production in each axilla measured gravimetrically at room temperature over a period of 5 minutes in men.
- Adolescents (12-17 years of age): > 50 mg of spontaneous resting axillary sweat production in each axilla measured gravimetrically at room temperature over a period of 5 minutes.
Maximum number of treatments per year is 2.
The PBAC considered Option 1 to be the most appropriate and
consistent with current clinical practice. The PBAC noted that
Option 2 uses gravimetric assessment as an objective measure for
diagnosis, but that it would be impractical for use in the clinical
setting.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Hyperhidrosis is a condition characterised by excessive sweat
production due to over-activity of the sweat glands of the palms,
axillae, soles of the feet or face. Hyperhidrosis can be classified
as either focal or generalised, and either primary or
secondary.
Current treatment options include non PBS-subsidised medical
treatments such as topical aluminium chloride salts,
anticholinergic drugs and inotophoresis or surgery.
Botulinum toxin type A would provide an alternative PBS-subsidised
treatment for the treatment of severe primary axillary
hyperhidrosis.
6. Comparator
The submission nominated placebo, administered by intradermal
injection, as the main comparator.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented three randomised trials comparing
botulinum toxin type A with placebo in patients with severe primary
axillary hyperhidrosis (trial 191622-505, 191622-016 and Connor
2006). Three open-label studies were also presented as supportive
evidence (study 191622-506, 191622-513 and 191622-075). Details of
the trials published at the time of the submission are in the table
below.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Direct randomised trials | ||
| Trial 191622-016 | ||
| Kowalski JW et al (2004) | Quality-of-life effect of botulinum toxin type A on patients with primary axillary hyperhidrosis: results from a North American clinical study population. | Journal of the American Academy of Dermatology 2004, 50(3): P50 Abstract P196 |
| Lowe NJ et al (2004) | Botulinum toxin type A in primary axillary hyperhidrosis: a 52-week, multicentre, double-blind, randomised, placebo-controlled trial. | Journal of the American Academy of Dermatology 2004, 50(3): P50 Abstract P195 |
| Trial 191622-505 | ||
| Lowe NJ et al (2002) | Effect of botulinum toxin type A on quality of life measures in patients with excessive axillary sweating: A randomised controlled trial. | Journal of Investigative Dermatology 2002, 119(1): 241. Abstract 202 |
| Naumann M et al (2001) | Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double-blind, placebo-controlled trial. | BMJ 2001, 323: 596-599 |
| Naumann MK et al (2002) | Effect of botulinum toxin type A on quality of life measures in patients with excessive axillary sweating: a randomised controlled trial. | British Journal of Dermatology 2002, 147(6): 1218-1226 |
| Connor 2006 | ||
| Connor KM et al (2006) | Botulinum toxin treatment of social anxiety disorder with hyperhidrosis: a placebo-controlled double-blind trial. | Journal of Clinical Psychiatry 2006, 67(1): 30-36 |
| Connor KM et al (2004) | Botulinum toxin treatment of social anxiety disorder with hyperhidrosis: a double-blind, placebo-controlled trial. | Neuropsychopharmacology 2004, 29(S1): S96 Abstract 81 |
| Supplementary studies | ||
| Study 191622-509 | ||
| Lowe PL et al (2003) Naumann M et al (2003) | Botulinum toxin type A in the treatment of bilateral primary axillary hyperhidrosis: efficacy and duration with repeated treatments. Botulinum toxin type A is a safe and effective treatment for axillary hyperhidrosis over 16 months: a prospective study. | Dermatologic Surgery 2003, 29(5): 545-548 Archives of Dermatology 2003, 139(6): 731-736 |
8. Results of Trials
The primary outcomes in the direct randomised trials were based on either gravimetric
assessment or Hyperhidrosis Disease Severity Scale (HDSS) response. The HDSS is a
self-reported scale where patients are asked to rate their condition on a 4-point
scale of: 1= never noticeable/never interferes with daily activities; 2= tolerable/sometimes
interferes; 3= barely tolerable/frequently interferes; 4= intolerable/always interferes.
For gravimetric assessment, a 50% responder was a patient who achieved at least a
50% reduction from baseline in axillary sweat production. For the HDSS, a responder
was defined as a patient who reported at least a two-grade improvement on the 4-point
scale.
Gravimetric responder analysis was the primary outcome in trial 191622-505, and a
secondary outcome in trial 191622-016. Statistically significant differences between
treatment groups in favour of botulinum toxin type A were observed at all stages of
evaluation for both trials. The meta-analysis presented used the gravimetric responder
analysis results at week 4 in trial 191622-505 and week 4, session 1 in trial 191622-016.
The results of the meta-analysis demonstrated that botulinum toxin type A was statistically
significantly superior to placebo at reducing baseline axillary sweating by at least
50% at 4 weeks post-first treatment.
Proportion of patients obtaining a 2-grade improvement on the HDSS
| Bot n/N (%) | Placebo n/N (%) | RR (95% CI) | RD (95% CI) | |
| 191622-016 a | 57/104 (54.8) | 6/108 (5.6) | 9.87 (4.45, 21.89) | 0.49 (0.39, 0.60) |
| Connor 2006 a,b | 15/20 (75.0) | 3/20 (15.0) | 5.00 (1.71, 14.63) | 0.60 (0.35, 0.85) |
Abbreviations: Bot: botulinum toxin type A; RR: relative risk; RD: risk difference;
CI: confidence interval
a Primary outcome in this trial
b Trial recruited patients diagnosed with social anxiety disorder
For the outcome of proportion of patients obtaining a 2-grade improvement on the HDSS,
the PBAC noted that the results were clinically and statistically significant in favour
of botulinum toxin type A over placebo.The PBAC noted that in the direct randomised
trials, statistically significantly more treatment-related adverse events were reported
in the botulinum toxin type A treatment arms compared to the placebo arm. In trial
191622-505, statistically significantly more placebo patients reported an infection,
predominantly described as a “common cold”. No individual adverse events were reported
statistically significantly more often in the botulinum toxin type A treatment arm
than the placebo arm. In trial 191622-016, more overall events, flu syndrome, pharyngitis
and non-axillary sweating (compensatory) events were reported in the botulinum toxin
type A arm than the placebo arm. These differences were statistically significant.
9. Clinical Claim
The submission described botulinum toxin type A as superior in
terms of comparative effectiveness and equivalent or inferior in
terms of comparative safety over placebo for the treatment of
primary axillary hyperhidrosis.
For PBAC’s view, see Recommendation and Reasons.
10. Economic Analysis
The submission presented a trial-based economic evaluation,
providing an estimate of the incremental cost per additional
responder following a single botulinum toxin type A injection,
based on the direct randomised trials (4-week duration) and a
cost-utility economic evaluation (one year duration). The
cost-utility economic evaluation presented a cost per quality
adjusted life year (QALY), using trial derived utilities that had
been extrapolated to 12 months.
The cost-utility economic evaluation provided an estimated
incremental cost per QALY of between $15,000 and $45,000 for
patients receiving 1.46 treatments per year.
A number of sensitivity analyses were conducted during the
evaluation to reflect higher potential costs and reduced effects of
botulinum toxin type A under the requested restriction. The cost
per QALY was increased (but within the same range) when a scenario
assuming a higher number of treatments per year and a lower utility
change from baseline was used.
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 between
10,000 and 50,000 in Year 5 with a financial cost per year to the
PBS estimated to be less than $10 million in Year 5.
The PBAC considered these estimates to be uncertain.
12. Recommendation and Reasons
The PBAC noted that no other second line treatments for severe
hyperhidrosis of the axillae were available on the PBS, and that
currently the only option for patients following failure of
aluminium based anti-perspirants was surgery. The PBAC agreed that
the appropriate comparator was placebo, as surgical options are
rarely used. The PBAC also agreed that there was significant impact
on the quality of life of the patients with hyperhidrosis and that
there was a clinical need for botulinum toxin.
Of the two requested listing options, the PBAC considered Option 1
to be the most appropriate and consistent with current clinical
practice. The PBAC noted that Option 2 uses gravimetric assessment
as an objective measure for diagnosis, but it would be impractical
for use in the clinical setting.
The submission presented three direct randomised trials
(191622-505, 191622-016 and Connor 2006) comparing botulinum toxin
type A with placebo in patients with severe primary axillary
hyperhidrosis. Three open-label studies (study 191622-506,
191622-516 and 191622-075) were also presented as supportive
evidence. The PBAC noted that while all trials used the
TGA-approved dose of 50 U into each axilla, there was variation
with regard to frequency of re-treatment between the trials. None
of the trials assessed the dosing frequency requested in the
restriction of a maximum of two treatments per year.
The primary outcomes in the direct randomised trials were based on
either gravimetric assessment or Hyperhidrosis Disease Severity
Scale (HDSS) response. The PBAC accepted the submission’s
claim of superiority in terms of comparative effectiveness and
equivalent or inferior in terms of comparative safety over placebo
for treatment of primary axillary hyperhidrosis, noting that the
results were clinically and statistically significant in favour of
botulinum toxin type A over placebo for all primary outcomes in the
direct randomised trials and that statistically significantly more
treatment-related adverse events were reported in the botulinum
toxin type A treatment arms compared to the placebo arms.
The PBAC noted that the average number of treatments per year used
in the economic evaluation were estimated to be 1.46 from trials
016 and 505/506, or 1.36 from trial 505/506 only. These trials
allowed treatment every 8 weeks. However, the requested listing
limited the number of treatment per year to two and sensitivity
analyses assuming two treatments per year were conducted during the
evaluation. The PBAC agreed with the sponsor’s
Pre-Sub-Committee Response that to better reflect the trial
approach up to 3 treatments per year may be more appropriate in the
PBS restriction, and this is consistent with the dosage in the
Product Information of repeat injections at intervals of no less
than four months. The average number of treatments per year in the
adolescent study 075 (1.90) was excluded from the economic
evaluation and was considered reasonable as the proportion of
adolescents in the subsidy pool was likely to be low.
The PBAC also considered that uncertainty existed with the
application of utility values for one year in the economic model.
The PBAC agreed that there was uncertainty in assigning constant
improved utility to patients for the entire year, with the
exception of allowing one week for onset of effect. It was
considered that there may be some loss of effect leading up to
requirement for subsequent treatment, which was not considered in
the model, and that it may not be reasonable to assume there is a
constant relationship between gravimetric response and utility as
was applied by this assumption.
The cost-utility economic evaluation provided an estimated
incremental cost per QALY of between $15,000 and $45,000 for
patients receiving 1.46 treatments per year. The PBAC noted that
the results of the sensitivity analysis conducted during the
evaluation indicated that the model was quite sensitive to both the
number of treatments per year, and the value used for the
difference in utility change from baseline between the treatment
groups. The cost per QALY increased (within the same range) when a
scenario considered by the PBAC to be more representative of the
likely Australian situation was used (three treatments per year and
lower utility change from baseline). Therefore, the PBAC considered
that the ICER is likely to be greater than the estimated base-case
if the uncertainty around the utility value and the duration of
response through the entire period between treatments is taken into
account. This was considered to be high in the context of the
condition.
The PBAC therefore rejected the submission on the basis of high and
uncertain cost-effectiveness.
The PBAC noted that the submission met the criteria for an
Independent Review.
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
Allergan Australia welcomes the PBAC’s acknowledgement of the
clinical need for BOTOX® for hyperhidrosis and the
significant impact of the condition on patients’ quality of
life. Allergan will continue to work with the PBAC to make
BOTOX® available under the PBS for the treatment of
hyperhidrosis.
