Botulinum toxin type A purified neurotoxin complex, lyophilised powder for I.M injection, 100 units, Botox® - November 2011
Page last updated: 16 March 2012
Public Summary Document
Product: Botulinum toxin type A purified
neurotoxin complex, lyophilised powder for I.M injection, 100
units, Botox®
Sponsor: Allergan Pty Ltd
Date of PBAC Consideration: November 2011
1. Purpose of Application
The submission sought to extend the current Section 100 listing
(Botulinum Toxin Program) to include the prophylaxis of headaches
in an adult patient with chronic migraine who meets certain
criteria.
2. Background
Botulinum toxin type A had not been previously considered by the
PBAC for this indication.
3. Registration Status
Botulinum toxin type A was registered by the TGA on 15 March 2011 for the indication:
Prophylaxis of headaches in adults with chronic migraine (headache on at least 15 days per month of which at least 8 days are with migraine).
4. Listing Requested and PBAC’s View
Section 100 Botulinum Toxin Program
Authority Required
Prophylaxis of headaches in an adult patient with chronic migraine
who fulfil the following criteria:
1. Patient has experienced an average of 15 or more headache days
per month of which at least 8 days are with migraine, over a period
of at least 6 months
2. Prior failure or intolerance to at least two migraine
prophylactic medications, which should include topiramate for
patients eligible for PBS-subsidised treatment with
topiramate.
Failure of oral prophylaxis is shown by persistence of 15 headache
days per month of which at least 8 days are with migraine after a
trial of at least 3 months duration, unless the patient experiences
intolerance of a severity necessitating permanent withdrawal from
treatment.
Details of the prior medication failures or intolerance(s) must be
documented in the patient's medical records when treatment is
initiated.
Treatment should be discontinued if the patient does not respond
after two treatments. Treatment response is defined as a 30% or
greater reduction from baseline in the number of headache days per
month.
Patients failing to meet the continuation criteria must have a
12-month break from treatment and can then re-trial therapy once
providing the initiation criteria are met.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Migraine is a primary headache disorder that manifests as severe
headache, typically with an intense throbbing pain that is
aggravated by routine physical activity. Patients may also have
associated symptoms such as nausea, vomiting, visual problems and
increased sensitivity to light or sound.
Chronic migraine (CM) is a sub-type of chronic daily headache (CDH)
and is defined as headache on at least 15 days per month, with at
least 8 headache days meeting the criteria for migraine without
aura. In contrast, patients with episodic migraine (commonly
referred to as ‘migraine’) have headache on less than
15 days per month. CDH including CM is associated with
significantly greater impairment in quality of life (QoL) compared
with episodic headache. Patients with CM also have higher rates of
co-morbid conditions including anxiety, depression, obesity and
cardiovascular diseases or risk factors compared to those with
episodic migraine.
Drug therapy options for patients with frequent headaches include
acute pain medications and preventive treatments (prophylaxis). The
aims of prophylaxis are to reduce attack frequency, severity and
duration; reduce the risk of medication overuse, defined as 10-15
days or more per month of certain analgesics; and improve
QoL.
The submission proposed that the place in therapy of botulinum
toxin type A for refractory chronic migraine is to provide initial
treatment to patients who have failed the available oral migraine
prophylactics and continuing treatment to patients who obtain
measurable improvement by 24 weeks.
6. Comparator
The submission nominated best supportive care (BSC), consisting of
no further prophylaxis but use of acute headache pain medications
as required as the comparator.
The PBAC considered that the nominated comparator was not
appropriate and that third-line prophylactic treatment options
would be a more appropriate comparator.
7. Clinical Trials
The submission presented two randomised trials, PREEMPT I and
PREEMPT II, as well as a pooled-data analysis, comparing botulinum
toxin type A with BSC in patients with chronic migraine. Chronic
migraine was defined as 15 or more headache days per month, of
which at least eight are with migraine.
The key outcome measures from the trials were mean change from
baseline in number of headache episodes (PREEMPT I) and mean change
from baseline in headache days (PREEMPT II).
Details of the studies published at the time of submission are
shown in the following table:
| Trial ID/First author | Protocol title/Publication title | Publication citation | |
|---|---|---|---|
| Pooled-analyses of direct randomised trials | |||
| PREEMPT I (191622-079) | |||
| Aurora SK et al 2010 | OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT I trial. | Cephalalgia 30 (7): 793-803 | |
| PREEMPT II (191622-080) | |||
| Diener HC et al 2010 | OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT II trial. | Cephalalgia 30 (7): 804-14 | |
| PREEMPT (pooled analysis) | |||
| Dodick DW et al 2010 | OnabotulinumtoxinA for treatment of chronic migraine: Pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. | Headache 50 (6): 921-36 | |
| Blumenfeld A et al 2010 | Method of injection of OnabotulinumtoxinA for chronic migraine: a safe, well-tolerated, and effective treatment paradigm based on the PREEMPT clinical program. | Headache 50: 1406-18. | |
8. Results of Trials
Comparative effectiveness
The results for the primary outcomes from the PREEMPT trials,
change from baseline in headache days per 28 days and headache
episodes per 28 days at week 24, across the direct randomised
trials are presented in the following table:
Change from baseline in headache days per 28 days and
headache episodes per 28 days at week 24 across the direct
randomised trials
| Trial | Botulinum toxin type A Mean (SD) | BSC mean (SD) | Mean difference (95% CI) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| N | Baseline | Change | N | Baseline | Change | ||||
| Change from baseline in headache days at week 24 (Primary outcome PREEMPT II) | |||||||||
| PREEMPT I | 341 | 20.0 (3.7) | - 7.8 (6.6) | 338 | 19.8 (3.7) | -6.4 (6.7) | -1.4 (-2.4, -0.40) | ||
| PREEMPT II | 347 | 19.9 (3.6) | -9.0 (6.5) | 358 | 19.7 (3.7) | -6.7 (6.7) | -2.3 (-3.25, -1.31) | ||
| Pooled | 688 | 19.9 (3.7) | -8.4 | 396 | 19.8 (3.7) | -6.6 | -1.8 (-2.52, -1.13) | ||
| Change from baseline in headache episodes at week 24 (Primary outcome PREEMPT I) | |||||||||
| PREEMPT II | 347 | 12.0 (5.3) | - 5.3 (5.3) | 358 | 12.7 (5.3) | -4.6 (4.8) | -0.7 (-1.65, -0.33) | ||
| Pooled | 388 | 12.2 (5.3) | - 5.2 | 396 | 13.0 (5.5) | -4.9 | -0.3 (-1.17, -0.17) | ||
| PREEMPT I | 341 | 12.3 (5.2) | - 5.2 (5.2) | 338 | 13.4 (5.7) | -5.3 (5.9) | 0.1 (-1.12, 0.39) | ||
BSC=best supportive care, CI = confidence interval, SD = standard deviation
The results from the pooled analysis of the PREEMPT I and PREEMPT II trials showed that both botulinum toxin type A and BSC demonstrated a large reduction in the number of headache days at week 24 compared to baseline (-8.4 and -6.6 days respectively). Botulinum toxin type A was associated with a statistically significantly greater reduction from baseline in headache days, mean difference -1.8 [95% CI: -2.52, -1.13].
Botulinum toxin type A was also associated with a statistically
significantly greater reduction from baseline in headache episodes
at week 24, mean difference -0.3 [95% CI: -1.17, -0.17].
The results of the post-hoc subgroup analysis of patients who had a
history of treatment with at least one prior prophylactic
medication demonstrated that botulinum toxin type A was associated
with a statistically significantly greater reduction from baseline
in headache days, mean difference -2.29 [95% CI: -3.15,
-1.13].
Post hoc analyses of the PREEMPT trials were also conducted to
determine the proportion of patients in both the botulinum toxin
type A and BSC arms that achieved a response defined as greater
than or equal to a 30% reduction in total headache days.
Comparisons were made with alternative definitions of response,
firstly a greater than or equal to 50% reduction in total headache
days and secondly a greater than or equal to 50% reduction in
moderate to severe headache days and/or a greater than or equal to
30% reduction in headache days. Analyses were conducted for the
total PREEMPT population and subgroups of patients with history of
two or more prior prophylactic treatments.
The difference between botulinum toxin type A and BSC response was
largest in patients who were pre-treated with at least two
prophylactics. However, it should be noted that increasing risk
difference in the more heavily pre-treated population was driven
more by a reduction in the BSC response rather than by increasing
probability of response to botulinum toxin type A.
For PBAC’s view of these results, see Recommendation and
Reasons.
A summary of the adverse events reported in the PREEMPT trials
through week 24 and for the pooled data analysis showed that the
botulinum toxin type A arms of both trials were associated with
more adverse events and serious adverse events than the BSC arms.
These differences were statistically significant using the pooled
data. Botulinum toxin type A treatment was associated with
statistically significantly greater incidence of eyelid ptosis,
neck pain, musculoskeletal stiffness, muscular weakness and myalgia
compared to the BSC treatment group. Additionally, although not
statistically significant, botulinum toxin type A was associated
with a numerically larger incidence of headache and migraine
adverse events than the BSC arm. The clinical trial publications
indicate that most adverse events were mild or moderate in severity
and resolved without sequelae.
The submission provided further safety data derived from: two
Phase-2 studies in patients with chronic migraine but using a
differential dose, seven exploratory Phase-2 studies in patients
with episodic migraine as well as a summary of adverse events
reported within the last periodic safety update review of licensed
and unlicensed indications for botulinum toxin type A. The
submission stated the nature of adverse events observed in patients
with chronic migraine was consistent with the known safety and
tolerability profile of botulinum toxin type A with multiple
injections to the head and/or neck area.
9. Clinical Claim
The submission described botulinum toxin type A as superior in
terms of comparative effectiveness and inferior in terms of
comparative safety over BSC for the prophylactic treatment of
chronic migraine.
The PBAC considered that the claim of superior comparative
effectiveness was not reasonable, however the claim that botulinum
toxin type A is inferior in terms of comparative safety was
reasonable.
10. Economic Analysis
The submission presented a stepped economic evaluation.
Transition probabilities across six headache-day defined health
states from a post-hoc subgroup analysis of patients with ≥2
prior prophylactic treatments were used within the economic model
to determine the reduction in headache days.
The submission estimated that botulinum toxin type A compared to
BSC treatment in patients with chronic migraine, having failed two
prior prophylactic treatments, resulted in an ICER of between
$15,000 and $45,000 per QALY. The PBAC considered that this was as
a result of an assumed continuous efficacy of botulinum toxin type
A treatment in the model.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The net financial cost/year to the PBS was estimated by the
submission to be between
$10 - $30 million in Year 5. The estimate was considered
uncertain.
12. Recommendation and Reasons
The PBAC noted that currently only certain medical specialities may
be authorised to prescribe botulinum toxin type A. The PBAC noted
the advice in the sponsor’s Pre-Sub-Committee Response that
the Faculty of Pain Medicine has chosen not to apply for
authorisation for pain specialists to prescribe botulinum toxin at
this time, and that prescribing of botulinum toxin type A for
chronic migraine would be limited to neurologists, who are
currently authorised prescribers for botulinum toxin type A for
other indications.
The PBAC considered that the nominated comparator of best
supportive care (BSC), consisting of no further prophylaxis but use
of acute headache pain medications as required, was not appropriate
and that third-line prophylactic treatment options would be more a
appropriate comparator. As the requested listing specified use of
botulinum toxin type A after failure or intolerance to at least two
migraine prophylactic agents, and given that more than two
prophylactic treatments are available, the PBAC considered that it
was more appropriate to compare botulinum toxin type A to other
prophylactic treatment. It is also likely that other oral
prophylactic treatments would be tried as third line and that
botulinum toxin type A may be more likely to be reserved for last
line use.
The PBAC noted the results from the pooled analysis of the PREEMPT
I and PREEMPT II trials showed that both botulinum toxin type A and
BSC demonstrated a large reduction in the number of headache days
at week 24 compared to baseline (-8.4 and -6.6 days respectively).
Botulinum toxin type A was associated with a statistically
significantly greater reduction from baseline in headache days,
mean difference -1.8 [95% CI: -2.52, -1.13]. Botulinum toxin type A
was also associated with a statistically significantly greater
reduction from baseline in headache episodes at week 24, mean
difference -0.3 [95% CI: -1.17, -0.17]. The PBAC noted that no
minimum clinically important difference (MCID) in either of these
outcome measures was specified within the PREEMPT trials. The PBAC
noted the large placebo effect in both PREEMPT trials and
considered that the benefit of botulinum toxin type A compared to
BSC was small, and is likely to be of borderline clinical
significance. The PBAC considered that the MCID was unlikely to be
as low as -1.8 headache days or
-0.3 headache episodes, particularly given the large BSC response
compared with baseline is taken into consideration.
The PBAC noted that prior prophylactic treatment was not an
inclusion criterion for the PREEMPT trials, and that the results of
a post-hoc subgroup analysis of patients who had a history of
treatment with at least one prior prophylactic medication
demonstrated that botulinum toxin type A was associated with a
statistically significantly greater reduction from baseline in
headache days, mean difference -2.29 [95% CI: -3.15, -1.13]. The
PBAC noted that this subgroup was not required to have failed two
previous prophylactic treatments and therefore considered that
these results may not be applicable to the requested PBS population
which requires failure of at least two migraine prophylactic
medications. Therefore, the PBAC considered that the claim of
superior comparative effectiveness is not reasonable.
From the pooled results, the PBAC noted that botulinum toxin type A
was associated with statistically significantly more adverse
events, and serious adverse events than BSC. The PBAC considered
that the claim the botulinum toxin type A is inferior in terms of
comparative safety is reasonable.
The PBAC noted the stepped economic evaluation produced a base case
incremental cost per extra quality adjusted life year (QALY) gained
of between $15,000 and $45,000. The results of univariate
sensitivity analyses presented in the submission indicated that the
ICER is most sensitive to the duration of the model, transition
probability estimates, the source of utility values and the
comparative efficacy results used.
The PBAC considered the main areas of economic uncertainty were:
- the transitional probabilities are not sufficiently robust as they were derived from post-hoc subgroup analyses that are not sufficiently powered to assess the transition between six separate health states;
- extrapolation from 48 weeks to 5 years is uncertain as a continued effect of botulinum toxin type A is highly uncertain;
- the utilities from the Burden of Illness Study (BIS) estimated from patient data, may overestimate the incremental benefit associated with moving between the health states.
The PBAC also noted that model did not include adverse events, or
the option to retrial botulinum toxin type A after 12 months,
further adding to the uncertainty in the ICER and that including
these in the model was likely to increase the ICER.
The PBAC considered that there was considerable uncertainty
regarding the submission’s estimates of usage insofar as the
prevalence of chronic migraine, the rate of diagnosis of chronic
migraine, and the proportion of neurologists who can administer
botulinum toxin type A were all likely underestimated. The PBAC
also considered that there was likely to be a considerable risk of
leakage of botulinum toxin type A into other off-label chronic
headache indications, use in patients who have not failed therapy
and for it to be used for its cosmetic effects.
The PBAC therefore rejected the submission on the basis of
uncertain clinical benefit and high and highly uncertain cost
effectiveness.
The PBAC also acknowledged and noted the consumer comments received
in its consideration of this item.
Recommendation:
Reject
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 believes that there is significant unmet clinical need in refractory chronic migraine and will work with the PBAC to make this treatment available for patients on the PBS.
