1 Appraisal Committee's preliminary recommendations

1.1 The Committee is minded not to recommend botulinum toxin type A for the prevention of headaches in adults with chronic migraine.

1.2 The Committee recommends that NICE requests further information on the clinical and cost effectiveness of botulinum toxin type A from the manufacturer, as described in 1.3 to 1.5. This information should be made available for the next Appraisal Committee meeting.

1.3 The information should include full deterministic and probabilistic economic analyses of botulinum toxin type A compared with placebo in adults whose chronic migraine has failed to respond to at least three prior preventive medications and whose medication overuse has been appropriately managed, and which incorporates the following assumptions:

• A neurologist outpatient follow-up cost of £140 for botulinum toxin type A and placebo administration and follow-up.
• Applying the routine care costs used in the placebo arm to people stopping treatment due to inadequate response with botulinum toxin type A.
• Resource use estimates specified in Blumenfeld et al. (2010).
• An average accident and emergency cost of £77.33.
• Transition probability matrices from the three or more prior preventive medications subgroup.
• Positive stopping rule applied to 24% of people who move from health states of chronic migraine to episodic migraine.
• A range of negative stopping rules (up to and including a 50% response rate and also a stopping rule for people whose migraine does not respond) based on the reduction in the number of headache days per 28 days applied to people with chronic migraine after two cycles of treatment.

1.4 Alternative scenario analyses should also be provided which explore the following:

• The impact of using different and the same utilities (within each health state) in the botulinum toxin type A and placebo arms on the revised base-case incremental cost-effectiveness ratios (ICERs).
• Removing the anomaly that for the botulinum toxin type A arm the utility in health state 5 (20–23 headache days per month) is lower than the utility in health state 6 (24–28 headache days per month).

1.5 The Committee also requires further clarification of the following:

• Why the utilities have been calculated in the way they have in terms of the choice of disease-specific outcome measure, the selection of the final regression models and the ability to differentiate between the model health states and between treatments.
• The cause of the lack of monotonic (defined as consistently increasing or decreasing) utilities in the botulinum toxin type A arm, the impact this has on the ICER and whether alternative methods for calculating utilities or defining health states could avoid this issue.
• Why different utilities were used in the botulinum toxin type A and placebo arm (including the evidence to support the size of the difference).
• Why there is a large difference between the deterministic and probabilistic ICERs.
• The costs incurred by only the UK group in the International Burden of Migraine Study (IBMS). Data should include the numbers and ages of patients, sites, resource use (in terms of contacts with outpatients, accident and emergency departments and NHS Direct), the reasons for contacts and the associated costs.

2 The technology

2.1 Botulinum toxin type A (Botox, Allergan) is a purified neurotoxin complex which produces seven neurotoxins that are structurally similar but immunologically distinct. It has neuromuscular transmitter blocking effects. It has a UK marketing authorisation ‘for the prophylaxis of headaches in adults with chronic migraine (headaches on at least 15 days per month of which at least 8 days are with migraine)’. The recommended reconstituted dose is 155–195 units, administered intramuscularly as 0.1 ml (5 units) injections to between 31 and 39 sites around the head and back of the neck. The recommended re-treatment schedule is every 12 weeks (see the summary of product characteristics).

2.2 The summary of product characteristics lists the following adverse reactions that may be associated with botulinum toxin type A treatment: blepharospasm, cervical dystonia, paediatric cerebral palsy, primary hyperhidrosis of the axillae and focal spasticity of the upper limb associated with stroke. It states that ‘in general, adverse reactions occur within the first few days following injection and are transient’. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3 The net price of a 200 unit vial is £276.40 (excluding VAT; ‘British national formulary’ [BNF] edition 62). The manufacturer estimates that the administration cost is £73 per treatment, based on a total treatment time of less than 30 minutes. The total cost for treatment and administration of treatment per 12 week cycle, assuming no vial sharing, is therefore expected by the manufacturer to be £349.40. Costs may vary in different settings because of negotiated procurement discounts.

3 The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of botulinum toxin type A and a review of this submission by the Evidence Review Group (ERG; appendix B).

3.1 The decision problem defined in the scope asked whether botulinum toxin type A is clinically and cost effective in adults whose chronic migraine has failed to respond to at least three prior pharmacological prophylaxis therapies and whose medication overuse has been appropriately managed, compared with standard management without botulinum toxin type A excluding invasive procedures. The manufacturer addressed this decision problem in its submission.

Clinical effectiveness

3.2 To establish the efficacy of botulinum toxin type A, the manufacturer performed a systematic review to identify randomised controlled trials comparing botulinum toxin type A with placebo. The manufacturer identified seven relevant trials, of which four were against an active comparator and were therefore excluded from consideration. Of the three remaining trials, two were large phase III trials and were the focus of the manufacturer’s submission. The third was a small trial (n = 60) that was not described.

3.3 Evidence from the two randomised controlled trials, PREEMPT 1 and PREEMPT 2 (phase III trials evaluating migraine preventive therapy), was presented, as well as the pooled results from these trials. The trials were identically designed with a 56-week treatment period. In total, 688 people were recruited into the botulinum toxin type A arms of the trials and 696 into the placebo arms. Patients were stratified by their use of acute headache pain medication at baseline. The first phase of the trial was a 24-week double-blind phase, in which patients received a series of 31–39 intramuscular injections of botulinum toxin type A or placebo (saline), at day 0 and week 12. In the second phase of the trial, from week 24 to 56, patients entered into a 32-week, open-label phase in which all patients continuing in the trials received botulinum toxin type A at weeks 24, 36 and 48.

3.4 The PREEMPT trials enrolled people aged 18 to 65 years who had a history of migraine headache disorder. All patients had to have had at least 15 headache days in the 28 days before week 0, and at least 50% of headache days had to be migraine or probable migraine days. Most people in the trials received at least one prior preventive treatment (> 61%), and approximately 35% of the patients had received three or more prior preventive treatments. Most people in the trials overused acute pain medication (> 64%). The PREEMPT trials recruited people from North America and Europe, including from the UK. Patients were excluded if they used headache preventive medications within 4 weeks of the start of baseline, or if their headache was attributed to other disorders such as medication overuse. However, chronic migraine patients with protocol-defined overuse of acute medications were included and this was a stratification factor at randomisation.

3.5 The characteristics of the patients in the trials were similar, with no statistically significant differences between baseline characteristics in the PREEMPT 2 trial. In PREEMPT 1, most differences between groups were statistically non-significant, except for mean headache episodes and mean migraine episodes which were higher in the botulinum toxin type A group compared with the placebo group, and the number of cumulative headache hours which were lower in the botulinum toxin type A group compared with placebo group.

3.6 All efficacy analyses from the two trials used the intention-to-treat population, which included all randomised patients.Results for most of the trial outcomes were statistically significant in favour of botulinum toxin type A. The reduction in frequency of headache days (the primary endpoint) was statistically significant in both trials. In PREEMPT 1, there was a reduction of 7.8 headache days from 20.0 (per 28 days) at baseline for patients treated with botulinum toxin type A, compared with a reduction of 6.4 headache days from 19.8 for those in the placebo arm (p = 0.006). In PREEMPT 2, there was a reduction of 9.0 headache days from a baseline of 19.9 in the botulinum toxin type A arm, compared with a reduction of 6.7 headache days from a baseline of 19.7 days for those in the placebo arm (p < 0.001). The difference between the two arms of the trials for the frequency of headache episodes was not statistically significant in the PREEMPT 1 trial, but was statistically significant in the PREEMPT 2 trial. The following were statistically significantly lower in the botulinum toxin type A arm compared with the placebo arm in both trials: total cumulative hours of headache on headache days; the frequency of migraine days, migraine episodes, and moderate to severe headache days. There was no difference in the intake of acute pain medication between the arms in both studies. The pooled results of the two trials were consistent with the results from the individual studies: for the outcome of frequency of headache days (per 28 days), the pooled botulinum toxin type A group had a statistically significant reduction of 8.4 headache days from 19.9 days at baseline, compared with a reduction of 6.6 headache days from 19.8 days in the pooled placebo group (p < 0.001).

3.7 The PREEMPT trials measured health-related quality of life, using the headache impact test 6 (HIT-6) and the migraine-specific quality of life questionnaire (MSQ). The HIT-6 was developed for use in people with general headache whereas the MSQ was developed specifically for people with chronic migraine. At 24 weeks, there was a statistically significant improvement from baseline in quality of life as measured by the HIT-6 for people in the botulinum toxin type A arm compared with those in the placebo arm in both trials. Both trials also reported statistically significant improvements from baseline in quality of life as measured by the MSQ in the botulinum toxin type A arm compared with the placebo arm.

3.8 The most frequently reported adverse events occurring at a higher incidence in the pooled botulinum toxin type A group than in the pooled placebo group were: neck pain, headache, migraine, eyelid ptosis, musculoskeletal stiffness and muscular weakness. Of these, neck pain was the only one to occur at a rate of 5% or more in the pooled botulinum toxin type A arm compared with the pooled placebo arm.

3.9 A subgroup analysis (which was submitted by the manufacturer as commercial in confidence and is therefore not presented) was conducted for people who had previously received three or more headache preventive medications, for the outcome of frequency of headache days (per 28 days), using the pooled data from the PREEMPT trials. Treatment efficacy for frequency of headache days was similar for the subgroup of people who had previously received three or more preventive treatments, those who had previously received two preventive treatments, and those who had previously received one or more preventive treatments.

Cost effectiveness

3.10 The manufacturer systematically reviewed economic evaluations of botulinum toxin type A for people with chronic migraine but no relevant published studies were identified.

3.11 The manufacturer developed a Markov model using the pooled data from the two PREEMPT trials, comparing botulinum toxin type A with placebo. Only approximately 35% of the population met the criteria set out in the NICE scope (people whose condition has failed to respond to three or more prior pharmacological prophylaxis therapies). Therefore the manufacturer used the population whose condition had failed to respond to one or more pharmacological therapies, which was approximately 64% of the trial population.

3.12 Six health states were defined in the model according to the number of headache days per month: 0–3 (health state 1), 4–9 (health state 2), 10–14 (health state 3), 15–19 (health state 4), 20-23 (health state 5) and 24 or more (health state 6). Patients could enter the model in any of the three chronic migraine states; chronic migraine was defined as 15 headache days or more per 28 days. The cycle length was 12 weeks, which is the same as the frequency of administration of botulinum toxin type A in the trials. The model used the transition probabilities observed in the clinical trials, which include the transitions between the six health states as well as an additional transition to discontinuation of therapy. For the placebo arm, the second cycle transition probability was repeatedly applied after week 24. For the botulinum toxin type A arm, the same transitional probability matrix was applied for the third, fourth and fifth cycles; this figure was calculated by averaging these three cycles. For people continuing on treatment in cycles 6–9, the same average figure was used. The time horizon used in the model was 2 years, in line with the manufacturer’s expected maximum treatment duration with botulinum toxin type A. For the first of the 2 years, trial data were used if possible, with extrapolation used for the second year, using the last observations from the trial.

3.13 As well as using the discontinuation data from the clinical trials in the model, two treatment (dis)continuation rules were applied. A negative stopping rule was applied at week 24 for people whose condition responded insufficiently to botulinum toxin type A. Insufficient response was defined as people having an improvement of less than two health states (a reduction of between 5 and 10 headache days per 28 days depending on both the number of headache days and the corresponding health state at the start of treatment) following two successive cycles of treatment. After discontinuation, they moved to the ‘off-treatment’ arm of the model. A positive stopping rule was applied at week 48 for people whose condition had moved to an episodic migraine classification (fewer than 15 headache days per 28 days). The model assumed that after 1 year, people whose condition had moved to an episodic migraine classification stopped treatment with botulinum toxin type A and remained stable in the episodic migraine states thereafter.

3.14 Two mapping equations were derived to map the MSQ data (as collected during the trials) to EQ-5D utility, so that utilities could be attached to each health state. One equation was used to predict utility scores for people in the chronic migraine health states, and the other was used for predicting utilities in the episodic health states. Utility was assumed to differ for each health state in this model and also between treatments within the same health state, the latter being justified on the grounds that treatment with botulinum toxin type A was shown to affect the severity and intensity of headaches, as well as the number of headache days. Utility was predicted for each health state using the patient-level data from the trials. This was done by grouping patients by health state and calculating the mean utility per treatment group. Utility values used in the model ranged between 0.479 and 0.746 depending on the treatment and on the number of headaches experienced. Adverse events affecting health-related quality of life were captured in the model by applying discontinuation rates and by using patient-level data to predict utility. There were assumed to be no additional costs relating to adverse events.

3.15 The manufacturer assumed that the relevant patient population would be managed in a specialist setting, with associated consultant-related costs. Administration time was assumed to be 30 minutes, at a mean cost of £73.00. Cost of treatment was calculated based on one 200 unit vial of botulinum toxin type A at £276.40, with no vial sharing, leading to a total cost of £349.40 per 12 week cycle. For people in the placebo arm (standard care), the cost was assumed to be £36.50 per 12 weeks, which is based on a 15 minute appointment with a consultant every 24 weeks to optimise acute therapy. Costs for GP visits, accident and emergency use, hospitalisation and the cost of triptan were modelled for each health state but only three different costs were used: health state 1, states 2–3 and states 4–6. These costs came from a recently presented poster by Bloudek et al. of Scottish resource use according to the IBMS. Costs and quality-adjusted life years (QALYs) were discounted at a rate of 3.5% per year.

3.16 In the base case, for people whose condition failed to respond to at least three prior preventive medications, the discounted total cost and QALYs for placebo were £1895 and 1.20 respectively, compared with a total cost of £2438 and 1.29 QALYs for botulinum toxin type A. This gave an incremental cost and incremental QALYs of £543 and 0.09 respectively and an ICER of £6083 per QALY gained for botulinum toxin type A compared with placebo. There was a 69.1% probability of botulinum toxin type A being cost effective if the maximum acceptable ICER was £20,000 per QALY gained. The manufacturer did not report a central estimate of the ICER calculated by probabilistic modelling. For the wider population, which included people whose condition had not responded to one or more prior preventive medications, the costs and QALYs were similar, with an ICER of £5828 per QALY gained for botulinum toxin type A compared with placebo.

3.17 The manufacturer presented a variety of sensitivity analyses, and for most of the cases the ICER for botulinum toxin type A compared with placebo stayed under £10,000 per QALY gained. Excluding the positive and negative stopping rules increased the ICER to £15,294 per QALY gained. Restricting the time horizon to 1 year increased the ICER to £14,098 per QALY gained.

3.18 The manufacturer submitted revised ICERs using corrected utilities for people whose condition failed to respond to at least three prior preventive medications. After correcting for this, the ICER for botulinum toxin type A compared with placebo increased from £6083 to £6434 per QALY gained.

Comments from the Evidence Review Group

3.19 The ERG noted that the trials were generally of good quality. The ERG pointed out that in the PREEMPT 1 trial, at baseline patients in the botulinum toxin type A group had a statistically significantly lower frequency of migraine episodes (11.5 compared with 12.7, p = 0.006) and frequency of headache episodes (12.3 compared with 13.4, p = 0.023), but had statistically significantly more cumulative hours of headache on headache days (295.7 compared with 274.9, p = 0.022) than those in the placebo group. The original primary outcome in PREEMPT 1 was to have been frequency of headache episodes, but this was changed to headache days because of new guidelines for the conduct of clinical trials in chronic migraine. This was considered reasonable by the ERG.

3.20 The ERG found botulinum toxin type A to be effective regardless of the number of previous preventive medications taken and that as the number of previous preventive medications rose, so did the relative effectiveness of botulinum toxin type A compared with placebo (reductions of 2.4 and 2.7 headache days per month for the one prior preventive medication and three or more prior preventive medications subgroups respectively). In addition, the ERG observed that the placebo effect decreased as the number of previous medications increased.

3.21 The ERG stated that a noticeable feature of the trial data was the size of the improvement on placebo, which lasted for at least 24 weeks and was only modestly less than on active treatment. In addition the ERG pointed out that the efficacy of botulinum toxin type A was greatest with the first injection and that the second injection had much less effect, with similar efficacy to that of the second placebo injection. The ERG therefore queried whether the effect of botulinum toxin type A treatment lasts longer than 12 weeks and whether a negative stopping rule could be applied after the first injection.

3.22 The ERG’s main concern about the design of the PREEMPT trials was about whether blinding was maintained and if not, what the effect of this was on the results of the trials. The ERG pointed out that in previous botulinum toxin type A trials, 70% of patients receiving botulinum toxin type A correctly guessed what they had received, because of changes in muscle tone such as reduced wrinkling of the forehead. The ERG further explained that because unblinding is an important factor in controlled trials of preventive treatment of chronic migraines, the International Headache Society guidelines recommend that subjects and investigators should be questioned at the end of trials about whether they thought the subject was assigned to the active or placebo group during the trial. This was not done in the PREEMPT trials.

3.23 The ERG considered the manufacturer’s model to be reasonable for the decision problem. The ERG noted that the model and trial datasets for headache days per month at week 24 corresponded poorly and that this overestimated the net impact of botulinum toxin type A by 53%. Yet this overestimate had no direct impact on cost effectiveness because it was the distribution between health states that determined the costs and QALYs within the model. The ERG observed that within the validation data, the model and trial were reported by the manufacturer as having no patients in health states 5 and 6 at week 24 in the botulinum toxin type A arm. The ERG noted that this could be due to the negative stopping rule being applied in both sets of data with these patients falling into the discontinuation category, but could not verify this. Uncertainty remained around this point and also the distribution between health states among those patients modelled as discontinuing due to the negative stopping rule but who were followed up within the trial. The ERG noted that there were no clinical data to support the use of the two stopping rules. The ERG queried whether the negative stopping rule at 24 weeks in the model would apply in practice, and whether the requirement for an improvement could be based on either one or two health states. It found that an improvement of only one health state within two cycles increased the ICER for the three or more prior preventive medications subgroup from £6083 per QALY gained to £8354 per QALY gained. The ERG stated that the positive stopping rule at week 48 was unlikely to be implemented. It queried how long people who had stopped treatment would remain stable before needing re-treatment, noting 2-year follow-up data from a published abstract by Rothrock et al. (2011), which estimated the duration of response to treatment with botulinum toxin type A based on a 50% reduction in the number of headache days per month. Of a total sample of 100 people with chronic migraine which responded to treatment with botulinum toxin type A, 68% maintained a good response to treatment with continued injections at a frequency of 3.2 months. A further, 24% were able to stop treatment and maintain a good response for at least 6 months; of these 8% relapsed back to chronic migraine. The ERG found that removing the positive stopping rule roughly doubled the ICER for the three or more prior preventive medications subgroup for botulinum toxin type A arm compared with placebo, from £6083 per QALY to £12,542 per QALY gained.

3.24 The ERG noted that the construction of the transition probability matrices for cycles 3, 4 and 5 in the botulinum toxin type A arm of the model was unusual in that the data are not specific to the time frames of these cycles, but rather are pooled between them. The ERG stated that alternative approaches may increase the ICER by between 5% and 10%.

3.25 The ERG noted that there were wide disparities between the model inputs for resource use used in the economic model, which were based on a poster by Bloudek et al., and those reported in a published paper by Blumenfeld et al. The ERG noted that the two sources had reported results from the same study, however Bloudek et al. appear to include costs based on Scottish implementation, with no information on the number and ages of the patients, GP visits, hospital outpatient and accident and emergency attendances, hospital admissions or medication use. The ERG noted that because the higher costs for health states 4–6 were driven by hospital admission costs and were the same in each of the health states 4–6, details of the Bloudek et al. poster were important because it could be that the manufacturer’s estimate of resource use was too high. It was for this reason that the ERG preferred the resource use detailed in Blumenfeld et al. which contained more detailed data.

3.26 The ERG noted that the manufacturer’s model generally assigned higher utility values for the botulinum toxin type A arm than the placebo arm for each health state and that this feature of the model accounted for about a half of the anticipated gain for botulinum toxin type A. It noted that for this to be valid, there would have to be a difference in other features such as: the number of headaches experienced during a headache day, the duration of these headaches, or the proportion of headaches that were migraines. The ERG noted that this was plausible, although it was unsure whether the substantial difference in utilities in each health state was justified given the small absolute differences in secondary endpoints in the PREEMPT trials. The ERG commented that the number of headache days per month was not included in the estimate of utilities, which instead relied on IBMS MSQ data. The manufacturer had outlined a regression analysis from the EQ-5D in the IBMS study and found that the EQ-5D and the number of headache days per month were statistically significantly negatively correlated. The ERG used these data and showed very little difference in utilities between botulinum toxin type A and placebo in a given health state. The ERG queried whether the IBMS MSQ data could be used to estimate utilities given that the IBMS study included a different population to that described in the decision problem. It noted that a more appropriate estimation of utilities would encompass both MSQ and HIT-6 data. The ERG also explained that there is an anomaly between the utility values in the botulinum toxin type A arm in which people in health state 5 (20–23 headache days per month) have a lower utility than those in health state 6 (24–28 headache days per month). The ERG commented that this may highlight some uncertainty between the mapping of MSQ data to utilities and correspondence with the model structure as defined by the number of headache days per month.

3.27 The ERG noted that the model included the cost of administering botulinum toxin type A and of placebo, based on 30 and 15 minutes of neurologist time respectively. The ERG stated that review of a patient and administration of botulinum toxin type A may take between 30 minutes and 1 hour, depending on the experience of the person injecting and the possibility of complications during administration. As a result the ERG commented that the cost of administering botulinum toxin type A based on 30 minutes of neurologist time may be too optimistic. It also noted that the appropriate cost of follow-up out-patient consultations should be the standard NHS neurological outpatient follow-up reference cost of £140. The ERG noted that administration of botulinum toxin type A was reported to be offset by cost saving because of reductions in GP visits, inpatient admissions and accident and emergency use but that they considered the amount of the cost saving to be overestimated.

3.28 The ERG explained that the model submitted by the manufacturer was non-linear, with a central probabilistic estimate of cost effectiveness more than double that of the deterministic estimate. It stated that some elements of the probabilistic modelling seemed unwarranted; for example, treating the identity matrix as having an uninformed prior and modelling it probabilistically. The ERG found that removing these elements reduced the degree of non-linearity but did not eliminate it. The ICER for the three or more prior preventive medications subgroup increased from the manufacturer’s deterministic ICER of £6083 per QALY gained to the probabilistic ICER of £11,447 per QALY gained if the ERG’s revisions were applied. If the ERG’s revisions were not applied the probabilistic ICER was estimated at £14,004 per QALY gained.

3.29 The ERG conducted a number of different exploratory sensitivity analyses. In these analyses, the ERG used the manufacturer’s model with a number of modifications. The modifications included:

• A neurologist outpatient face-to-face follow-up cost of £140 for botulinum toxin type A administration and placebo follow-up (instead of £73 administration cost of botulinum toxin type A administration and £36.50 follow-up placebo cost, based on 30 and 15 minutes of neurologist time respectively).
• Placebo routine care costs incorporated for patients stopping therapy in the botulinum toxin type A arm (instead of no ongoing routine care costs).
• Resource use estimates from Blumenfeld et al., who included all UK participants from the IBMS study (instead of from Bloudek et al. who appeared to use costs based on Scottish implementation).
• Transition probability matrices from the three or more prior preventive medications patient subgroup (instead of from the one prior preventive medication population).
• An average accident and emergency cost of £77.33 (instead of £90.94).

3.30 The ERG reported that applying all the above modifications (using the manufacturer’s utility values based on the one-prior treatment) resulted in an increase in the ICERs for botulinum toxin A compared with placebo to give a deterministic ICER of £10,257 per QALY gained and a probabilistic ICER of £16,165 per QALY gained. The ERG reported that there was a 67% probability of botulinum toxin type A being cost effective if the maximum acceptable ICER was £20,000 per QALY gained, and a 87% probability of botulinum toxin type A being cost effective if the maximum acceptable ICER was £30,000 per QALY gained.

3.31 The ERG also explored the impact on the deterministic ICER of varying the negative and positive stopping rules and applying the same utility values for each arm. In these analyses, all the modifications outlined in 3.30 were applied and the utilities from the three or more prior preventive medications subgroup were used. The ERG also used 2-year follow-up data from a published abstract by Rothrock et al. (2011), in which 24% of people with chronic migraine who responded to treatment with botulinum toxin type A were able to stop treatment and maintain a good response for at least 6 months; of these 8% relapsed back to chronic migraine.

3.32 Applying the same utilities from the three or more prior preventive medications patient subgroup to both arms (based on the updated utility data from the manufacturer) resulted in lower QALYs for botulinum toxin type A with no change in costs, compared with the base case. When the manufacturer’s base case positive and negative stopping rules and different utilities were used the deterministic ICER for botulinum toxin compared with placebo was £11,267 per QALY gained, compared with £20,324 per QALY gained when the same utilities were applied to both arms for each health state. When the positive stopping rule was excluded (compared to using the positive stopping rule for people who move from chronic to episodic migraine) the ICER for botulinum toxin A compared with placebo increased from £11,267 to £19,483 per QALY gained when different utilities were used in the botulinum toxin A and placebo arms. When a positive stopping rule was applied to 24% of people who had moved from a health state of chronic migraine to episodic migraine (based on the study by Rothrock et al.) the ICER for botulinum toxin A compared with placebo increased from £11,267 to £17,438 per QALY gained. The ERG also applied various negative stopping rules: no negative stopping rule, an improvement of at least one health state within the first cycle; improvement of at least one health state within two cycles; and the manufacturer’s base case of an improvement of two health states in two cycles. When no negative stopping rule was applied and different utilities were used in the botulinum toxin A and placebo arm the ICER for botulinum toxin A compared with placebo was £13,986 per QALY gained. When different negative stopping rules were applied the ICER for botulinum toxin A compared with placebo ranged from £9618 to £13167 per QALY gained. The scenario that had the most impact on the model results for botulinum toxin type A compared with placebo was when no positive and negative stopping rules were applied. This led to an ICER of £24,387 per QALY gained if different utilities for the three or more prior preventive medications patient subgroup were applied to both arms, or £46,290 per QALY gained if the same utilities for the three or more prior preventive medications patient subgroup were applied to both arms. The ERG also remarked that applying separate estimates for the transition probabilities for cycles 3, 4 and 5 to be more in line with patient data would further increase the ICERs by 5–10%.

3.33 Full details of all the evidence are in the manufacturer’s submission and the ERG report, which are available from www.nice.org.uk/guidance/TAXXX

4 Consideration of the evidence

4.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of botulinum toxin type A, having considered evidence on the nature of chronic migraine and the value placed on the benefits of botulinum toxin type A by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.2 The Committee considered the impact of chronic migraine on the everyday life of people with the condition. It heard from the patient experts that chronic migraine is accompanied by severe pain, which impacts greatly on people’s quality of life, affecting their ability to work and participate in social activities. The patient experts also noted that people with chronic migraine often experience anxiety and depression related to their condition. The Committee considered chronic migraine to be a debilitating condition which significantly affects health-related quality of life.

4.3 The Committee considered current clinical practice for the treatment of chronic migraine. The Committee heard from the clinical specialists that it is important for people first presenting with chronic migraine to try a range of oral preventive treatment options before considering treatment with botulinum toxin type A. The clinical specialists stated that there is no one measure of response to treatment and that response is multifaceted. The Committee heard from the clinical specialists that a good response to treatment is typically considered to be a 30–50% reduction in the frequency of headache days or headache episodes. The Committee also noted that when a person’s response to treatment is assessed, clinicians also take account of any improvement in the person’s quality of life, and that improvements may not always be accompanied by substantial reductions in the number of headache days. It heard from clinical specialists that people considered for treatment with botulinum toxin type A are assessed for oral medication overuse before treatment starts, and that this is monitored during treatment. The Committee also heard from the patient experts that many people with chronic migraine would consider any degree of response to treatment to be valuable and that further treatment options were important.

4.4 The Committee considered the administration of botulinum toxin type A and monitoring of the potential benefit associated with treatment. It heard from clinical specialists that an initial consultation typically lasts between 45 minutes and 1 hour and includes administration of botulinum toxin type A, which can take between 15 and 30 minutes depending on the experience of the person administering the injection. After treatment patients are asked to keep a headache diary. The clinical specialists stated that the re-treatment interval with botulinum toxin type A in practice varies. Some clinical practices have routine follow-up about every 3 months. This will be either a telephone consultation with a consultant or headache specialist nurse, or a 30-minute clinic appointment with the consultant during which repeat injections may be administered. In other clinical practices there is no routine follow-up and patients must request an appointment to be considered for further treatment with botulinum toxin type A. The Committee concluded that the re-treatment interval with botulinum toxin type A is variable in practice, being three months in some patients but at much greater intervals in others.

4.5 The Committee considered the evidence on the clinical effectiveness of botulinum toxin type A for the prevention of headaches in adults with chronic migraine from the PREEMPT trials, which compared botulinum toxin type A with placebo. The Committee noted that the pooled results for the intention-to-treat population indicated a statistically significant reduction in frequency of headache days per month, migraine days per month and cumulative headache hours with botulinum toxin type A compared with placebo, but considered the absolute benefit of botulinum toxin type A over placebo to be modest. It also noted the statistically significant reduction in the frequency of headache episodes, migraine episodes and frequency of acute headache medication days with botulinum toxin type A compared with placebo, but that the absolute differences between the treatments were small. The Committee observed that there was no statistically significant difference in how often acute pain medication was taken. Furthermore, the Committee noted the large placebo effect seen in the trials and that this placebo effect may have been increased by people in the active treatment arm realising that they were receiving botulinum toxin type A because of its side effects. The Committee noted that the duration of follow-up in the PREEMPT trials was short and the study design, which meant that all patients received the active drug from week 24, could not exclude natural improvements in people’s condition over time. The Committee heard from clinical specialists that at baseline, patients in the clinical trials had fewer headache days per month (a mean of 19) than people with chronic migraine in secondary care in the UK (a mean of 25–26 headache days per month). The clinical specialists said that this might explain why the benefit observed in the trials was less than what they would expect to see in clinical practice. The Committee discussed the duration of the therapeutic effect of botulinum toxin type A and heard from the clinical specialists and patient experts that when a person’s condition responds to botulinum toxin type A, the re-treatment interval varies, and that many patients need treatment for longer than 2 years. It concluded that, although the clinical trial evidence demonstrated statistically significant benefits of botulinum toxin type A treatment compared with placebo for a number of outcomes, the absolute differences were small to modest and the magnitude of the effect of botulinum toxin type A was confounded by the large placebo effect seen in the clinical trials.

4.6 The Committee considered the clinical trial evidence in light of the views of the patient experts and clinical specialists. The Committee noted the improvements in quality of life for patients whose condition responded to botulinum toxin type A. The Committee then considered the use of botulinum toxin type A in clinical practice in the UK. The Committee heard from clinical specialists that if the chronic migraine was responding to botulinum toxin type A, the treatment would be continued until the number of headache days was reduced to fewer than 15 headache days per 28 days (episodic migraine). The clinical specialists estimated that people would have at least two treatments. They said that after this approximately 50% of people would continue on treatment, and of those 30% would need five cycles of treatment before their condition was reclassified as episodic migraine. The remaining patients would continue to receive treatment for longer than 2 years. Alternatively, if chronic migraine does not respond adequately to botulinum toxin type A after at least two courses of treatment, and there is little benefit to the patient, treatment is discontinued and patients would receive standard care. The Committee noted that the clinical trial evidence on the effectiveness of botulinum toxin type A was for 1 year. The Committee was aware of the abstract by Rothrock et al. (2011), which estimated duration of response to treatment with botulinum toxin type A, with response to treatment defined as a 50% reduction in the number of headache days per month. The Committee noted that only 24% of the patients who responded to treatment were able to stop treatment and maintain a good response for at least 6 months. The Committee concluded that because there are no long-term clinical trial data, Rothrock et al.’s estimates are likely to be the best estimates of the duration of benefit for people who respond to botulinum toxin type A in clinical practice in the UK.

4.7 The Committee discussed the side effects of treatment with botulinum toxin type A for chronic migraine. It noted the adverse events reported in the trials with botulinum toxin type A (see section 3.8). It heard from the patient experts that there is often pain around an injected site lasting a few days following treatment with botulinum toxin type A. However people would be willing to tolerate the adverse effects of botulinum toxin type A treatment to reduce the frequency or severity of chronic migraine. The Committee concluded that botulinum toxin type A is generally well tolerated; a conclusion supported by the patient experts.

4.8 The Committee considered the cost effectiveness of botulinum toxin type A compared with standard care, based on the manufacturer’s economic model and the critique by the ERG, in the context of the decision problem. The Committee was aware that the scope specified that the population should include adults with chronic migraine whose condition has failed to respond to at least three prior pharmacological prophylaxis therapies, and whose medication overuse has been appropriately managed. The Committee was aware that the manufacturer had focused on this population in a sensitivity analysis and that its main submission compared botulinum toxin type A with placebo in people whose condition has failed to respond to at least one prior preventive medication. The Committee noted comments from the clinical specialists that people first presenting with chronic migraine will be prescribed a range of oral preventive medication options before treatment with botulinum toxin type A is considered. The Committee concluded that the main decision problem proposed by the manufacturer, comparing botulinum toxin type A with placebo in people whose condition has failed to respond to at least one prior preventive medication, did not reflect clinical practice. It concluded that it was only relevant for the Committee and the NHS to consider the clinical and cost effectiveness of botulinum toxin type A in people whose chronic migraine has failed to respond to at least three prior preventive medications.

4.9 The Committee discussed the manufacturer’s cost-effectiveness estimates for adults whose chronic migraine has failed to respond to at least three prior preventive medications, and whose medication overuse has been appropriately managed. The Committee noted that the model was based on the movement of patients through health states related to the number of headache days per month, which resulted in the manufacturer’s deterministic ICER for botulinum toxin A compared to placebo of £6,000 per QALY gained. It noted that a central estimate of the probabilistic ICER was not presented by the manufacturer. It further noted the ERG’s concerns over some of the model inputs and assumptions, particularly: the levels of resource use and associated costs based on the IBMS study; the calculation of and differences in the utilities for people treated with botulinum toxin type A compared with placebo; and the use of negative and positive stopping rules.

4.10 The Committee considered the ERG’s concern that the cost of administering botulinum toxin type A and of no treatment, based on 30 and 15 minutes of neurologist time respectively, may be too optimistic. The Committee was aware that the clinical specialists stated that consultations can take up to 30 minutes regardless of whether the patient is treated with botulinum toxin type A or not because of the extra discussion about management if the patient is not to be treated with botulinum toxin type A. The Committee concluded therefore that the placebo follow-up cost should be the same as the administration cost of botulinum toxin type A. It also concluded that it would be more appropriate to apply the standard NHS neurological outpatient follow-up reference cost of £140.

4.11 The Committee considered the lack of ongoing routine care costs for people who discontinue botulinum toxin type A because of lack of efficacy. In light of evidence from the clinical specialists that people who discontinue botulinum toxin A treatment because of lack of efficacy would receive standard care, the Committee considered it appropriate for routine care costs to be applied to these people. The Committee concluded that the routine care costs used in the placebo arm should be applied to people who discontinue botulinum toxin type A because of lack of efficacy in the model.

4.12 The Committee considered the marked increase in resource use (particularly inpatient admissions and to a lesser extent accident and emergency use) associated with chronic migraine compared with episodic migraine as presented in the manufacturer’s model. The Committee heard from clinical specialists that people with chronic migraine often present at accident and emergency departments because of the chronic debilitating nature of the condition but they are rarely admitted as inpatients. The Committee therefore considered the assumptions related to the increased accident and emergency costs to be appropriate but not the assumptions about inpatient costs with chronic migraine. The Committee also considered the ERG’s concern that the appropriate average accident and emergency cost to include is £77.33 rather than the £90.94 used by the manufacturer. The Committee concluded that the appropriate accident and emergency cost to include in the model was £77.33.

4.13 The Committee considered the most appropriate choice of data on which to base resource use. It was aware that the Blumenfeld et al. published paper and the Bloudek et al. poster gave different figures for average resource use by health state for: GP visits, inpatient admissions, and accident and emergency use. It heard from the manufacturer that Bloudek et al. reported resource use based on all patients included in the IBMS study. The manufacturer’s representative at the meeting stated that an exploratory analysis based on resource use from UK patients gave similar results to those reported in Blumenfeld et al. The Committee considered that there was still uncertainty about the applicability of the IBMS data for resource use and costs related to the use of botulinum toxin type A in the NHS. The Committee concluded that in the absence of costs for UK patients, Blumenfeld et al. was the appropriate source for resource use because they were clearer about the number and ages of the patients, GP visits, hospital outpatient and accident and emergency attendances, hospital admissions and medication use, but concerns remained about the applicability of this data to the UK. The Committee concluded that additional clarification was needed from the manufacturer on the level of resource use specific to UK patients.

4.14 The Committee discussed the updated utilities submitted by the manufacturer. The Committee considered the way in which the MSQ coupled with additional patient characteristics had been mapped onto EQ 5D utilities as drawn from the IBMS data, and noted that either this mapping function or the underlying trial based patient level data that had been applied to it led to an anomaly between the utility values in the botulinum toxin type A arm in which people in health state 5 (20–23 headache days per month) have a lower utility than those in health state 6 (24–28 headache days per month).The Committee heard from the manufacturer’s representative that this anomaly resulted in large differences in the results of the deterministic and probabilistic analyses. The Committee concluded that there was still considerable uncertainty about the cause of the anomaly between the utility of health state 5 and 6 in the botulinum toxin type A arm, and its effect on the ICERs. It concluded that additional clarification was needed from the manufacturer and that the anomaly needed to be resolved in any revised analyses, so that utilities were monotonic (defined as consistently increasing or decreasing) as the health states progressively changed.

4.15 The Committee considered the fact that different utilities were used within a health state depending on the treatment arm, with higher utilities in the botulinum toxin type A arm than in the placebo arm. The Committee noted that the ERG’s additional sensitivity analysis (based on the updated utility values from the manufacturer) showed that the different utilities accounted for up to half of the utility gain in the model. The Committee noted that when the same utility was used across health states regardless of the treatment arms, the ICERs approximately doubled. The Committee noted that it was plausible that patients might have a higher utility in the botulinum toxin type A arm because, as well as fewer headache days (which was already captured in the model), they may also have less severe and intense headaches. However, the Committee considered that the rationale and evidence base behind this assumption needed clarifying. It was aware that the ERG considered it more appropriate to estimate utilities using both MSQ and HIT-6 data. The Committee concluded that further clarification should be requested from the manufacturer on this issue.

4.16 The Committee considered how appropriate the stopping rules assumed by the manufacturer were. It considered the negative stopping rule used in the manufacturer’s model, in which patients stopped treatment if after two cycles there was no improvement in at least two health states. The Committee noted the evidence from clinical specialists that a ‘response’ in practice is based on a clinically relevant reduction in outcomes and that treatment is stopped only if there is little or no benefit to the patient after at least two treatment cycles. The Committee broadly accepted that a negative stopping rule after two cycles of treatment was clinically relevant, but it considered that the degree of benefit needed should be defined to make it relevant to clinical practice. The Committee regarded the day-to-day use by clinicians of a reduction in two health states, as used in the model, was impractical and arbitrary. It also regarded this definition as too variable in terms of the reduction in headache days per month needed (this depends on the number of headache days per month at the start and also on which health state patients start in). The Committee noted that using the number of headache days per month to determine benefit was a ‘blunt instrument’, and that some patients and clinicians wanted to continue with botulinum toxin type A treatment even after small reductions in the number of headache days per month. The Committee also noted that the Association of British Neurologists stated that a 50% response rate was an accepted definition of response, but this Association questioned whether this was appropriate for a population of people with chronic migraine. The Committee concluded that the most plausible negative stopping rule (beyond one in which botulinum toxin type A was stopped if there was no benefit) would have to be clinically relevant and practical. It recognised the limitations of using reductions in headache days per month, but also noted that this was the primary endpoint in the PREEMPT studies. The Committee concluded that it needed more information from the manufacturer about whether a negative stopping rule was appropriate and practical, and how it could be clearly constructed and applied. The Committee therefore requested additional information from the manufacturer on the impact of a range of negative stopping rules (based on a percentage reduction in response rate based on headache days per month applied to people with chronic migraine after two cycles of treatment with botulinum toxin A) on the ICER.

4.17 The Committee then considered whether the positive stopping rule assumed by the manufacturer, in which patients stopped treatment if their condition moved to an episodic migraine classification and remained stable in episodic migraine states thereafter, was appropriate. The Committee noted the limited duration of follow-up in the PREEMPT studies and the absence of clinical data on the use of this stopping rule. It also noted its earlier conclusion that with no clinical trial data on duration of response, it would be reasonable to estimate the benefit of treatment in people whose migraine responded to botulinum toxin type A from the results of the Rothrock et al. study, which included people whose headache days per month reduced by 50%. It noted that 24% of people were able to stop treatment and maintain a good response for at least 6 months after stopping treatment. The Committee considered that this was the most appropriate figure on which to base a positive stopping rule, with the remaining people staying on treatment to maintain their response. The Committee concluded that was uncertainty as to whether a positive stopping rule would be implemented in clinical practice; however, it requested that additional analyses be conducted based on a positive stopping rule applied to 24% of patients whose chronic migraine responds to treatment with botulinum toxin type A, and the likely duration of treatment in patients continuing on therapy.

4.18 The Committee considered the ERG critique of the manufacturer’s model, in particular the large differences between the deterministic and probabilistic ICERs generated using the manufacturer’s model. It noted that the ERG considered that this was caused by the transition probabilities used in the model. The Committee heard from the manufacturer’s representative that the difference between the deterministic and probabilistic estimates was caused by the anomaly in the utilities in the botulinum toxin type A arm of the model in which utility for health state 5 was lower than health state 6 (see paragraph 4.14). The Committee concluded that it was uncertain what caused the difference between the deterministic and probabilistic ICERs and recommended that further clarification be sought from the manufacturer.

4.19 The Committee considered the cost-effectiveness of botulinum toxin type A compared with placebo based on ICERs presented by the manufacturer and in the ERG’s additional sensitivity analyses. It noted that the manufacturer’s deterministic ICER for botulinum toxin type A compared with placebo in the three or more prior preventive medications subgroup was £6400 per QALY gained. However, it also noted that the economic model contained a number of inappropriate assumptions and that sensitivity analyses conducted by the ERG suggested that the deterministic ICER could be as high as £46,000 per QALY gained if certain assumptions were varied. The Committee noted the considerable uncertainty in the economic analyses particularly related to the use of different utilities within a given health state in the botulinum toxin type A and placebo arm, the use of different positive and negative stopping rules and the large difference in the deterministic and central probabilistic estimates. On the basis of the evidence presented, the Committee was unable to conclude whether botulinum toxin type A was a cost effective use of NHS resources compared to standard care. The Committee was therefore minded not to recommend botulinum toxin type A for the prevention of headaches in adults with chronic migraine. The Committee recommended that a revised economic model and analyses should be requested from the manufacturer which includes Committee’s preferred assumptions relating the resource use, costs and stopping rules. It also recommended that further clarification should be requested from the manufacturer on a number of issues related to the calculation of utilities in the model and the difference between the deterministic and probabilistic ICERs which should be made available for a second Appraisal Committee meeting (see sections 1.2 to 1.5).

4.20 The Committee discussed whether NICE’s duties under the equalities legislation required it to alter or add to its preliminary recommendations in any way. It heard from the patient expert that chronic migraine is more prevalent in women than men. However, given that the recommendation did not differentiate between any groups of people, the Committee concluded that its recommendations did not limit access to the technology for any specific group compared with other groups.

4.21 The Committee discussed whether botulinum toxin A should be considered an innovative technology. It heard from the manufacturer that botulinum toxin A is the only technology with a UK marketing authorisation for the prevention of headaches in adults with chronic migraine. It also heard from patients experts that for people who respond to botulinum toxin treatment, it is associated with a dramatic improvement in health related quality of life. The Committee noted that the method of administration of botulinum toxin type A was novel compared to other preventative treatments used in the management of chronic migraine. However, given that the Committee was minded not to recommend botulinum toxin type A for the prevention of headaches in adults with chronic migraine and recommended that a revised economic model, analyses and clarification should be requested from the manufacturer (see section 4.19). the Committee was unable to conclude whether any significant or substantial health benefits were not included in the model.

Summary of Appraisal Committee's key conclusions

TAXXX	Appraisal title: Botulinum toxin type A for the prevention of headaches in adults with chronic migraine		Section
Key conclusion
The Committee is minded not to recommend botulinum toxin type A for the prevention of headaches associated with chronic migraine. The Committee recommends that NICE requests further information on the clinical and cost effectiveness of botulinum toxin type A from the manufacturer, as described in 1.3 to 1.5. •          A revised base case model which incorporated the Committee’s preferred assumptions and a range of negative stopping rules. •          Scenario analysis on the impact of using  different compared with the same utility values within a given health state for  the botulinum toxin type A and placebo arm, and removing the anomaly between health state 5 and 6 in the botulinum toxin type A arm. •          Clarification of the way in which utilities have been calculated, anomalies in the model (related to the lack of monotonic utilities in the botulinum toxin type A arm, the use of different utilities in the botulinum toxin type A and placebo arm, and the large difference between the deterministic and probabilistic ICER) and further information on resource use incurred by the UK group in the IMBS study.			1.1 1.2 1.3 1.4 1.5
Current practice
Clinical need of patients, including the availability of alternative treatments		The Committee considered chronic migraine to be debilitating condition which seriously affects health-related quality of life. The Committee heard from the patient experts that many people with chronic migraine would consider any degree of response to treatment to be valuable and that therefore further treatment options were important.	4.2 4.3
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee noted the improvements in quality of life in patients whose condition responded to botulinum toxin type A. It heard from the manufacturer that botulinum toxin A is the only technology with a UK marketing authorisation for the prevention of headaches in adults with chronic migraine. It also heard from patients experts that for people who respond to botulinum toxin treatment, it is associated with a dramatic improvement in health related quality of life. The Committee noted that the method of administration of botulinum toxin type A was novel compared to other preventative treatments used in the management of chronic migraine. However, given that the Committee was minded not to recommend botulinum toxin type A for the prevention of headaches in adults with chronic migraine and recommended that a revised economic model, analyses and clarification should be requested from the manufacturer (see section 4.19). the Committee was unable to conclude whether any significant or substantial health benefits were not included in the model.	4.6 4.21
What is the position of the treatment in the pathway of care for the condition?		The Committee concluded that the most appropriate use of botulinum toxin type A would be in people whose chronic migraine has failed to respond to at least three prior preventive medications.	4.8
Adverse effects		The Committee noted the adverse events reported in the trials with botulinum toxin type A (see section 3.8). It heard from the patient experts that there is often pain around an injected site lasting a few days following treatment with botulinum toxin type A. However people would be willing to tolerate the adverse effects of botulinum toxin type A treatment to reduce the frequency or severity of chronic migraine. The concluded that botulinum toxin type A is well tolerated; a conclusion supported by the patient experts.	4.7
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee considered the evidence on the clinical effectiveness of botulinum toxin type A to treat chronic migraine from the PREEMPT trials, which compared botulinum toxin type A with placebo. The Committee noted the absence of clinical data on the use of the positive stopping rule, and that there were no clinical trial data on duration of response.	4.5 4.17
Relevance to general clinical practice in the NHS		At baseline, patients in the clinical trials had fewer headache days per month (a mean of 19) than people with chronic migraine in secondary care in the UK (a mean of 25–26 headache days per month). The PREEMPT studies had a limited duration of follow-up (1 year).	4.5 4.16
Uncertainties generated by the evidence		The large placebo effect seen in the trials may have been increased by people in the active treatment arm realising that they were receiving botulinum toxin type A because of its side effects. The duration of follow-up in the PREEMPT trials was short and the study design, which meant that all patients received the active drug from week 24, could not exclude natural improvements in people’s condition over time.	4.5 4.5
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		The Committee did not consider there to be any relevant subgroups.	4.8
Estimate of the size of the clinical effectiveness including strength of supporting evidence		Although the clinical trial evidence demonstrated statistically significant benefits of botulinum toxin type A treatment compared with placebo for a number of outcomes, the absolute differences were small to modest and the magnitude of the effect of botulinum toxin type A was confounded by the large placebo effect seen in the clinical trials.	4.5
Evidence for cost effectiveness
Availability and nature of evidence		There was no published literature on the cost effectiveness of botulinum toxin compared with placebo. The Committee considered the cost effectiveness of botulinum toxin type A compared with standard care, based on the manufacturer’s economic model and the critique by the ERG, in the context of the decision problem.	3.10 4.8
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee noted that a central estimate of the probabilistic ICER was not presented by the manufacturer. It further noted the ERG’s concerns over some of the model inputs and assumptions. These include:The cost of administering botulinum toxin type A and of no treatment, based on 30 and 15 minutes of neurologist time respectively. The lack of ongoing routine care costs for people who discontinue botulinum toxin type A because of lack of efficacy. The marked increase in resource use (particularly inpatient admissions and to a lesser extent accident and emergency use) associated with chronic migraine compared with episodic migraine. The average accident and emergency cost. The IBMS data for resource use and costs related to the use of botulinum toxin type A. The way in which utilities had been mapped from the MSQ to the EQ-5D. The anomaly between the utility values in the botulinum toxin type A arm in which people in health state 5 (20–23 headache days per month) have a lower utility than those in health state 6 (24–28 headache days per month). Different utilities were used within a health state depending on the treatment arm, with higher utilities in the botulinum toxin type A arm than in the placebo arm. The negative stopping rule in which patients stopped treatment if after two cycles there was no improvement in at least two health states. The positive stopping rule in which patients stopped treatment if their condition moved to an episodic migraine classification (fewer than 15 headache days per 28 days) and remained stable in episodic migraine states thereafter.	4.9 4.10 4.11 4.12 4.13 4.13 4.14 4.15 4.16 4.17
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		Utilities were generated by mapping MSQ coupled with additional patient characteristics onto EQ5D utilities as drawn from the IBMS data. Different utilities were used within a health state depending on the treatment arm to account for the reduction in the severity and duration of headaches with botulinum toxin type A (over and above the reduction in headache days per month estimated in the economic model). The Committee did not consider there to be any health related benefits that had not been included in the economic model.	4.14
Are there specific groups of people for whom the technology is particularly cost effective?		The main decision problem proposed by the manufacturer, comparing botulinum toxin type A with placebo, in people whose condition has failed to respond to at least one prior preventive medication, did not reflect clinical practice.	4.7
What are the key drivers of cost effectiveness?		The Committee considered the key cost drivers to be: ·         Different utilities between the botulinum toxin and placebo arm for a given health state ·         Different positive and negative stopping rules ·         The ICER based on the deterministic and central probabilistic estimate	4.19
Most likely cost-effectiveness estimate (given as an ICER)		On the basis of the evidence submitted to the Committee, it was unable to conclude as to whether the use of botulinum toxin A was cost effective compared to standard care.	4.19
Additional factors taken into account
Patient access schemes (PPRS)		Not applicable	-
End-of-life considerations		Not applicable	-
Equalities considerations and social value judgements		The Committee heard from the patient expert that chronic migraine is more prevalent in women than men. It concluded that its preliminary recommendations do not limit access to the technology for any specific protected group compared with other people.	4.19

5 Implementation

5.1 The Secretary of State and the Welsh Assembly Minister for Health and Social Services have issued directions to the NHS in England and Wales on implementing NICE technology appraisal guidance. When a NICE technology appraisal recommends use of a drug or treatment, or other technology, the NHS must usually provide funding and resources for it within 3 months of the guidance being published. If the Department of Health issues a variation to the 3-month funding direction, details will be available on the NICE website. When there is no NICE technology appraisal guidance on a drug, treatment or other technology, decisions on funding should be made locally.

5.2 NICE has developed tools to help organisations put this guidance into practice (listed below). These are available on our website (www.nice.org.uk/guidance/TAXXX). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6 Related NICE guidance

Published

• Percutaneous closure of patent foramen ovale for recurrent migraine. NICE interventional procedure guidance (2010).
• Deep brain stimulation for intractable trigeminal autonomic cephalalgias. NICE interventional procedure guidance (2011).

Under development

NICE is developing the following guidance (details available from www.nice.org.uk):

• Diagnosis and management of headaches in young people and adults. NICE clinical guideline. Expected date of publication December 2012.

7 Proposed date for review of guidance

7.1 NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in June 2015. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Peter Clarke
Chair, Appraisal Committee
February 2012

Appendix A: Appraisal Committee members, guideline representatives and NICE project team

A Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are four Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Professor Peter Clark (Chair)
Consultant Medical Oncologist, Clatterbridge Centre for Oncology

Professor Jonathan Michaels (Vice Chair)
Professor of Clinical Decision Science, University of Sheffield

Professor Darren Ashcroft
Professor of Pharmacoepidemiology, School of Pharmacy and Pharmaceutical Sciences, University of Manchester

Dr Matthew Bradley
Therapy Area Leader, Global Health Outcomes, GlaxoSmithKline

Dr Ian Campbell
Honorary Consultant Physician, Llandough Hospital

Dr Ian Davidson
Lecturer in Rehabilitation, University of Manchester

Professor Simon Dixon
Professor in Health Economics, University of Sheffield

Dr Martin Duerden
Assistant Medical Director, Betsi Cadwaladr University Health Board

Gillian Ells
Prescribing Advisor, NHS Sussex Downs and Weald

Dr Jon Fear
Consultant in Public Health Medicine, Head of Healthcare Effectiveness NHS Leeds

Paula Ghaneh
Senior Lecturer and Honorary Consultant, University of Liverpool

Dr Susan Griffin
Research Fellow, Centre for Health Economics, University of York

Professor John Hutton
Professor of Health Economics, University of York

Professor Peter Jones
Emeritus Professor of Statistics, Keele University

Dr Steven Julious
Senior Lecturer in Medical Statistics, University of Sheffield

Dr Vincent Kirkbride
Consultant Neonatologist, Regional Neonatal Intensive Care Unit, Sheffield

Rachel Lewis
Advanced Nurse Practitioner, Manchester Business School

Professor Paul Little
Professor of Primary Care Research, University of Southampton

Professor Femi Oyebode
Professor of Psychiatry and Consultant Psychiatrist, The National Centre for Mental Health

Dr John Radford
Director of Public Health, Rotherham Primary Care Trust

Dr Phillip Rutledge
GP and Consultant in Medicines Management, NHS Lothian

Dr Brian Shine
Consultant Chemical Pathologist, John Radcliffe Hospital, Oxford

Dr Murray D Smith
Associate Professor in Social Research in Medicines and Health, University of Nottingham

Paddy Storrie
Lay Member

Dr Lok Yap
Consultant in Acute Medicine and Clinical Pharmacology, Whittington Hospitals NHS Trust

B Guideline representatives

The following individuals, representing the Guideline Development Group responsible for developing NICE’s clinical guideline related to this topic, were invited to attend the meeting to observe and to contribute as advisers to the Committee.

• Serena Carville, Project Manager and senior research fellow developing the NICE guideline for the diagnosis and management of headaches

C NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Helen Starkie and Scott Goulden
Technical Leads

Eleanor Donegan
Technical Adviser

Kate Moore
Project Manager

Appendix B: Sources of evidence considered by the Committee

A  The Evidence Review Group (ERG) report for this appraisal was prepared by Warwick Evidence:

• Royle P, Cummins E, Walker C et al, Evidence review group report: Botulinum toxin type A for the prophylaxis of headaches in adults with chronic migraine, December 2011

B The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I Manufacturer/sponsor:

• Allergan

II Professional/specialist and patient/carer groups:

• Migraine Action
• Migraine Trust
• Association of British Neurologists
• British Association for Study of Headache
• British Pain Society
• Institute of Neurology
• Migraine in Primary Care Advisors
• Primary Care Neurology Society
• Royal College of Anaesthetists
• Royal College of Nursing
• Royal College of Physicians
• United Kingdom Clinical Pharmacy Association

III Other consultees:

• Department of Health
• Welsh Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):

• British National Formulary
• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety – Northern Ireland
• Healthcare Improvement Scotland
• Medicines and Healthcare Products Regulatory Agency
• National Hospital for Neurology and Neurosurgery
• Warwick Evidence
• National Institute for Health Research Health Technology Assessment Centre
• National Clinical Guidelines Centre

C The following individuals were selected from clinical specialist and patient expert nominations from the non-manufacturer/sponsor consultees and commentators. They gave their expert personal view on botulinum toxin type A by attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Fayyaz Ahmed, Consultant Neurologist, nominated by British Association for the Study of Headache – clinical specialist
• Dr Paul Shanahan, Consultant Neurologist, nominated by the National Hospital for Neurology and Neurosurgery – clinical specialist
• Elaine Ransome, nominated by the Migraine Trust – patient expert
• Wendy Thomas, Chief Executive of Migraine Trust, nominated by the Migraine Trust – patient expert

D Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Allergan