Galcanezumab for preventing migraine

3.1 Migraine is a headache disorder with recurring attacks usually lasting between 4 and 72 hours. The patient expert explained the debilitating effect of migraine on their daily life with symptoms including fatigue, severe head pain, sensitivity to light, difficulty concentrating, nausea, stiff neck or back, feeling down, and sensitivity to sound. These symptoms were noted to adversely affect someone's ability to do their usual activities, including work, and to negatively affect their family. Chronic migraine is defined as 15 or more headache days a month with at least 8 of those having features of migraine. Episodic migraine is defined as less than 15 headache days a month. The clinical and patient experts explained that the severity and frequency can fluctuate over time and that recovery from a migraine can take a few days. The committee concluded that migraine, particularly chronic migraine, is a debilitating condition that substantially affects both physical and psychological aspects of health-related quality of life.

3.2 The committee understood that current oral treatment options for preventing migraine include drugs that are used to treat other conditions including beta-blockers, antidepressants and anticonvulsant medications. The patient expert explained that these treatments can have significant side effects and any beneficial effects do not last or may not work at all for some people. This leads many people to try different medications to find one that works. The clinical expert stated that there is a risk of medication overuse with some of the current treatments for migraine such as triptans, which needs to be managed. The committee noted that NICE's technology appraisal guidance on botulinum toxin type A for the prevention of headaches recommends botulinum toxin type A for people with chronic migraine that has not responded to at least 3 previous oral preventive drugs. The clinical expert stated that some people who are eligible for botulinum toxin type A are unable to have it because there is no local specialist centre to administer it, or they have to wait a long time for it. The committee acknowledged that there may be an increase in the number of specialist centres, which may increase treatment access. A clinical expert also noted that face-to-face appointments are currently restricted in the NHS because of the COVID‑19 pandemic, so there is a greater demand for virtual appointments. The committee understood that this has reduced the availability of botulinum toxin type A and increased the need for a migraine-specific self-administered treatment that could be managed with virtual appointments. The committee concluded that effective and well-tolerated migraine-specific treatment options are needed.

3.3 The company's submission focused on people with migraine for whom at least 3 previous oral preventive treatments had failed (defined as lack of a clinically meaningful response, intolerance to the treatment or the treatment was contraindicated or unsuitable). The company considered this group to reflect people most in need of treatment options, who would likely be offered galcanezumab in NHS clinical practice. The clinical expert explained that the aim of treatment is to reduce the frequency, severity or duration of migraine and improve quality of life. The committee noted that, in chronic migraine, a 30% reduction in migraine frequency is considered a clinically meaningful response to treatment. In episodic migraine, a 50% reduction is considered a clinically meaningful response. If clinical response is less than this, or the person is not able to have an adequate dosage for long enough or has adverse events, treatment is stopped and another oral preventive treatment is tried. The clinical expert explained that it is important for people to try a range of oral preventive treatments before considering more specialist treatment, such as botulinum toxin type A (for chronic migraine) or galcanezumab. The committee concluded that an insufficient response to an adequate trial of at least 3 oral preventive treatments represents usual NHS practice before more specialist treatment is considered. It also concluded that a clinically meaningful response is a 30% reduction in migraine frequency for chronic migraine and a 50% reduction for episodic migraine.

3.4 The company presented clinical-effectiveness evidence for galcanezumab, compared with placebo for episodic migraine and compared with placebo and botulinum toxin type A for chronic migraine. It considered that placebo was representative of best supportive care, because people were allowed to use the acute treatments they would usually take when preventive treatments failed. The clinical experts agreed that it is most likely that people would have best supportive care for episodic migraine, and botulinum toxin type A or best supportive care for chronic migraine, after 3 preventive oral treatments had failed. The committee was aware of NICE's recently published technology appraisal guidance recommending fremanezumab for chronic migraine but noted that fremanezumab treatment was not routine clinical practice in the NHS at the time of its decision making, so it is not considered a comparator for galcanezumab. The committee concluded that best supportive care is the most appropriate comparator in episodic migraine, and that botulinum toxin type A and best supportive care are both relevant comparators in chronic migraine.

3.5 The company defined high-frequency episodic migraine as between 8 and 14 migraine headache days a month. The clinical expert explained that there is no internationally recognised classification of high-frequency episodic migraine and that it is not a clearly defined clinical subgroup. They also noted that the definition of high-frequency episodic migraine is arbitrary, and a person's quality of life is negatively affected irrespective of which type of migraine they have. The nature of the condition means that some people's migraine can be episodic one month and chronic the next, according to the definitions. The committee concluded that high-frequency episodic migraine is not a distinct subgroup and agreed not to consider it further.

3.6 The company's systematic literature review identified 4 randomised controlled trials evaluating galcanezumab:

3.7 The company presented clinical-effectiveness results for the subgroup of people for whom 3 or 4 preventive migraine therapies failed to produce clinically meaningful improvement from CONQUER, REGAIN, EVOLVE‑1 and EVOLVE‑2. The results showed:

3.8 The duration of the blinded placebo-controlled phase was 3 months for CONQUER and REGAIN and 6 months for EVOLVE. The ERG noted the uncertainty about the long-term benefits of galcanezumab for extrapolating beyond these phases to an assumption of lifetime treatment. The committee concluded that the long-term benefits of galcanezumab compared with best supportive care remained uncertain.

3.9 The committee acknowledged that there is a high unmet need in the group of people for whom 3 preventive treatments and botulinum toxin type A have failed, because they have a high disease burden and no further treatment options. The clinical expert stated that galcanezumab has a potential role as a treatment option when botulinum toxin type A has failed. However, considering that access to botulinum toxin type A varies within the NHS and it is more burdensome to administer than galcanezumab, the clinical expert agreed that the preferred position for galcanezumab would be after 3 oral preventive treatments have failed. This is the same position as other drugs in the same class as galcanezumab; that is, anti-calcitonin gene-related peptides (CGRPs). At technical engagement, the company provided the patient numbers from CONQUER for people with chronic migraine who had galcanezumab after 3 oral preventive treatments and botulinum toxin type A. The company explained that the patient numbers are too small to provide meaningful results from any analysis. The company presented a post-hoc analysis for galcanezumab as a fourth-line treatment after botulinum toxin type A has failed. The results showed a significant decrease in migraine frequency for galcanezumab compared with placebo. The company considered these results to be representative of the effect of galcanezumab after 3 oral treatments and botulinum toxin type A have failed. The ERG agreed that the company's model did not consider this potential sequence and that there is no clinical evidence to support the use of galcanezumab as a fifth-line treatment after botulinum toxin type A. The committee acknowledged the results from the trials, which showed the clinical effectiveness of galcanezumab treatment after failure of botulinum toxin type A (see section 3.7). It concluded that while there is uncertainty in the evidence, galcanezumab may be clinically effective as a fifth-line treatment after 3 oral treatments and botulinum toxin type A.

3.10 The committee was not presented with any evidence to support subsequent treatment with other anti-CGRPs, if the initial clinically meaningful response to treatment with galcanezumab is subsequently lost. The committee was aware although the scope included 2 medicines in this class as potential comparators, neither was established practice in the NHS at the time of the decision-making and therefore did not formally compare galcanezumab with them. However, the committee heard from the clinical expert that there is no clinical evidence to support any difference in efficacy between the different anti-CGRP drugs. The committee noted that treatment preferences are not outlined in the British Association for the Study of Headache's guidelines, and therefore considered it reasonable that the least expensive drug would be used unless an alternative was more suitable for the patient. The committee concluded that treatment with another anti-CGRP drug, after failure of a previous anti-CGRP drug, is not supported by evidence and is not recommended.

3.11 The company's model assumed that people stopped galcanezumab treatment at 3 months if their symptoms had not responded. This 'negative' stopping rule was applied to people having less than a 50% reduction in monthly migraine days for episodic migraine, and less than a 30% reduction in monthly migraine days for chronic migraine. The committee considered the 30% and 50% thresholds. It agreed these are appropriate measures of treatment response and are consistent with NICE's technology appraisal guidance on botulinum toxin type A for preventing chronic migraine and the British Association for the Study of Headache's guidelines. The committee concluded that it was appropriate to include a negative stopping rule at 3 months if there was insufficient response to treatment based on the agreed thresholds.

3.12 There was no direct evidence comparing galcanezumab with botulinum toxin type A for chronic migraine so the company did an indirect comparison, using data from:

3.13 The utility values used in the model were generated from mapping the Migraine Specific Questionnaire results to the EQ-5D-3L using the Gillard et al. (2012) algorithm. The committee understood that the company used estimated utility values for the population of patients who had a history of 3 or more failed prior preventatives from the relevant clinical trials (CONQUER, EVOLVE‑1, EVOLVE‑2 and REGAIN). The company presented evidence for a treatment-related difference in utility values. This demonstrated that utility values for galcanezumab were higher across all mean migraine headache day values compared with placebo. Also a regression analysis showed a large, statistically significant benefit of galcanezumab compared with placebo. The ERG considered this evidence to be of high quality and explained that the use of differential utilities applied to galcanezumab and comparators would allow for improvements in migraine severity to be captured beyond the number of migraine headache days. The committee noted that using differential utilities is not consistent with the approach used in NICE's technology appraisal of fremanezumab for preventing migraine. However, the ERG explained that compelling evidence for differential utilities has been presented by the company, which has not been presented in previous appraisals. The company provided the results of a correlation study as further evidence to support the use of differential utilities, and it demonstrated that galcanezumab reduced the levels of impairment and burden between migraine attacks. The ERG considered that the correlation study results provided evidence that galcanezumab improves the burden of migraine beyond that captured by the Migraine Specific Questionnaire. The patient expert described how galcanezumab reduced the impact of migraine attacks and improved recovery between attacks. The ERG noted that any differences in baseline (before treatment) utility values between treatment arms are accounted for in the applied statistical model and there is a statistically significant difference in utility values after treatment. The committee acknowledged that there may be important aspects of the burden of migraine that are missed if only considering the frequency of migraine headache days. It acknowledged the uncertainties in using differential utility values, so it also considered a scenario of equal utility values. However, the committee concluded that there is evidence for the use of differential utility values between treatments.

3.14 The company assumed that galcanezumab could be self-administered by subcutaneous injection. At the technical engagement stage, the clinical experts suggested that most people would be capable of self-administering galcanezumab. However, they noted that some disabled people, people who have a learning disability, are older or who have a phobia of needles may need help. They also noted that additional services may be needed to train people how to self-administer treatment. The committee noted that NICE's guidance on fremanezumab for preventing migraine concluded that it was unlikely that everyone will be able to self-administer treatment. It agreed that applying administration costs for 10% of people having galcanezumab was reasonable but acknowledged that this had little effect on the model results.

3.15 The company submission did not include costs associated with monitoring galcanezumab treatment. The clinical expert explained that people having galcanezumab are likely to need monitoring at regular intervals, and the committee acknowledged that monitoring is important for new treatments. The company and the ERG did not consider it appropriate to include the costs of monitoring without also including the benefits of positive discontinuation associated with it (that is, stopping treatment because it has been successful). However, the committee did not consider it appropriate to include positive discontinuation because there are no clear criteria for when people should stop treatment. It also understood that positive discontinuation could be challenging to implement in clinical practice. The committee concluded that additional monitoring costs for galcanezumab should be included in the model to account for an appointment with a consultant every 6 months.

3.16 NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee is more cautious about recommending a technology if it is less certain about the ICERs presented. The committee considered that the impact on NHS resources of introducing galcanezumab may be higher for episodic migraine than for chronic migraine. This is because episodic migraine is more common than chronic migraine. Because of the uncertainty in the clinical and economic evidence, the committee agreed that an acceptable ICER would be towards the lower end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained) for episodic migraine.

3.17 The company's revised base-case ICER for galcanezumab compared with best supportive care for episodic migraine was within the range NICE normally considers an acceptable use of NHS resources. The company's revised base case included the committee's preferred assumptions:

3.18 The company's revised base-case ICER for galcanezumab compared with best supportive care for chronic migraine was below the range NICE normally considers an acceptable use of NHS resources. The company's revised base case included the committee's preferred assumptions:

3.19 The company's revised base-case ICER for galcanezumab compared with botulinum toxin type A for chronic migraine was below the range NICE normally considers an acceptable use of NHS resources. The company's revised base case included the committee's preferred assumptions:

3.20 The committee noted that clinical evidence was not available for galcanezumab as a fifth-line treatment after botulinum toxin type A has failed (see section 3.9), and that no cost-effectiveness evidence had been provided. However, it acknowledged the post-hoc analysis showing the effect of galcanezumab as a fourth-line treatment after botulinum toxin type A had failed. It noted that the company considered these results to be representative of the effect of galcanezumab as a fifth-line treatment. The committee considered the uncertainty in the evidence for galcanezumab when used as a fifth-line treatment after botulinum toxin type A. However, it acknowledged that galcanezumab was clinically effective and cost effective as a fourth-line treatment after botulinum toxin type A and accepted this as a proxy for fifth-line use. It concluded that galcanezumab is cost effective compared with best supportive care for chronic migraine after botulinum toxin type A has failed.

3.21 No equalities issues were identified by the company. The clinical and patient submissions highlighted that migraine can be classed as a disability under the Equality Act 2010. Because migraine is most common in people of working age and affects more women than men, women may be further disadvantaged in the workplace. It was also noted that there may be unequal access to specialist headache clinics. The committee considered these issues and concluded that there were no specific adjustments needed to the NICE methods in this instance.

3.22 The committee acknowledged that galcanezumab administration may be considered more convenient and less unpleasant than administration of botulinum toxin type A. But it concluded that the modelling had adequately captured the benefits of galcanezumab.

3.23 The committee noted that the most relevant comparator for episodic migraine was best supportive care. It considered that the evidence showed that galcanezumab is clinically effective compared with best supportive care. It also considered that high-frequency episodic migraine was not a clinically distinct subgroup and did not consider it further. At technical engagement, the company submitted a revised base case, which included a confidential simple discount patient access scheme for galcanezumab and most of the committee's preferred assumptions. Applying the additional committee assumption that monitoring costs for galcanezumab should be included, the most plausible ICER was likely to be towards the lower end of what NICE normally considers an acceptable use of NHS resources. Therefore, galcanezumab is recommended for preventing episodic migraine in adults after at least 3 oral preventive treatments have failed. Treatment with galcanezumab should be stopped if migraine frequency does not reduce by at least 50% after 12 weeks of treatment.

3.24 The committee recognised the high degree of burden that chronic migraine has on quality of life and daily functioning. It acknowledged that people with chronic migraine have the most severe form of the condition and that there is an unmet need for effective treatments. The committee noted that the most relevant comparators for chronic migraine were botulinum toxin type A and best supportive care. It considered that galcanezumab is a clinically effective treatment compared with placebo. However, the committee considered that there was uncertainty about whether galcanezumab is more clinically effective than botulinum toxin type A. At technical engagement the company submitted a revised base case, which included a confidential simple discount patient access scheme for galcanezumab and most of the committee's preferred assumptions. Applying the additional committee assumption that monitoring costs for galcanezumab should be included, the most plausible ICER is likely to be below what NICE normally considers an acceptable use of NHS resources compared with best supportive care and botulinum toxin type A. Therefore, galcanezumab is recommended for preventing chronic migraine in adults after at least 3 preventive treatments have failed. This includes the chronic migraine population for whom treatment with botulinum toxin type A has failed. Treatment with galcanezumab should be stopped if migraine frequency does not reduce by at least 30% after 12 weeks of treatment.