Economic evaluations in migraine: systematic literature review and a novel approach

Figures & data

Table 1. Inclusion Criteria for the Economic Evaluations SLR and Updates.

Population	Adult patients with chronic or episodic migraine
Interventions	Select preventive pharmacological interventions including angiotensin converting-enzyme inhibitors, angiotensin receptor blockers, anticonvulsants, beta-blockers, Botox, calcium channel blockers, CGRP inhibitors and receptor inhibitors, leukotriene receptor antagonists, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, serotonin agonists, tricyclic antidepressants, and vitamins, minerals, and co-enzymes
Comparators	Any comparator
Outcomes	Outcomes of relevant study designs, including: Costs Life-years gained QALYs Incremental costs and QALYs Incremental cost-effectiveness ratios
Study design	Original economic evaluations considering both the costs and benefits of alternative interventions. Specifically, the following types of analysis: Cost-effectiveness Cost-utility Cost-benefit Cost-minimisation Cost-consequence
Other	Economic evaluations from United Kingdom or Irish perspectives English language Human subjects only In addition, SLRs of economic evaluations were included at the abstract  review stage, then excluded following hand-searching of their reference  lists at the full-text review stage

Abbreviations. CGRP, calcitonin gene-related peptide; QALY, quality-adjusted life-year; SLR, systematic literature review.

Table 2. Details of the Relevant Economic Evaluations Identified in the Systematic Review.

Reference	Country and Perspective	Summary of Model Structure	Patient Population	QALYs (Interventions and Comparators)	Costs and Outcomes	ICER (Cost per QALY Gained)
NICE [8] Royle et al. [9]	England and Wales; NHS perspective	Model type: Cost-utility analysis using a state-transition (Markov) model to estimate the cost-effectiveness of onabotulinumtoxinA vs placebo (triptans plus pain relief only) in patients with chronic migraine Health states: 6 health states according to number of headache days/month: 0–3; 4–9; 10–14; 15–19; 20–23; ≥24. Patients could enter the model in any of the 3 chronic migraine states Inputs: Clinical data were incorporated from the pooled phase 3 PREEMPT clinical trials programme Health state utility values were collected in PREEMPT using the MSQ and mapped to the EQ-5D Costs included medicine acquisition and administration costs; cost of care consisting of GP visits, ED visits, hospitalization costs, and triptan costs The model used 12-week cycles with a time horizon of 2 years Deterministic and probabilistic sensitivity analyses were conducted The cost year was 2009/2010 Costs and QALYs were discounted at 3.5% per annum	Patients with chronic migraine, defined as ≥15 headache days/month for ≥3 months, of which at least 8 days are with migraine	Discounted totals ≥1 Prior oral prophylactic population: OnabotulinumtoxinA: 1.31 Placebo: 1.22 Incremental QALYs: 0.09 ≥3 prior oral prophylactic population: OnabotulinumtoxinA: 1.29 Placebo: 1.20 Incremental QALYs: 0.09 Totals ≥1 prior oral prophylactic population: OnabotulinumtoxinA: 1.34 Placebo: 1.24 ≥3 prior oral prophylactic population: OnabotulinumtoxinA: 1.32 Placebo: 1.23	Discounted totals ≥1 Prior oral prophylactic population: OnabotulinumtoxinA total costs: £2,388 Placebo total costs: £1,839 Incremental total costs: £549 ≥3 prior oral prophylactic population: OnabotulinumtoxinA total costs: £2,438 Placebo total costs: £1,895 Incremental total costs: £543 Totals ≥1 prior oral prophylactic population: OnabotulinumtoxinA total costs: £2,419 Placebo total costs: £1,879 ≥3 prior oral prophylactic population: OnabotulinumtoxinA total costs: £2,471 Placebo total costs: £1,936	≥1 prior oral prophylactic population: £5,828/QALY gained ≥3 prior oral prophylactic population: £6,083/QALY gained
Batty et al. [10]	England and Wales; NHS perspective	Model type: Cost-utility analysis using a state-transition (Markov) model to estimate the cost-effectiveness of onabotulinumtoxinA vs placebo in patients with chronic migraine Health states: 13 health states: 6 on treatment, 6 off treatment, and death. The on- and off- treatment states were divided by the number of headache days per 28 days Inputs: Clinical data were incorporated from the pooled phase 3 PREEMPT clinical trials program Health state utility values were collected in PREEMPT using the MSQ and mapped to the EQ-5D Costs included cost of care, consisting of GP visits, ED visits, hospitalization costs, and triptan costs The model used 12-week cycles with a time horizon of 2 years Scenario and probabilistic sensitivity analyses were conducted (5,000 simulations were performed) The cost year was 2010 Costs and QALYs were discounted at 3.5% per annum	Patients with chronic migraine, defined as ≥15 headache days/month	Discounted totals OnabotulinumtoxinA: 1.30 Placebo: 1.20 Incremental QALYs: 0.09 Totals OnabotulinumtoxinA: 1.34 Placebo: 1.24	Discounted totals Costs: OnabotulinumtoxinA total costs: £2,997 Placebo total costs: £1,630 Incremental total costs: £1,367 Totals Costs: OnabotulinumtoxinA total costs: £3,077 Placebo total costs: £1,680 Incremental total costs: £1,367 Life-years (undiscounted): OnabotulinumtoxinA: 2.06 Placebo: 2.06 Incremental LYs: 0.00	£15,028/QALY gained (discounted)
SMC [11]	Scotland; NHS perspective	Model type: Cost-utility analysis using a state-transition (Markov) model to estimate the cost-effectiveness of onabotulinumtoxinA injections given every 12 weeks vs BSC in patients with chronic migraine who had previously failed on oral prophylactic therapy due to side effects or lack of efficacy and were in the care of a headache specialist in a secondary care centre Health states: Clinical trial data were used to categorize patients into various health states in the model using mean headache days over a 28-day period. There were 7 health states in total Inputs: Clinical data were incorporated from patient-level data from the post-hoc pooled analysis of key clinical trials BSC was assumed to encompass use of off-label treatments such as gabapentin, venlafaxine, and greater occipital nerve blocks or, alternatively, patients may not have been given prophylaxis but were managed by acute treatments only Health state utility values were derived using EQ-5D data from the IBMS Costs included medicine acquisition and administration costs. Other resource use was estimated from the IBMS The model used a time horizon of 2 years Sensitivity analyses were conducted The model cycle length was not reported No discounting was reported	Patients with chronic migraine, defined as headaches on at least 15 days per month, of which at least 8 days are with migraine, who have failed oral prophylactic therapy due to side effects or lack of efficacy and were in the care of a headache specialist at a secondary care centre	QALY gain: 0.08 (onabotulinumtoxinA vs BSC)	Incremental total costs: £1,394	£17,436/QALY gained
SMC [12]	Scotland; NHS perspective	Model type: Cost-utility analysis using a state-transition (Markov) model to estimate the cost-effectiveness of onabotulinumtoxinA injections given every 12 weeks vs BSC in patients with chronic migraine who had failed ≥3 oral prophylactic therapies, where medication overuse has been appropriately managed, and who are in the care of a headache specialist in a secondary care centre Health states: Clinical trial data were used to categorize patients into on-treatment and off-treatment health states within the model using mean headache days over a 28-day period Inputs: Clinical data were incorporated from the post-hoc pooled analysis of the phase 3 PREEMPT clinical trials program Health state utility values were derived from estimating EQ-5D values by transforming MSQ scores collected from the clinical studies Costs included medicine acquisition and administration costs and cost of care, consisting of GP visits, ED visits, and hospitalization costs The model used a time horizon of 2 years Scenario analyses were conducted The model cycle length was not reported No discounting was reported	Patients with chronic migraine, defined as headaches on at least 15 days per month, of which at least 8 days are with migraine, who have failed ≥3 oral prophylactic therapies, where medication overuse has been appropriately managed and who are in the care of a headache specialist in a secondary care centre	QALY gain (onabotulinumtoxinA vs BSC): 0.08	Incremental total costs (onabotulinumtoxinA vs BSC): £1,012	£12,176/QALY gained
SMC [13]	Scotland; NHS perspective	Model type: Cost-utility analysis using a state-transition (Markov) model to estimate the cost-effectiveness of onabotulinumtoxinA vs BSC in patients with chronic migraine who had failed ≥3 oral prophylactic therapies and for whom medication overuse is appropriately managed Health states: Clinical trial data were used to categorize patients into on-treatment and off-treatment health states in the model using mean headache days over a 28-day period Inputs: Clinical data were incorporated from the post-hoc pooled analysis of the phase 3 PREEMPT clinical trials program Health state utility values were based on EQ-5D values from a European observational study of onabotulinumtoxinA in patients with chronic migraine Costs included medicine acquisition and administration costs, cost of care, consisting of GP visits, ED visits, hospitalization costs, and triptan costs The model used 12-week cycles with a time horizon of 3 years Scenario analyses were conducted No discounting was reported	Patients with chronic migraine, defined as headaches on at least 15 days per month of which at least 8 days are with migraine, who have failed ≥3 oral prophylactic therapies and for whom medication overuse is appropriately managed	QALY gain (onabotulinumtoxinA vs BSC): 0.12	Incremental total costs (onabotulinumtoxinA vs BSC): £1,301	£10,816/QALY gained
SMC [14], Brown et al. [15]	UK; UK NHS and societal perspectives	Model type: Cost-utility analysis using a decision-tree model to estimate the cost-effectiveness of topiramate vs no preventive treatment (acute treatment only) in patients with migraine Health states: On entering the model, patients could either receive topiramate or no treatment. Those receiving topiramate treatment could have one of the following clinical responses: ≥75%, 75%–50%, or <50% for mean reduction in monthly migraine frequency Inputs: Clinical data were incorporated from topiramate clinical trials The model assumed 40% of topiramate patients drop out in the first month of treatment and receive no clinical benefit for the 1-year period Health state utility values were derived from transformations of SF-36 data collected as part of topiramate clinical trials Costs included cost of care, consisting of GP visits, ED visits, hospitalization costs, and triptan costs The time horizon was 1 year Sensitivity analyses were conducted The cost year was 2005 No discounting was reported	Patients with migraine (base-case frequency is 6/month)	QALY gain (topiramate vs no preventive treatment): 0.0384 No treatment: NR Incremental QALYs: NR	Costs/month: Topiramate total costs: £37.13 No treatment total costs: £18.80 Incremental total costs per migraine averted: £10.13	£5,728/QALY gained

Abbreviations. BSC, best supportive care; ED, emergency department; EQ-5D, EuroQol 5-dimensions; GP, general practitioner; IBMS, International Burden of Migraine Study; ICER, incremental cost-effectiveness ratio; MSQ, Migraine Specific Quality of Life Questionnaire; NHS, National Health Service; NR, not reported; QALY, quality-adjusted life-year; UK, United Kingdom.

Table 3. General Quality Appraisal of Economic Evaluations.

Reference	NICE^8 Royle et al.^9	SMC^11	SMC^12	SMC^13	Batty et al.^10	SMC^14, Brown et al.^15
Study design
Was the research question stated?	Y	Y	Y	Y	Y	Y
Was the economic importance of the research question stated?	Y	Y	Y	Y	Y	Y
Was/were the viewpoint(s) of the analysis clearly stated and justified?	Y	Y	Y	Y	Y	Y
Was a rationale reported for the choice of the alternative programs or interventions compared?	Y	Y	Y	Y	Y	Y
Were the alternatives being compared clearly described?	Y	Y	Y	Y	Y	Y
Was the form of economic evaluation stated?	Y	Y	Y	Y	Y	Y
Was the choice of form of economic evaluation justified in relation to the questions addressed?	Y	Y	Y	Y	Y	Y
Data collection
Was/were the source(s) of effectiveness estimates used stated?	Y	Y	Y	Y	Y	Y
Were details of the design and results of the effectiveness study given (if based on a single study)?	N/A	N/A	N/A	N/A	N/A	N/A
Were details of the methods of synthesis or meta-analysis of estimates given (if based on an overview of a number of effectiveness studies)?	Y	N	N	N	Y	N
Were the primary outcome measure(s) for the economic evaluation clearly stated?	Y	Y	N	N	Y	Y
Were the methods used to value health states and other benefits stated?	Y	Y	Y	Y	Y	Y
Were the details of the subjects from whom valuations were obtained given?	N	N	N	N	N	N
Were productivity changes (if included) reported separately?	N	N/A	N/A	N/A	Y	N
Was the relevance of productivity changes to the study question discussed?	Y	N	N	N	Y	Y
Were quantities of resources reported separately from their unit cost?	N	N/A	N	N	Y	Y
Were the methods for the estimation of quantities and unit costs described?	Y	N/A	Y	Y	Y	Y
Were currency and price data recorded?	Y	Y	Y	Y	Y	Y
Were details of price adjustments for inflation or currency conversion given?	N/A	N/A	N/A	N/A	N/A	Y
Were details of any model used given?	Y	Y	Y	Y	Y	Y
Was there a justification for the choice of model used and the key parameters on which it was based?	Y	Y	Y	Y	Y	Y
Analysis and interpretation of results
Was the time horizon of cost and benefits stated?	Y	Y	Y	Y	Y	Y
Was the discount rate stated?	Y	N	N	N	Y	N
Was the choice of rate justified?	N	N/A	N/A	N/A	Y	N/A
Was an explanation given if cost or benefits were not discounted?	N/A	N	N	N	N/A	N
Were the details of statistical test(s) and confidence intervals given for stochastic data?	N/A	N/A	N/A	N/A	N/A	N/A
Was the approach to sensitivity analysis described?	Y	Y	Y	Y	Y	Y
Was the choice of variables for sensitivity analysis justified?	Y	Y	Y	Y	Y	Y
Were the ranges over which the parameters were varied stated?	Y	N	Y	N	Y	Y
Were relevant alternatives compared in the incremental analysis?	Y	Y	Y	Y	Y	Y
Was an incremental analysis reported?	Y	Y	Y	Y	Y	Y
Were major outcomes presented in a disaggregated and aggregated form?	Y	Y	Y	Y	Y	Y
Was the answer to the study question given?	Y	Y	Y	Y	Y	Y
Did conclusions follow from the data reported?	Y	Y	Y	Y	Y	Y
Were conclusions accompanied by the appropriate caveats?	Y	Y	Y	Y	Y	Y

Abbreviations. N, no; N/A, not applicable; Y, yes.

Table 4. Migraine-Specific Quality Appraisal of Economic Evaluations.

Reference	NICE^8 Royle et al.^9	SMC^11	SMC^12	SMC^13	Batty et al.^10	SMC^14, Brown et al.^15
Clinically meaningful criteria
The model structure captures MMD frequencies between 0 and 28, reflecting the nature of migraine as a spectrum disease	N	N	N	N	N	N
Include a discontinuation rule based on treatment response (treatment response being defined by % reduction in MMDs)	N	N	N	Y	N	N
Include other forms of discontinuation (AE-related, positive)	Y	Y	Y	Y	Y	Y
Scientifically robust criteria
The evaluation should closely reflect migraine trial results as a form of validation	N	N	N	N	N	N
The structure allows accurate and simultaneous tracking of both MMD frequency for QALY estimation and response status for response-based discontinuation rule	N	N	N	N	N	N
The model reflects how patients are distributed across MMD frequencies in order to capture the non-linear impact of migraine day loss/gain	Y	Y	Y	Y	Y	N

Key, N, no; Y, yes.

Figure 1. Illustration of CE Model Structure.

Figure 2. Detail of Assessment Period.

NICE. Botulinum toxin type A for the prevention of headaches in adults with chronic migraine. [cited May 2, 2019]. Available from: https://www.nice.org.uk/guidance/ta260.

 Google Scholar

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, 2012. [cited August 22, 2019]. Available from: https://www.nice.org.uk/guidance/ta260/documents/migraine-chronic-botulinum-toxin-type-a-evidence-review-group-report2

 Google Scholar

Batty AJ, Hansen RN, Bloudek LM, et al. The cost-effectiveness of onabotulinumtoxinA for the prophylaxis of headache in adults with chronic migraine in the UK. J Med Econ. 2013;16(7):877–887.

 PubMedGoogle Scholar

SMC [Internet]. SMC advice: botulinum toxin A (Botox) 2011. [cited October 23, 2018]. Available from: https://www.scottishmedicines.org.uk/files/advice/botulinum_toxin_type_A_Botox_FINAL_MARCH_2011_AMENDED_22.03_for_website.pdf

 Google Scholar

SMC [Internet]. SMC advice: botulinum toxin A (Botox) 2013. [cited October 23, 2018]. Available from: https://www.scottishmedicines.org.uk/files/advice/botulinum_toxin_type_A_Botox_RESUBMISSION_Final_March_2013_for_website.pdf

 Google Scholar

SMC [Internet]. SMC advice: botulinum toxin A (Botox) 2017. [cited October 23, 2018]. Available from: https://www.scottishmedicines.org.uk/files/advice/botulinum_toxin_A_BOTOX_2nd_Resub_FINAL_Jan_2017_for_website.pdf

 Google Scholar

SMC [Internet]. SMC advice: topiramate (Topamax) 2006. [cited October 23, 2018]. Available from: https://www.scottishmedicines.org.uk/files/topiramate_Topamax_297_06.pdf

 Google Scholar

Brown JS, Papadopoulos G, Neumann PJ, et al. Cost-effectiveness of migraine prevention: the case of topiramate in the UK. Cephalalgia. 2006;26(12):1473–1482.

 PubMed Web of Science ®Google Scholar