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Amgen Response to ICER’s Draft Evidence Report and Voting Questions on CGRP Inhibitors as Preventive Treatments for Patients with Episodic or Chronic Migraine

SUMMARY OVERVIEW

Amgen, jointly with Novartis, appreciates the opportunity to comment on ICER’s draft evidence report and voting questions on Calcitonin Gene-Related Peptide (CGRP) Inhibitors as Preventive Treatments for Patients with Episodic or Chronic Migraine. Migraine causes profound disability, impaired quality of life and personal suffering.1 Treatment experienced migraine patients who are unresponsive to current therapy face the grim reality of living with this disabling condition without relief. Patient sentiment captures the need for additional treatment options and desperation of sufferers: succinctly expressed by one patient, “For a chronic migraine, there are no triggers, life is my trigger. For chronic migraineurs there are no cures, there are only patches that will get you through to the next bout. Have we tried, acupuncture, herbal remedies, diets, standing upside down on our heads? Yes.”2 CGRPs could serve as transformative new options for these patients. It is for this reason that payers have indicated to us that erenumab is an important innovation that could make a meaningful difference in the lives of patients.  

Consideration must also be given to employers. One of the largest healthcare payers of migraine costs is the self-insured employer, who have the additional burden of costs from lost productivity in migraine.3,4 Each employee with frequent migraine costs employers as much as $13,000, a hidden cost representing nearly three times what individuals pay in insurance premiums.5,6,7 Yet migraine sufferers are comparatively silent in their healthcare cost footprint in comparison to other conditions. A full 70% of costs of migraine are incurred by the patient, employer and society. 8 It is critical that patient voices are heard in the attribution of value of CGRPs: this disabling condition and the value of new treatment options goes beyond the scope of the healthcare payor perspective.  

We would like to commend ICER for accurately reflecting the position of erenumab in the treatment paradigm in the base-case, which is patients who have failed previous preventive therapies. There are further opportunities for ICER to strengthen the analysis and accurately reflect migraine’s burden. Our comments and recommendations are summarized below:  

  1. ICER’s base-case does not include indirect burden: ICER should capture patient indirect costs in the base-case so as not to underestimate the value of CGRPs to patients.
  2. ICER’s estimate of productivity costs is derived from patients with very low disease severity (2 MMDs as opposed to 8 MMDs in the erenumab clinical trials): ICER should adjust these costs to the baseline severity of migraine in CGRP trials.
  3. ICER’s analysis underestimates direct health care costs: ICER should revise its hospitalization, drug and ED costs and rates and conduct a robust sensitivity analysis around these.
  4. ICER’s analysis does not quantify uncertainty in the network meta-analysis (NMA) nor its implication on clinical effectiveness results: ICER should focus the NMA on the base-case analysis, remove the comparison in all-comers and adjust for heterogeneity in the studies analyzed.
  5. ICER’s model estimates utility based on a distribution of migraine severity, which does not capture the treatment effect of erenumab: ICER should map QALYs from quality-of-life scales measured in the relevant population (erenumab Phase III studies).
  6. Patients seeking care for CGRPs or generic prevention will experience a placebo effect even in clinical practice: ICER should exclude these effects in the base-case for consistency.
  7. ICER’s model overestimates the number of CM patients treated with preventative migraine therapy in the budget impact analysis: ICER should revise the size of the patient population that may be treated by CGRPs to be consistent with published prevalence numbers and other market analyses reports.

As part of this assessment, ICER have also invited us to participate in the transparency pilot allowing access to the model that was used for this assessment. We are grateful to ICER for this opportunity and will be providing feedback as a companion piece to this letter as follow-up.

DETAILED COMMENTS AND RECOMMENDATIONS  

1) ICER’s base-case does not include indirect burden: ICER should capture patient indirect costs in the base-case so as not to underestimate the value of CGRPs to patients.  

ICER’s exclusion of indirect burden of migraine in the base-case does not align with established, accepted methodologies in economic evaluations of new treatments. 9,10,11,12 This approach is inconsistent with ICER’s previous assessment of Botox® for migraine, which included indirect/lost productivity costs in all scenarios. Comprehensive capture of all productivity costs should form the backbone of the base-case rather than a scenario analysis. Lost productivity costs are 70% of total costs in migraine.8 Omitting these from the base-case captures only 30% of CGRP value and could result in migraine patients experiencing discrimination in favor of treatments that offset more costs to the healthcare system. The gold standard for health economic assessment methodology, the Second Panel on Cost-Effectiveness in Health and Medicine, recommends that all cost-effectiveness analyses capture both the healthcare payor and the societal perspective (in this case, societal is defined as all costs incurred by society due to migraine, including the often overlooked costs to patients). 9,10,11,12 

2) ICER’s estimate of productivity costs is derived from patients with very low disease severity (2 MMDs as opposed to 8 MMDs in the erenumab clinical trials): ICER should adjust these costs to the baseline severity of migraine in CGRP trials.  

ICER productivity costs for episodic migraine patients of $245 per month (used in the scenario analysis) underestimates the real burden in prevention-eligible episodic migraine patients by a factor of two.18 ICER used the International Burden of Migraine Study (IBMS)14,15 for indirect costs in which a headache day frequency per month was 2.1 for episodic migraine (EM) and 14.56 for chronic migraine (CM).  In contrast, the average monthly migraine day (MMD) in the erenumab pivotal studies was 8.36 (SD= 2.5) in EM16 and 17.8 (SD=4.7) in CM.17 Moreover, EM patients in erenumab randomized controlled trials (RCTs) had to have at least 4 MMDs during the baseline period to be enrolled into these studies. Hence, ICER applies costs of a significantly less severe migraine population leading to the undervaluation of erenumab in EM, especially when applied to indirect costs. Using monthly productivity costs for EM patients with 8 MDs (derived from STRIVE)16 gives a productivity cost of approximately $490 per month (derived from Lipton et al. 18; see Appendix A for further explanation).   The accuracy of ICER’s analysis could be strengthened by incorporating data from the treated erenumab EM patient population given a wide variation observed in lost productive time (LPT) across EM patients. In a study by Stewart et al.19, among employed individuals with migraine, the average LPT (absenteeism and presenteeism) per worker per week specifically due to headache was:

  • 2.2 (SD=4.5) hours for those with 0–3 days of headache/month
  • 3.5 (SD=6.5) hours for those with 4-9 days of headache/month
  • 4.9 (SD=7.3) hours for those with 10-14 days of headache/month

Variability in LPT is considerable, especially in the EM population. Hence, ICER’s use of a single number for lost productivity across the whole EM population grossly understates the burden among these patients. Lipton et al.,18 more accurately reflect this variation at a migraine day level in their model, calculating calculates the average costs of absenteeism and presenteeism days assuming the median hourly gross wage obtained from the US Bureau of Labor Statistics over an 8-hour working day (the degree of productivity loss on each presenteeism day i.e., days where productivity is reduced by at least 50% is not known). The publication uses question two from the Migraine Disability Assessment (MIDAS) which defines a presenteeism day as lost productivity of at least 50%.  We would highlight that this is not an overestimation of the impact of migraine but consistent with the definition from the well-validated MIDAS questionnaire. If ICER took this approach basing the number of days of productivity losses on erenumab clinical trial data (capturing the sex, age and employment status of the clinical trial populations and the baseline migraine days of 8 mentioned above) it would make productivity costs more accurate.

3) ICER’s analysis underestimates direct health care costs: ICER should revise its hospitalization, Botox® and ED costs and rates and conduct a robust sensitivity analysis around these.

ICER’s direct cost estimates are too low owing to underestimates in the main cost drivers of emergency department visits, hospitalization and Botox® cost shown in Table 1 and summarized below:

  1. Emergency Department (ED) cost: ICER uses $473 for migraine related ED from Messali et al.14 which is 1.5 to nearly four times less than the estimates from Insigna20 and Bonafede et al.21 This difference is attributable to Messali et al.'s value excluding services in the ED for migraine patients such as fees for provider administered injectables, MRI and CT scans, which the latter two references include.
  2. ED visit rates: ICER's ED visit rates for migraine patients in EM are too low.  ICER uses 14/100 patients per year14 in EM and 19.6/100 patients per year in CM, whereas other references estimate this as 17/100 patients/per year.  34% of migraine patients have at least one ED visit in a 12-month period compared to 14.3% among non-migraine controls.21
  3. Hospitalization rates: ICER uses a rate of 0.342 hospitalizations per day per 100 patients (from AHRQ Statistical Brief #111).28 This is an inaccurate reflection of migraine hospitalization rates because a) it is an ED visit rate not a hospitalization rate; and b) it is the migraine hospitalization rate as a proportion of the general US population, not the higher reported hospitalization rate among migraine patients.22 ICER's model input should be specific to the population it is modelling. We recommend ICER use the rate from Munakata et al., which is seven migraine-specific hospitalizations per 100 migraine patients.22,23
  4. Drug costs: ICER estimates the cost of Botox® based on the Federal Supple Schedule (FSS) which underestimates its cost.24 We recommend instead using the WAC cost which is more representative of the costs payors would incur. The current Wholesale Average Cost (WAC) or List price for a 200 unit vial for Botox® is $1,202 for an annual drug cost of $5,16925 and annual administration cost of $649.26,27

These differences are important as combined, they work to diminish the costs that CGRPs offset, which results in an underestimation of the value of these innovative treatments to patients. This is especially important as these inputs are unavailable by migraine frequency and previous treatment status. Hence, we also suggest conducting robust sensitivity analyses around medical resource use and direct cost estimates.  

Table 1: Comparison of Hospital and ED Rates in ICER’s model vs. other published sources

  ICER Published resource 
Hospitalization rate 0.342 / 100 US population per year28 7 /100 migraine patients per year22
ED visits rates EM: 3.5 % per 3 months – 14 / 100/ year14
CM: 4.9% per 3 months – 19.6 / 100/ year 14

17 /100 patients per year22

 

ED costs per visit  $ 473.8214 $ 77520
$ 170021

4) ICER’s analysis does not quantify uncertainty in the network meta-analysis (NMA) nor its implication on clinical effectiveness results: ICER should focus the NMA on the base-case analysis, remove the comparison in all-comers and adjust for heterogeneity in the studies analyzed.  

We commend ICER for recognizing the relevant patient population for CGRPs (those who have failed a prior preventive therapy) and rating the evidence as promising but inconclusive for EM and comparable or better for CM (See Appendix B, Table A). Aligning with this, in evaluating clinical effectiveness we recommend that ICER removes the comparison of CGRPs to current preventive therapy (as presented in the scenario analyses). Comparison of erenumab and CGRPs against generic prevention should not be undertaken given their place in the treatment paradigm and observed heterogeneity in the results.

The NMA includes studies conducted over two decades during which methods for collecting outcomes and design of clinical trials have evolved tremendously. The methods to define outcomes and included patient populations (in terms of baseline number of MMDs, medication overuse, use of concomitant therapy, etc.) vary substantially between the studies. This introduces significant heterogeneity in the networks.  ICER has acknowledged that the heterogeneity in the CM model was fairly high (0.68 [0.03, 3.02]). We recommend that ICER accounts for the resulting heterogeneity in the NMA.  

Lastly, ICER’s rating of the evidence could be enhanced by: 1) adding clarity on what was considered as a comparator for each phenotype and patient subgroup; and 2) adding clarity on the derivation of the efficacy numbers highlighted in ICER’s draft report, page 48, “Efficacy: Results suggest a modest reduction in monthly migraine days (1.3-2.4 fewer migraine days per month), a modest reduction in days using acute medications (0.9-2.5 fewer days per month), and a greater proportion of patients experiencing a reduction in migraine days by at least 50% (OR 1.9-2.3) with erenumab compared with placebo.”29  

5) ICER’s model estimates utility based on a distribution of migraine severity, which does not capture the treatment effect of erenumab: ICER should map QALYs from quality-of-life scales measured in the relevant population (erenumab Phase III studies).  

Reduction of interictal burden is an important benefit with prevention which is not captured in ICER’s analysis. ICER uses utilities in the model collected from patients and the general public to form a QALY for a given state of health. These utilities are not representative of the erenumab patient population recruited in the Phase III studies or patients who are eligible for prevention. ICER misinterprets Lipton et al. stating, “Lipton et al. derived utility estimates from the International Burden of Migraine Study that included participants from 10 countries,” 30 This is not where Lipton et al. derive these utilities. It is correct that the algorithm to map utilities from Migraine-Specific Quality-of-Life Questionnaire (MSQ) and Headache Impact Test 6 (HIT6) was based on the IBMS data, however, the treatment effect on utilities for erenumab and placebo map from the MSQ and HIT6 collected in erenumab Phase III trials. This is critical since as pointed out by ICER, “Lipton et al. derived utility measures that are different across placebo and treatment, such that patients had 1) a utility gain associated with the treatment that was independent of migraine day reduction.” This treatment effect for erenumab is likely due to the effect on interictal burden, reduction of other migraine symptoms and reduced severity. ICER’s approach to modeling utility does not account for this treatment benefit. Hence, ICER should map from HRQoL scales collected in the relevant population (erenumab Phase III studies) in order to capture this treatment benefit that goes beyond a reduction in MDs.

ICER overestimates baseline QALY values for chronic migraine patients when not experiencing a migraine, which underestimates the benefit of erenumab. ICER uses QALY values on pain-free migraine days of 0.95 from patients averaging 1-6 migraine attacks from Xu et al.31 versus 0.87 from patients averaging 5 MMDs from Stafford et al.32,33 Stafford et al.’s value for a non-migraine day is lower than Xu et al. because patients in the Stafford et al. manuscript were more severe and are a better proxy for the patients enrolled in the erenumab Phase III trials (averaging 8 MMDs).  Hence, ICER’s use of Xu et al., does not adequately capture the impact of migraine on a patient’s quality of life and interictal burden. Moreover, the values in Stafford et al. are consistent with other studies in representative populations that report a mean utility of migraine patients when not experiencing a migraine day (MD) as 0.82.34 This is further supported by Amgen Phase III studies, which measured a utility of 0.84 for patients with zero MDs.35  

6) Patients seeking care for CGRPs or generic prevention will experience a placebo effect even in clinical practice: ICER should exclude these effects in the base-case for consistency.  

Clinical trials in migraine prevention typically have strong observed placebo effects.36 Migraine placebo response is predominantly due to regression to the mean since migraine day frequency and severity vary markedly over time within individual patients.37 ICER uses placebo adjusted rates from erenumab studies but not for clinical practice. These also occur in clinical practice but are not measurable because administration of placebos, such as sham injections, is not a plausible treatment option. This severely underestimates the efficacy of erenumab as it accounts for placebo effects in the erenumab clinical trials but not those in clinical practice: these occur in both settings and ICER should standardize the approach for consistency.  

7) ICER’s model overestimates the number of CM patients treated with preventative migraine therapy in the budget impact analysis: ICER should revise the size of the patient population that may be treated by CGRPs to be consistent with published prevalence numbers and other market analyses reports.  

The ICER report states that 95.6% of CM patients currently receive preventive treatment, which is an overestimate. While this number is based on the Adelphi Migraine Disease Specific Programme (DSP), a real-world, cross-sectional survey of physicians and their patients with migraine, it only samples patients who present at a doctor’s office, i.e., are trying to access care for their migraine. Hence, this number vastly overstates the percentage of patients with chronic migraine who are receiving preventive migraine therapy. Considering a one million patient plan, approximately 3% of patients currently or previously on migraine preventive therapy would start an anti-CGRP in year one.38 These estimates are consistent with independent analyst estimates at 2%.39 This would apply to the base-case scenario where patients with at least 4 MMDs and experience with one prior preventive therapy are eligible for an anti-CGRP. Another study, estimates that only 12-13% of patients who need prevention are currently receiving it.40

Areas for further clarification

  • Since the efficacy estimates for the base-case analysis were not transparent, we are unable to comment if the efficacy data were used appropriately. Amgen provided ICER data in treatment experienced patients from Amgen publications. However, it is not clear what the efficacy estimates are for this base-case. It is also unclear if NMA results for efficacy for treatment experienced patients were used in the base-case analyses
  • It is unclear how the erenumab open label extension (OLE) data were incorporated in the clinical and value assessments. Erenumab is the only CGRP with robust published data. We recommend that these data be included in the evaluation of benefit that erenumab brings to patients.

CONCLUSION

Migraine remains an extremely disabling condition, especially for those who have exhausted all treatment options. It is of paramount importance that the perspective of migraine patients is heard and actioned. This is also critical to employers as additional prevention could reduce the impact of migraine on productivity by reducing disability.  ICER has the opportunity to provide a more complete and thorough analysis by ensuring that patient, employer and societal considerations are fully captured in their base-case. In addition, we have highlighted several technical recommendations that will strengthen ICERs analysis and more accurately reflect the value of CGPRs.

Appendix A  

Indirect cost derivation from Lipton et al.18 Since erenumab episodic pivotal trials had an average of 8 monthly migraine days (MMD) at baseline, these patients as per the Lipton 2018 publication are predicted to have 0.95 (95% CI: 0.94–0.96) absenteeism days and 2.34 (95% CI: 2.32–2.35) presenteeism days (derived from MIDAS question 1 and question 2). This represents a conservative estimate since these are based on Q1 (for absenteeism) and Q2 (for presenteeism) from the MIDAS questionnaire.  The model estimates are consistent with episodic trial data presented in the poster by Buse et al41. where the change from baseline in absenteeism over months 4, 5, and 6 for 140 mg –4.2 (0.2), p < 0.001; and for placebo, –2.6 (0.2). Presenteeism change for 140 mg was –3.3 (0.2) days; and placebo was –2.0 (0.2) days; p < 0.001 for each erenumab group vs placebo. Based on the average wage, these productivity losses are expected to result in average costs per month of $197.52 ($196.38– $198.65) and $242.86 ($241.46–$244.26), for absenteeism and presenteeism respectively. These productivity losses are expected to result in average costs per month of $ 490 (CI$) in EM patients representative of the erenumab EM trials (average MMD 8).    

Appendix B   Table A: ICER’s rating of the evidence

  All patients Patients with prior treatment failure
EM Insufficient Promising but inconclusive
CM Insufficient Comparable or better

REFERENCES  

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  7. To get this number, the average individual premium was taken from eHealth of $393 for 2017, multiplied by 12 to get the annual premium and then the total employer cost of 13K was divided by this number to get to 2.75.  From: eHealth.  How Much Does Obamacare Cost in 2017? 2017.  Link
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  26. Estimating a unit drug cost based on the Federal Supple Schedule(FSS) underestimates cost. The FSS is a multiple award, multi-year federal contract that is available for use by a Federal Government agency, for example the VA or the DoD. It is almost always the lowest price reimbursed for a drug versus the price in commercial plans.
  27. Current WAC or List price for a 200 unit vial for BotoxÒ is $1,202 and for a 12 week dosing schedule gives 4.3 administrations in a year for an annual drug cost of $5,169 (Source: Analysource.com accessed April 20th, 2018); Administration costs are $151 per administration and for a 4.3 multiplicative factor gives an annual total of $649; (Source: CMS Physician Fee Schedule United States, 2016)
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  35. Amgen data on File.
  36. If placebo effects are due to regression to the mean, the trial placebo response will be seen in routine practice even if the placebo is not administered. However, if placebo effects are due to practice generalizable expectancy, the placebo response will only be seen in routine practice if the placebo is actually administered.
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  38. Amgen data on file (previously communicated to ICER).
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