Alirocumab for Treatment of High Cholesterol: Effectiveness and Value New Evidence Update February 15, 2019 ©Institute for Clinical and Economic Review, 2019 Page 1 Alirocumab for High Cholesterol – Final New Evidence Update CVD Policy Model Group Jeffrey A. Tice, MD Dhruv S. Kazi, MD, MSc, MS Professor of Medicine Associate Director University of California San Francisco Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology Rick Chapman, PhD, MS Beth Israel Deaconess Medical Center Director of Health Economics Institute for Clinical and Economic Review Pamela G. Coxson, PhD Mathematics Specialist David M. Rind, MD, MSc Department of Medicine, University of California San Chief Medical Officer Francisco Institute for Clinical and Economic Review Joanne Penko, MS, MPH Steven D. Pearson, MD, MSc Research Analyst President Center for Vulnerable Populations, Department of Institute for Clinical and Economic Review Medicine, University of California San Francisco ICER would also like to thank Daniel A. Ollendorf, Kirsten Bibbins-Domingo, MD, PhD, MAS PhD, Director, Value Measurement and Global Professor Health Initiatives, Center for Evaluation of Value Department of Medicine, Department of Epidemiology and and Risk in Health, Tufts Medical Center, for his Biostatistics, and Center for Vulnerable Populations, contributions to the preliminary New Evidence University of California San Francisco Update issued in March 2018. The role of the CVD Policy Model Group is limited to the development of the cost-effectiveness model, and the resulting ICER reports do not necessarily represent the views of the CVD Policy Model Group. About ICER The Institute for Clinical and Economic Review (ICER) is an independent non-profit research organization that evaluates medical evidence and convenes public deliberative bodies to help stakeholders interpret and apply evidence to improve patient outcomes and control costs. Through all its work, ICER seeks to help create a future in which collaborative efforts to move evidence into action provide the foundation for a more effective, efficient, and just health care system. More information about ICER is available at http://www.icer-review.org. The funding for this report comes from government grants and non-profit foundations, with the largest single funder being the Laura and John Arnold Foundation. No funding for this work comes from health insurers, pharmacy benefit managers, or life science companies. ICER receives approximately 19% of its overall revenue from these health industry organizations to run a separate Policy Summit program, with funding approximately equally split between insurers/PBMs and life science companies. Alirocumab is manufactured by Regeneron and Sanofi, both of which are ICER members. For a complete list of funders and for more information on ICER's support, please visit http://www.icer-review.org/about/support/. ©Institute for Clinical and Economic Review, 2019 Page 2 Alirocumab for High Cholesterol – Final New Evidence Update Background ICER's New Evidence Update for alirocumab (Praluent®, Regeneron/Sanofi) is based on results from the ODYSSEY outcomes trial published in the New England Journal of Medicine on November 7, 2018.1 We used the results published in the manuscript to update our preliminary cost- effectiveness analyses and associated value-based price benchmarks for this drug. ICER's value- based price benchmarks suggest a price range that would align fairly with the added benefits of new treatment options for patients and the health care system. ICER previously assessed the cost-effectiveness of alirocumab and evolocumab (Repatha®, Amgen Inc.) shortly after these drugs were first granted regulatory approval in the United States in 2015,2 and performed a New Evidence Update for evolocumab in September 2017 following the release of outcomes data from the FOURIER trial.3 A preliminary new evidence update for alirocumab was published on March 10, 2018, following presentation of the results at the American College of Cardiology's 2018 Scientific Session.4,5 Summary of Clinical Trial Results The ODYSSEY Outcomes trial1 was a multi-site randomized controlled trial testing alirocumab versus placebo in patients with the following eligibility criteria: 1) age ≥ 40 years; 2) hospitalization for acute coronary syndrome with myocardial infarction (MI) or unstable angina 1-12 months prior to randomization; 3) a run-in period of 2-16 weeks of high-intensity or maximally-tolerated dose of atorvastatin or rosuvastatin; and 4) following the run-in period, at least one of the following lipid entry criteria: low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL (1.8 mmol/L), non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL (2.6 mmol/L), or Apolipoprotein B ≥80 mg/dL. In the ODYSSEY Outcomes Trial, the primary outcome was a composite of coronary heart disease (CHD) death, non-fatal myocardial infarction (MI), ischemic stroke (fatal and non-fatal), and hospitalization for unstable angina. The incidence of the primary outcome (see Table 1 below) was lower in the alirocumab arm of the trial (hazard ratio [HR]: 0.85, 95% confidence interval [CI] 0.78- 0.93). There was a non-significant reduction in CHD death (HR: 0.92) and cardiovascular disease death (HR: 0.88) and a nominally significant reduction in all-cause mortality (HR: 0.85, 95% CI 0.73- 0.98). ©Institute for Clinical and Economic Review, 2019 Page 3 Alirocumab for High Cholesterol – Final New Evidence Update Table 1. Primary and Key Secondary Outcomes of the ODYSSEY Outcomes Trial Entire Cohort Outcome HR (95% CI) Primary outcome: CHD death, non-fatal MI, ischemic stroke, unstable angina 0.85 (0.78-0.93) CHD death 0.92 (0.76-1.11) ASCVD death 0.88 (0.74-1.05) All-cause death 0.85 (0.73-0.98) CHD: coronary heart disease, CVD: atherosclerotic cardiovascular disease, HR: hazard ratio, LDL-C: low density lipoprotein cholesterol, MI: myocardial infarction The prespecified subgroup analysis by baseline LDL-C (<80 mg/dL, 80-100 mg/dL, ≥100 mg/dL) was not significant for the primary endpoint (Table 2). In addition, there was not a dose-response effect by baseline LDL-C level: the hazard ratios for the 80-100 mg/dL group did not fall between the other two groups. In a post-hoc analysis, the absolute benefit of alirocumab was significantly greater in the subgroup of patients with a high baseline LDL-C level (≥100 mg/dL) on maximally tolerated statin therapy (p < 0.001 for the primary endpoint, Table 2 below), but this may be a chance finding. There were dose adjustments of alirocumab based on achieved LDL-C. Among the 9,462 patients assigned to treatment with alirocumab 75 mg every two weeks, 2,615 (27.6%) had up-titration to 150 mg every two weeks; of these, 805 were subsequently down titrated back to 75 mg every two weeks. Patients receiving 75 mg alirocumab who had two consecutive LDL-C measurements below 15 mg/dL were switched to placebo; this occurred with 730 (7.7%) of patients on alirocumab. This protocol raises the possibility that patients with a higher baseline LDL-C might have experienced a greater dose intensity of alirocumab, which could have led to different relative efficacy in the higher LDL-C subgroup. However, no data have been presented to substantiate this hypothesis. Although the data were not new in the recent publication of ODYSSEY,1 the graphic representation in figure S6 showing LDL-C results over time contrasted with the primary end point hazard ratios, both by baseline LDL-C, led us to conclude in this updated report that differential changes in dose intensity of alirocumab were an unlikely explanation for the results. Patients with a baseline LDL-C between 80 and 100 mg/dL had the smallest reduction in the primary endpoint, while the reductions in LDL-C in this intermediate subgroup were intermediate and similar in shape over time to the other two subgroups, without any discontinuities as might be seen at the time of dose alterations. Additionally, while there is some evidence that differential relative effects on outcomes may be seen in patients with baseline LDL-C above 100 mg/dL,6 many trials of lipid-lowering therapies that have examined clinical outcomes have shown consistent relative effects across LDL-C levels.7-9 For example, no differential relative effect across LDL subgroups was seen in the FOURIER trial of evolocumab.10 Thus, we feel it is appropriate to assume a constant relative effect of alirocumab ©Institute for Clinical and Economic Review, 2019 Page 4 Alirocumab for High Cholesterol – Final New Evidence Update across LDL-C levels for our base-case analysis, which is consistent with the non-significant interaction by LDL-C level in the prespecified analysis of the ODYSSEY Outcomes trial.1 Table 2. Primary and Secondary Outcomes by Categories of Baseline LDL Cholesterol in the ODYSSEY Outcomes Trial P-value for Outcome LDL-C Category HR (95% CI) interaction <80 mg/dL 0.86 (0.74-1.01) 0.09 Primary outcome: CHD death, non-fatal 80 to <100 mg/dL 0.96 (0.82-1.14) MI, ischemic stroke, unstable angina ≥100 mg/dL 0.76 (0.65-0.87) <80 mg/dL 1.00 (0.73-1.39) * CHD death 80 to <100 mg/dL 1.17 (0.81-1.68) ≥100 mg/dL 0.72 (0.53-0.98) <80 mg/dL 0.96 (0.71-1.29) * ASCVD death 80 to <100 mg/dL 1.12 (0.80-1.56) ≥100 mg/dL 0.69 (0.52-0.92) <80 mg/dL 0.89 (0.69-1.14) * All-cause death 80 to <100 mg/dL 1.03 (0.78-1.36) ≥100 mg/dL 0.71 (0.56-0.90) *Not reported because the interaction with CHD death was NS. CI: confidence interval, ASCVD: atherosclerotic cardiovascular disease, HR: hazard ratio, LDL-C: low density lipoprotein cholesterol, MI: myocardial infarction, NS: not significant. There were no new adverse events identified in the ODYSSEY Outcomes trial. The total number of adverse events and serious adverse events were numerically lower in the alirocumab group. As expected, there were more local injection site reactions in the alirocumab group compared with placebo (3.8% versus 2.1%). There was no increase in new diabetes, neurocognitive events, creatinine kinase elevations, or liver enzyme elevations. ©Institute for Clinical and Economic Review, 2019 Page 5 Alirocumab for High Cholesterol – Final New Evidence Update Summary of Updated Cost-Effectiveness Analysis Results We updated our estimates of the long-term cost-effectiveness of alirocumab based on data from the ODYSSEY Outcomes trial as described above. This analysis was conducted in partnership with an independent research group led by Dr. Dhruv Kazi at Beth Israel Deaconess Medical Center, Boston and Dr. Kirsten Bibbins-Domingo at the University of California, San Francisco. The team used the Cardiovascular Disease (CVD) Policy Model, an established simulation model that systematically combines data from vital statistics, epidemiologic studies, clinical trials, and registries to project the morbidity, mortality, and direct medical costs related to cardiovascular disease in the US population . The model used for this analysis was structurally similar to that previously described in ICER's final report on PCSK9 inhibitors developed as part of deliberations held by the New England Comparative Effectiveness Public Advisory Council in October 2015, which was subsequently published in the peer-reviewed literature.11-13 As before, the analyses adopted a health system perspective and assessed costs and outcomes over a lifetime horizon. We assumed the annual price of alirocumab to be the US list price announced in February 2019 ($5,850 per year).14 We applied the reduction in major coronary heart disease (CHD) events and stroke as observed in the ODYSSEY Outcomes trial to CHD and stroke events in the CVD Policy Model to project changes in health outcomes and costs if all patients eligible for alirocumab based on the eligibility criteria of the ODYSSEY Outcomes trial would receive the drug. Cost-effectiveness was presented in terms of incremental cost per quality-adjusted life year (QALY) gained for treatment with alirocumab + statin compared with statin alone among patients who meet the inclusion criteria of the ODYSSEY Outcomes Trial. We performed additional deterministic and probabilistic sensitivity analyses to examine the robustness of the results to uncertainty in model inputs. In particular, we varied the price of alirocumab to identify the price at which it would become cost-effective relative to statin therapy at willingness-to-pay thresholds of $100,000 per QALY and $150,000 per QALY. In the probabilistic sensitivity analysis, we performed 1,000 trials that varied all key input parameters simultaneously, sampling with replacement from pre-specified statistical distributions. These results were used to create 95% uncertainty intervals (UIs) around the point-estimates of the incremental cost- effectiveness ratio. We also performed a subgroup analysis to examine the cost-effectiveness of alirocumab therapy among patients with a recent MI and a baseline LDL-C ≥100mg/dL despite maximal statin therapy. This high-risk group was assumed to have a higher baseline risk of events compared with the entire trial-eligible population but an identical relative risk reduction as the trial- eligible population (see discussion under Summary of Clinical Trial Results above). See Table 3 below for a description of key differences between the preliminary and final New Evidence Updates and a related analysis published in Annals of Internal Medicine. ©Institute for Clinical and Economic Review, 2019 Page 6 Alirocumab for High Cholesterol – Final New Evidence Update Table 3. Key Differences Between ICER Preliminary New Evidence Update, Annals Publication, and ICER Final New Evidence Update ICER Preliminary ICER Final New Evidence Data Element New Evidence Annals Paper15 Update Update4 Base Case Statin + Intervention Statin + Alirocumab Statin + Alirocumab Alirocumab Comparator Statin alone Statin + Ezetimibe Statin alone Annual cost of Alirocumab $7186.52 $7186.52 $5850.0014 Sensitivity Analyses (LDL-C ≥ 100mg/dL subgroup) Baseline MACE Rate (per 100 6.2 7.2* 7.2* patient-years) HR for MI and CVD-mortality Subgroup Overall Overall *The simulation model was further refined between reports to fully capture the increased risk of MACE in this subgroup. HR: hazard ratio, MACE: major adverse cardiovascular event (a composite of CVD death, non-fatal MI, and non- fatal stroke), MI: myocardial infarction, CVD: cardiovascular disease Finally, in a scenario analysis, we examined how the results in the subgroup of patients with an initial LDL-C ≥100mg/dL would change if we assumed a higher relative risk reduction, as described in the initial ODYSSEY Outcomes presentation. Based in part on the biologic plausibility arguments discussed above, some believe there is a greater relative reduction in events in patients with a baseline LDL ≥100 mg/dL. A statistically non- significant interaction term (p = 0.09) does not exclude this possibility and so we performed a scenario analysis in patients with a baseline LDL ≥100 mg/dL using the point estimate for the hazard ratio in that subgroup. Summary results are presented in Table 4 below. Please see the accompanying peer-reviewed publication for complete methodological details and additional results.15 ©Institute for Clinical and Economic Review, 2019 Page 7 Alirocumab for High Cholesterol – Final New Evidence Update Table 4. ICERs and Threshold Prices, Based on Patient Population Incremental Annual Annual Annual Value- Cost Price to Price to Price to Based Price Effectiveness Achieve Achieve Achieve Benchmark Ratio $50,000 $100,000 $150,000 Range ($/QALY) /QALY /QALY /QALY Assumes observed reduction in major CHD events $251,000 $2,311 to All eligible patients ($161,000 to $1,138 $2,311 $3,484 $3,484 $552,000) Only patients with LDL-C ≥100 mg/dL $218,000 (assuming higher baseline risk but identical $2,656 to ($139,000 to $1,315 $2,656 $3,997 relative risk reduction as the entire trial- $3,997 $484,000) eligible population) CHD: coronary heart disease, LDL-C: low density lipoprotein cholesterol, MI: myocardial infarction, QALY: quality- adjusted life year In the scenario analysis in which we assume a higher relative risk reduction in patients with a recent MI and an initial LDL-C ≥100mg/dL than in the entire trial-eligible population, the ICER for alirocumab is $119,000 per QALY (95% UI, $90,000 to $187,000) relative to statin therapy. To achieve a cost-effectiveness threshold of $100,000 per QALY relative to statin therapy, the price of alirocumab would have to decline to $4,928 in this scenario, and to achieve a threshold of $150,000 per QALY, the annual price could be increased to $7,417. We discuss above the basis for our decision to move this analysis from the base case in the preliminary new evidence update to a scenario analysis in this final version. The threshold prices shown here for this scenario are somewhat higher than in the preliminary version because we were able to incorporate more accurate information on the increased risk of events in patients with a higher baseline LDL-C. Potential Budget Impact We performed a potential budget impact analysis as part of the final New Evidence Update. Potential budget impact was defined as the total net cost of using alirocumab added to statin treatment compared with statin treatment alone for the treated population, calculated as health care costs (including drug costs) minus any offsets in these costs from averted health care events. Estimates of the eligible population that are likely to be considered for PCSK9 inhibitor treatment have been contentious. For this update, we used an estimate of the eligible population of US adults aged 40-80 years with ASCVD and LDL-C ≥70 mg/dL despite statin therapy. Kazi et al. have estimated this population as approximately 8,947,000 individuals in the US in 2015, based on 2005- 2012 National Health and Nutrition Examination Surveys (NHANES).12 All costs were undiscounted ©Institute for Clinical and Economic Review, 2019 Page 8 Alirocumab for High Cholesterol – Final New Evidence Update and estimated over a five-year time horizon, assuming equal uptake over each of the five years (i.e., 20% of 8,947,000, or 1,789,400 patients per year). ICER's methods for estimating potential budget impact are described in detail elsewhere and have been recently updated.16 The intent of our revised approach to budgetary impact is to document the percentage of patients who could be treated at selected prices without crossing a budget impact threshold that is aligned with overall growth in the US economy. For 2018-19, the five-year annualized potential budget impact threshold that should trigger policy actions to manage access and affordability is calculated to total approximately $991 million per year for new drugs. Table 5 illustrates the per-patient budget impact calculations for alirocumab treatment, based on the most recent list price of $5,850 per year and the prices to reach $150,000, $100,000, and $50,000 per QALY ($3,484, $2,311, and $1,138 per year, respectively), compared to statin only. Table 5. Per-Patient Budget Impact Calculations for Alirocumab plus Statin Compared to Statin Only, Over a Five-Year Time Horizon Average Annual per Patient Budget Impact List Price $150,000/QALY $100,000/QALY $50,000/QALY Alirocumab + Statin $32,138 $29,772 $28,599 $27,426 Statin $26,847 Difference $5,291 $2,925 $1,752 $579 QALY: quality-adjusted life year The average potential budgetary impact compared to statin only when using the current list price was an additional per-patient cost of approximately $5,300. Average potential budgetary impact at the cost-effectiveness threshold prices for the drug ranged from approximately $2,900 per patient using the annual price to achieve $150,000 per QALY ($3,484) to approximately $580 per patient using the annual price to achieve a $100,000 per QALY cost-effectiveness threshold ($1,138). As shown in Figure 1, approximately 3% of eligible patients could be treated in a given year without crossing the ICER annual budget impact threshold of $991 million at alirocumab's current list price. Approximately 6% of the eligible population could be treated before exceeding the $991 million threshold at the $150,000 per QALY threshold price and approximately 11% at the $100,000 per QALY threshold price, increasing up to approximately 32% at the $50,000 per QALY threshold price. ©Institute for Clinical and Economic Review, 2019 Page 9 Alirocumab for High Cholesterol – Final New Evidence Update Figure 1. Potential Budget Impact Scenarios at Different Prices of Alirocumab Treatment $10,000 $9,000 $8,000 $7,000 $6,000 WAC Annual Price $5,000 $4,000 $150,000 per QALY $3,000 $100,000 per QALY $2,000 $1,000 $50,000 per QALY $0 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Percent of Patients Treated Without Crossing Annual BI Threshold As illustrated in the above analysis, treating the entire potentially eligible population with alirocumab therapy would result in a substantial budget impact. While it is unclear if these therapies will likely be prescribed more narrowly or in the larger population indicated by the drug's FDA label, policymakers may need to continue to evaluate strategies to ensure affordable access to alirocumab. Comment The new evidence from the ODYSSEY Outcomes trial does not alter ICER's cost-effectiveness assessment for another PCSK9 inhibitor, evolocumab. In September 2017, after assessing new data from the FOURIER outcomes trial, ICER announced that the value-based price benchmark for a year's treatment with evolocumab would change to a range from approximately $1,700 to $2,200. The primary reason that this price range is lower than the updated range calculated for alirocumab is that, although the FOURIER trial showed that evolocumab combined with statin therapy is effective in reducing the incidence of cardiovascular events such as MI and stroke, the evidence did ©Institute for Clinical and Economic Review, 2019 Page 10 Alirocumab for High Cholesterol – Final New Evidence Update not demonstrate a reduction in CV or all-cause mortality. In contrast, the point estimates for CV and all-cause mortality in ODYSSEY (0.88 and 0.85, respectively) were consistent with the reduction seen in CV events, although under the hierarchical statistical analysis, neither result was statistically significant. The degree of LDL-C reduction observed in both the ODYSSEY Outcomes and FOURIER trials was similar. Thus, under the LDL hypothesis (the hypothesis that the magnitude of the benefit from lipid therapy is proportional to the magnitude of the LDL reduction regardless of the agent used to lower LDL-cholesterol) one would expect that the outcomes would be similar.17 However, not all trial results have been consistent with the LDL hypothesis, and it is difficult to ascribe a class effect to PCSK9 inhibitors based on the available evidence. There are several possible explanations for why ODYSSEY Outcomes suggested a mortality benefit for alirocumab while FOURIER found no such signal for evolocumab. First, this may be related to differences in the populations enrolled in the trials: ODYSSEY Outcomes included only patients who had experienced an acute coronary syndrome in the preceding 12 months and these patients may have derived a greater benefit from PCSK9 inhibitor therapy. Second, the apparent difference between the two trials may be a chance finding. Finally, there may be actual differences in the clinical effectiveness of the two drugs. While we feel that it is not possible to be certain of the explanation for the differing results in ODYSSEY Outcomes and FOURIER, clinicians and patients must consider the possibility that these reflect true differences in the effects on mortality of alirocumab and evolocumab. ©Institute for Clinical and Economic Review, 2019 Page 11 Alirocumab for High Cholesterol – Final New Evidence Update References 1. Schwartz GG, Steig PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. New England Journal of Medicine. 2018;0(0). 2. Tice JA, Kazi DS, Ollendorf DA, et al. PCSK9 Inhibitors for Treatment of High Cholesterol: Effectiveness, Value, and Value-Based Price Benchmarks; Final Report. In: Instittue for Clinical and Economic Review; 2015. 3. Tice JA, Kazi DS, Ollendorf DA, et al. Evolocumab for Treatment of High Cholesterol: Effectiveness and Value; New Evidence Update. In: Institute for Clinical and Economic Review; 2017. 4. Tice JA, Kazi DS, Ollendorf DA, et al. Alirocumab for Treatment of High Cholesterol: Effectiveness and Value; Preliminary New Evidence Update. In: Institute for Clinical and Economic Review; 2018. 5. Schwartz GG, Szarek M, Bhatt DL, et al. The ODYSSEY Outcomes Trial: Topline Results Alirocumab in Patients After Acute Coronary Syndrome. Paper presented at: American College of Cardiology Scientific Session (ACC 2018); March 10, 2018; Orlando, FL. 6. Navarese EP, Robinson JG, Kowalewski M, et al. Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering: A Systematic Review and Meta- analysis. Jama. 2018;319(15):1566-1579. 7. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7-22. 8. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. The New England journal of medicine. 2015;372(25):2387-2397. 9. Kjekshus J, Pedersen TR. Reducing the risk of coronary events: evidence from the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol. 1995;76(9):64c-68c. 10. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. New England Journal of Medicine. 2017;376(18):1713-1722. 11. Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of pcsk9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. Jama. 2016;316(7):743-753. 12. Kazi DS, Penko J, Coxson PG, et al. Updated cost-effectiveness analysis of pcsk9 inhibitors based on the results of the fourier trial. Jama. 2017;318(8):748-750. 13. Kazi DS, Penko J, Ollendorf DA, Coxson PG, Bibbins-Domingo K. EFfect of money-back guarantees on the cost-effectiveness of proprotein convertase subtilisin/kexin type 9 inhibitors. Annals of Internal Medicine. 2018;168(12):896-898. 14. Regeneron and Sanofi offer Praluent® (Alirocumab) at a new reduced U.S. list price [press release]. February 11 2019. 15. Kazi DS, Penko J, Coxson PG, Guzman D, Wei PC, Bibbins-Domingo K. Cost-effectiveness of alirocumab: A just-in-time analysis based on the odyssey outcomes trial. Annals of Internal Medicine. 2019. 16. Pearson SD. The ICER Value Framework: Integrating Cost Effectiveness and Affordability in the Assessment of Health Care Value. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2018;21(3):258-265. 17. Jarcho JA, Keaney JF, Jr. Proof That Lower Is Better--LDL Cholesterol and IMPROVE-IT. The New England journal of medicine. 2015;372(25):2448-2450. ©Institute for Clinical and Economic Review, 2019 Page 12 Alirocumab for High Cholesterol – Final New Evidence Update