|
 
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| REVIEW ARTICLE |
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| Year : 2019 | Volume
: 3
| Issue : 4 | Page : 140-146 |
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Cross-country comparison in the evaluation of evolocumab by health technology assessment agencies in England, Canada, and Australia
Swaroop Varghese1, Marc-Alexander Ohlow2, Narendra Kumar3
1 Department of Cardiology, Harz Hospital Quedlinburg, Quedlinburg, Bad Berka, Germany
2 Department of Cardiology, Central Hospital, Bad Berka, Germany
3 Department of Cardiology, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| Date of Submission | 04-Aug-2019 |
| Date of Acceptance | 08-Nov-2019 |
| Date of Web Publication | 23-Dec-2019 |
Correspondence Address:
Dr. Narendra Kumar
Department of Cardiology, Manchester University NHS Foundation Trust, Oxford Road, Manchester, M13 9WL
United Kingdom
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/hm.hm_17_19
Evolocumab is a proprotein convertase subtilisin/kexin type 9 inhibitor drug which has shown great treatment effects in the treatment of uncontrolled hypercholesterolemia, particularly elevated low-density lipoprotein cholesterol levels. Due to its significant costs, several health technology assessment agencies (HTA) worldwide have exercised caution in issuing its recommendation across different patient groups. This study attempts to review the processes and compare the approach adopted by the HTA agencies in England (National Institute for Care and Health Excellence [NICE]), Canada (Canadian Agency for Drugs and Technologies in Health [CADTH] Common Drug Review), and Australia (Pharmaceutical Benefits Advisory Committee [PBAC]) in the evaluation of evolocumab. Between July and August 2018, the websites of CADTH, the NICE in England, and the PBAC of the Pharmaceutical Benefits Scheme in Australia were searched for technology appraisal documents pertaining to evolocumab. The search included the initial appraisal, resubmissions, as well as the final recommendation made between 2015 and 2018. Significant variability exists between the recommendations and clinical and economic assessment processes in the evaluation of evolocumab across the three selected HTAs. More collaborative efforts may be required to align the interagency HTAs. Keywords: Evolocumab, health technology assessment, health technology assessment agencies, hypercholesterolemia, proprotein convertase subtilisin/kexin type 9 inhibitors
How to cite this article:
Varghese S, Ohlow MA, Kumar N. Cross-country comparison in the evaluation of evolocumab by health technology assessment agencies in England, Canada, and Australia. Heart Mind 2019;3:140-6 |
How to cite this URL:
Varghese S, Ohlow MA, Kumar N. Cross-country comparison in the evaluation of evolocumab by health technology assessment agencies in England, Canada, and Australia. Heart Mind [serial online] 2019 [cited 2023 May 31];3:140-6. Available from: http://www.heartmindjournal.org/text.asp?2019/3/4/140/273867 |
| Introduction | |  |
Hypercholesterolemia
Primary hypercholesterolemia is a recognized risk factor in cardiovascular (CV) disease (CVD). The two forms that increase the risk of developing CV events are familial hypercholesterolemia (FH) (heterozygous which is more common; homozygous which is rare) and preexisting clinical atherosclerotic CVD (ASCVD).
Previous research has shown that a decrease of 1 mmol/L of low-density lipoprotein (LDL)-cholesterol (LDL-C) results in an approximate 20% decrease in the risk of major CVD events.[1] In a retrospective cohort study, significant long-term clinical and economic burden was demonstrated in patients with hyperlipidemia associated with the occurrence of CV events.[2]
Apart from dietary and lifestyle modifications, statins have been the standard first-line therapy. The second most commonly used drug is ezetimibe, which is usually used in combination with statins rather than monotherapy. However, even on statin therapy, 80% of established CVD patients do not achieve LDL-C levels <70 mg/dl [Table 1].[3]
Evolocumab
Evolocumab (Repatha, Amgen) is a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme involved in the downregulation of LDL receptors. This increases receptor density and lowers LDL-C. It reduces LDL-C levels by approximately 60%.[4] It is administered subcutaneously and is available in two dosage forms: 140 ng/ml and 420 mg/3.5 ml.
Commonly reported adverse reactions include nasopharyngitis, upper respiratory tract infection, influenza, back pain, arthralgia (joint pain), and nausea.
The price tag for evolocumab in the United States is $14,000 per year, whereas a generic statin costs $250 per year,[5] whereas the cost of 30-day generic ezetimibe may be well <$10.
Evolocumab received marketing authorization in the European Union on July 17, 2015, for the following approved indications:
- “Hypercholesterolemia and mixed dyslipidemia: Evolocumab is indicated in adults with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia, as an adjunct to diet: in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or alone, or in combination with other lipid-lowering therapies in patients who are statin intolerant, or for whom a statin is contraindicated
- Homozygous FH (HoFH): It is indicated in adults and adolescents aged 12 years and above with HoFH in combination with other lipid-lowering therapies.”
Decision context
Assessments for drugs or devices evaluating their clinical and cost-effectiveness are usually undertaken by the health technology assessment (HTA) agencies of the respective countries. HTA agencies play an important role in informing policy and decision makers whether or not new technologies should be reimbursed by public health-care systems. Studies have shown that the outcomes vary substantially for the same technology assessed across different countries.[6]
| Objectives | | |
The clinical effectiveness and the costly nature of evolocumab has encouraged this study to review the processes and compare the assessments undertaken to evaluate this drug by the HTA agencies in Canada (Canadian Agency for Drugs and Technologies in Health [CADTH] Common Drug Review (CDR), England (National Institute for Health and Care Excellence [NICE]), and Australia (Pharmaceutical Benefits Advisory Committee [PBAC]).
This article has the following objectives:
- Comparing the recommendations by each of the HTAs
- Identifying the key drivers of decisions across the HTAs
- Identifying the similarities and differences in the requirements of HTA agencies
- Comparing the evidence and methods for economic and clinical evaluation across CDR, NICE, and PBAC.
A general overview of the HTA agencies considered in this study is shown in [Table 2].[12]
| Methods | | |
Between July and August 2018, the websites of CADTH, the National Institute for Care and Health Excellence (NICE) in England, the Pharmaceutical Benefits Advisory Committee (PBAC) of the Pharmaceutical Benefits Scheme (PBS) in Australia were searched for technology appraisal documents pertaining to evolocumab. The search included the initial appraisal, resubmissions, as well as the final recommendation made between 2015 and 2018. The HTA agency recommendations for Canada, England, and Australia were identified by generic name and indication. Regulatory approval dates were identified from the regulatory authorities' online databases.
Data extraction and outcomes of interest
The authors read each appraisal document separately and the information on variables such as time of submission, type of recommendations, clinical evidence, clinical end points, surrogate end points, comparators, clinical evidence, economic model used, stakeholder consultations, incremental cost effectiveness ratios (ICERs), and uncertainties. Risk share agreements and funding decisions were extracted. The findings were reviewed, summarized, and consequently compared. The precise recommendations by each of the HTAs as well as the trials reviewed by each HTA are in detail described in [Appendix Table 1][Additional file 1].
The following outcomes of interest were considered:
- Date of market access and appraisal publication
- Comparability of the decision-making processes
- Comparability of the decision-making criterion
- General methodological considerations.
| Comparisons | | |
Timing of submission
The NICE and PBAC did not mention explicitly the dates of the first application for review to that of the final recommendation. CADTH Canadian Drug Expert Review Committee (CDEC), however, mentions in their CDR Project Status Report the date of the first application accepted for review as July 15, 2015, with the CDEC final recommendation posted on February 23, 2016 (~28 weeks). The date of resubmission was March 6, 2017, with final recommendation posted on November 24, 2017 (~32 weeks).
Type of recommendation
The recommendations for evolocumab vary across NICE, PBAC, and CADTH CDEC [Appendix Table 1].
- While the PBAC issued positive (authority required) recommendations for evolocumab for the treatment of both HoFH, in 2016, and heterozygous FH (HeFH, in 2018) patients, the NICE and CADTH CDEC (list with clinical criteria and/or condition recommendation) issued positive recommendations for HeFH populations only. These recommendations were focused on the populations with persistently high levels of LDL-C (which were specified) despite standard therapies
- In adults with non-FH or mixed dyslipidemia with ASCVD and persistently elevated LDL-C levels despite standard therapy, both CADTH CDEC (reimburse with clinical criteria and conditions) and NICE recommend the treatment with evolocumab. In contrast, the PBAC rejected this indication
- It must be noted that evolocumab has been recommended as the treatment across the three HTAs only with a price reduction (CADTH CDEC, PBAC) or the discount agreed in the patient access scheme (NICE)
- The available strengths of evolocumab such as 140 mg/ml and 420 mg/3.5 ml were approved by the PBAC and CADTH CDR, but the NICE felt that there was no evidence backing the dosage strength of 420 mg/3.5 ml
- Another observation is that the NICE has published just one appraisal until now, whereas the CADTH CDR and PBAC reassessed the recommendations of evolocumab regularly.[7],[8],[9],[10],[11]
Rationale for the recommendations
All the three HTA bodies recognized that the clinical needs of groups such as those with severe forms of FH, who were at high risk for CVD, or those with statin intolerance and benefitting marginally from ezetimibe, were largely unmet. Alternatives had to explored because lipoprotein apheresis, which is otherwise a last line of therapy, is not only expensive and troublesome for the patients but also difficult to access, therefore would readily be avoided.
Due to high ICER and high and uncertain patient population numbers, the PBAC refused listing evolocumab for the treatment of non-FH patients with ASCVD and/or very high LDL-C levels.[7],[8],[9],[10]
Budget impact
Apart from mentioning the annual costs of evolocumab, the budget impact was not explicitly mentioned by either NICE or CADTH CDR. PBAC, in its resubmission in March 2018, estimated a net effective cost to PBS of $30–$60 million in the 6th year of listing, with a total net effective cost to PBS of more than $100 million over the first 6 years of listing after including revised financial estimates and reduced price offer and after removing cost offsets from ezetimibe substitution (PBAC, 2018).[7],[8],[9],[10],[11]
Incremental cost effectiveness ratio and its variations in subgroups: National Institute for Care and Health Excellence, 2016; Canadian Agency for Drugs and Technologies in Health, 2017; and Pharmaceutical Benefits Advisory Committee, 2016[7],[8],[9],[10],[11]
National Institute for Care and Health Excellence, 2016
The company estimated the ICERs for the following subgroups for whom evolocumab is recommended:
- Non-FH or mixed dyslipidemia with CVD in people at high risk of CVD whose LDL-C concentrations are persistently above 4.0 mmol/l: lower than £37,000 (based on LAPLACE-2 population) and £29,200 (based on the Clinical Practice Research Datalink [CPRD] population) per quality-adjusted life-year (QALY)
- HeFH with CVD in people whose LDL-C concentrations are persistently above 3.5 mmol/l: lower than £33,600/QALY gained
- Non-FH or mixed dyslipidemia with CVD in people at very high risk of CVD whose LDL-C are 62;3.5 mmol/l: no specific ICER
- HeFH without CVD in people whose LDL are persistently >5 mmol/l: no specific ICER.
Canadian Agency for Drugs and Technologies in Health Canadian Drug Expert Review Committee
- In patients with primary hyperlipidemia and in high-risk patients with hyperlipidemia, the incremental cost utility ratio (ICUR) for evolocumab plus medium- or high-intensity statins ranged from:
- $124,922 to $180,427/QALY compared with medium- or high-intensity statins alone
- $263,929 to $397,180/QALY compared with ezetimibe plus medium- or high-intensity statins.
- In patients with HeFH, the ICUR for evolocumab plus high-intensity statins ranged from $23,822 to $68,813/QALY when compared with high -intensity statins alone or ezetimibe plus high-intensity statins
- In patients with statin intolerance, the ICUR for evolocumab alone ranged from $95,842 to $172,177/QALY when compared with no treatment or ezetimibe
- In patients with ASCVD who required additional lowering of LDL-C, at the recommended dose of 140 mg every 2 weeks, the ICUR for evolocumab plus statins versus statins alone showed $1,007,961/QALY whereas the ICUR for evolocumab plus statins versus ezetimibe and statins sowed $1,478,417/QALY.
Pharmaceutical Benefits Advisory Committee
- Based on the economic model, treatment with evolocumab was associated with costs per QALY gained ranging from $45,000–$75,000 to $105,000–$200,000 against ezetimibe and $45,000/QALY–$75,000/QALY to $45,000/QALY–$75,000/QALY against placebo (when used as an add-on therapy for patients with HeFH). The European Society of Cardiology advised that these estimates should not be considered reliable given major concerns regarding the calculation of baseline risk, implementation of treatment adherence, and the general uncertainty associated with the transformation of LDL levels to CV outcomes. The results of sensitivity analyses conducted during the evaluation indicate that evolocumab is likely to be considered cost-effective in patients with non-FH (cost per QALY gained from ranging $75,000/QALY–$105,000/QALY, $105,000/QALY–$200,000/QALY, or more than $200,000/QALY vs. ezetimibe)
- Based on the economic model 2016, treatment with evolocumab was associated with a cost per QALY gained of $15,000/QALY–$45,000/QALY compared to placebo and 15,000/QALY–$45,000/QALY compared to ezetimibe
- In the major submission to PBAC in November 2017, a stepped economic evaluation was presented for the treatment of:
FH with ASCVD with ICERs of $15,000–$45,000/QALY gained versus ezetimibe and $15,000–$45,000 versus placebo-FH with very high LDL-C levels with ICERs of $15,000–$45,000/QALY gained versus ezetimibe and $15,000–$45,000 versus placebo.
Key items of clinical evidence considered and type of study/trial design
In a systematic review by the company, which was submitted to NICE, four Phase III, double-blind, randomized controlled trials (RCTs) evaluating the efficacy and safety of evolocumab for primary hypercholesterolemia or mixed dyslipidemia were identified: LAPLACE-2, GAUSS-2, RUTHERFORD-2, and DESCARTES. All trials had background therapy such as moderate-to-high-intensity statin therapy (LAPLACE-2); statin with or without other lipid-lowering therapies (RUTHERFORD-2); nonezetimibe lipid-lowering therapy (GAUSS-2); or diet alone or in combination with atorvastatin, ezetimibe, or both (DESCARTES). The comparators in these trials were ezetimibe and placebo [Appendix [Table 2][Additional file 2].
In the submission to PBAC in March 2016, apart from the four RCTs mentioned above, two other RCTs, namely TESLA and MENDEL-2, were included. In addition, observational studies such as OSLER-1, OSLER-2, and TAUSSIG, providing a supportive comparison of long-term outcomes with evolocumab versus standard of care in HoFH and HeFH patients, were included. The main comparators to evolocumab were ezetimibe and placebo, whereas the nominated secondary comparator was alirocumab, another PCSK9 inhibitor. In the resubmission 2017, further two RCTs such as FOURIER (including an additional safety substudy investigating neurocognitive effects: EBBINGHAUS) and GLAGOV were included. A randomized two-stage clinical trial (GAUSS 3) was also added. Apart from that, a series of trials with various study designs were also analyzed which indirectly compared evolocumab with alirocumab [Appendix [Table 2].
The CDR systematic review (2016) included the same four RCTs (LAPLACE-2, RUTHERFORD-2, DESCARTES, and GAUSS-2) as NICE. The comparators were ezetimibe, placebo, and statins. In a resubmission in 2017 evaluating the listing of evolocumab for HeFH or ASCVD patients who require additional lowering of LDL-C, CDR included two RCTs: FOURIER and GLAGOV: the comparators were ezetimibe, placebo, and alirocumab. In addition, the company submitted data from a post hoc subgroup analysis of patients with ASCVD from LAPLACE-2 and OSLER-2 trials and a network meta-analysis (NMA) comparing evolocumab to alirocumab and to ezetimibe in patients already on statins.[7],[8],[9],[10]
Key clinical end points/surrogate end points considered
All the three HTAs (2015 and 2016) considered the primary end points as the percent change from baseline LDL-C levels. LDL-C levels were considered as surrogate measures.
After the inclusion of the FOURIER trial in the reviews of CADTH CDR and PBAC in 2017, the primary outcome was a composite of major CV events (CV death, myocardial infarction [MI], stroke, and hospitalization for unstable angina or coronary revascularization) and the secondary outcome was a composite of CV death, MI, or stroke. Other secondary outcomes were all-cause mortality, as well as individual outcomes of the composite and other composites such as CV death, hospitalization for worsening heart failure, and ischemic fatal or nonfatal stroke or transient ischemic attack.[7],[8],[9],[10],[11]
Clinical and safety evidence
The NICE[7] considered the four RCTs to be relevant and of good quality and suitable for assessing the clinical effectiveness of evolocumab for primary hypercholesterolemia (nonfamilial and HeFH). It felt that the company's submission focused on the LDL-C levels. At both the dosages (140 mg every 2 weeks and 420 mg monthly), evolocumab lowered LDL-C by 60%–70% effectively when compared with placebo and around 40% when compared with ezetimibe. Similar results were seen also in high-risk groups such as those with HeFH and those who cannot tolerate statins. The NICE committee also noted that evolocumab was tolerated well. Across the included RCTs, the most commonly reported adverse events were nasopharyngitis, influenza, headache, myalgia, and upper respiratory tract infections. Compared to placebo or ezetimibe, the NICE felt that evolocumab was clinically effective in reducing LDL-C in patients with primary hypercholesterolemia.
The PBAC[9] acknowledged the clinical trial evidence, similar to NICE, that demonstrated a significant decrease in LDL outcomes when treated with evolocumab compared to ezetimibe or placebo, and that there was no difference in the adverse events with either fortnightly or monthly dosing of evolocumab.
The PBAC review in 2017 agreed with the clinical claim that evolocumab is superior in terms of efficacy and similar in terms of safety compared to ezetimibe. Based on the FOURIER trial, evolocumab was found superior in terms of efficacy and similar in terms of safety compared to placebo. It was also found superior in terms of efficacy and similar in terms of safety compared to alirocumab (lower doses). The PBAC also considered that the claim of similar safety profile when compared to ezetimibe and placebo was reasonable.
CADTH CDEC (2016) findings were consistent with that of NICE. With the inclusion of FOURIER and GLAGOV trials, CDEC review in 2017 was similar to that of PBAC regarding the clinical and safety effects of evolocumab over placebo.[7],[8],[9],[10],[11]
Concerns on clinical evidence
The NICE[7] noted that the four RCTs (LAPLACE-2, GAUSS-2, RUTHERFORD-2, and DESCARTES) were not powered to measure the CV outcomes and measured primarily the surrogate end points such as LDL-C, which was considered as an important limitation. The concern of whether LDL-C lowering translates to long-term outcomes was raised by both NICE and PBAC.
Another concern was that none of the trials compared evolocumab with ezetimibe for HeFH or evolocumab plus ezetimibe for any population.
The CADTH CDR[8] pointed out that neither FOURIER nor GLAGOV was sufficiently long in order to assess the long-term safety. It was also observed that there was no difference in all-cause or CV mortality between evolocumab and placebo, which may be explained due to the relatively short follow-up period. The GLAGOV trial was not powered to assess clinical outcomes such as mortality and CV mortality/morbidity because its primary outcome (change in percent atheroma volume) is a surrogate with no established minimum clinically important difference. The NMA provided by the manufacturer provided little value in comparing evolocumab to alirocumab or ezetimibe, as it did not include the FOURIER results and also did not evaluate the clinical outcomes.
PBAC, 2017 noted, after the FOURIER analysis, that though the treatment with evolocumab was associated with a decreased risk of MI, coronary revascularization, and ischemic stroke compared to placebo, there was no difference in angina, coronary death, CV death, or all-cause mortality between treatment arms. Due to varying trial characteristics and study designs, the exchangeability of the evolocumab and alirocumab trials was unclear. In addition, the major heterogeneity between the studies made the robustness of the results used in the indirect analysis for both evolocumab and alirocumab unclear. Furthermore, the analyses presented in the resubmission do not directly address the comparative efficacy of evolocumab versus dose titration with alirocumab.[7],[8],[9],[10],[11]
What evidence was there of stakeholder consultation? How were stakeholders involved?
The committee at the NICE[8] heard from patient experts about the effect of primary hypercholesterolemia on daily life and social relationships and also about prioritizing the treatment of patients with FH because the chronic exposure to high concentrations of LDL-C increases the risk of CVD, even if the concentrations are not high. It was also discussed that though evolocumab was likely to be used for primary hypercholesterolemia in practice, it may also be used for mixed dyslipidemia; despite maximum statin and ezetimibe therapy, the LDL-C concentrations remain very high.
Similarly, in 2016, the CDR received patient inputs regarding their complaints and experiences from two patient groups (Heart and Stroke Foundation and FH Canada Patient Network). The information was obtained through online surveys, online forums, interviews, closed discussion groups, and literature searches. During the 2017 review, the CDR received additional input from a clinical expert with experience in treating patients with ASCVD as well as from a patient group, the Cardiac Health Foundation of Canada, and provided information about the outcomes and issues relevant to those affected by atherosclerosis.
During the sponsor hearing at the PBAC in 2017, the sponsor reiterated the high unmet clinical need of the FH population, and that further steps were required to establish a more cost-effective approach to make PCSK9 inhibitors available in the larger non-FH population. The clinician argued that the intermediate outcomes of reduced MI and stroke led to better survival in spite of the lack of mortality benefits in the FOURIER trial. The consumer comments pointed out the high clinical unmet need for patients, both with and without FH who need effective therapies to lower LDL-C (2017). The PBAC received inputs also from the Chair of the FH Australasia network and FH Family Support Group of Western Australia about the clinical need and potential benefits of evolocumab.[7],[8],[9]
Economic model used and whether it was deemed adequate
National Institute for Care and Health Excellence
The company used a cost-effective analysis using a de novo Markov economic analysis in assessing the cost-effectiveness of evolocumab in reducing CVD for primary hypercholesterolemia (heterozygous – familial and nonfamilial) or mixed dyslipidemia. The perspective of the analysis was that of the NHS and personal social services. Costs and health effects were modeled over a lifetime time horizon and discounted at an annual rate of 3.5%. The cycle length was yearly, and the comparators were ezetimibe and statins. The company modeled three separate populations: non-FH without CVD, non-FH with CVD, and heterozygous-FH (with or without CVD). The model consisted of 24 mutually exclusive states. The baseline CV risk was estimated using FRAMINGHAM Heart Study, REACH registry. Moreover, calibration–estimation was calculated from an analysis of data from (CPRD) and Hospital Episode Statistics.
Canadian Agency for Drugs and Technologies in Health Common Drug Review
The manufacturer employed a cost–utility analysis for the submissions in 2016 and 2017. The analysis was conducted from the perspective of a Canadian publicly funded health-care system. Costs and health effects were modeled over a lifetime time horizon of 120 years (submission in 2016) and 40 years (submission in 2017).
In 2016, the company modeled four patient populations:
- As an add-on to medium- or high-intensity statins in patients with primary hyperlipidemia and/or mixed dyslipidemia, compared with medium- or high-intensity statins alone or in combination with ezetimibe
- As an add-on to medium- or high-intensity statins in high-risk patients with non-familial hyperlipidemia with a prior CV event, compared with medium- or high-intensity statins alone or in combination with ezetimibe
- In patients with HeFH as an add-on to high-intensity statins, compared to high-intensity statins alone or in combination with ezetimibe
- In patients who are statin intolerant, compared with ezetimibe or no treatment.
While the comparators in 2016 were ezetimibe and medium- or high-intensity statins, in the submission in 2017, the comparators were medium- or high-intensity statins alone. The population in 2017 were those with ASCVD.
The baseline CV risk was based on CPRD, a retrospective observational cohort study on multiple UK cohorts and LDL-C levels from the study population (LAPLACE-2).
Pharmaceutical Benefits Advisory Committee
In 2016, the company presented a modeled economic analysis assessing the cost-effectiveness of fortnightly evolocumab when used as a replacement or as an add-on therapy to ezetimibe in patients with FH. The resubmission in 2017 presented a stepped economic evaluation (cost-effectiveness analysis/cost–utility analysis) evolocumab for the treatment of HeFH (patients with atherosclerotic disease or very high LDL-C levels) as well as evolocumab for the treatment of non-FH patients with established atherosclerotic disease either as a replacement to ezetimibe or as an add-on to the existing therapies.
The main comparators were ezetimibe and placebo. The cycle length was monthly, and the time horizon was 35 years. The discount rate was 5% for costs and outcomes. The economic model structure was modeled in the following five core health states: baseline health state, MI with no history of stroke, ischemic stroke (with or without a history of MI), CV death, and non-CV death.
The baseline risk assumptions were broadly based on CV risk estimates in untreated hypercholesterolemia populations and epidemiology estimates of increased risk associated with FH. It assumed a CV event rate of 0.05 events/patient-year, which is an equivalent to a 5-year risk of 23% in patients with both FH with very high LDL-C levels and in those with non-FH with atherosclerotic disease. Patients with FH and atherosclerotic disease (LDL-C >3.3 mmol/L) would have twice the event rate of non-FH with atherosclerotic disease (0.10 events/patient-year). This economic model was most sensitive to the assumed reduction in coronary death associated with LDL-C lowering.[7],[8],[9],[10],[11]
Concerns on economic evidence
Neither evolocumab nor ezetimibe has demonstrated a reduction in CV death. Hence, treatment with evolocumab was associated with very high ICERs if no mortality benefit was assumed. However, the structure of the economic model did not easily allow investigation of other alternatives such as a delayed impact on mortality or only having mortality reduction directly linked to MIs and ischemic stroke.
Concerns raised by any other uncertainties
The PBAC (2018) felt that there was a need for further treatment criteria to define statin intolerance, such as requirement for challenging after a treatment break with a lower dose or alternative statin.
Is there a possibility of risk share? Type of risk share and overall objective
Both NICE and PBAC have a risk share arrangement (RSA) with possibly different objectives. During the PBAC submission in 2016, the sponsor willingly offered a RSA in order to account for the financial uncertainty associated with the PBS listing of evolocumab. The sponsor requested a special pricing arrangement where the sponsor would provide a confidential percentage rebate based on the total commonwealth expenditure.
In HoFH, the PBAC recommended a combination type of risk-sharing agreement (including both financial and performance-based components) that included a cap, based on the number of patients treated (consistent with the estimates in the submission for the HoFH population) with a particular percent rebate for use above the cap in any year (March 2016).
During a minor resubmission in November 2017, the PBAC considered a new RSA which would incorporate a cap on financial estimates for PCSK9 inhibitors in order to account for the potential use in the non-FH population. The sponsor proposed a tiered financial cap arrangement to address uncertainty in the extent of use.
The NICE reported that the company agreed on a patient access scheme (PAS) with the department of health. This financial agreement scheme provides a simple discount to the list price of evolocumab, with the discount applied at the point of purchase. The level of discount is commercial in confidence.
The CADTH CDR did not have a RSA. The CADTH CDR noted that a substantial price reduction of 50%–80% would be required for evolocumab to be considered a cost-effective option compared with statins alone or ezetimibe plus statins.[7],[8],[9],[10],[11]
Overall summary of the key criteria based on which the recommendation was based
The clinical high unmet need in severe FH groups of patients with significant proven lowering of LDL-C levels was recognized throughout all the HTAs as the key criteria for recommending evolocumab in this category. Apart from that, the NICE based their added recommendation taking into consideration the patient's and clinician's input of those who are at high risk for CVD and who are poorly controlled on statins or ezetimibe. The clinical evidence and the surrogate measure (LDL-C) were deemed acceptable. The PABC recognized the newer clinical evidence (FOURIER), but issued a negative recommendation primarily due to cost-effectiveness resulting from uncertainty. The CADTH CDEC issued positive recommendations after taking clinical evidence (FOURIER) into consideration.[7],[8],[9],[10],[11]
| Conclusions | | |
This study highlights many significant similarities but also looks at some of the differences in the practices, processes, and policies of different HTAs. Similar degree of comprehensiveness in research, greater transparency in the processes, and similar methodological approaches in evaluation may lead to a more horizontal alignment of the HTA evaluations across countries.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
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| 3. | Wong ND, Young D, Zhao Y, Nguyen H, Caballes J, Khan I, et al. Prevalence of the American college of cardiology/American heart association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the national health and nutrition examination survey 2011-2012. J Clin Lipidol 2016;10:1109-18. |
| 4. | Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809-19. |
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[Table 1], [Table 2]
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