A Thesis entitled. Cost-Effectiveness of oral agents in Relapsing-Remitting Multiple Sclerosis Compared to Interferon-Based Therapy in Saudi Arabia

Transcription

1 A Thesis entitled Cost-Effectiveness of oral agents in Relapsing-Remitting Multiple Sclerosis Compared to Interferon-Based Therapy in Saudi Arabia By May Alskaabi Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Masters of Science Degree in Pharmaceutical Science Dr. Varun Vaidya, Committee Chair Dr. Diane M. Cappelletty, Committee member Dr. Sadik Khuder, Committee member Dr. Amanda Bryant-Friedrich, Dean College of Graduate Studies The University of Toledo May 2017

2 Copyright 2017, May Fahad Alskaabi This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author.

3 An abstract of Cost-Effectiveness of oral agents in Relapsing-Remitting Multiple Sclerosis Compared to Interferon-Based Therapy in Saudi Arabia By May Alskaabi Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Pharmaceutical Science The University of Toledo May 2017 Multiple sclerosis (MS) is a disabling neurologic disease characterized by chronic inflammation and demyelination of the central nervous system (CNS). 1 MS affects predominately patients aged years. 2 In recent years, there has been considerable innovation and scientific progress made in the treatment of relapsing-remitting multiple sclerosis (RRMS), a subtype of MS that affects approximately 90% patients of MS patients. 1 As a result of these advancements, three new oral disease modifying drugs (DMDs) namely Fingolimod (Gilenya ), Teriflunomide (Aubagio ), and Dimethyl fumarate (Tecfidera ) were approved by the FDA in 2010, 2012, and 2013, respectively. 1,2 Clinical trials and new evidence have shown that these new agents are accompanied with high efficacy and relatively safe compared to Interferon-beta (IFN-ß) therapy. However, there are few head-to head studies that have compared oral agents with conventional treatments especially in Middle Eastern countries. In addition, doubts have been expressed about the effectiveness of these treatments, which have compounded the problems associated with estimating the relative cost effectiveness of iii

4 such interventions. For these reasons, we performed a cost-effectiveness analysis to determine which treatment option is appropriate for Saudi population. To date, this is considered the first CEA to use real-world cost data and offer a comprehensive comparison between the new oral DMDs from a Saudi healthcare payers (KFSH&RC) perspective. iv

5 For my parents and siblings. Thank you for your constant love and support. v

6 Acknowledgment I would like to start by thanking God for giving me the strength and the ability to carry on through this entire journey. I would love to extend my thanks to: Dr. Varun Vaidya, the advisor of my research project for his continuous support and infinite dedication to his students and work, Dr. Sadik Khuder and Dr. Diane M. Cappelletty for their guidance and assistance in this project, Dr. Sharrel Pinto for her wisdom and helping me to bring the best in me throughout this entire learning experience. Special thanks to my fellow graduate students: Monika Salkar, Janvi Sah, Mohammad Al-owairdhi, it has been nice working with all of them. Special thanks to my Boss Dr. Ahmad Al-jedai, the director of Pharmacy Division at King Faisal Specialist and Research Center (KFSH&RC) for his support and guidance. I m also grateful to Dr. Abdulrazaq Al-jazairi for believing in me in the first place and helped me through the entire admission process to Toledo University. Lots of thanks to my fellow colleagues at the pharmacy department: Mr. Abdulqader Almoeen, Shimaa Alolabi, Noura Khurais and Maher Mominah for their help in providing me with the data I needed to complete this project. I dedicate this thesis to my family, relatives, and friends who have been a source of emotional support through this entire journey. I would like to thank my best friend Dema Alissa, who has been always by my side through tough times, she believed in my capabilities and potentials when I couldn t do so, she kept on pushing me to the limits, then I realized that sky is the limit when you have the will and determination to accomplish and excel in achieving vi

7 your goal. I couldn t ask for a better friend, thank you for being who you are, my success in this program would not have been possible without your constant support. Finally, I would like to express my deepest gratitude towards my parents and siblings for their unconditional love and support. Mom and Dad, I owe you my success at work, studies and in life, thank you for raising me as a strong, independent woman who can achieve whatever she dreams of. vii

8 Table of Contents Abstract... iii Acknowledgements... vi Table of Contents... viii List of Tables... xi List of Figures... xii 1. Introduction Background Overview of Multiple Sclerosis Disease Modifying- Therapy Interferon Beta-1 formulations Emerging treatments Prevalence of MS in Saudi Arabia Economic burden from the Saudi healthcare system Pharmacoeconomics (PE) Cost-effectiveness analysis Cost-utility analysis Need for study Goal of the study Objectives Literature review...20 viii

9 2.1 Etiology of MS Diagnosis of MS Economic, Clinical and Humanistic burden of MS in the US and Europe Pharmacoeconomic studies in the US Pharmacoeconomic studies in Europe Pharmacoeconomic studies in other countries Conclusion Methods 3.1 General description of the study design Study population Data collection Markov model Development of Markov structure model Data inputs Transition probabilities and efficacy data Health gains: Utilities Cost data Building Markov Model in TreeAge Pro software Sensitivity analysis Results 4.1 Base-case scenario One-way sensitivity analysis Monte Carlo simulation...65 ix

10 5. Discussion Limitation Conclusion References A. Supplementary materials x

11 List of Tables 1.1 Economic and health indicators of Saudi Arabia Descriptions of Markov model Health States Transition Probabilities and relapse rates for EDSS states Relative Risks for DMT Efficacy on EDSS Progression and Relapse Rates Base case utility estimates Costs of DMDs per patient per year Direct medical costs Total average direct medical costs according to EDSS score per patient per year in Saudi Riyals Results from the base-case analysis: DMDs vs. Rebif (WTP= $100,000) Results from the base-case analysis: DMDs vs. Avonex (WTP= $100,000) Summary results from Monte Carlo simulation of 1000 iterations for all DMDs A.1 Kurtzke Expanded Disability Status Scale (EDSS) A.2One-way sensitivity analysis parameters range A.3 Sensitivity analysis results of changing range of Utility score of Health state A.4 Sensitivity analysis results of changing range of Utility score of Health state A.5 Sensitivity analysis results at different ranges of disutility score of mild/moderate relapse A.6 Sensitivity analysis results at different ranges of disutility score of sever relapse xi

12 List of Figures 1.1 Healthy nerve cell vs. Nerve cell damaged by MS Disease activity in RRMS Global distribution of MS Schematic representation of the Modified Markov model Direct elicitation method of driving utility weights (Standard Gamble) Markov model build in TreeAge Pro Suite Software Cost-effectiveness analysis scatterplot of all DMDs Net monetary benefits (NMB) versus WTP of all DMDs Tornado diagram comparing between Avonex and Rebif Tornado diagram comparing between Fingolimod and Rebif Tornado diagram comparing between Dimethyl Fumarate and Rebif Tornado diagram comparing between Teriflunomide and Rebif Scatterplot of all 1000 simulations of all DMDs Scatterplot of all simulated ICERs of Avonex vs. Rebif on CE plane Scatterplot of all simulated ICERs of Fingolimod vs. Rebif on CE plane Scatterplot of all simulated ICERs of Teriflunomide vs. Rebif on CE plane Scatterplot of all simulated ICERs of DMF vs. Rebif on CE plane Cost-effectiveness acceptability curve for all DMDs at different levels of threshold xii

13 A.1 ICER values from Sensitivity analysis at different utility values of health state A.2 ICER values from Sensitivity analysis at different utility values of health state A.3 ICER values from Sensitivity analysis at different utility values of mild/moderate relapse A.4 NMB values from Sensitivity analysis at different utility values of mild/moderate relapse A.5 ICER values from Sensitivity analysis at different utility values of sever relapse A.6 NMB values from Sensitivity analysis at different utility values of sever relapse xiii

14 Chapter 1 Introduction This chapter discusses Multiple sclerosis in details, treatment options that help in slowing disease progression and economic burden associated with the management of the disease from the Saudi healthcare perspective. The chapter also provides the goal and the objectives of the study. 1. Background Overview of Multiple Sclerosis Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the Central Nervous System (CNS); it is characterized by demyelination of axons in the brain and spinal cord, with axonal damage or destruction (Figure 1.1). 1 MS affects predominately patients aged years. The symptoms of MS vary, depending in part on the location of lesions within the CNS. Common symptoms include sensory disturbances in the limbs, optic nerve dysfunction, pyramidal tract dysfunction, bladder or bowel dysfunction, sexual dysfunction, ataxia (the loss of full control of bodily movements), and diplopia (double vision). 2 Although there is large variability in symptom manifestation and disease progression, MS is still the most common cause of non- traumatic disability in young adults and is associated with an average reduction in life span of 5 to 10 years. 1 Four different clinical courses of MS have been defined. The 1

15 first, relapsing-remitting MS (RRMS) is characterized by self-limited attack neurologic dysfunction. The second clinical course, secondary progressive MS (SPMS), begins as RRMS, but at some point the attack rate is reduced and the course becomes characterized by a steady deterioration in function unrelated to acute attacks. The third clinical type is primary progressive MS (PPMS), which is characterized by a steady decline in function from the beginning without acute attacks. The fourth type, progressive relapsing MS (PRMS), also begins with a progressive course although these patients also experience occasional attacks. 3 Since this study will focus on RRMS the next section will elaborate more on RRMS. Relapsing-remitting MS (RRMS) is the most common type of MS that occurs in % of patients. 5 Within 1-2 decades 40-60% of those patients develop SPMS. Most people with RRMS are diagnosed in their 20s and 30s (although it can occur in childhood or later adulthood), while the onset of PPMS tends to be in ones 40s or 50s. 5 RRMS is characterized by clearly disease attacks or relapses followed by remission with full recovery or with sequel and residual deficit. 4 These attacks develop acutely, evolving over days to weeks. Between attacks the patient is neurologically and symptomatically stable. 4, 5 However, there is no apparent progression of the disease during the periods of remission. At different points in time, RRMS can be further characterized as either active (with relapses and/or evidence of new MRI activity) or not active, as well as worsening (a confirmed increase in disability over a specified period of time following a relapse) or not worsening as shown in figure Progression of multiple sclerosis is measured by the disability caused by the disease. The Expanded Disability Status Scale (EDSS) known as Kurtzke EDSS is a common measure of MS 2

16 disability and is the primary clinical outcome in many MS clinical trials. The scale ranges from 0, defined by a normal neurological examination, to 10, defined as death due to MS. Refer to table 1.1 for more details in page 73. Note that The Functional Systems (FS) are the main 8 parts of the CNS regulating body functions which are: Pyramidal - weakness or difficulty moving limbs, Cerebellar - coordination loss or tremor, Brainstem - speech and swallowing problems, Sensory - touch and pain, numbness or loss of sensations, Bowel/bladder dysfunction, visual loss, Cerebral - mental function loss and others which is any other neurological findings due to MS. 6 Figure 1.1: Healthy nerve cell vs. Nerve cell damaged by MS (Source: healthinformatics.wikispaces.com/multiplesclerosis Figure 1.2: Disease activity in RRMS (Source: 3

17 1.1.2 Disease Modifying- Therapy Since MS is not a curable disease. Treatment regimens are currently targeting symptom management and slow down disease progression. In RRMS, the main aim behind treating patients is to reduce the frequency and severity of relapses. In addition, recent studies have shown that early treatment with Disease- modifying Therapies (DMTs) is associated with significant improvement in the patient s quality of life. 14 Ideally, treatment goals of RRMS are to: treat acute relapses, improve health-related QOL, reduce the frequency and severity of relapses, delay disability accumulation, and postpone the onset of the progressive phase of the disease. 15,17 For example, when acute exacerbations occur (such as vision loss or loss of coordination), they are commonly treated with a short duration of high-dose oral or intravenous corticosteroid. If spasticity occurs, it can be addressed with muscle relaxants, however therapy with DMTs is designed to prevent relapses and progression of disability rather than treat specific symptoms or exacerbations of the disease. 16 These agents modify the immune response that occurs in MS through various immunomodulatory or immunosuppressive effects. There are no specific guidelines to follow for the treatment of MS. Clinical guidelines for treatment of MS is still underdeveloped since that the American Academy of Neurology (AAN) and the MS Council for Clinical Practice Guidelines have not published comprehensive guidelines including all current DMTs in the US since At that time, fingolimod, teriflunomide, dimethyl fumarate, pegylated interferon beta-1a, glatiramer acetate 40 mg, natalizumab, and alemtuzumab were not commercially available. Unlike US, in Britain the Association of British Neurologists (ABN) has published MS treatment guidelines in Another consensus was published by The 4

18 Middle East North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS) in 2015, which consists of group of neurologists from different Arabic speaking countries in order to set treatment recommendations for healthcare providers in the absence of updated clinical guidelines Interferon (IFN) β-1 formulations Since DMTs have been approved in the United States for relapsing forms of MS; most of these therapies are approved for use in other industrialized nations. The ANN in their guidelines report 19 has classified treatment into three main categories: antiinflammatory, immunomodulatory, and immunosuppressive therapy. Immunomodulatory treatment includes: injectable Interferon beta (IFN-ß) and Glatiramer acetate (Copaxone ) which are considered as first line therapy to treat relapsing forms of MS. IFN- ß is available in three forms: IFN- ß 1a (Avonex ), IFN- ß 1b (Betaseron ) and IFN- ß 1a (Rebif ). Although the precise mechanisms through which IFN- ß achieves its anti-inflammatory and immunomodulatory effects remain uncertain, several modes of action have been proposed. Dominant MOA was believed to be modulation of the immune system by reducing T cell migration from the periphery into the CNS by decreasing the production of adhesion molecules and increasing the production of metalloproteases on the vascular endothelium that constitutes the blood brain barrier. 20 Betaseron was the first agent approved by the FDA in 1993 for the treatment of RRMS. The recommended dose is 250 mcg SC every other day. Following Betaseron, Avonex was approved in 1996 with a dose of 30 mcg IM once a week. Rebif was approved in2002 with a dose of 44 mcg SC 3 times weekly. IFNs have similar adverse effects which can include: Flu-like symptoms, injection site reaction, allergic reaction, fatigue, 5

19 emotional instability, reversible elevated liver enzymes. 19 Clinical trials have reported two major efficacy measures of Disease modifying-drugs (DMDs), which are: Magnetic resonance imaging (MRI) activity and clinical outcomes which include: Annualized Relapse Rate (ARR) and disease progression (which can be measured by degree of disability). In regards to IFNs trails, there was a 34 %, 18% & 32% reduction in ARR with Beatseron, Avonex and Rebif compared to placebo respectively 20,21, and in terms of disease progression; there was a 30 %,37% & 29 % decrease in sustained disability progression with Rebif, Avonex and Beatseron respectively compared to placebo. 20,21 In regards to MRI activity, there was an 83 %, 36% & 78 % reduction in MRI active lesions with Beatseron, Avonex and Rebif compared to placebo respectively. 21 Glatiramer acetate GA (Copaxone ) was approved by the FDA in 1997.Copaxone is a random polypeptide made up of four amino acids. The proposed mechanism of action relates to its immunologic effects such as the induction of antigen-specific suppressor T cells, inhibition of antigen presentation, displacing bound myelin basic protein (MBP), or causing an immune deviation in CD4_ T cells from a Th1 to a Th2 phenotype. 19 In a two year, multicenter, randomized control trial, GA showed a 29% annual decrease in the frequency of relapses Emerging treatments In 2000, Mitoxantrone MX (Novantrone ) is an antineoplastic immunosuppressive agent was approved by the FDA. 23 MX Acts through the suppression of T cells, B cells, and macrophages, and it imposes its cytotoxic effect byintercalating with DNA and inhibiting the topoisomerase II enzyme activity for DNA repair. The recommended dose of MX is 12 mg/m 2 as an IV infusion once every 6

20 three months for two to three years (cumulative dose up to 140 mg/ m 2 ). 23 MX is indicated only for patients with progressive MS or worsening RRMS non-responsive to first line therapy. Its use in clinical practice has significantly declined in recent years due to a high rate of serious adverse events including cardiotoxicity (12%) and leukemia (0.8%). 24 Natalizumab (Tysabri ) was approved by the FDA in Despite the significant reduction (68%) in ARR and delayed accumulation of physical disability by 42% however, Tysabri is indicated as monotherapy for the treatment of patients with aggressive relapsing forms of MS, but it is reserved as second line treatment for RRMS due to the risk of multifocal leukoencephalopathy (PML). 25 It is a humanized monoclonal antibody and a selective adhesion molecule inhibitor, that interferes with the influx of inflammatory cells into the brain by binding to the α4 subunit of the α4β1 integrin expressed on the surface of immune cells, preventing its interaction with the vascular cell adhesion molecule (VCAM1) on the endothelial cells. 25 recommended dose of Tysabri is 300 mg intravenous infusion over one hour every four weeks. 25 Fingolimod (Gilenya ) was the first, once-daily oral medication approved by the FDA in September 2010 for the treatment of RRMS. 26 Gilenya acts on the sphingosine- 1- phospate receptor and blocks the capacity of lymphocytes to egress from lymph nodes, thus reducing the number of lymphocytes into the peripheral circulation to start the inflammatory cascade associated with myelin destruction. 26 Fingolimod gained FDA approval on the basis of 2 randomized, double blind, controlled trials titled FREEDOMS and TRANSFORMS. It reduced the ARR by 55% and 52% compared to placebo and IFN-beta 1a IM respectively, and the risk of disability progression by 30% compared to 7

21 placebo only. 24, 26 Careful monitoring is required when patient to be initiated on Gilenya due to the risk of bradycardia. A baseline ECG and BP measurement should be performed with the first dose of Gilenya; the patient should be monitored for a minimum of 6 hours for signs and symptoms of bradycardia. 26 The recommended does is 0.5 mg orally once a day. 26 Teriflunomide (Aubagio ) is the second oral disease-modifying agent for the treatment of RRMS approved by the FDA in September It is a selective reversible inhibitor of dihydroorotate dehydrogenase enzyme that blocks pyrimidine synthesis in rapidly proliferating cells, including auto-reactive T and B-lymphocytes. 27 Based on the TOWER and TEMSO trials, Aubagio at a dose of 14 mg daily reduced ARR by 36.3% and 31%, and the risk of disability progression by 31.5% and 30% respectively when compared to placebo. The lower dose (7mg) failed to show significant effect on disability measures. In TEMSO trail, Aubagio has reduced total brain lesion volume (measured by MRI activity) by 39.4% and 67.4% in the 7 mg and 14 mg dose groups, respectively, compared with placebo. In general, Aubagio is well tolerated and considered the safest oral agent among the three new oral drugs. Adverse events can include: diarrhea, nausea, hair thinning, elevation of serum liver enzymes and mild leucopenia. 27 Dimethyl fumarate, previously known as BG-12 or DMF, is the latest oral agent for the management of RRMS that was approved by the brand name Tecfidera in March The mechanism of action is not completely understood, but DMF and its metabolite, monomethyl fumarate (MMF), were reported to activate the nuclear factor (erythroid-derived 2)-like 2 pathway that is involved in the cellular response to oxidative 8

22 stress. MMF was identified as a nicotinic acid receptor agonist. On the basis of this mechanism; DMF may have protective properties for neurons and could further modulate immune response. In the DEFINE study, both doses of DMF (240 mg twice or three times per day) showed a significant reduction in ARR (53% and 48%), and disability progression (38% and 34%) as compared to placebo. DMF was generally safe and well tolerated; the most common AEs included flushing and gastrointestinal AEs (e.g. diarrhea, nausea, vomiting). In November 2014, the FDA released a Drug Safety Communication alert because of a fata case of progressive multifocal leukoencephalopathy (PML) in a patient on DMF. The patient was on DMF for four and a half years. Consequently, it is advised that patients receiving DMF who experience lymphopenia should be monitored regularly and at close intervals as clinically indicated Prevalence of MS in Saudi Arabia There are approximately 400,000 cases of MS in North America and approximately 2.5 million worldwide; women are affected two or three times as often as men (female: male = 3:1). 2 The overall incidence of MS is increasing worldwide, as well; with 200 individuals diagnosed each week. 2 The estimated prevalence of MS around the world is 30 per100, Since this study is going to be conducted on Saudi patients the next section will discuss the prevalence of MS in Saudi population. Based on the Kurtzke EDSS classification, the Arabian Gulf Region is located in a low-risk zone for MS; however, recent studies suggest a moderate-to-high prevalence nearby (20 60 MS per 100,000 individuals) as shown in figure 1.3, with an increase in incidence in recent years. 9 Due to the under-reporting of cases, there are limited epidemiological data and relatively few 9

23 studies published in regards to the prevalence of MS in Saudi Arabia. 10 However, many neurologists from Saudi Arabia have indicated that MS is prevalent and in increase. 9,10 For this reason, an official national registry needs to be established to record MS cases for research purposes and more epidemiological studies need to be conducted. Some epidemiological studies have been conducted in Saudi Arabia and in the Arabian Gulf region to reveal the reasons behind the increased prevalence of MS especially in the recent years. 10 One of the suggested hypotheses is that the increase in younger population could contribute in the recent years high incidence, 9 since that the Saudi 9, 10 community is a very young population where 54% are below the age of 18 years. Consanguineous marriages were also believed to play a role in MS development, since its common in Saudi Arabia. 11 In 2011 Al Jumah et al. correlated the prevalence of familial multiple sclerosis (FMS) and rate of parental consanguinity (PC). 12 He concluded that MS patients with a history of PC were more likely to have FMS, suggesting a potential role of consanguinity. Lastly, vitamin D deficiency has been recently noted in the Gulf region despite the area s sunny climate. Although those countries have a sunny environment, vitamin D deficiency is one of the main public health problems. Studies in Saudi Arabia revealed that 28% to 80 % of adults had vitamin D deficiency. 9 10

24 Figure 1.3: Global distribution of MS (Source: Published on: February 18, 2015) Economic burden from the Saudi healthcare system perspective Health care services in Saudi Arabia have been given a high priority by the government. During the past few decades, health and health services have improved greatly in terms of quantity and quality. Currently the Ministry of Health (MOH) is the major government provider and financer of health care services in Saudi Arabia. 37 In accordance with the Saudi constitution, the government provides all citizens and expatriates working within the public sector with full and free access to all public health care services. 37 There was a sharp increase in the health care budget from SAR 30 Billion (6.3% of Gov t budget) in 2008 to SAR Billion (11.8% of Gov t budget) in King Faisal Specialist Hospital and Research Center (KFSH&RC) is considered one of the biggest referral hospitals not only in Saudi Arabia, but also in the Middle East. KFSH&RC is semi-governmental body that accepts patients by referral orders and treats patients with full and free coverage. Since this study is going to be conducted on 11

25 Saudi population, the following section will discuss costs associated with the management ofms patients treated at KFSH&RC. MS patients get referrals to Neuroimmunology clinic to be seen by different neurologists in order to confirm MS diagnosis and receive required care. Each neuroimmunolgy clinic visit cost around SAR 820 per patient, which is equal to $3075. In order to confirm MS diagnosis there are several tests need to be done. Brain MRI test cost ranges between SAR 1,233 to SAR 1,543 per patient with an average cost of SAR 1,525 ($407) per test per patient. CSF analysis is one of the diagnostic tests used to confirm MS diagnosis. Each Lumbar Puncture (LP) procedure cost ranges from SAR 887 to SAR 1600 ($236 - $427) per patient. Patients who experienced relapses and needed urgent care, each Emergency Department (ED) visit cost SAR 600 ($160) per patient not including other interventions or medications administered in the ER to manage relapses. One dose of IV methylprednisolone administered in the ER cost SAR 90.5 per patient to manage relapse. In regards to medications, DMDs occupy a huge part of the economic burden of the disease (80%-90% of total cost). There is definitely a variation in cost across DMDs. Approximately, a year supply per patient will cost around SAR 23,808 ($6,349) of Rebif (22 mcg S.C injection). 77 Rebif (44 mcg S.C injection) and Avonex (30 mcg IM injection) have similar cost per patient per year, which is around SAR 47,616 ($12,698). 77 A year supply of Fingolimod per patient cost around SAR 123,704 ($32,988). 77 While a year supply of the oral once daily dose of Teriflunomide will cost around SAR 46,800 ($12,480) per patient. 77 SAR 36,720 for the 120 mg strength of DMF and SAR 73,440 ($19,589) for the 240 mg strength of DMF for a twice daily dosing per patient per year. 77 There was a sharp increase in the total expenditure on MS medications in the last 4 years. 12

26 In 2010, the total cost of MS medications was almost doubled from SAR 6,627, tosar 14,176,889 in 2011 when fingolimod became available for use at KFSH&RC. The two following years (2012 and 2013) had almost the same spends on MS medications (SAR 14,936,879). There was a huge increase in total expenditure on MS medications in 2014 which was around SAR 17,062,160, when the three oral agents became available in the Saudi market. Neurologists started to prescribe oral agents more than injections in 2015 while the cost kept on increasing in which it reached SAR 21,317,163. In addition to DMDs, MS patients use other medications to manage symptoms caused by their illness. For example, the acquisition cost of Solifenacin (used to control urinary incontinence) increased from SAR 928,333 in 2013 to SAR 1,099,697 in Baclofen (muscle relaxant) cost has increased from SAR 298,833 in 2013 to SAR 650,696 in Other vitamins and supplements used to treat MS patients symptoms such as Ergocalciferol (Vitamin D2) and Calcium Carbonate had also a sharp increase in their acquisition costs in the past 4 years. Not mentioning antidepressants costs and other commodities used in the management of the disease such as walking aids, physiotherapy and psychological therapy. 1.2 Pharmacoeconomics (PE) The rising cost of health care services is a major concern to patients, healthcare system, and the government. Currently, PE studies have evolved as a significant and important field of research. PE evaluation plays a major role in the decision-making process in the healthcare field. It provides healthcare providers and policy makers with information to help them make an informed and cost-conscious decision in regards to resource allocation and optimizing institution budget.the science of PE is rapidly growing and in need for future research. PE identifies measures and compares the costs and 13

27 consequences of pharmaceutical products and services. There are four main types of PE evaluations: cost-effectiveness analysis (CEA), cost-utility analysis (CUA), cost-benefit analysis (CBA), and cost-minimization analysis (CMA). CEA, CUA, and CBA are considered full economic evaluation methods, while CMA is considered a partial economic evaluation method. Full economic evaluation has 2 major components: costs and outcomes of the compared alternatives. The cost component is always measured in monetary unit, while outcome component can be measured in various ways such as life years saved, case treated and utility terms. CEA is the most commonly used method to compare between two or more alternatives Cost-effectiveness analysis (CEA) Cost-effectiveness analysis is the oldest method used in health economics. It is a full economic evaluation where costs and consequences of treatment regimens are compared. CEA is used in situations where decision makers are considering a limited range of options within a given field, and within a given operating budget. Costs are measured in monetary units whereas consequences are measured as clinical and humanistic endpoints. In the treatment for hypertension for instance, mm Hg blood pressure reduction can be used as an effectiveness measure. Similarly, in the treatment of dyslipidemia, percentage of serum cholesterol reduction is utilized as an outcome measure. Other effectiveness measures can be used such as episode-day free in asthma, and years of life gained from adopting certain treatment. Incremental Cost-effectiveness Ratio (ICER) is a ratio in which it is used to calculate the difference in costs over the difference in effectiveness of two 14

28 alternatives.icer = Cost/ Effect = (CA CB) / (EA EB). It provides an estimate of the cost corresponding to a change in the measured effect through a change in drug therapy and thereby provides information regarding the relative efficiency of alternative options. For example: Osteoporosis Drug A vs. Drug B on fracture risk reduction ($/fracture avoided). Cost data can be obtained from insurance claims, pharmacy claims and hospitals records. Effectiveness data are usually obtained from clinical trials or existing literature. In general, researchers support the idea of adopting clinical data derived from the literature or clinical trials. However, ideally economic evaluation should incorporate clinical data on effectiveness (treatment performance in practice) rather than efficacy (performance of a treatment in controlled settings). It is challenging to utilize real world data for many reasons: time consuming, it takes so much time to gather and clean data for a study, high costs associated with data collection, and finally missing data is always a concern when a study to be conducted from payer s or provider s perspective because it may generate bias. However, many researchers have indicated that further population-based studies are required when comparing alternative treatment in a certain population is intended, in order to generate more consistent and relevant clinical and costs data. Selecting the perspective (viewpoint) from which the study is going to be conducted is important in PE research. Of natural, different stakeholders (physicians, patients, family caregivers, payers, hospitals, regulatory agencies, employers, manufacturers, and researchers) may have different perspectives on the use and the value of healthcare services and certain drug products available in the market. For example, if comparing the value of alteplase (tissue plasminogen activator, or t-pa) with that of 15

29 streptokinase from a patient or societal perspective, t-pa may be the best-value alternative because a 1% reduction inmortality rates is observed in this large population. Yet, from a small community hospital's perspective, streptokinase may represent a better value because it provides similar outcomes for less money. Again, perspective is critical because the value placed on a treatment alternative will depend heavily on the point of view taken Cost utility analysis CUA is similar to CEA in terms of measuring costs in monetary units, while the difference in CUA is that health gains are measured as Quality Adjusted Life Years (QALYs). Utilities are cardinal values that reflect an individual s preferences for different health outcomes. They are measured on an interval scale with zero reflecting states of health equivalent to death and one reflecting perfect health. Utility measurement consists of two main components, 1) the definition and description of a set of health states of interest and 2) the valuation of those health states (that is, measurement of the strength of preference for each health state). Thus, QALYs captures utility values that reflect an individual s preferences for different health outcomes. Another advantage of QALYs is that it combines number of years gained (mortality) with the quality of those years gained (morbidity) from adopting a certain therapy as one common measure, which it can make it easier and applicable when comparing among different treatment options across different diseases. The results in CUA are expressed as cost (Dollars or Euros) per QALY gained ($/QALY). 1.3 Need for study Saudi Arabia is one of the biggest countries in the Middle Eastern region. It is one 16

30 of the richest and fastest growing countries in the Middle East. It is the world s largestproducer and exporter of oil, which constitutes the major portion of the country s revenues. 37 According to the World Health Organization (WHO), the Saudi health care system is ranked 26th among 190 of the world s health systems. 37 Despite these achievements, the Saudi health care system faces many challenges which require new strategies and policies by the Saudi Ministry of Health (MOH) as well as effective cooperation with other sectors. The biggest challenge that faces the Saudi healthcare system is containing cost. 37 Since the government (MOH) is the primary source of funding to the majority of healthcare institutions, this lead to considerable cost pressure on the government, particularly in view of the rapid growth in the population, the high price of new technology and the growing awareness about health and disease among the community. 37 Saudi Arabia's pharmaceutical market, valued at SAR 28.4bn (USD7.6bn) in 2014, to remain the largest pharmaceutical market in the Middle East and Africa region for the foreseeable future. 62 Medicines purchasing power is expected to grow, as reported by the BMI report; the pharmaceutical spending per capita will increase from USD245 in 2014 to USD371 in 2019 and USD504 by Specific demographics, economics and health indicators of Saudi Arabia are presented in table 1.2. Fortunately, a case study was conducted by AlRashood et.al that compares the efficacy, safety and tolerability of fingolimod versus IFN users from two hospitals in Riyadh including KFSH&RC. 66 The results have shown that fingolimod users recorded lower rate of serious side effects than IFN users and better clinical 17

31 outcomes that include an overall reduction in relapse and disability progression rates. 66 In addition, patients quality of life was significantly enhanced among fingolimod users in comparison with IFN users. 66 Therefore, oral DMDs might contribute in the development of MS treatment guidelines and considered as first line options in the near future. MS is a very costly disease with a significant economic burden to the healthcare system. Given the prevalence and its predicted increase in the future in Saudi Arabia, and costs associated with management of the disease (MS ranked second behind congestive heart failure) 34, economic evaluation is important in making informed decisions. In the current economic downturn occurring in Saudi Arabia, and with the budget cuts facing the healthcare system, cost-effectiveness analysis (CEA) of therapies in MS has become an important part of the decisionmaking process in order to use resources efficiently in the face of the rapidly escalating costs of MS. This study was conducted from a payer s perspective (KFSH&RC) in order to assess CE of oral DMDs compared with IFNs in Saudi Arabia. 18

32 Table 1.2 Economic and health indicators of Saudi Arabia Indicator Value Reference Total population (2015) 31,540, Total Population (Projected, 2016) 32,158, Gross national income per capita (PPP international $, 2013) 53, GDP/capita $ (2014) 24, Total expenditure on health per capita (Intl $, 2014) 2, Total expenditure on health as % of GDP (2014) CPI: Consumer price index (2014) Annual general Inflation rate (%, 2015) Life expectancy at birth M/F (years, 2015) 73/ Goal of the study The main aim behind conducting this study is to determine from a payer s perspective (KFSH&RC) if the additional costs with the use of the oral DMDs are worth the benefits associated with them compared to conventional treatment (IFN) in the treatment of RRMS. 1.5 Objectives 1. To determine the cost per QALY with IFN (Rebif or Avonex) treatment. 2. To identify the cost per QALY with the use of each one of the three new oral agents (Gilenya, Aubagio, and Tecfidera). 3. To analyze the incremental cost-effectiveness ratio (ICER) of oral DMDs compared to IFNs in the treatment of RRMS in Saudi Arabia from a payer s perspective (KFSH&RC). 19

33 Chapter 2 Literature review This chapter will discuss the etiology and diagnosis of the disease. It will also elaborate more on the economic burden of the disease in the US and different other countries. Summarizing pharmacoeconomic studies performed in the US, Europe and other countries. Due to the lack of head-to-head randomized controlled trials (RCTs) between DMTs (especially oral agents), 18,38 and the absence of long-term observational studies it makes it more challenging to determine the cost-effectiveness of MS treatments, and generalize results across different populations. 2.1 Etiology of MS There are a number of hypotheses for what contributes to the development of MS, but researchers have not revealed the exact cause of the disease yet. 4 The most dominant theory suggests that an inflammatory immune-mediated pathogenesis is involved in the development of MS. 5 The process is believed to start after autoreactive T cells cross the blood-brain barrier. 7, 8 A cascade of events ensues with injury to the myelin membrane resulting in denuded axons that are unable to transmit action potentials efficiently. 7 This 20

34 slowed or blocked nerve conduction results in the variety of symptoms seen in MS. Symptoms may regress as inflammation subsides or as partial re-myelination occurs;however, eventual irreversible axonal injury, scarring, and exhaustion of the oligodendrocyte (mature cells that synthesize myelin) progenitor pool leads to progressive loss of neurologic function. 7, 8 The pathologic hallmark of MS is CNS plaque or lesions representing the end stage of the inflammation, demyelination and neuronal and axonal degeneration processes. Another theory adopted the idea of viral infection occurred in childhood. Some researchers studied the link between the exposure to Epstein - Barr virus (EBV) and the development of MS. 8 EBV has been shown to cause demyelination and inflammation of nerve fibers. It is possible that the virus adopts molecular mimicry, and cross-reactivate the T-cells targeted against their viral epitope with those on the myelin sheath. 8 This is why there is a huge influx of T-cells across the blood brain barrier. Again, these are all theories have not been proved yet. Some evidence suggests that genetic and environmental factors may play substantial roles in disease development. 8 Vitamin D deficiency was believed to contribute to the development of MS. 7, 8 the link between vitamin D deficiency and MS is now well established worldwide, with evidence confirming its protective role and suggesting that low vitamin D may contribute in explaining the increase in MS incidence. 8 Finally, The role of genetics is evident by many reports showing familial aggregation of the disease, high concordance rate among twins (30% chance of developing MS ) 7, association with Major Histocompatibility Complex (MHC) and the increased risk among relatives of MS patients. Genome-wide association studies (GWAS) showed an association between a subset of single- nucleotide polymorphism (SNPs) and MS. 8 21

35 2.2 Diagnosis of MS Understanding the diagnosis of MS is crucial in order to allow for early intervention. Many studies have shown that early initiation of Disease- modifying Therapies (DMTs) may improve the long-term course of MS and reduce permanent neurological damage. 2 Recent studies have shown the efficacy of DMTs for reducing the rate of relapses in patients with RRMS and slowing the course of MS progression. 2 In patients with clinically isolated Syndrome (CIS) which is a single attack (relapse) consisting of one or more neurological symptoms secondary to a demyelinating inflammatory event, DMTs have been shown to delay the conversion from CIS to clinically definite MS (CDMS). 6,7 An attack or relapse is defined as a presence of new or worsening of a neurological symptom for more than 24 hours with the absence of fever and infection. 39 To determine the time between attacks there should be 30 days gap between the onset of event 1 and onset of event 2. 7 The diagnosis of MS is based on clinical signs and symptoms and MRI markers. The McDonald criteria developed by the International Panel on the Diagnosis of MS and most recently revised in 2010 provide guidelines for the diagnosis of MS and include clinical, laboratory, and magnetic resonance imaging (MRI) criteria. 6,7 There is no specific diagnostic tool to confirm MS; mainly a combination of clinical symptoms and MRI findings can lead to earlier diagnosis. 7 Differential diagnosis is also important to eliminate other possible conditions that show same symptoms and signs. For a definitive diagnosis of MS, the clinical evidence of this attack should be confirmed by neurological examination findings, visual evoked potential response (for patients with prior visual disturbance), or MRI evidence of 22

36 demyelination in the CNS area that is suggested by the symptoms. 7, 13 There is still debate about the diagnostic value of oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF). Some neurologists especially in Europe point out that OCBs are still valuable for distinguishing MS from other causes of T2 lesions, particularly neuromyelitis optica (NMO). 7 Furthermore, in some cases of CIS, OCBs have a greater predictive value than MRI. According to The latest McDonald MS Diagnosis Criteria, MRI provides evidence of dissemination of lesions in space and time. 7 Dissemination in space means the presence of more than T2 lesions in at least two out of four areas of the CNS: periventricular, juxtacortical, infratentorial, or spinal cord. 7 While dissemination in time means the presence of a new T2 and/or gadolinium- enhancing lesion(s) on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI or simultaneous presence of asymptomatic gadolinium- enhancing and non-enhancing lesions at any time Economic, Clinical and Humanistic burden of MS in the US and Europe Due to the early age of onset (between years) and symptoms that impair patients quality of life, MS imposes a substantial economic and humanistic burden on individuals, healthcare systems, and society. 29 Considering the lifelong non- curable nature of MS, the management of the disease requires chronic pharmacological and non- pharmacological treatment. Many studies have shown that total costs of MS varied substantially across countries, but are significant worldwide. 30 Costs associated with MS can be classified into three main categories: 1. Direct costs, which include medical (drug treatment, hospitalizations, 23

37 hospital visits for routine check-up, diagnostic testing, and physical therapy) 30, and non- medical costs (informal care provided by family and friends, mobility devices e.g., wheelchairs, scooters, and transportation services) Indirect costs, which include loss of work productivity and early retirement. 30, 3. Intangible costs such as quality of life and degree of pain relieved. According to a report prepared by the MS international federation, the total annual cost per person in the U.S. is estimated to be $50,707 in Medical costs accounted for 47 % of total cots ($23,975); non-medical cost was around 15% ($7,844) of the total cost. Indirect costs accounted for 37 % ($18,888) of the total cost. 30 Total costs for all people with MS in the U.S. is approximately $28 billion annually. 31 Results from a systematic review (Adelman et.al, 2013) revealed that on average, direct costs comprised 77% (range 64 91%) of total costs. Prescription medications accounted for the majority of direct costs. On average, indirect costs comprised 23% (range 9 36%) of total costs. 34 In 2012, four specialty classes accounted for over 75% of total expenditure for specialty drugs: (1) inflammatory conditions, (2) MS, (3) cancer, and (4) human immunodeficiency virus. Moreover, in recent years, the healthcare and managed care communities have witnessed a huge shift in expenditure from medical benefits towards pharmacy benefits, especially for newer oral agents that treat cancer or manage MS. 29 Despite the availability of more treatment options, costs for all MS DMTs have increased sharply. 32 Between 2008 and 2012, U.S DMTs sales doubled from $4 billion to nearly $9 billion annually. 32 Currently, the average annual cost for IFNß-1b (Betaseron ) 24

38 is over $60,000 in the U.S. Thus, second generation DMTs (Oral agents) cost has increased from 8 % to 17 % annually since their approval. For example: fingolimod used to cost $50,775 since approval date, while in 2013 the cost has increased by 8%, which made the cost of fingolimod to be $63,806. Similarly, with teriflunomide and DMF both of them used to cost $47,651and $57,816 respectively at the date of approval while in 2013, the cost has increase by 17% ($57,553) for teriflunomide and by 14% ($63,315) for DMF. 32 In regards to direct non-medical costs, over a third of cases, people with MS and their families paid 100% of the cost of mobility aids such as canes, crutches, walkers, and wheelchairs. 30 Although, direct medical and non-medical costs occupy a significant portion of total cost of MS management, indirect costs has been a concern for health care providers recently. 30, 33 MS has a significant negative impact on patient s QOL and productivity. 35 As discussed earlier (in the overview and diagnosis sections), relapses can cause either temporary or permanent neurological damage, which may result in hospitalization that can be associated with a level of disability that disturbs work, social and family life. 35 Productivity is compromised in patients with MS, and impaired mobility in particular has been suggested to be an important factor contributing to lost productivity. 35 Although, the majority of individuals with MS are employed at the time of diagnosis, approximately half leave their jobs within a decade. 33 In a study by Scheinberg et al., 53% of patients reported physical difficulty as their primary reason for leaving their job. 35 A great work published by Kobelt and colleagues to estimate the productivity loss costs in different European countries in ,14 Kobelt et.al studies have found that the costs of productivity losses are high on a per person basis

39 Additionally, studies found that total productivity losses in terms of cost per patient per year (2005) ranged from 8,775 in Spain to 38,218 in Sweden, with most countries ranging from 11,000 to 16,000 Euros. 30 On the other hand, only one cross-sectional study was conducted by Kobelt et.al to estimate productivity loss associated with relapses in MS patients in the US. Study has shown that 37% of the total cost ($47,215) was for production losses. 36 As mentioned earlier, an intangible cost is the third category that makes up the total of MS costs. Intangible costs are related to changes in health states brought by healthcare intervention, such as changes in pain, social functioning and the ability to perform activities of daily living, as well as maintaining mental health: anxiety, depression, etc. 30, 34 Thus, quality of life (QOL) has become a key component in measuring effectiveness of a specific intervention, and has been widely used as an outcome measure in healthcare specially in chronic diseases. A chronic illness such as MS can dramatically affect patient s QOL for many years. As a result, a significant but unquantifiable component of the economic burden of MS is its impact on QOL. Several studies have indicated that there is a 30%, 40%, and 50% decline in physical functioning for mild, moderate, and sever MS respectively, 30 A decline in social functioning with a range of 20%-30% across severity levels of MS. 30 Additionally, there is a 10 % reduction of mental functioning across different severity levels of MS Pharmacoeconomic studies in the US Although that the first US study was published in 2004 (Prosser), 18,38 The US recorded the highest number of PE studies among all other countries. 38 The majority of the studies were conducted from a societal perspective with a time horizon ranged from 26

40 2 years to patient s lifetime. Prosser et al. study is one of the most recognized works done in the field of MS treatments. 40 They performed CUA from a societal perspective with a time horizon of 10 years. 40 The study aim was to determine the CE of three immune- modulatory treatments (IFNβ-1a (Avonex), IFNβ-1b (Betaseron), and glatiramer acetate GA) vs. no treatment for newly diagnosed non-primary progressive MS patients. Clinical data were obtained from RCTs, QALYs were utilized as the main outcome for the study using standard gamble method. 40 Although, this study was conducted from a societal perspective, indirect costs (productivity loss) were not included in the base-case analysis. 40 Study results showed that IFNβ-1a (Avonex) had the best outcome with an ICER of $2,200,000/QALY for women and $1,800,000/QALY for men, compared with no treatment. 40 Surprisingly, study results were sensitive when treatment duration changed. In the sensitivity analysis results, no treatment strategy yielded more QALYs than any of the other DMTs (when time of treatment changed from 10 to 5 years). 40 Bell and colleagues published first CE study on RRMS patients in The study was carried out from a societal perspective with a lifetime horizon. ICERs were also reported as dollars/qalys. Comparators were symptom management alone vs. symptom management in combination with one of the four immune-modulators (GA, M IFNβ-1a, SC IFNβ-1a, or SC IFNβ-1b). Results showed that GA is the best treatment strategy in the treatment of RRMS with $258,465/QALY. Another study (Noyes et al. 2011) 41 was conducted on RRMS patients using societal perspective with time horizon of 10 years. Similarly, they compared all IFNs and GA with supportive care. Noyes s study also showed that all DMTs yielded in small health gains compared to their costs, 27

41 and stated that early initiation of DMTs was associated with lower ICERs (lowest cost for better outcome). 41 Goldberg et al. (2009) repeated the work done by Noyes but with a shorter time horizon (2 years) and a different perspective (payer). 42 They also compared first line treatment (IFNs & GA) with supportive care in the treatment of RRMS. The primary outcome measure is relapse avoided (RA) not QALYs. Results have shown that the 2- year reductions in relapses for treatment with GA, IFNβ-1a IM (Avonex), IFNβ-1a SC (Rebif), and IFNβ-1b (Betaseron) were 0.66, 0.42, 0.74, and 0.70, respectively. In the base case analysis, Rebif, Betaseron, and GA had the most favorable costs per relapse avoided ($80,589; $87,061; and $88,310; respectively and Avonex had the least favorable ICER ($141,721 per relapse avoided). 42 Another study was conducted from a payer s perspective (O Day et al. 2011) to assess CE of recent treatments (Fingolimod vs. Natalizumab) with 2 years time horizon. Relapse avoided was also utilized as an outcome measure to determine the effectiveness of both regimens in the treatment of RRMS. Results indicated that natalizumab is dominating fingolimd in the treatment of RRMS. In other words, natalizumab was associated with the lowest cost ($86,461) with the highest outcome (0.74 relapses avoided) compared to fingolimod. A recent CE study published in 2014 by Zhang and colleagues compared first line treatment (IFN) with oral agents (fingolimod, teriflunomide and dimethyl fumarate). 44 They reported incremental net monetary benefit (INMB) as their primary outcome, and ICER as the second objective of the study. 44 NMB is a simple approach in which saved costs of adopting a certain health program can be reported and compared to other alternative programs. NMB is calculated by first assuming a willingness to pay (WTP) threshold, then converting health benefits (QALYs) into the common metric of dollars. 28

42 The cost associated with each treatment strategy is then subtracted, resulting in the net benefit of each strategy expressed in the monetary units. ICER limitation is that ratios cannot be simply interpreted, in which it gives no idea of the size or scale of the treatment being considered. Thus, NMB came into play to solve this issue by considering multiple WTP thresholds and allowing for transparent comparison between alternatives. Going back to Zhang et.al study, the results have shown that DMF dominated all other therapies in terms of NMB and ICER. DMF had the lowest cost ($200,145) with the highest QALY (3.69), and INMB of $80,611 at a WTP of $ 150, To summarize results from the literature review of US studies, although that the majority of the studies reported base-case results from a societal perspective, however, most of them didn t report indirect costs which may not seem practical in a country like the US that has many stakeholders involved in the healthcare system with different interests. 37 In addition, indirect costs associated with MS treatment are believed to matter more to the society than direct costs since most of them are not covered by insurance. The majority of the studies used a Markov model approach, which allows for long-term analysis, up to a lifetime in scope. In addition, Markov modeling also allows for transition between disease states for cohorts of patients, which reflects the natural disease progression of MS (e.g. progression of disability or presence of relapses). For modeling treatment effects, most studies obtained clinical data from RCTs. Outcomes included incremental cost per QALY gained (the cost-utility endpoint), as well as cost-effectiveness outcomes such as cost per relapse avoided which are sponsored by drug manufacturers or conducted from a payers perspective. 29

43 2.5 Phramcoeconomic studies in Europe Most of European countries started using economic evaluation earlier than US to assess CE of MS treatments. In 1998, Parkin et al. published the first CE study from UK societal perspective with a time horizon of 2, 5 &10 years. 37, 45 what is unique about this study it didn t only look at the costs and effectiveness associated with each treatment but instead, it assessed and measured the QOL of patients during relapse and remission phase. They collected data on QOL using EQ5D and MSQOL-54 surveys. Both instruments are patient self-reported multidimensional health-related QOL surveys, which generate scores about overall health. The difference between two measures is that EQ-5D contains five dimensions about overall health in which it can be used in different disease; while MSQOL-54 combines both generic and MS-specific items into a single instrument. 46 Utilities were calculated based on the scores generated from each surveys. Results showed that patients who are in the remission group have better QOL than patients who experienced relapses. 45 In regards to CUA results, IFNβ-1b was the most favorable treatment to manage RRMS with a cost-utility ratio of 327,300/QALY, 328,000/QALY and 228,000/QALY for 2, 5 & 10-year decision analytical model respectively, despite the small amount in QALYs gained in relative to other treatment options (IFNβ-1a & GA). 45 Another remarkable work was done by Gani et.al in They evaluated the CE of natalizumab versus other DMTs (IFNs &GA) and supportive care in patients with highly active RRMS (HARRMS) in UK, using Markov model over 30 years time horizon. 49 ICERs were 2,300/QALY gained as compared with IFN-β, 2,000/QALY as compared with GA and 8200/QALY as compared with supportive care. 49 Kobelt and colleagues did one of the most comprehensive and well-recognized 30

44 CE analyses in the field of MS treatment. In fact, Kobelt et.al conducted several studies on different MS patients population (SPMS, RRMS) in different European countries. 18,30,37 In 2008, Kobelt et.al published a study that compares between natalizumab and other DMTs using Markov model. 47 The study was conducted from Swedish societal perspective with a time horizon of 20 years. Results have shown that natalizumab dominated all other DMTs in the treatment of RRMS. 47 In other words, natalizumab had the best outcomes with the least cost compared to other treatments, and offered additional health benefits at a similar cost to other DMTs. 47 Kobelt and colleagues extended their work and published another study in France. In 2009, the study was carried out from French societal perspective. 48 A Markov model was developed to estimate costs and utility over 20 years using survey data. 48 Results were presented as Euros/QALYs in which that treatment with DMTs yielded with 15,385/QALY versus no DMTs treatment. 48 Productivity losses were also estimated to be 47% of the total annual costs per patient ( 44,400). 48 In 2010, another CE study was published by Nuijten et.al. This study was conducted from German societal perspective with a time horizon of 4 years using a decision analytical model (decision tree). 50 The main aim of the analysis was to compare the CE of IFNβ-1a 44 µg SC with that of other available first-line treatments for RRMS from the German societal perspective in Outcome measures were presented as cost/ra. Results have shown that IFNβ-1a 44 µg SC is the most favorable option in the treatment of RRMS ( 51,250/RA) compared to other treatments vs. no active treatment. When the cost of disease progression was excluded, the cost per relapse avoided remained favorable for IFNβ-1a 44 µg SC ( 54,292) compared with 31

45 the other agents. To summarize results from the literature review of European CE studies, UK has recorded the highest number of CE studies among other European countries. Costs and outcomes varied widely between countries and also between studies within the same country. In general, majority of the studies have expressed results in QALYs as well as euros or pounds per relapse avoided when a shorter time horizon is utilized. In addition, outcomes were sensitive to the DMT acquisition cost, the time horizon of the analysis, and the estimation of the treatment effects. Studies with longer treatment duration reported worse (higher) incremental cost- effectiveness ratios (ICERs), which can be explained by the lack of observational studies in which enables generalizing results to a broader population outside clinical trial monitoring and to real-life clinical practice settings. 2.6 Pharmacoeconomic studies in other countries There are few studies done outside the US and Europe. The literature review results revealed that there are only three studies done outside the US and Europe. Jankovic and colleagues conducted the first study in 2009 from a Serbian societal perspective. 52 They adopted a previously published model from the US (Bell et.al), and utilized the Serbian healthcare resources utilization and drug costs with a 40 years time horizon. The aim of this study was to compare the CE of five treatment strategies in patients diagnosed with RRMS (symptom management alone and in combination with SC GA, IM IFNβ-1a, SC IFNβ-1a, or IM IFNβ-1b). One QALY gained costs more than a billion of Serbian dinars (more than 20 million US dollars), making each of the fourimmunomodulatory therapies cost-ineffective. The unfavorable ICER in this analysis was driven by high drug acquisition costs and a low QALY gain from DMTs. 32

46 The two other studies were conducted in the Middle East, specifically in Iran. The first study was conducted by Nikfar and Colleagues in 2013 from an Iranian societal perspective, a Markov model was developed based on EDSS score. 53 Disease progression data were obtained from natural history studies and multicenter randomized controlled trials. 53 In addition, a cross sectional study has been developed to evaluate cost and utility among RRMS and SPMS. The aim of the study was to compare CE of different forms of IFNs in combination with symptom management versus symptom management alone. 53 Results were expressed as dollars/qaly. 53 ICERs for Avonex, Rebif and Betaferon were $18,712, $11,832, and $15,768 respectively compared to symptom management alone. 53 ICERs for available copied biopharmaceuticals (CBPs) (CinnoVex, Recigen & Ziferon) of IFNs in Iran were $847, $6964 and $11913 respectively compared to symptoms management. 53 Which means, that CinnoVex is the most CE regimen in the treatment of RRMS in Iran since it has the lowest ICER value relative to other agents compared to symptoms management alone. 53 In a later study, Najafi et.al (2014) have also conducted a CE study to compare two different forms of IM IFNβ-1a (Avonex & CinnoVex) in the treatment of RRMS. 54 In this study, the Ministry of Health and Medical Education (MOHME) perspective was adopted. HRQoL was used as an outcome measure and costs were measured and valued from a third party payer perspective (MOHME). 54 Results showed that patients in CinnoVex group reported significantly higher scores in both physical (69.5 vs. 50.9, P<0.001) and mental (63.3 vs. 56.6, P=0.03) aspects of HRQoL than Avonex group. On the other hand, annual cost of CinnoVex and Avonex were $2410 and $4515 per patient, respectively. Thus, CinnoVex (generic) dominated 33

47 Avonex (brand) in the treatment of RRMS in Iran. 54 Which means that CinnoVex was less expensive and more effective than Avonex, which may be attributed to the affordability and accessibility of generics in Iran. 2.7 Conclusion There is a lot of uncertainty and variation in results drawn from CE studies on MS treatments either in the US, Europe, and other countries. Sources of variation are the absence of standardized guidelines on how to conduct CEA/CUA in which it will generate variation in the model used to estimate costs and effectiveness of intended treatment options. In addition, there s a variation in modeling approach used in each study that can include variation in patients characteristics (age, gender, country, age at onset ), treatment duration chose, time horizon and the perspective of the study chosen. It is very challenging to estimate the CE of DMDs, especially the newer agents (oral) due to the absence of head-to-head RCTs and long-term efficacy data. Thus, observational and follow-up studies are required, especially in countries that lack previous country- specific models and novel epidemiological data that provide the natural history of the disease in that specific population. In conclusion, with the growing focus on evidence-based medicine and the need for enhancing delivery of healthcare services while reducing costs, there s a huge need for pharmacoeconomic studies in order to help decision makers and healthcare providers to make an informed and cost-conscious decision regarding costly alternatives available in the market. Regardless of all methodological shortcomings and criticisms for ignoring social costs in many studies, CEA can still provide insights into 34

48 how to reduce the economic burden of MS. With almost 2 decades worth of DMT efficiency data, it seems that the time has come to expect more population-based CEA. 35

49 Chapter 3 Methods An economic evaluation was performed from a payer s perspective (KFSH&RC) to compare between the CE of oral agents (fingolimd, teriflunomide & dimethyl fumarate) and IFN-β products used by KFSH&RC neurologists in the treatment of RRMS. Health gains was measured as QALYs. Costs were measured in Saudi Riyals (SAR) and equivalent US dollars. A simulated Markov model was developed based on EDSS scores to estimate costs per QALY for each treatment. ICERs were expressed as US/QALY and equivalent SAE/QALY at a WTP of US$100, General description of the study design Efficacy data were measured as final outcome, which are QALYs. An adopted Markov model was used to estimate cost per QALY for treatment options. Costs of drugs were obtained from the Pharmaceutical Care Division at KFSH&RC and other direct medical costs were gathered from the financial department. 20 years time horizon was used in the base case analysis to capture the chronic nature of the disease and account for the uncertainty regarding the long-term efficacy of all treatments. 36

50 3.2 Study population A hypothetical cohort of 1000 MS Saudi patients will enter the model. Assuming we have equal number of patients in each treatment group (200 patients) for the five comparators used in the model in order to make a fair comparison between all 10, 59 interventions. According to the recent observational study done in Saudi Arabia patients characteristics and disease pattern resembles the western type of MS, including the signs and symptoms and the estimated number of cases in women versus men patients; in which that women are at twice or thrice the risk of developing MS than men. 10 Sadly, the mean age at onset was estimated in Saudi population to be 25 years old which is lower than other countries in the region number of cases for the last 5 years (from ) was chosen as an estimate of a total number of cases treated in the last six years at KFSH&RC based on a recent statement made by Professor Bohlega in 2008 which he indicated that MS is profoundly in increase and prevalent with a total number of cases around 40/100,000 individuals. 9 So, assuming that the prevalence is constant, the total number of cases in Saudi Arabia now will be 12,863 per 32 million individuals (the current estimated population size in Saudi Arabia according to the United Nations), 60 and looking at the current mean age which is 25 years old and the female/male ratio 60 in the total population adding the genetic and environmental factors discussed earlier indicates that Saudi Arabia is located in the moderate-to-high risk zone. So, since we are not including the total number of MS cases in the current analysis, we are assuming that KFSH&RC are treating 50% of the total number of cases (6,431) since it is a big referral hospital in the center of the kingdom, which makes up a total of 1000 cases per year in the last six years. Since the ratio of female/male is the 37

51 double and the mean age is 25 years old according to the latest observational study, 9,10 the base case presented in this paper is a hypothetical cohort of 1000 MS Saudi patients with 700 females and 300 males at mean age of 25 ± 5 years old diagnosed with RRMS with an initial EDSS score of (Mild disease). 3.3 Data collection Data on cost were gathered for 2015 year. The reason behind choosing that period of time is the novelty and availability of cost data, since that the financial department started using Venus Billing System that implements CPT codes for medical interventions started in Medication costs were obtained from the Pharmacy 40, 56,58 division. Efficacy data on treatment options were obtained from the literature. Ideally the model would use effectiveness measures and transition probabilities from patients medical records or national disease registries from Saudi Arabia, however, none of these data were used due to the lack of proper documentation or easily accessible; therefore, the EDSS progression rates were obtained from a report published in the literature by the Canadian Agency for Drugs and Technologies in Health. 56 Utility weights used for each health state and treatment type were obtained from Prosser study Markov model Decision-analytical modeling has been widely used by experts to investigate the cost-effectiveness profiles of healthcare programs and pharmaceutical services. 55 One of most commonly used methods in PE is Markov model. 55 Markov modeling is a technique that allows presentation and analysis of random events over time. The 38

52 principle of Markov modeling is that the disease of interest is divided into discrete states, by which the progression of disease falls from the least sever state (or from onset) to the most sever or most of the time death, over a certain amount of defined time. Each disease state has its own transition probability assigned to it, in which it allows patients move from a different state to another. The patient can only be in one health state at a time which is can be called as mutually exclusive and there will always be a chance (probability) of reaching the absorbing state which it can be death, disability etc. 3.5 Development of Markov structure model A modified Markov model is used based on a previously published cohort simulation by CADTH (Canadian Agency for Drugs and Technologies in Health). 56 The original model classified RRMS into five health states based on EDSS scores. Each disease state is defined according to the Kurtzke EDSS (table 2) 56, as well as severity of relapses. Severity of relapses was classified as mild, moderate and severs. They were defined based on previous publication (O'Brien et al., 2003) 57, in which mild or low intensity relapse can be defined as symptomatic management by home meds and regular physician office visits, moderate intensity episodes (relapses) require the use of the emergency room (ER), or an observational unit, or administration of acute treatments requiring formal intervention, such as intravenous (IV) methylprednisolone given in an outpatient or home setting. High intensity or sever episodes can be defined as the management of relapses that requires hospitalization. This model was structured based on a cohort of 1000 newly diagnosed RRMS patients with a mean age of 25 years old from Saudi Arabia using EDSS scores as defined health states, and the annualized relapse rates for each treatment option. The model was built in the absence of observational studies on Saudi population. Parameters on EDSS progression rates, 39

53 relapse rates and treatment efficacy were obtained from the literature years time horizon was utilized with an annual cycle length, where all patients will be followed through the model until they reach the absorbing state (health state 5). The patients will only move in one direction in this model (unlike the original model), which means patients will only move forward (get worse) assuming that DMDs will only slow down the progression of the disease and have no effect on improving EDSS scores. In health state 1 and 2 (EDSS from 0.0 to 5.5), five different scenarios were assumed, during one cycle, patient could remain in the same health state (no change occur), relapse and remain in the current health state; relapse and progress to the next severe state; progress to the next sever state without relapsing according to treatment efficacy on disease progression, or die. Relapses were assumed to occur only in patients in the health states 1 and 2 (EDSS 0.0 to 5.5). Although relapses may occur for states with EDSS greater than or equal to 6, as per clinical expert opinion, the severity of disability may mask signs of relapses. 56 In health state 3 and 4 three different scenarios are presented in this paper, patient could remain in the same health state, progress to the next sever state according to the natural history of the disease, or die. Based on clinical experts opinion, for the base case scenario, an assumption was made that once patients progress to an EDSS of 6 or secondary-progressive multiple sclerosis (SPMS), they would withdraw treatment. 56 So, for this reason the base case analysis will not include patients who are already reached SPMS stage. Upon researching literature on the best source to obtain transition probabilities, this paper used transition probabilities between RRMS states reported in CADTH report. 56,58 Relative risks for DMDs efficacy on EDSS progression and relapse rates were also 40

54 driven from the CADTH report. 56 DMDs used in this model were first-line options only and the most commonly prescribed treatments at KFSH&RC including: Interferon beta- 1a (Avonex ), (Rebif ) 44 mcg, dimethyl fumarate (Tecifidera ), fingolimod (Gilenya ), teriflunomide (Aubagio ). Additionally, the cost of DMDs will be zero in the third and the fourth health state and the outcomes will be in measured in negative values (dis- utilities) for relapses regardless to the treatment. Table 3.1 Descriptions of Markov model Health States (Source: CADTH: Therapeutic Review of RRMS 56 ) Health state Description Health state 1 No/few limitations (EDSS 0 to 2.5) Health state 2 Moderate limitations (EDSS 3 to 5.5) Health state 3 Walking aid or wheelchair (EDSS 6 to 7.5) Health state 4 Restricted to bed (EDSS 8 to 9.5) Health state 5 Death (EDSS 10) No MS symptoms (0) to minimal disability in two functional systems (2.5) Moderate disability in one area or mild disability in up to four areas but still able to walk unassisted and accomplish full daily activities (3), to disability that precludes full daily activities, but still able to walk unassisted (5.5) Requires walking aid such as cane, crutch, or brace to walk 100 meters (6), to restricted to wheelchair (7 to 7.5) Restricted to bed with some ability to selfcare (8), to requiring assistance for all activities of daily living (9 to 9.5) Death due to MS 41

55 Health State 1 EDSS Health State 2 EDSS Health State 3 EDSS Health State 4 EDSS Health State 5 EDSS 10 Mild/Moderate Relapse Severe Relapse Figure 3.1: Schematic representation of the Modified Markov model (Source: CADTH: Therapeutic Review of RRMS 56

56 3.6 Data inputs Model inputs are categorized into two main categories: Efficacy data and cost data. Due to the lack of observational studies on MS patients in Saudi Arabia and based on a literature review, health outcomes were obtained from the Prosser paper that is based on a large-scale observational study in the US. 40 Regarding cost data, this analysis will only consider direct medical costs that are covered by the payer (KFSH&RC) since that indirect costs and productivity loss couldn t be obtained for this specific population. Transition probabilities were driven from the CADTH report Transition probabilities and Efficacy data The chance that the patients will move between states within a cycle is termed transition probability. Transition probabilities could be obtained from RCTs or observational studies. Transition probabilities within RRMS heath states were driven from CADTH report based on a long-term observational study performed in Canada. 58 Relative risks of disability progression and annual relapse rates across treatments were obtained from the CADTH report. 56 The relative risks of sustained disability progression of each treatment option were multiplied by the natural history transitional probabilities to estimates each state transition probability of all the five comparators. For example: the transition probability for EDSS 0 is was multiplied by the RR of sustained disability progression for Avonex arm which is equal to which in turn it will reduce the probability from to The probability of staying in the same health state was then increased by the percentage of patients who did not progress because of the treatment effects, so that the sum of the transitional probabilities remained 1. This paper assumed that mild/moderate relapses accounts for 77% and will keep patients in the same state calculating the state reward as 43

57 disutility for mild relapses, while sever relapses (23%) were assumed it will transit the patient to next sever state calculating the state rewards in disutility for sever relapses. Probability of relapses were estimated for each treatment option using the same technique Patients who discontinue treatment will progress according to rates for natural disability progression, but will retain benefits received. All patients were assumed to be adherent until they reach EDSS score 6+ due to intolerance or ineffectiveness. Base-case estimates of transition probabilities and efficacy data are presented in table 3.2 & 3.3. Table 3.2 Transition Probabilities and relapse rates for EDSS states (source: CADTH 56) Health state Probability Lower bound Upper bound EDSS EDSS EDSS EDSS EDSS EDSS EDSS NA NA EDSS NA NA EDSS NA NA EDSS NA NA 44

58 Table 3.3 Relative Risks for DMT Efficacy on EDSS Progression and Relapse Rates (source: CADTH 56 ) DMD Efficacy on EDSS Progression and Relapse Rates Efficacy on EDSS progression Efficacy on relapse rate DMD Relative Risk (basecase inputs) Lower bound Upper bound Interferon beta-1a 30 mg (Avonex) Interferon beta-1a 44 mcg (Rebif) Fingolimod (Gilenya) Teriflunomide 14 mg (Aubagio) Dimethyl fumarate mg (Tecfidera) Interferon beta-1a 30 mg (Avonex) Interferon beta-1a 44 mcg (Rebif) Fingolimod (Gilenya) Teriflunomide 14 mg (Aubagio) Dimethyl fumarate 240 mg (Tecfidera) Health Utility: Health benefits were measured in the form of QALYs. As mentioned earlier, QALYs is a preference-based measure that combines both mortality and morbidity of life-years gained from adopting a certain intervention or using a specific treatment. In order to calculate QALYs, there are different strategies to generate health related quality of life (HRQoL) weights. There are direct elicitation techniques such as Visual analogue scale (VAS), Time Trade Off (TTO) and Standard Gamble (SG) methods. 45

59 Based on a literature review, Utility weights for each health state were obtained from Prosser study. 40 Prosser et. al paper presented the utility weights for each health state and disutility by severity of relapses based on patients preference. 40 The study used the standard gamble method to measure patient and community preferences for treatment and heath states in patients with RRMS. Standard gamble method is a technique used by health economist to assign a value for health states of interest based on consumer preference. The standard gamble involves an element of risk faced by the individuals. The choice is between the certainty of remaining in a particular health state, or taking a gamble of either being in full health or risking death (with a 30% probability of death in Figure 3.2). The probability of experiencing death is varied until the individual is indifferent between the certainty and the gamble. The more severe the health state, the greater is the risk of death that the patient would accept to be cured of it. If the individual were indifferent under the scenario illustrated in figure 3.2, the utility generated would be 0.7. Although this paper is adopting a payers perspective, utilizing HRQoL reported by patients is the most validated method to assess the long-term cost-effectiveness of any medical intervention, and allows for more comprehensive comparison between different alternatives. Utility scores driven from Prosser study were gathered via 30 minutes computer interview administered to a convenience sample from San Diego, USA. Utility scores from Prosser study were used in the base case analysis (Table 3.4). QALYs were discounted at 3 % per year. 46

60 Figure 3.2: Direct elicitation method of driving utility weights (Standard Gamble) Table 3.4 Base case utility estimates (Source: Prosser 40 ) Health State Utility weights Lower bound Upper bound (Base-case estimates) Health state 1 (EDSS 0-2.5) Health state 2 (EDSS 3-5.5) Health state 3 (EDSS 6-7.5) Health state 4 (EDSS 8-9.5) Health state 5 (EDSS 10) (death) Disutility associated with mild or moderate relapse Disutility associated with severe relapse Cost data Since this study is adopting a payers perspective (KFSH& RC), only direct medical cost were included in the analysis. All Costs were presented in local currency (Saudi Riyals) and converted into US dollars. Cost data were gathered for more than 400 MS patients identified through Venus billing system by CPT code for neuro- immunology clinic visits in Costs were gathered in two steps: first, costs 47

61 of DMDs and other medications used for symptoms management were collected from the Integrated Clinical Information System (ICIS) via pharmacy portal (PharmNet ) (table 3.5). Second, Other medical costs were driven from the financial department including: physician office visits, ER visits, hospitalization, laboratory and imaging tests, walking aids and other specialist care. CPT codes and cost for each intervention are presented in the table 3.6. Cost data varies from service to another; pharmacy items were not identified according to CPT coding system. Hospital cost is used to measure the cost of medications, while contract price was used to measure the cost of medical interventions and multiplied by the quantity of service provide in order to estimate hospital cost when missing. The base case analysis included the average cost per person per year in relates to EDSS scores in which it was estimated according to patients consumption of DMDs and medical services based on previous published studies (table 3.7). 69, 70,71 Cost were measured in 2015 Saudi Riyals value and 3% discount rate was applied to account for inflation rate of 3.2 % as reported by latest global medical trend rates report

62 Table 3.5 Costs of DMDs per patient per year (Source: 1.KFSH&RC Pharmaceutical Care Division), 2. Saudi Food and Drug Authority (SFDA) Drug name Dose and frequency Cost per patient per year (SAR) 1 Cost in US Dollars ($) Consumer price per year (SAR) 2 Interferon ß-1a (Rebif 44 mcg) 44 mcg SC 3 times weekly 19,440 5,184 SAR 57,277 $15,274 Interferon ß-1a (Avonex ) 30 mcg IM once a week 102,912 27,444 SAR 56,614 $15,097 Fingolimod (Gilenya ) 0.5 mg orally Once daily 120,492 32,132 SAR 123,704 $ 32,988 Teriflunomide (Aubagio ) 14 mg orally once daily 93,672 24,980 SAR 46,800 $12,480 Dimethyl fumarate 120 mg orally twice 136,800 36,480 SAR 37,034 (BG-12) daily $ 9,876 (Tecfidera ) 240 mg orally twice 145,656 38,842 SAR 73,256 daily $19,535

63 Outpatient resources cost (Visits, Times) Service name CPT code Hospital Cost per patient (SAR) Brain MRI 70551,70552, Cervical Spine MRI 72156, Lumbar Spine MRI 72148, Thoracic Spine MRI 72157, Lumbar Puncture for CSF analysis Emergency Department visit Neuroimmunology follow-up visit Neuroimmunology new follow-up visit Demyelination (Multiple Sclerosis) follow- up visit Demyelination adult new follow-up Multiple Sclerosis New Follow-up Physical therapy visit 99214,99215,97116, 97110, 105 (average) 99211, 99213, ,97035,97542,99242 Ophthalmology visit (average) Visual Evoked Potentials (VEP) Laboratory tests (Diagnosis and monitoring) (Hospital cost per patient per test) Complete Blood Count 85027, , 23 Hepatic Profile Thyroid Panel 83970, 84443, , 50, 43 Cerebrospinal fluid (CSF) analysis Prescription Drugs (average hospital cost per patient per year) Antidepressants Escitalopram 279 Fluoxetine Null 350 Amitriptyline 50 50

64 Antispasmodics Baclofen 33 Tizanidine 71 Gabapentin and Pregabalin Null 450 Clonazepam and Diazepam 30 Fampridine Anti-fatigue (Amantadine) Null 5, Urinary incontinence medications Oxybutynin Solifenacin Tolterodine Imipramine Null Relapse treatments Intravenous (IV) Null methylpredniso lone Oral Corticosteroids Pain Killers Tylenol#3 (Acetaminophen + Null codeine) Over The Counter medications (OTC) , Pain killers Acetaminophen Ibuprofen Null Naproxen Vitamins and supplements Calcium carbonate Null Cholecalciferol (Vitamin D3) Ergocalciferol (Vitamin D2) Inpatient services (Average hospital cost per patient per visit/item) Hospitalization Null 941 Medical supplies Null 224 Table 3.6 Direct medical costs (Source: KFSR&RC Pharmacy Division and Financial department), 1 $US = 3.75 SAR 51

65 Table 3.7 Total average direct medical costs according to EDSS score per patient per year in Saudi Riyal (source: calculated), 1 $US = 3.75 SAR Item EDSS 1 EDSS 2 EDSS 3 EDSS 4 EDSS 5 EDSS 6 EDSS 7 EDSS 8 EDSS 9 Emergency Visits Neurology clinic Visits Hospitalization , Radiology 542 1,637 3,159 3,537 4,698 4,771 2,045 1, Laboratory Tests Other Specialist Visits Medical Supplies ,145 Other Tests and Services ,122 21,938 44,327 DMDs 52,545 66,976 50,383 32,736 33,138 21, Prescription Medications ,279 3,094 18,582 25,449 3,518 8, Relapse Treatment , OTC Total 53,617 69,913 56,548 42,373 70,790 73,416 17,522 33,881 37,881 Total without DMDs 1,072 2,937 6,164 9,637 33,138 51,757 17,522 33,881 37,881

66 3.7 Building Markov Model in TreeAge Pro suite software As shown in Figure 3.3 a graphical representation of the model built in TreeAge software to run a computer generated simulation on a hypothetical cohort of 1000 RRMS patients to estimate the cost-effectiveness of oral DMDs versus IFN formulations (Avonex & Rebif). Each comparator has the same number of Markov states, cycle length (1 year) and 20 years time horizon. The cohort proportion of all treatment arms was assumed to start at health state 1 (probability equals to 1 at health state 1). Each treatment option arm sub-states were assigned a transition probability according to the treatment effect on EDSS progression rate and relapse rate that allows patients to move from state to another through the entire model. Direct medical costs were also assigned to each health state and sub-state including medications cost, relapse cost and other resource utilization average cost per patient. Mortality rates for this cohort was driven from the life expectancy table data of the Saudi population reported by WHO in ,69 53

67 Figure 3.3: Markov model build in TreeAge Pro Suite Software 54

68 3.8 Sensitivity analysis: The present model estimated the cost effectiveness of oral DMDs versus IFNs using data from different sources; therefore, an extensive sensitivity analysis was conducted to test for the uncertainty of the base-case analysis results. A one way- sensitivity analysis was performed to test the robustness of the pairwise comparison of the three new oral DMDs versus IFN-b1a formulations (Avonex and Rebif) and the robustness of the optimal therapy selection by using incremental net monetary benefit (INMB) as the outcome. INMB was used as an outcome to offer results on the best approach for optimizing organization budget. The lower and upper bounds of each health states utility weights were used to test the uncertainty of the population preference. The lower and upper bound for relative risks of DMDs efficacy on EDSS progression and relapse rate were also tested for treatment uncertainty in efficacy. Since this paper is adopting a payers perspective, cost is an important factor in which it should be studied from different angels. Since that SFDA sets the regulations for drugs registration and pricing in Saudi Arabia, the maximum retailers price will be set as the minimum cost for DMDs. A probabilistic sensitivity analysis based on a second order Monte Carlo simulation (1,000 times) was also performed to test the robustness of the base-case scenario results. In Monte Carlo simulation a random value is selected for each parameter, based on the range of estimates. The model is calculated based on this random value. The result of the model is recorded, and the process is repeated. A typical Monte Carlo simulation calculates the model hundreds or thousands of times, each time using different randomly selected values. The distribution of each parameter was driven from the CADTH report to test for the uncertainty of each variable used in the model

69 Transition probabilities were characterized by beta distributions, dis-utilities of relapses were characterized by log- normal distributions, utility values were characterized by beta distributions, 56 and relapse rates were assumed to follow dirichlet distributions to fit the model inputs, while costs were assumed to be normally distributed. The elements for each distribution function were driven from the ScHARR report when available

70 Chapter 4 Results 4.1 Base-case Scenario Treatment with DMDs yielded cumulative rewards ranges between 9 to 10 QALYs. Over 20 years, the total costs per patient were ranged between $300k to $430k. The accumulated QALYs were 9.72, 9.78, 10.01, and for teriflunomide, Rebif, Avonex, dimethyl fumarate and fingolimod respectively. Assuming a WTP of US$100,000 Rebif has shown to be the most optimal drug in the treatment of RRMS (figure 4.1). Figure 4.1: Cost-effectiveness analysis scatterplot of all DMDs 57

71 From the results: fingolimod is the only oral DMD appeared to be cost-effective strategy along with IFN formulations for treating patients with RRMS on a long run. Avonex had the lowest ICER with a value of $337,282/QALY, which makes it the most cost effective (CE) treatment option compared to Rebif in this analysis. Fingolimod is the second CE option following Avonex with an ICER value of $347,338/QALY. Teriflunomide and DMF are unfavorable options in this analysis. In other words, both of them are not considered cost-effective strategies due to the low benefits offered considering their high cost. The NMB of oral DMDs at a WTP of $100,000 (SAR 375,000) are slightly lower than NMB of Rebif, which means that oral DMDs are costly options but with a higher benefits than IFNs except for teriflunomide. The ICERs and INMB of oral DMDs versus Rebif as a common baseline are presented in table 4.1. DMDs Cost QALY ICER ($/QALY) vs. Rebif Interferon b1a (Rebif 44 mcg) $298,892 SAR 1,120,530 Teriflunomide $360,631 SAR 1,351,990 Interferon b1a (Avonex 30 mcg) $374,502 SAR 1,655,307 Fingolimod $391,603 SAR 1,468,100 Dimethyl Fumarate (DMF) $426,030 SAR 1,609,040 NMB $679,440 SAR 2,547, Dominated $611,857 SAR 2,293, $337,282 SAR 1,264, $347,338 SAR 1,302, $531,329 SAR 1,991,930 $626,247 SAR 2,348,130 $613,420 SAR 2,299,680 $ 576,230 SAR 2,160,260 INMB vs. Rebif - $ -67,583 SAR -253,365 $ -53,193 SAR -199,418 $ -66,020 SAR -247,506 $ -103,210 SAR -386,929 Table 4.1 Results from the base-case analysis: DMDs vs. Rebif (WTP= $100,000) 58

72 The ICERs and INMB of oral DMDs versus Avonex as a reference are presented in table4.2. Figure 4.2 plots the NMB of all DMDs versus WTP of $100,000 threshold. When using Avonex as a common baseline option, teriflunomide has shown to be the only costeffective approach among other oral DMDs including Rebif with an ICER value of $45,836/QALY. DMDs Cost QALY ICER ($/QALY) vs. Avonex Interfer $374,502 on b1a SAR 1,655,307 (Avone x) Teriflunomide $360,751 SAR 1,352,380 Fingolimod $391,603 SAR 1,468,100 Dimethyl Fumarate (DMF) Interferon b1a (Rebif 44 mcg $426,030 SAR 1,609,040 $298,892 SAR 1,120,530 NMB $626,247 SAR 2,348, $45,836 SAR 171, $427,525 SAR 1,602, $5,152,800 SAR 19,317, $314,687 SAR 1,180,076 $611,857 SAR 2,293,820 $613,420 SAR 2,299,680 $576,230 SAR 2,160,260 $679,440 SAR 2,547,190 INMB vs. Avonex - $-14,390 SAR -53,947 $-12,827 SAR 48,088 $ -50,017 SAR -187,511 $53,193 SAR 199,418 Table 4.2 Results from the base-case analysis: DMDs vs. Avonex (WTP= $100,000) 59

73 Figure 4.2: Net monetary benefits (NMB) versus WTP of all DMDs From the graph above, it shows that Rebif has the highest NMB value ($679,440) at a WTP of $100,000, which means it is a good treatment approach for a limited budget. While the other oral DMDs and the other form of IFN-b1a IM (Avonex) had a lower NMB value due to the high cost of these agents. Avonex is the second in order after Rebif in terms of NMB with a value of $626,247, which is equal to SAR 2,348,130 at a WTP of $100,000. Fingolimod is the third in order after Avonex with a NMB value of $613,420 that is equal to SAR 2,299,680. Although that DMF had slightly higher benefits than the other DMDs except for fingolimod, DMF has the lowest NMB value of $576,230 and that could be attributed to the high annual cost per patient based on a payers perspective (KFSH&RC). 60

74 4.2 One-way sensitivity analysis A tornado diagram was carried out to test for multiple variables at the same time to compare between oral DMDs and Rebif using NMB as an outcome. The parameters were chosen based on their effect on the base-case analysis results. According to the literature, efficacy of DMDs on relapse rate, utility weights of each health state and the cost of medications had the greatest impact on the base-case analysis results. Other variable such as the age of the cohort was also tested in one-way sensitivity analysis. Generally, the results for the base- case analysis were somehow stable to the changes in most parameters. Utility of health state 4 (EDSS 8-9.5) has shown to be the most sensitive parameter for all pairwise comparisons between other DMDs versus Rebif (figures 4.3, 4.4, 4.5, 4.6). As the utility of health state 4 increases the effectiveness of each treatment option improves leaving Avonex as the most cost-effective and cost-saving strategy with the an ICER ranges between $91k to $195k per QALY gained for each utility range. As expected, fingolimod has shown to be the optimal therapy among oral DMDs in most cases following Avonex when utility weights of state 4 changed. For the comparison between Avonex and Rebif, utility weight of health state 3 was the second sensitive factor in the analysis in which it generated the except that fingolimod was the second cost effective therapy following Avonex. When lowering the cost of Avonx to the consumer price set by the SFDA as the minimum range Avonex remained the optimal therapy selection followed by fingolimod in most cases 61

75 .Figure 4.3: Tornado diagram comparing between Avonex and Rebif For the sensitivity analysis of fingolimod versus Rebif, the top five parameters were efficacy measures since that the cost of fingolimod didn t change significantly from hospital cost to retailers price (narrow range). The probability of sever relapses in case of fingolimod was the fourth variable that changed the base-case results significantly. As the probability increased the benefits (effectiveness) offered by fingolimod decreased making it the least favorable option in the analysis. Changing the range of the fifth variable, which is the probability of having mild/moderate relapses from 0.01 to 0.4 in fingolimod arm generated the lowest ICERs of fingolimod versus Rebif and decreased the NMB values drastically (figure 4.4). In general, fingolimd is considered a cost-effective therapy 62

76 due to its high efficacy (benefits) offered in return to the extra amount paid from a payers perspective. Figure 4.4: Tornado diagram comparing between Fingolimod and Rebif For the sensitivity analysis of teriflunomide and DMF, the cost of both agents was the second sensitive parameter in the analysis. When the cost of DMF increased to the maximum retailers price ($68,378) set by the SDFA the yielded ICERs were the lowest among all other DMDs in comparison to Rebif. Adding to that, the NMB has drastically decreased due to the high cost of DMF although that DMF had the highest QALYs among other comparators (figure 4.5). In case of teriflunomide analysis, when the highest range of the cost changed to 63

77 nearly the double ($43,452) of the base-case input, teriflumomide was dominated by other treatment options in almost all cases producing the lowest ICERs and the NMB values were close to DMF ranges. Changing the probability of sever relapses from using teriflunomide had a significant impact on the results making other treatments dominate teriflunomide resulting in high ICERs. Detailed results of the one-way sensitivity analysis are presented in Tables in page at the end of document under appendix section. Figure 4.5: Tornado diagram comparing between Dimethyl Fumarate (DMF) and Rebif 64

78 Figure 4.6: Tornado diagram comparing between Teriflunomide and Rebif 4.3 Monte Carlo Simulation The model ran the results of the base-case analysis for 1000 times using different random values based on the distribution of each variable. The results of the probabilistic analysis were demonstrated on scatterplot showing the simulated estimates of QALYs difference against cost difference for all DMDs. As shown in figure 4.7 the results are inconclusive on which treatment is the most cost-effective option and that might be due to the cost of medications and the overall cost of disease-related management. Therefore, an individual scatterplot was drawn for the four DMDs (Avonex, fingolimod, teriflunomide and DMF) versus Rebif as a common comparator. 65

79 Figure 4.7: Scatterplot of all 1000 simulations of all DMDs For the comparison between Avonex and Rebif, Avonex showed to be superior to Rebif at 0.7% only of all iterations and Rebif was superior in almost 50% of the cases as shown in figure % of the observations have shown that Avonex is cost-effective but at a higher cost (ICER>$100,000) and cost-effective at ICER< $100,000 at only 10% of cases. 66