Cost-effectiveness of cladribine tablets, alemtuzumab, and natalizumab in the treatment of relapsing-remitting multiple sclerosis with high disease activity in England

Abstract

Aims: Cladribine tablets were the first oral short-course treatment approved for highly active relapsing multiple sclerosis (MS). The Association of British Neurologists guidelines currently recommend two infusion therapies, alemtuzumab and natalizumab, to treat high disease activity relapsing remitting MS (HDA-RRMS). This analysis assessed the cost-effectiveness of cladribine tablets in HDA-RRMS compared with alemtuzumab and natalizumab, from the perspective of the National Health Service (NHS) in England.

Materials and methods: A cohort-based Markov model with 11 health states (10 Expanded Disability Status Scale [EDSS] plus death) was developed. Transition matrices from the British Columbia registry were used to model the natural history of EDSS. The treatment effect on EDSS was modelled using hazard ratios for 6-month confirmed disability progression from an indirect treatment comparison (ITC). Relapses and drug-related adverse events were modeled via annualized relapse rates and event probabilities, with associated costs and quality-adjusted life year (QALY) losses. Utilities were derived from trials and the literature, and costs from NHS and literature sources. Uncertainty was assessed via probabilistic and deterministic sensitivity analyses.

Results: Cladribine tablets were dominant (i.e., less costly and more effective) vs alemtuzumab and natalizumab in pairwise comparisons, and the dominant strategy in fully incremental analyses. Incremental cost was driven largely by drug acquisition and administration costs, and incremental QALY gain largely by differences in delayed EDSS progression. Cladribine tablets had a 93% probability of being cost-effective at a threshold of GBP 30,000 per QALY gained, and remained dominant across the scenario analyses tested. The greatest influence on results was the treatment effect on disability progression derived from the ITC.

Limitations: Uncertainty over the efficacy of DMT beyond trial durations. In line with other comparative effectiveness analyses, the network meta-analysis informing this cost-effectiveness analysis was associated with a degree of uncertainty. No treatment switching analyses were undertaken.

Conclusions: Cladribine tablets are a cost-effective alternative to alemtuzumab and natalizumab in the treatment of HDA-RRMS from the perspective of the NHS in England.

Keywords:

• Cladribine tablets
• alemtuzumab
• natalizumab
• multiple sclerosis
• cost-effectiveness

Introduction

Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system (CNS) that results in progressive disability¹. It is the most common debilitating neurological disease among young adults², and is associated with a substantial negative impact on quality-of-life, and with high medical and societal costs^3–5. Approximately 89,000 people are estimated to be living with MS in England, with a further 4,040 new cases diagnosed each year (incidence rate = 7 per 100,000)⁶. Approximately 85% of patients present with relapsing-remitting MS (RRMS), which is characterized by periodic acute exacerbations of disease activity (relapses) followed by periods of remission¹. The course of RRMS is variable. Patients who experience frequent relapses and/or high disease activity as detected by magnetic resonance imaging (MRI), either whilst untreated or during treatment, are classified by the Association of British Neurologists (ABN) as having “more active disease”⁷, also termed high disease activity RRMS (HDA-RRMS). There is no universal definition of HDA-RRMS, but the European Medicines Agency (EMA) set out criteria for highly active disease in the licensing of natalizumab and fingolimod, defining it as^8,9:

• failure to respond to an adequate course of at least one disease-modifying therapy (DMT), presenting with at least one relapse in the previous year while on therapy and at least nine T2-hyperintense lesions or at least one gadolinium-enhancing lesion, or

• treatment naïve, with at least two disabling relapses in the last 1 year and at least one gadolinium-enhancing lesion or significant increase in T2-lesion load.

The ABN recommends the use of DMTs for all individuals with RRMS⁷. Treatment options are currently grouped in two categories. Category 1 comprises drugs classed as “moderate efficacy” by the ABN, and includes beta interferons, glatiramer acetate, teriflunomide, dimethyl fumarate, and fingolimod⁷. Category 2 contains drugs classed as having “high efficacy”, and is currently comprised of alemtuzumab and natalizumab. Category 2 agents have the potential for more serious side-effects and/or have a less well-established safety profile than the Category 1 agents⁷. The choice of agent is a trade-off between efficacy and the risk from adverse effects, and is a joint decision between physician and patient. The ABN recommends that patients with HDA-RRMS should be offered category 2 drugs⁷.

In Europe, natalizumab’s license is restricted to “highly active RRMS”⁹, while alemtuzumab is licensed for “active RRMS”¹⁰. Despite alemtuzumab’s broad license, the ABN recommends that its use should generally be confined to persons with high disease activity because of its potential adverse effects⁷. It considers alemtuzumab and natalizumab to be of equivalent efficacy. The current ABN guidelines, published in 2015⁷, are broadly in line with recommendations by the National Institute for Health and Care Excellence (NICE), which has appraised both therapies. NICE currently recommends alemtuzumab for the treatment of patients with active disease, which is inclusive of patients with high disease activity¹¹. Natalizumab is recommended for persons with rapidly evolving severe MS only; this is a sub-set of high disease activity¹².

Natalizumab and alemtuzumab are administered via infusions in a hospital setting. Alemtuzumab is administered as five consecutive daily infusions in the first year, followed by three consecutive daily infusions in the second or subsequent years¹⁰. Real-world cohort studies suggest that retreatment with alemtuzumab beyond year 2 is required by ∼40–50% of patients in England^13,14. Natalizumab is administered via infusion every 4 weeks, with treatment after 2 years of continued therapy considered only following a re-assessment of the potential benefit and risk⁹.

In August 2017, oral DMT cladribine tablets (Mavenclad) were approved by the EMA for the treatment of “highly active relapsing MS”¹⁵, meaning it is now available as a treatment option in HDA-RRMS. The safety and efficacy of cladribine tablets in RRMS were assessed in 1,326 patients with RRMS in the CLARITY trial and its extension, CLARITY-EXT¹⁶. Compared with placebo, patients receiving cladribine tablets 3.5 mg/kg showed statistically significant and clinically meaningful improvements in the annualized relapse rate (ARR) and disability progression¹⁶. The results suggested that the effects were greatest in patients with HDA-RRMS, and that benefit might be expected in other relapsing forms of MS¹⁷. The CLARITY EXT study assessed the efficacy of cladribine tablets in patients treated for 2 additional years beyond the initial 2 years of treatment in CLARITY. The results of this study demonstrated that, in the majority of patients, the clinical benefits of 2 years of treatment can be maintained for at least 4 years without re-initiation of therapy¹⁸.

Cladribine tablets have a similar administration frequency to alemtuzumab, involving a short fixed course in year 1 that is repeated in year 2, followed by observation in years 3 and 4¹⁵. Oral administration confers benefits over existing category 2 treatments in terms of ease of administration, the ability to administer outside of a hospital setting, and avoidance of infusion-related adverse events. Short-course treatment with cladribine tablets and alemtuzumab reduces the burden of regular treatment courses required for regularly administered drugs such as natalizumab. The extent to which cladribine tablets are a cost-effective alternative to existing category 2 drugs for HDA-RRMS has not previously been assessed. The objective of this study was, therefore, to assess the cost-effectiveness of cladribine tablets vs alemtuzumab and natalizumab in the treatment of HDA-RRMS from the perspective of the National Health Service (NHS) in England.

Methods

Model structure

A Markov state transition model was developed in Microsoft Excel 2010 to predict the lifetime costs and effectiveness of treatment with alemtuzumab, natalizumab, and cladribine tablets in persons with HDA-RRMS. The analysis followed the NICE reference case¹⁹, with costs based on the NHS in England perspective, and effectiveness assessed in terms of quality-adjusted life years (QALYs). Incremental cost-effectiveness was measured in terms of the incremental cost per QALY gained. The conventional NICE threshold of £30,000 per QALY gained was used to assess cost-effectiveness¹⁹. The base case analysis considered a 50-year time horizon with costs and QALYs discounted at a rate of 3.5% per year.

The Markov model comprised a natural history reference model developed using data on the disability and relapse status of people receiving best supportive care (BSC); and a treatment-adjusted model, which combined the natural history reference model with data on the comparative efficacy and safety of treatment vs placebo²⁰. The reference and treatment-adjusted models used the same core 11-health state structure, as illustrated in Figure 1. This comprised 10 health states representing disability status according to the Expanded Disability Status Scale (EDSS)²¹, and a single state for death from all causes. The treatment-adjusted model included an additional 10 states to model the costs and QALYs following discontinuation of DMT. Categorization of the EDSS was based on the approach used by Palace et al.²².

Figure 1. Health state structure of the 11-state model including periods on and off DMT.

At model entry, the cohort was proportionally assigned to the 10 EDSS states according to the baseline EDSS distribution in the HDA-RRMS population of the CLARITY study. The overall intention-to-treat population in CLARITY is considered generalizable to clinical practice in England, sharing a similar baseline profile to patients enrolled to the UK multiple sclerosis Risk Sharing Scheme (age 39.4 years, relapses in the past 2 years [median = 3], disease duration 8.8 years) reported in Palace et al.^22,23. The population considered in the analysis was HDA-RRMS, as defined by the ABN guidelines, rather than the populations defined by the NICE guidance on alemtuzumab¹¹ and natalizumab¹².

The model used an annualized cycle period to predict EDSS status over a lifetime horizon following approaches used in previous economic analyses^23–28. In each cycle, the cohort was at risk of disability progression (moving to a higher EDSS state); improving in disability status (moving to a lower EDSS state); remaining at their current level of disability (remaining in their current EDSS state); or death.

The natural history transition probabilities were modeled using the transition probability matrices from Palace et al.²². The original BCMS analysis was performed on a cohort of people with active RRMS that fulfilled the 2001 ABN criteria for interferon beta and glatiramer acetate use. This includes persons with less active forms of RRMS than HDA-RRMS. EDSS progression in persons with HDA-RRMS is expected to be 0.06–0.086 points faster per year than active RRMS²⁹. An acceleration parameter (AP = 1.484) was included in the model to increase the probability of EDSS progression in the BCMS active RRMS natural history model, prior to adjustment for the effect of DMT. The AP was calculated from the ratio of progression rates in HDA-RRMS vs non-HDA-RRMS patients in the placebo arm of CLARITY. This adjustment was applied to EDSS states 0–6, as progression rates are expected to return to baseline levels once patients develop secondary progressive MS and transition to EDSS > 7.0. Transition probabilities are shown in Table 1.

Table 1. Annual transition probabilities (%) for EDSS states (MS age of onset ≥28 years), after adjustment for HDA-RRMS.

EDSS From\To	0	1–1.5	2–2.5	3–3.5	4–4.5	5–5.5	6–6.5	7–7.5	8–8.5	9–9.5
0	58.3	27.8	9.9	3.0	0.6	0.2	0.2	0.0	0.0	0.0
1–1.5	5.8	59.8	22.0	8.5	2.3	0.6	0.9	0.1	0.0	0.0
2–2.5	1.6	12.1	50.9	23.3	6.2	2.6	3.0	0.2	0.1	0.0
3–3.5	0.6	5.0	12.0	43.8	12.6	8.1	16.1	1.4	0.5	0.0
4–4.5	0.2	2.2	6.7	11.5	37.7	14.2	23.0	3.5	0.9	0.1
5–5.5	0.1	0.5	2.9	5.9	8.7	36.8	37.1	5.3	2.6	0.1
6–6.5	0.0	0.1	0.4	2.5	3.1	4.1	67.4	15.5	6.2	0.6
7–7.5	0.0	0.0	0.1	0.2	0.7	0.4	11.7	69.3	16.1	1.6
8–8.5	0.0	0.0	0.0	0.0	0.1	0.1	1.9	5.6	90.3	2.1
9–9.5	0.0	0.0	0.0	0.0	0.0	0.0	0.2	0.6	17.4	81.8

Source: Palace et al.²², adjusted for HDA-RRMS.

The cohort was also at risk of experiencing one or more acute relapse events during each cycle. In line with previous analyses, these events were modeled independently of EDSS by applying ARR to the number of patients alive in each model cycle. The ARR from the placebo arm of CLARITY (HDA-RRMS, mean ARR = 0.46 [SE = 0.043]) was modeled to decline over time based on data from the BCMS registry³⁰ (22.9% decline per 5 years).

Costs and QALYs were calculated from the time spent in each EDSS state and number of relapses. Costs and QALYs were modeled using the lifetable or mid-cycle approach, with the exception of acquisition and administration costs for cladribine tablets and alemtuzumab, which were applied at model entry and start of year 1, in line with their short-course posology. Costs covered under the NHS perspective included drug acquisition, administration, and monitoring; the support and treatment given for relapse events; direct EDSS-related medical costs; and costs for managing drug-related adverse events. A societal perspective that includes the substantial wider societal costs of MS was also included as a sensitivity analysis.

Clinical inputs

The treatment-adjusted model combines the reference model described above with the comparative efficacy and safety of DMT vs placebo (proxy for best supportive care [BSC]). As with the natural history model, the treated cohort was at risk of progressing, improving, staying in the same EDSS state, or entering the death state.

Treatment with a DMT was assumed to alter the natural course of disease by: decreasing the probability of progressing in EDSS state over time, vs BSC/placebo (defined as 6-month confirmed disability progression [CDP]); decreasing the ARR vs BSC; and altering the incidence of drug-related adverse events. There was no assumed effect of DMT on the probability of improving in EDSS or the probability of death, which were fixed to the values used in the natural history model. The probability of remaining in the same EDSS state was increased to reflect that fewer patients progressed on DMT.

The comparative efficacy of DMT vs placebo for disease progression (6-month CDP) and ARR was estimated from a Bayesian indirect treatment comparison of aggregate randomized controlled trial (RCT) data (Table 2; see Supplementary material for details of methods). Patients were assumed to benefit from treatment while “on DMT”. Following previous NICE appraisals, these effects were assumed to gradually wane over time, with 100% of effect maintained in years 0–2, 75% of effect in years 2–5, and 50% of effect from year 5 onwards.

Table 2. Efficacy inputs to the economic analysis.

Treatment comparison	Hazard ratio for 6-month CDP	ARR	Source
Cladribine tablets vs placebo	0.180 (95% CrI = 0.076–4.21)	0.350 [0.243–0.505]	Indirect treatment comparison^20 of CLARITY^16^,^38, PRISMS^46, CAMS223^39 and CARE-MS-I^40
Alemtuzumab vs placebo	0.357 (95% CrI = 0.165–0.765)	0.355 [0.246–0.512]
Natalizumab versu placebo	0.360 [95% CrI = 0.170–0.770]	0.308 [0.225–0.420]	CDP: AFFIRM study^47 (rapidly evolving severe sub-group) ARR: indirect treatment comparison as above^20

Abbreviations. ARR, Annualized relapse rate; CDP, Confirmed disability progression; Crl, Credible interval.

In each model cycle, patients “on DMT” were at risk of discontinuing treatment from loss of efficacy, loss of tolerability, and development of secondary-progressive MS (SPMS; assumed based on transitioning to EDSS state ≥7.0). This is in line with the ABN recommendations for when clinicians should consider stopping treatment. It was assumed that any patient transitioning to EDSS state ≥7.0 would be considered to have SPMS and, hence, discontinued from therapy; other EDSS cut-offs for discontinuation were explored as sensitivity analyses.

Discontinuation rates were derived from the RCTs referred to in Table 2. Alemtuzumab and cladribine tablets are short-course treatments: most patients are expected to receive two short courses of treatment and then undergo observation for disease progression. The probability of discontinuation (2.266% and 4.854% for alemtuzumab and cladribine tablets, respectively) was, therefore, applied to the first cycle only to capture discontinuations between the first and second courses. A fixed constant annual probability of discontinuation of 6.0% was applied to natalizumab. Patients who discontinued treatment were assumed to retain the cumulative benefits of DMT up to the point of discontinuation. Upon discontinuation, patients immediately switched to BSC, with progression and relapse rates based on the natural history model.

The probability of experiencing drug-related adverse events was modeled based on clinical trial data identified in the systematic literature review, and from published literature sources. Model inputs related to adverse events are shown in Table 3. Adverse-event-related costs were based on NHS reference costs³¹; details of their derivation are given in the Supplementary material.

Table 3. Model inputs related to adverse events: probability, QALY loss, and cost.

Event type	Probability of event			QALY loss per event	Cost	Source of probability
	Cladribine tablets	Alemtuzumab	Natalizumab
Infusion site reaction (applied at all treated cycles)	0%	90.1%	23.6%	−0.011	£0	Trials: CLARITY^16^,^38, PRISMS^46, CAMS223^39, and CARE-MS-I^40 AFFIRM study^47 (rapidly evolving severe sub-group)
Applied as one-off at start of model
PML	–	–	0.213%	−0.200	£1,268.11	Network meta-analysis^20 of CLARITY^16^,^38, PRISMS^46, CAMS223^39, and CARE-MS-I^40 AFFIRM study^47 (rapidly evolving severe sub-group)
Malignancy	0.60%	0.60%	0.60%	−0.116	£11,427.59	Pakpoor et al.^48
Hypersensitivity reaction	–	–	4.0%	–1.000	£156.68	Source: AFFIRM study (Polman et al.^47); no reactions reported for other agents
Gastrointestinal disorder	24.5%	22.8%	22.8%	−0.240	£707.28	Network meta-analysis^20 of CLARITY^16^,^38, PRISMS^46, CAMS223^39, and CARE-MS-I^40 AFFIRM study^47 (rapidly evolving severe sub-group)
Thyroid-related events	5.1%	11.3%	1.2%	−0.110	£543.63
Immune thrombocytopenic purpura	–	1.8%	–	−0.0069	£939.54
Serious infection	2.8%	2.3%	1.9%	−0.0073	£3,287.62
Influenza like illness	1.3%	1.1%	0.1%	−0.0040	£6.79

Source of disutilities^36,49–51: Costs were based on NHS reference costs³¹.

Abbreviations. PML, Progressive multifocal leukoencephalopathy; QALY, Quality-adjusted life year.

Cost inputs

The total cost of intervention and comparator treatment comprised three components: drug acquisition, drug administration, and drug monitoring (Table 4). These costs were assumed to apply for the duration that patients remain on therapy. The proportion of patients treated with cladribine tablets and alemtuzumab was set to 100% in years 1 and 2. This was applied to all patients eligible for treatment after excluding persons who progressed to EDSS ≥7.0, developed SPMS, or were intolerant to therapy. In line with the summary of product characteristics for cladribine tablets and alemtuzumab, no further treatment after year 2 was applied in the base case. Annualized direct medical costs were assigned to each EDSS health state based on Hawton and Green³² (Supplementary Table S9).

Table 4. Total drug acquisition cost by therapy in the model (list price).

Cost component	Cladribine tablets	Alemtuzumab	Natalizumab
Drug acquisition cost per year. Source: BNF^52	£26,175 (year 1) £26,175 (year 2)	£35,225 (year 1) £21,135 (year 2)	£14,690 (all years)
Notes	Based on weight distribution as per summary of product characteristics	Five administrations of 12 mg vial in year 1, followed by 3 administrations in year 2	13.0 4-weekly infusions of single 15 ml-vial per year
Drug administration cost per year. Source: DoH^31; DoHSC^53	£0 (all years)	£2,782 (year 1) £1,681 (year 2)	£7,159 (all years)
Notes	No supervised or specialist administration required	5 day case admissions in year 1 followed by 3 admissions in year 2	13.0 day case admissions for infusion in a year
Drug monitoring cost per year^31^,^53	£584 (year 1) £215 (year 2)	£444 (year 1) £267 (year 2)	£540 (year 1) £547 (year 2+)
Notes	Year 1 1 × MRI scan 3 × complete blood counts 2 × neurology visits 1 × tuberculin skin test 1 × HBV test 1 × HCV test Year 2 3 × complete blood counts 1 × neurology visits 1× tuberculin skin test 1 × HBV test 1 × HCV test	Year 1 12 × complete blood counts 12 × biochemistry tests for serum creatinine levels 12 × urinalysis tests with microscopy 4 × thyroid function test (thyroid stimulating hormone level) 1 × tuberculin skin test 0.65 × human papilloma virus test (females only – assumption 65%) 2 × neurology visits Year 2 12 × complete blood counts 12 × biochemistry tests for serum creatinine levels 12 × urinalysis tests with microscopy 4 × thyroid function test (thyroid stimulating hormone level) 0.65 × human papilloma virus test (females only – assumption 65%) 1 × neurology visits	Year 1 1 × JC virus test 2 × biochemistry test 1 × MRI scan 2 × neurologist visit Year 2 2 × JC virus test (6-monthly) 2 × biochemistry test 1 × MRI scan 2 × neurology visits

Abbreviations. JC, John Cunningham; HBV, Hepatitis B virus; HCV, Hepatitis C virus; MRI, Magnetic resonance imaging.

Utilities

Utilities for EDSS 0–5.0 were taken from the CLARITY trial¹⁶. Hawton and Green³³ was selected as the most appropriate source for other EDSS-related health-state utilities (HSU), as it is based on clinician-assessed EDSS and a large patient sample that is representative of the UK MS population. A utility decrement of −0.071 was assigned to relapse, derived from Orme et al.³⁴. EDSS-related utility loss for caregivers was also included, based on Acaster et al.³⁵. HSU and associated costs are shown in Supplementary Table S9.

Sensitivity analyses

Deterministic and probabilistic sensitivity analyses were performed. Each parameter in the analysis was varied between its lower and upper 95% confidence or credible interval, or by 50% of its mean value if statistical measures of variance were not available. Probabilistic sensitivity analyses were based on 2,000 iterations, and all major parameters were sampled.

In addition, scenario analyses were performed to test the robustness of the analysis to variations in underlying model assumptions and to the use of alternative input parameters (e.g. different utility sets or transition matrices for the natural history of disease). This included the use of a societal perspective (including both direct non-medical and indirect costs), alternative time horizons, alternative stopping rules, and re-initiation of cladribine tablets and alemtuzumab treatment after year 2. Finally, a cost-minimization scenario analysis was run assuming no difference in efficacy between cladribine tablets, alemtuzumab, and natalizumab. The incremental cost-effectiveness ratios were generated for each scenario (apart from the cost-minimization scenario) and then compared against the base case results.

Results

Base case results

Cladribine tablets was dominant (i.e. less costly and more effective) vs alemtuzumab and natalizumab in the pairwise comparisons, and the dominant strategy in the fully incremental analyses. Results of the deterministic base case cost-effectiveness analysis are shown in Table 5.

Table 5. Results of the deterministic base case cost-effectiveness analysis.

Treatment	Total cost (£)	LY	QALY	Incremental cost of cladribine tablets vs comparator (£)	Incremental LY of cladribine tablets vs comparator	Incremental QALY of cladribine tablets vs comparator	ICER vs cladribine (QALY)	Incremental net health effects (QALY)
Cladribine tablets	92,484	21.476	9.450
Alemtuzumab	104,136	21.476	8.482	−11,652	0.000	0.968	Cladribine dominant	1.356
Natalizumab	212,969	21.476	7.739	−120,485	0.000	1.710	Cladribine dominant	5.727

A detailed breakdown of the results is shown in Table 6. Incremental total cost was driven largely by differences in drug acquisition and administration costs. Cladribine tablets is an oral treatment and, therefore, does not require day admissions for infusions. Both cladribine and alemtuzumab are short course treatments, whereas natalizumab requires ongoing infusions and accrued much greater drug acquisition and administration costs. The incremental total QALY gain was driven largely by differences in delayed EDSS progression.

Table 6. Breakdown of base case results.

	Cladribine tablets	Natalizumab	Alemtuzumab	Cladribine tablets vs natalizumab	Cladribine tablets vs alemtuzumab
Costs (discounted)
Drug acquisition	50,009	108,929	54,846	−58,920	−4,837
Drug administration	0	53,083	4,343	−53,083	−4,343
Drug monitoring	780	4,052	692	−3,272	89
Total Drug	50,789	166,064	59,881	−115,275	−9,092
Total AE	363	308	384	55	−21
Total relapse	8,768	9,695	8,969	−927	−201
Total EDSS cost	32,565	36,902	34,903	−4,337	−2,338
Total cost	92,484	212,969	104,136	−120,485	−11,652
QALYs (discounted)
Total AE	−0.01	0.00	−0.01	0.00	0.01
Total relapse	−0.10	−0.11	−0.10	0.01	0.00
Total EDSS-based QALYs	11.20	9.65	10.34	1.55	0.86
Total EDSS caregiver QALY loss	−1.64	−1.80	−1.74	0.15	0.10

Abbreviations. AE, Adverse event; EDSS, Expanded Disability Status Scale; QALY, Quality-adjusted life year.

Deterministic sensitivity analysis results

Results of the deterministic analyses were expressed in terms of net health effects rather than the incremental cost-effectiveness ratio (ICER), because in the base case cladribine tablets were dominant vs their comparators, and hence had a negative ICER. A negative ICER cannot be directly interpreted, because it can correspond to either the dominant (positive QALY and negative cost) or dominated (negative QALY and positive cost) quadrants of the cost-effectiveness plane. A positive net health effect shows that cladribine tablets are cost-effective at a threshold of £30,000 per QALY gained vs their comparator in a given scenario. A negative net health effect indicates that cladribine tablets may not be a cost-effective option at this threshold.

The results of the deterministic sensitivity analyses are summarized in Figures 2 and 3. Versus alemtuzumab, the most sensitive parameters were the effect of treatment on disability progression, followed by the discounting rate for outcomes. Versus natalizumab, the discounting rates for costs and outcomes were the most sensitive parameters, followed by the effect of treatment on confirmed disability progression. Discounting for effects had a large effect on the results because the QALYs accrue gradually over time because of delayed disability progression. Discounting for costs affects the natalizumab comparison because of differences in how the therapies are costed (i.e. the ongoing cost of natalizumab vs the fixed cost for cladribine tablets). Uncertainty around the ARR had a limited impact on the results.

Figure 2. Tornado diagram for deterministic sensitivity analyses, cladribine tablets vs natalizumab.

Figure 3. Tornado diagram for deterministic sensitivity analyses, cladribine tablets vs alemtuzumab.

Probabilistic sensitivity analysis results

The probabilistic sensitivity analysis results (shown in Table 7 and Figure 4) were consistent with the base case results. Cladribine tablets were dominant, and had a high probability (92–93%) of being cost-effective at conventional thresholds (GBP 20,000 and GBP 30,000 per QALY gained). There was an overlap in credible intervals for QALYs, but not for cost in the comparison with natalizumab.

Figure 4. Multi-way cost-effectiveness acceptability curve.

Table 7. Probabilistic sensitivity analysis results.

Intervention	Costs	Lower bound	Upper bound	QALY	Lower bound	Upper bound	Mean incremental costs	Mean incremental QALY	ICER vs cladribine tablets (QALY)	Probability CE at 20k	Probability CE at 30k
Cladribine tablets	92,567	87,586	98,782	9.519	7.624	11.138	Reference			93.0%	91.6%
Alemtuzumab	104,080	98,390	111,517	8.596	6.494	10.518	−11,513	0.923	Cladribine dominant	7.0%	8.4%
Natalizumab	213,912	188,547	237,221	7.826	6.072	9.391	−121,345	1.693	Cladribine dominant	0.0%	0.0%

Abbreviations. CE, Cost-effective; QALY, Quality-adjusted life year.

Results of scenario analyses

Cladribine tablets remained dominant vs alemtuzumab and natalizumab across the scenario analyses tested, further supporting the consistency of the results. Results are shown in Table 8.

Table 8. Results of scenario analyses.

	Incremental results vs alemtuzumab			Incremental results vs natalizumab
	Cost	QALY	ICER	Cost	QALY	ICER
Base case	−11,652	0.968	Cladribine dominant	−120,485	1.710	Cladribine dominant
Time horizon - 20 years	−10,639	0.628	Cladribine dominant	−111,070	1.027	Cladribine dominant
Time horizon - 10 years	−9,735	0.305	Cladribine dominant	−79,606	0.434	Cladribine dominant
Societal perspective	−22,965	0.968	Cladribine dominant	−140,901	1.710	Cladribine dominant
Discounting 1 (0% cost, 6% QALY)	−14,093	0.673	Cladribine dominant	−169,292	1.150	Cladribine dominant
Discounting 2 (6% cost, 0% QALY)	−10,877	1.840	Cladribine dominant	−98,193	3.404	Cladribine dominant
Stopping rule 6 (EDSS 6 assumed as SPMS and treatment discontinued)	−11,034	0.856	Cladribine dominant	−75,631	1.353	Cladribine dominant
Stopping rule 8 (EDSS 8 assumed as SPMS and treatment discontinued)	−11,794	1.002	Cladribine dominant	−145,127	1.930	Cladribine dominant
No discontinuation with natalizumab after 2-years	−11,652	0.968	Cladribine dominant	−197,531	1.178	Cladribine dominant
Re-initiation of treatment in a proportion of patients receiving a full course of alemtuzumab and cladribine tablets	−13,288	0.968	Cladribine dominant	−114,167	1.710	Cladribine dominant
Equal (cladribine tablets) efficacy across treatments (cost-minimization analysis)	−8,548	NA	NA	−258,841	NA	NA
Exclusion of caregiver utility	−11,652	0.866	Cladribine dominant	−120,485	1.557	Cladribine dominant
Baseline EDSS from Hawton et al.	−11,386	0.902	Cladribine dominant	−118,288	1.634	Cladribine dominant

Abbreviations. EDSS, Expanded Disability Status Scale; ICER, Incremental cost-effectiveness ratio; NA, Not applicable; QALY, Quality-adjusted life year.

Discussion

This analysis shows that cladribine tablets are a cost-saving alternative to both alemtuzumab and natalizumab in adults with HDA-RRMS in the context of the NHS in England. Predicted lifetime cost-savings range from £11,652 vs alemtuzumab to £120,485 vs natalizumab. The costs saved vs natalizumab were largely the result of avoiding long-term expenditure on drug acquisition and administration because of cladribine tablets’ unique oral short-course formulation. In comparison to alemtuzumab, cladribine tablets yield cost savings largely through reduced administration costs by avoiding day case admissions for infusions, and from costs saved by delayed EDSS progression. Because of its predicted numerically superior effect on EDSS progression (hazard ratio of 0.18 vs placebo, compared with 0.36 for alemtuzumab or natalizumab vs placebo), cladribine tablets were predicted to yield per-person lifetime QALY gains ranging from 0.968–1.710 vs existing treatments. Based on these results, cladribine tablets are considered the dominant treatment strategy in patients with HDA-RRMS.

Cladribine tablets are the first oral DMT to demonstrate an effect on disease progression vs placebo in persons with HDA-RRMS that is at least comparable to the effect of natalizumab vs placebo, and the predicted effect of alemtuzumab vs placebo from indirect comparison. This supports the use of cladribine tablets as an alternative treatment option for this patient group. As an orally administered, short-course treatment, cladribine tablets have several benefits over hospital-based treatments administered by infusion, whether the infusion regimen involves a fixed course or continuous treatment. Patients are spared the inconvenience and expense of traveling to the clinic for treatment, and the associated effects of infusion-related adverse events. Oral treatment also generates cost savings for the health system in terms of reducing the costs of day case admissions for infusions, which our analysis shows are particularly high for infusion-based treatments that involve continuous rather than fixed-course regimens.

The model structure used in this analysis has some differences from previous MS models. The health state structure used is a simplified version of the 21-health state structure used in previous RRMS health technology appraisals in the UK, which included 10 EDSS states for RRMS, 10 EDSS states for SPMS, and a single state for death. The simplified 11-health state structure excludes the EDSS states for SPMS, and instead models disability progression in patients who develop SPMS together with those who remain in RRMS. The pooling of the RRMS and SPMS states is consistent with the approach taken by Palace et al.²² when modeling the natural history of RRMS for the UK Risk Sharing Scheme. Palace et al.²² did not consider MS course (i.e. RRMS vs SPMS) as a covariate in the analysis, because SPMS is “simply a later stage of the relapsing-remitting form of the disease and the transition has considerable overlap” (page 3). Quality-of-life is driven by EDSS rather than by the form of MS, a principle that NICE accepted in recent appraisals¹².

Furthermore, the addition of SPMS-specific health states requires the use of SPMS-specific transition rates from the London Ontario registry, which is the only available source of SPMS-specific natural history data²². A number of concerns have been documented in relation to the London Ontario registry, including post-hoc censoring of the data for backward transitions (i.e. improvement in EDSS state), which has resulted in models that predicted a faster overall rate of progression and an implausibly low accumulation of QALYs relative to life years^11,22,36. Also, the London Ontario registry contains EDSS measures collected in the 1970s and 1980s, and these may not reflect the experience of present-day MS patients²². In the NICE technology appraisal TA441 (daclizumab for RRMS)³⁷, London Ontario data were replaced by matrices derived from the British Columbia (BC) registry and published by Palace et al.²². In this appraisal, it was concluded that the BC dataset provided a more appropriate set of transitions for the natural history of RRMS than London Ontario, and was, hence, the preferred source of natural history data. This approach was also supported by clinical and health technology assessment experts from whom we sought advice. We therefore decided to use the BC data.

The parameters with the largest influence on results in our analysis were treatment effect on 6-month CDP, discounting, and discontinuation of natalizumab. As shown in previous analyses, EDSS progression was the key determinant of modeled QALYs, with the effect of DMT on EDSS having a large influence on results. The rates of discounting and natalizumab discontinuation had a large influence on results when comparing cladribine tablets vs natalizumab, as the costs of natalizumab accrued gradually over time and were, therefore, sensitive to future discounting rates and the duration of exposure. In comparison, the drug costs for alemtuzumab and cladribine tablets were accrued in the first 2 years, where discounting rates had a limited impact. As reported elsewhere, the treatment effect on relapse rate had a limited impact on results. Addition of societal costs increased the cost savings predicted for cladribine tablets. The results of sensitivity and scenario analyses indicated that the cost-effectiveness of cladribine tablets was robust to the assumptions made.

There are important limitations with our analysis. The efficacies of alemtuzumab and natalizumab in persons with HDA-RRMS were estimated from a NMA of 6-month CDP²⁰ in the HDA-RRMS populations of CLARITY^16,38 and PRISMS, and combined with data from sub-sets of the full HDA-RRMS population for alemtuzumab (CARE-MSI³⁹, CAMMS223⁴⁰), and natalizumab (AFFIRM). Despite the ABN recommendations, no trial data have been published on the efficacy of these therapies in the full HDA-RRMS population, meaning that the use of sub-set data was required in the NMA. The generalizability of the sub-set data to the full HDA-RRMS is not known, and is, therefore, a source of uncertainty in the analysis. Importantly, the results of the indirect comparison suggest that natalizumab and alemtuzumab are of equivalent efficacy, consistent with the expectations of the ABN⁷. The efficacy for cladribine tablets is based on data from CLARITY, which provides evidence on the efficacy of cladribine tablets vs placebo without the need for indirect comparison. To address the uncertainty surrounding the comparative efficacy of cladribine tablets, alemtuzumab, and natalizumab, a cost-minimization analysis was conducted. Results indicated that cladribine tablets were cost saving vs both comparators when considering no difference in efficacy.

The results of the base case analysis are subject to the limitations and uncertainties surrounding the long-term effectiveness of DMT in RRMS. As with previous analyses^23–28, the effectiveness of DMT was modeled based on the results of 2-year clinical trials extrapolated to a lifetime horizon.

Evidence of the comparative efficacy of DMT vs placebo beyond 2 years is limited due to the ethical problems of studying long-term placebo use in persons with HDA-RRMS. Our analysis follows a precedent set in past NICE appraisals by including a waning effect that gradually reduced the effect of DMT beyond year 2. The parameters used followed assumptions made in previous committee appraisals, and are not currently evidence-based. Because of the uncertainty surrounding waning, the same waning effects (75% of effect in years 2–5, 50% of effect in years 5+) were applied to all therapies. Scenario analyses demonstrated that cladribine tablets remained a cost-effective treatment option, even when incorporating the cost of treatment re-initiation in a proportion of patients beyond year 2^41,42. It should be noted that treatment re-initiation with cladribine tablets is not required as part of the marketing authorization for cladribine tablets. Furthermore, the HTA assessment in the UK was accepting of only 2 years of treatment⁴³. In line with previous cost-effectiveness analyses, it should be noted that, whilst treatment switching may occur in clinical practice, this was not considered in our study due to a lack of clinical data to support this type of analysis.

The analysis may also under-estimate the QALY gains for cladribine tablets by not capturing the health benefits of oral short-course treatment, including its ease of administration, the avoidance of hospital admission and frequent re-treatment. While the analysis considered the adverse effects of infusion site reactions, the absence of data reflecting the health state utility, or preferences of persons on oral vs infusion therapies required the use of a common set of EDSS utilities by treatment. As a result, any patient preference towards oral treatment vs infusion is not considered in the analysis. In a discrete choice experiment that systematically investigated patient preferences for the characteristics of all available DMTs, the attributes of cladribine tablets were considered to provide one of the most preferred treatment options overall, and the most preferred oral treatment option⁴⁴. Hence, the inclusion of treatment preferences would be expected to increase the QALY gains for cladribine tablets, further proving their cost-effectiveness.

No previous studies have considered the cost-effectiveness of cladribine tablets, alemtuzumab, and natalizumab in HDA-RRMS, limiting the potential for comparison to other studies. In addition, previous studies have used a slightly different structure based on the London Ontario dataset, which is no longer considered as the best source of natural history data in RRMS. Caution is needed when comparing between studies that use different datasets and/or structures. The inclusion of backward transitions within the natural history models used in our study precludes any attempt to compare the results of this analysis to existing published studies that use the London Ontario data, which censored backward transitions.

Other treatments are licensed for HDA-RRMS that were not considered in this analysis, including fingolimod, which was recommended by NICE for this population⁴⁵. Our analyses focus on the recommendations of the ABN, which suggest that natalizumab and alemtuzumab should be used in this population. The favorable disability progression (6-month CDP) outcome observed with cladribine tablets in HDA-RRMS supports its being placed amongst these high-efficacy drugs. The ABN considers fingolimod to be of moderate efficacy compared with alemtuzumab and natalizumab, and hence it is not recommended by them for use in persons with HDA-RRMS⁷. Furthermore, safety and tolerability are also important aspects in treatment decision-making. Deterministic sensitivity analyses in this study found that disutilities from adverse events had no substantive impact on the cost-effectiveness results.

This evaluation may be useful to decision-makers in their assessment of cladribine tablets for use in their healthcare systems. The National Institute for Health and Care Excellence (NICE) recently assessed cladribine tablets with many of the parameters presented here, and recommended it as an option for treating rapidly evolving severe and highly active multiple sclerosis in adults, sub-sets of the HDA-RRMS population considered in this analysis43.

Conclusion

Cladribine tablets are a cost-saving alternative to the ABN recommended (category 2) treatments of alemtuzumab and natalizumab in persons with HDA-RRMS in the context of the NHS in England. Furthermore, the use of cladribine tablets as an alternative to current category 2 treatment is expected to yield additional QALYs over a lifetime horizon. As a result, cladribine tablets are considered a cost-effective treatment option in this population.

Transparency

Declaration of funding

This study was funded by EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany.

Declaration of financial and other relationships

RH was an employee of PAREXEL International, who acted as a paid health technology consultant to EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany. GH and SLW are employees of EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany. No authors received payment for the development of this manuscript. Peer reviewers on this manuscript have received an honorarium from JME for their review work. One reviewer discloses that they were an investigator on the CLARITY and CLARITY extension studies that were used for this cost-effectiveness analysis and, as a member of the steering committee for the trial, they were paid as a consultant by Merck-Serono. The remaining reviewers have no relevant financial relationships to disclose.

Acknowledgments

Editorial assistance was provided by Jo Whelan (Textpharm Ltd., Oxford, UK) funded by EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany.