Introduction
Multiple sclerosis (MS) is a chronic autoimmune-mediated inflammatory disease of the central nervous system that affects an estimated 2.8 million people worldwide [
1,
2]. Of these, approximately 85% are diagnosed with relapsing–remitting multiple sclerosis (RRMS), which is characterized by periodic acute exacerbations of disease activity (relapses) that can lead to neurological disability over the patient’s lifetime [
2]. Several disease-modifying therapies (DMTs), targeted at delaying the progression of disability, have received regulatory approval over the past 20 years, significantly increasing the number of treatment options and improving quality of life for patients [
3]. The number of DMTs on the market, coupled with the reality that RRMS requires long-term treatment wherein most patients will switch DMTs at least once over the course of their disease, poses challenges for physicians regarding the choice of, and appropriate times to switch, a patient’s DMT [
4,
5]. Additionally, health economists and policymakers are challenged with how to evaluate DMTs appropriately in order to capture the heterogeneity of disease trajectories and treatment patterns in patients with RRMS [
6,
7].
Currently, the majority of health economic models for RRMS are Markov models, which typically evaluate a single line of treatment in a cohort of patients with RRMS [
6,
7]. As such, these models are not able to address questions regarding treatment sequencing. Here we describe an approach, based on an innovative model framework, designed to address the challenges regarding treatment sequences in RRMS. This approach replicates the process of clinical decision-making, through simulating a ‘virtual’ physician who makes treatment decisions according to his or her evolving understanding of a patient’s disease as it manifests over time. As a computational model of physician behaviour, this approach has the potential to simulate individual patient trajectories in the current treatment landscape in order to support treatment switching and treatment positioning decisions in RRMS.
In the current paper, the implementation of this innovative approach to modelling treatment sequences in patients with RRMS is described in detail, along with results of several validation exercises. In addition, the modelling framework was applied as a case study to explore the impact of different decision-making criteria on the optimal sequence of DMTs, as well as to determine the costs, quality of life, and hospital resource usage associated with each sequence.
Discussion
New modelling approaches are needed to address questions regarding treatment sequences in RRMS, including what decisions rules are currently used when considering the benefit–risk profiles of different DMTs in clinical settings and what thresholds should be used to determine that a DMT is not performing consistent with expectations. The approach described in the current paper is proposed to help decision-makers address these complex questions and provides an innovative framework for the explicit modelling of treatment sequences in RRMS. The model focuses not only on what treatment a patient will, or should, switch to but also on when a patient should switch treatment. The conceptualisation of the (virtual) physician as someone who updates his/her view of a patient’s expected severity each time he/she observes the patient was introduced to reflect the fact that physicians develop an understanding of the patient over time and, in theory, can make more informed treatment decisions as time progresses.
The internal validation of the DES showed that disease severity, survival, and number of relapses are appropriately simulated for natural history. It is worth noting that the narrower CrIs calculated by the DES compared to the reference model can be partially attributed to the large number of patients simulated. The external validation showed that the outcomes of the DES and Markov model matched the reference models reasonably well, except for some differences which relate to modelling choices. The most prominent difference was the discontinuation rate, which was modelled using a user-adjustable decision rule in the DES and may have resulted in different discontinuation rates than those used in the Markov model. The relapse outcomes also differed between the models; however, given the ARR in the DES has been validated against the average relapse rate from the BCMS registry, we are confident that the DES simulates relapses appropriately. Differences were also observed in natural history progression of the Markov model compared to the reference cost-effectiveness model [
16,
32]. These are as expected as Palace et al. [
16] used a selection of patients from the BCMS registry with relatively severe disease (at least two relapses in the last 2 years), whereas the severity groups in our model captured patients from the BCMS registry without any requirements for disease activity. In addition, our Markov model provided no allowance for backward transitions (i.e. EDSS improvements) because these are considered temporary improvements, whereas backward transitions are included in the reference model [
16]. Any other differences in Markov model outcomes are as expected and are attributable to different inputs and modelling choices. Overall, the results of the Markov model are considered robust and reliable.
One of the challenges with patient-level DES are the data requirements. The current implementation of the model used published, aggregate data and the key assumptions were validated in a Delphi study [
18]. Although natural history was consistently based on the BCMS registry [
13,
14,
31] and the validation process showed that the model can reproduce the published population level estimates, the use of aggregate data to populate the DES means that the covariance between simulated patient characteristics could not be included, neither could any relation between disability worsening and relapses nor a correlation between treatment effects within a patient. As such, the individual outcomes might be incorrect. A possible next step in the development of this model would be to fill these gaps using data from real-world studies. For example, magnetic resonance imaging test results were omitted from the current model because, as a result of the high correlation with relapses, it was deemed inappropriate to include them in the patient-level simulation, based on published aggregate data only [
18]. However, the inclusion of radiology in the DES next to relapses and disability worsening, as well as in the decision rule for treatment switching, may potentially improve the model. Similarly, the probability of PML was only modelled for natalizumab treatment; real-world data on the incidence of PML in other DMTs for RRMS would be useful.
The virtual physician uses a likelihood function to update his/her belief of the patient’s disease severity. This likelihood function describes what a physician learns about the patient’s severity when the physician makes observations regarding disability worsening. Currently, a Gompertz distribution with a shape parameter of 0.1 was used to model this relationship between EDSS steps and a patient’s severity. This assumption was based on the progressive nature of RRMS and the assumed uncertainty in this relationship. Additional research is required to determine the accuracy of the current likelihood function and/or propose suitable alternatives. One of the key challenges in modelling treatment sequences in RRMS, as well as other autoimmune diseases including rheumatoid arthritis, is locating evidence for the effectiveness of treatments when given in later lines [
17,
34,
35]. Whereas this model does not present a solution to this data gap, modelling treatment sequences in more detail makes knowledge gaps apparent and enables researchers to investigate the impact on treatment decisions. In addition, the physician’s choice of treatment will be affected by factors other than perception of disease severity, including patient choice, lifestyle, pregnancy, and co-morbidities; further research is required to develop the model to incorporate these factors.
This innovative framework enables the user to explore different decision criteria for choosing the optimal treatment strategy. In the case study, it was possible to improve on the current treatment guidelines strategy in terms of reducing the proportion of patients who reach EDSS6, duration of time spent on the first three lines of treatment, and associated quality of life. This was accomplished by choosing the optimal treatment sequence based on minimising the expected number of EDSS steps or relapses. However, this improvement does come at a financial cost. The treatments that minimise EDSS steps and relapse rates are more costly in terms of drug acquisition and administration costs. Optimising treatment by maximising cost-effectiveness is the least expensive treatment sequence, but also has the lowest QALYs. Furthermore, in addition to direct patient benefits, an important consideration in identifying optimal treatment sequences is the impact a treatment sequence may have on hospital capacity. Our analyses indicated that the capacity required over time is dependent on the choice of sequence, with resource use peaking 10–15 years after treatment initiation. The required capacity is presented in terms of the number of patients on each of the treatments requiring infusion visits. However, this may not be a clear indicator of the capacity required in the hospital as it is unlikely that all these patients would require their infusion visit at the same time. It is therefore important to consider treatment schedules along with the operating hours of the units.
It should be noted that the choice of the base-case treatment guidelines using the NHS treatment algorithm [
33] may not be representative of the treatment sequence used in practice. A change in the treatment guidelines sequence will have a subsequent impact on the relative costs and benefits of the other sequences compared to it. Furthermore, these analyses focused on the relative benefits of treatment sequences for the first three treatment lines, in order to compare the results to the NHS treatment algorithm which gave no clear information on treatments that should be used in the fourth and subsequent treatment line [
33]. In addition, there was limited information on the effectiveness of treatments when given in later treatment lines [
17,
34,
36]. This lack of information adds some strength to our decision to concentrate on the first three treatment lines. Alternatively, focusing on the first three treatment lines may underestimate the treatment benefits to the extent that improvement could appear in later lines. An example of this is when patients are given less efficacious and less costly treatments in earlier treatment lines. Those patients with more severe RRMS would likely switch away from these treatments quickly to more effective and costly treatments, whereas patients with milder RRMS may stay on these earlier treatment lines for longer. Furthermore, as the benefits of the treatment are deferred until later lines for the more severe patients, this would mean that the total number of QALYs gained from the treatment sequence would be increased, impacting the value of the cost-effectiveness scenario.