Living with secondary progressive multiple sclerosis in Europe: perspectives of multiple stakeholders

Multiple sclerosis (MS), a neuroinflammatory disease characterized by demyelination and axonal loss [1], is usually diagnosed at a young age (age: 20–40 years). MS prevalence rises with increase in latitude; it is the lowest in eastern sub-Saharan Africa (3.3 cases per 100,000), central sub-Saharan African (2.8) and Oceania (2.0), and the highest in North America (164.6), Western Europe (127) and Australasia (91.1). Additionally, there is a strong female preponderance [2]. As of 2015, approximately 700,000 people in Europe were living with MS [3], and, after traffic accidents, MS is the leading cause of disability in young adults globally [4]. MS manifests itself distinctively in patients and significantly affects their quality of life, healthcare costs, work capacity and productivity [5,6].

Secondary progressive MS (SPMS) is characterized by a progressive accumulation of disability after an initial relapsing course, with approximately 80% of patients initially diagnosed with relapsing-remitting MS (RRMS) transitioning to SPMS within 20 years if not adequately treated [7,8]. The diagnosis of SPMS is often established retrospectively owing to indistinct clinical features of disease progression, unclear diagnostic guidance in the 2017 revised McDonald criteria, and lack of imaging and biomarkers to monitor the transition [9–11]. SPMS is further distinguished as either active (with relapses and/or evidence of new MRI activity) or nonactive, with progression (accumulation of disability over time, independent of any relapse) and without progression [12] assessed generally using the Expanded Disability Status Scale (EDSS) [9,13]. The recent explanation on classification criteria of MS phenotypes emphasizes the inclusion of time frame, while defining the current disease state through assessment of activity (evidenced by clinical relapses or imaging) and assessment of progression (clinical evidence of disability worsening that is independent of relapses) over a given period of time in patients who are in a progressive phase of the disease. In addition, the terms worsening and progressing, or disease progression, should be used more accurately when describing the MS disease course [11]. The recommended time frame for evaluating active disease or a progressing disease is at least once in a year.

Periodic monitoring of disease activity and progression, as well as availability of potential disease-modifying therapies (DMTs), govern treatment decisions [12,14,15]. Hence, a holistic understanding of the SPMS patient journey is critical to identify overarching unmet needs encountered by all key stakeholders involved in the management of MS. This paper is based on a meeting of MS experts held in December 2019 and highlights unmet needs and country-specific idiosyncrasies in order to identify key priority areas to improve the MS ecosystem across Europe.

Methods

The detailed step-by-step methodology followed for this study is described below.

Primary & secondary research

Primary and secondary research was conducted across seven European countries (France [FR], Germany [DE], Italy [IT], Spain [SP], the UK, Switzerland [CH] and Norway [NOR]) to gather a preliminary understanding of the unmet needs and future expectations across different stakeholders. Primary research comprised in-depth qualitative interviews with 58 randomly selected local experts encompassing the main stakeholders involved in the management of SPMS (specialized neurologists, MS nurses and payers) (Figure 1).

International expert group meeting

Validated findings from the primary research were used to identify key topics and develop a discussion guide for the faculty of experts invited to the international expert group meeting. The meeting was organized into three workshops: healthcare professionals (HCPs) – six international MS clinical experts from SP, DE, CH, FR, UK and NOR; payers – six experts in access and price negotiation from SP, UK, FR, DE and NOR; and nurses – four MS nurses from centers of excellence in the UK, DE, FR and IT. Early interviews during the primary research revealed that the patient journey could be divided into five steps – prediagnosis, diagnosis, work-up and treatment decision, monitoring and re-assessment, and this was adapted for subsequent interviews. Different aspects were discussed separately with neurologists and nurses, including current and future expectations regarding SPMS disease awareness and epidemiology, patient identification, diagnosis, disease management, treatment decisions and monitoring, and the role of treatment cost, as well as the role of multi-stakeholders in the patient journey. The payers’ discussion was focused on disease awareness and epidemiology, current treatment options and unmet needs, disease and economic burden, access level and restrictions, current and future value drivers, and future pricing and reimbursement drivers in MS.

Consensus

The outcome of the expert group meeting validated the preliminary understanding of the unmet needs and future expectations across different stakeholders. An alignment and consensus around the main topics characterizing the current SPMS patient journey is presented in the following sections.

Results

Current patient journey through SPMS

SPMS disease awareness: perception versus reality

An integral part of the SPMS patient journey is to identify the disease transition from RRMS to SPMS. With the definition of clinical MS courses in 1996, the latest revision in 2020 emphasized the importance of a time-based assessment of the current disease status of an MS patient. However, an ambiguity around the disease definition was seen among neurologists, payers and nurses across the participating European countries [9,11]. SPMS is largely perceived as a continuum of RRMS, and an increasing tendency exists among clinicians to diagnose the disease based on the cessation of inflammatory activity (relapses or MRI activity), rather than the recognition of progressive clinical disability independent of relapses (even when they are still occurring), as described by the 2013 consensus criteria [9,11].

Primary and secondary research shows that neurologists confined to a limited number of MS centers have a robust understanding of SPMS diagnosis. However, the less specialized HCPs and nurses may have suboptimal knowledge regarding the SPMS diagnosis and its clinical course. In addition, it is noteworthy that the clinicians exhibit a reluctance to confirm the SPMS diagnosis owing to the lack of effective treatment. Experts in MS management consider symptomatic cognitive decline/depression/fatigue, along with MRI findings, and EDSS assessment, vital for the assessment of SPMS. However, there is a time lag in worsening of symptoms and evaluation of disease activity with MRI [16]. The prolonged patient journey and symptomatic variability also make it challenging to distinguish the point of transition from RRMS to SPMS. In this regard, nurses play a significant role in determining the first signs of disease progression and relaying the information to the neurologists. Community nurses have better clarity on the patient’s symptomatic transition as they dedicate more time to and closely monitor their patients [17,18]. Therefore, although the diagnosis of SPMS is primarily a neurologist’s role, the responsibility of the nurses in providing insights on symptomatic self-reporting cannot be undermined.

Across the seven countries, approximately 20–30% of the currently DMT-standard of care-treated MS patients are diagnosed with SPMS. The uncertainty in disease definition across clinicians, insufficient MS-specialized neurologists, delayed diagnosis, drug label constraints and unavailability of effective treatment options suggest under-reporting of the SPMS disease burden. Moreover, payers rely on real-world evidence (RWE) studies to estimate MS prevalence, which can be a concern since the data from controlled settings may not truly represent the real-world burden. Figure 2 summarizes the perspectives of MS specialists and payers toward perception of SPMS population by country.

SPMS: symptoms to diagnosis

In the UK and Germany, nurses are frequently the first to recognize and record the symptomatic changes that support the diagnosis of SPMS. Furthermore, in the UK, nurses involved in the initial patient assessment are mostly involved in diagnosis.

In Italy, SPMS diagnosis relies exclusively on the patient’s response, due to the absence of an objective tool for quantification of progression. Because of the slow progression of SPMS, disease worsening is nonapparent in terms of EDSS scores during the initial progressive phase. To confirm an SPMS diagnosis, patients’ clinical symptoms are first reviewed, followed by evaluation of disease activity through MRI.

In the UK, the National Institute for Health and Care Excellence (NICE) guidelines recommend at least one annual MS consultation and therefore, it is difficult to see a patient every 3–6 months to confirm disease worsening. Occasionally, it may take up to 3–4 years to determine the progression as the interval between doctor visits and MRI is approximately a year. Most patients initially experience a denial phase toward the SPMS diagnosis owing to the unavailability of effective treatment options and potential loss of motor function.

Apart from specialized neurologists, physiotherapists in Germany and the UK, rehabilitation specialists and social workers in France and the UK, and neuropsychologists in Italy, are usually involved in the detection and diagnosis of SPMS. In Germany and the UK, detection of disease progression depends on the size and dynamic of the center. The role of the caregiver is also important in comprehending the signs of progression, although currently it is overlooked (Figure 3).

Management of SPMS

There was a general agreement that the current treatment goal for SPMS is to halt disease progression (defined as no change in the EDSS score) and prevent worsening of symptoms. The management of SPMS includes: pharmacological management of the disease, in other words, drugs with a relapsing indication or symptomatic drugs; and nonpharmacological management, in other words, rehabilitation and physiotherapy to manage symptoms such as fatigue, brain fog and spasticity [19].

Although several DMTs are approved for the relapsing form of the disease, very few DMTs are specifically approved for SPMS [20]. Cladribine received European Commission (EC) approval in 2017 for relapsing MS (RMS and active SPMS) [21]. Siponimod, a selective modulator of sphingosine-1-phosphate receptor, was also approved by the EC in 2020 for the management of active SPMS [22]. Mitoxantrone is approved by the US FDA and recommended as per the American Academy of Neurology and European Committee for Treatment and Research in Multiple Sclerosis guidelines for the treatment of SPMS [15,23]. In some cases, neurologists view ocrelizumab (and other high-efficacy therapies) as an alternative to treat RMS patients, as it can be prescribed without confirmation of SPMS diagnosis and patients can be switched back to other RRMS treatments if they do not respond to ocrelizumab.

Multiple barriers exist in the management of patients with SPMS. A huge knowledge gap concerning SPMS and its management exists among general neurologists. In all countries, neurologists are reluctant to switch treatment during transition, mainly owing to the lack of safe and cost-effective treatment options. Recent therapeutic agents faced challenges in reimbursements, which in turn increased the off-label use of MS drugs. The key barriers to treatment reimbursement vary from country to country. In Germany, lack of information on recommended treatments in health insurance and no acceptance of indirect comparisons by the Federal Joint Committee (GBA – Gemeinsamer Bundesausschuss) are the key deterrents to SPMS treatment reimbursement. In France, unavailability of robust epidemiology data to justify volume estimations acts as a barrier to treatment reimbursement. In Italy and Spain, RWE may be useful in optimizing drug positioning, and in facilitating patients’ treatment access and outcomes. With regard to budget impact analysis and cost–effectiveness, payers from all countries primarily focus on direct medical and nonmedical costs. The indirect medical costs play a secondary role in cost–effectiveness analysis, and societal costs do not impact price and reimbursement decisions. The heterogeneity in the active SPMS population that includes rapidly progressive and older patients who are without treatment access, hinders the cost/benefit evaluation of a therapeutic agent.

Monitoring & reassessment

Owing to the long patient journey, continuous monitoring to check disease progression is vital in MS, and nurses play a primary role in this regard. A higher monitoring frequency for patients with RRMS, which usually varies from 3 months to a year, could help identify new SPMS cases. While neurologists play a key role in diagnostic and treatment decisions, nurses and other HCPs are important for prediagnosis and monitoring (Figure 4). Moreover, the role of nurses is not so much focused on the detection of progression signs and diagnosis of SPMS, but rather on monitoring. In the UK, nurses can provide critical information to the MS physicians, which may be relevant during the diagnosis. In Germany, nurses are usually involved in monitoring patients every 3–6 months, which may help in detecting transition to SPMS. In all seven countries, monitoring depended on the size and dynamics of the MS center. The patient’s caregiver and family also play a pertinent role in monitoring, in terms of support and assessment of the symptoms of disease progression. Neurologists are largely involved in the treatment, monitoring and periodical reassessment of patients with SPMS. In Spain, Italy and France, most patients are managed at MS centers of excellence. In the UK, in addition to neurologists, general practitioners with expertise in neurology play an important role in patient management; while in Germany, monitoring and reassessment is done by neurologists at MS centers, as well as office-based neurologists. However, the responsibilities of the multidisciplinary teams and rehabilitation specialists in monitoring patients with SPMS are currently limited.

According to the panel discussion, nearly 10–30% of patients with SPMS (UK and Norway: 10–20%; France: ∼30%; Italy, Switzerland and Spain: <10%; Germany: ∼20%) are lost in the system after SPMS detection owing to apprehension regarding the lack of effective treatment, long waiting times for MRI and mobility issues. However, once patients start receiving their SPMS treatment, adherence is not a grave concern unless there are cognitive or emotional issues, ineffective treatment or any adverse effects. As per the experts’ opinion, only 5–10% of patients with SPMS reportedly display nonadherence to treatment.

Future patient journey

Expectations from neurologists

The primary objective for neurologists should be early diagnosis of SPMS and timely initiation of appropriate treatment, with no anticipation of major disruptive events impacting diagnosis. However, this remains aspirational considering the time it takes to confirm SPMS.

Expectations from MS nurses

Nurses play an active role in the recognition of disease transition and often discuss this with their patients. Consistent communication with patients and increased awareness of the disease among nurses may facilitate an earlier diagnosis. Patient-reported outcomes (PROs) are essential in the identification of the right signs of disease progression [24]. In the UK, although the focus is on RRMS, an increased awareness of SPMS is imperative for early diagnosis.

More DMT options necessitate safety monitoring of new drugs, progression monitoring and patient education on the expanded drug access. During the treatment phase, a greater workforce, digital tools and setting the right expectations on the effectiveness of emerging therapies among patients, neurologists and caregivers could galvanize SPMS management [25].

Overall, change in the relapsing-remitting monitoring approach, greater attention to SPMS detection, and increased contact and collaboration between nurses and physicians will potentially expedite SPMS reporting. Digital applications to support remote patient tracking may aid in patient monitoring, and nurses would need to be trained in using these platforms.

Expectations from payers

To shape a distinct SPMS landscape in the future, clarity on SPMS definition, epidemiological data and increased awareness on SPMS is essential. Availability of data on indirect comparisons, RWE and subgroup of patients with rapid progression will be useful in decision-making on disease budget allocations [26]. More adaptive trial designs that can demonstrate satisfactory effect sizes in subgroups of patients with rapid progression are imperative.

Payers expect EDSS scores to remain as the gold standard for their evaluations. A composite end point that measures both inflammation and disease progression could be useful for physicians, but not for payers as it will not allow for comparisons with already existing products. Payers do foresee value in digital tools and applications, although with a low impact on price and reimbursement. However, digital applications independent of patient input are preferred as patients tend to get demotivated about feeding in their data after a few months of treatment.

Role of pharmaceutical industry

Although significant progress has been achieved in RRMS treatment, the same is yet to be replicated in SPMS disease diagnosis and treatment. This lack of development can be explained by an insufficient understanding of SPMS pathophysiology [27] and unclear diagnostic criteria [28]. The pharmaceutical industry is expected to provide support for minimizing the ambiguity in SPMS disease definition [13] and improving patients’ disease awareness. Pharmaceutical companies must remain highly involved in raising awareness and continue educational initiatives, such as congresses, symposiums and workshops, training programs, patient networks and digital applications for tracking patients’ evolution and detection of disease progression. Digital tools [29] can gather real-world data that can encourage patient education and transcend barriers to disease awareness.

For SPMS research to be compelling and clinically impactful, collaborative efforts are needed between the pharmaceutical industry and multi-stakeholders involved in SPMS patient care. There is a pressing need for pharmaceutical companies and HCPs to support nurse education, particularly on the psychological impact of SPMS on patients. Increased awareness in patients and caregivers on the disease and its treatments through dedicated communities is also necessary. Furthermore, inclusion of PROs in the clinical trials will highlight the real-added value of new treatments. Pharmaceutical resources for the training and education of HCPs must be strengthened (Figure 5).

Discussion

A high level of heterogeneity exists in current clinical practice regarding the diagnosis and standard of care for SPMS. In most countries, neurologists are the key prescription decision-makers, and payers have limited control in this regard, except in complex SPMS cases for which neurologists may seek advice from multidisciplinary teams while choosing the right treatment. Furthermore, regulating neurologists’ treatment decisions is challenging, given the lack of clarity in differentiation between MS phenotypes and lack of head-to-head treatment comparisons in clinical trials. Therefore, it is essential to address different aspects in the patient journey of SPMS.

Essentially, disease monitoring in an SPMS patient involves patient history, clinical examination and MRI markers of disease progression when available. Patients’ feedback regarding the worsening of their condition and side effects of the ongoing treatment is fundamental in understanding the efficacy of any therapy. Therefore, it would be desirable to take into consideration more PROs together with MRI and other clinical outcomes, in particular, the outcomes relevant for patients. Additionally, increased awareness of SPMS and advancements in monitoring the approach of patients with RRMS may help detect SPMS earlier. In this regard, digitals tools are key, as patients could monitor themselves and report outcomes. The universal implementation of digital tools, validated with long-term cohort data and the opinions of allied multidisciplinary teams, remains vital for the monitoring and reassessment of patients with SPMS [25].

Complete MS biosignature development will be crucial, which could lead to the use of serum levels of neurofilament light chain, GFAP, along with the established MRI markers of disease progression to monitor disease advancement instead of waiting for the clinical worsening [30,31]. It is also essential for clinicians managing patients with SPMS to improve collaboration and referral pathways as patients display multiple symptoms and potential organ toxicities due to DMTs. The recent emergence of oral medications, an easier mode of administration specifically approved for SPMS, offers new therapeutic options and potentially improved treatment adherence. Neurologists also discussed the potential of combination therapies that would reduce inflammation and simultaneously improve myelin regeneration; however, such therapies are not anticipated in the near future.

The outcome of pipeline products for SPMS remains uncertain, predominantly due to the lack of treatment sequencing and the prospects of overlapping drug labels. For novel SPMS drugs, the indications to include younger as well as older patients remain an enigma owing to the lack of evidence. Positioning of potential DMTs for SPMS would ideally be based on populations investigated in controlled settings. Clear communication of the value of DMTs will be key for optimizing price and reimbursement. For emerging therapies in SPMS, a detailed analysis of the clinical profile is essential to make a precise price assessment [30]. Moreover, studies on the possibility of using RRMS drugs for SPMS have revealed unsatisfactory outcomes [31–34].

The reduced efficacy of RRMS biologics in SPMS is unlikely to have an impact on the price potential of therapies specifically approved for SPMS, as drug prices are compared within the same indication. However, due to budget constraints, the emerging oral therapies for SPMS are most likely to compete with interferons on drug price and should be priced lower than ocrelizumab; for instance, to secure access at both national and regional levels across the major countries in Europe.

Patient access to novel effective treatment options will facilitate and encourage the diagnosis of SPMS. Therefore, it is fundamental for drug developers to explicitly communicate the added value of new drugs and make the information readily available to patients and stakeholders involved in SPMS patient care. Pharmaceutical companies can substantiate treatment usefulness through RWE generation and obtain broad access for patients with SPMS. The long-term cohort data would be helpful to validate the use of digital tools and aids [35].

Limitations

This is a qualitative research study. The participants responded to the questions and provided their feedback based on their expertise. We included a panel of 58 local experts, randomly selected from seven European countries, to get a balanced regional view; however, it would be beneficial to include the opinions of the stakeholders from other countries as well. The perspectives of SPMS patients and caregivers were not included in this expert panel discussion.

Conclusion

The perception of MS as ‘one disease’ has undergone a paradigm shift, with no clear differentiation between RRMS and SPMS. Ambiguity also exists regarding the definition of SPMS and identification of active versus nonactive forms of the disease. Although there are a number of challenges in clinical management (diagnosis and treatment) of patients with SPMS, it is evident that the collaborative efforts of the associated stakeholders (neurologists, nurses, caregivers, payers, patients and the pharmaceutical industry), along with advances in the understanding of SPMS pathophysiology and diagnostic criteria, robust assessment guidelines, enhanced disease awareness and availability of RWE in the future, will allow for optimal care that will improve the quality of life of people living with SPMS.