PCORI Scientific Program Area: Assessment of Prevention, Diagnosis and Treatment Options

Transcription

1 Research Prioritization Topic Brief Topic 18: Multiple Sclerosis Comparative effectiveness of treatment programs for recurring/remitting multiple sclerosis (MS). PCORI Scientific Program Area: Assessment of Prevention, Diagnosis and Treatment Options Dr. Gillian Sanders Schmidler, PhD, and Team The Duke Clinical Research Institute April 16,

2 Criteria Introduction Overview/definition of topic Relevance to patient-entered outcomes Burden on Society Recent incidence and prevalence in populations and subpopulations Brief Description DESCRIPTION OF CONDITION Multiple sclerosis (MS) is a neurologic condition typically affecting young adults and is characterized by an autoimmune disorder that causes damage (by demyelination) of nerves within the central nervous system (CNS). Patients have one of four types of MS: o relapsing-remitting (most common) o secondary progressive o primary progressive o progressive relapsing Patients have distinct episodes of CNS dysfunction (or relapses) that, at least partially, resolve over time. Most patients with relapsing-remitting MS will eventually enter a secondary progressive phase in which recovery between relapses becomes less often and for shorter periods of time. MS is a leading cause of disability in young adults; treatments for this condition are costly, including expensive medications and ongoing rehabilitation. SYMPTOMS 1,2 Patients have episodes of CNS dysfunction, lasting at least 24 hours, which at least partially resolve over time. CNS dysfunction most commonly first appears as sensory disturbances or visual loss, often due to optic neuritis (inflammation of the optic nerve), but also as motor weakness, diplopia (double vision), gait disturbances, or other neurologic symptoms. MS is associated with increased mortality, higher rates of cognitive decline, depression, and global fatigue. OUTCOMES Radiologic findings are used to diagnose MS (multiple characteristic T2 lesions seen with magnetic resonance imaging (MRI) in areas of the CNS that vary over time). The extent of disability resulting from MS varies depending on the type of MS. INCIDENCE (NEW CASES) 3 More than 200 cases of MS are diagnosed weekly in the United States. 3 Incidence generally occurs between 20 and 50 years of age, peaking at about 30 years of age. 4 Incidence is increasing, particularly among women. PREVALENCE (PROPORTION OF POPULATION LIVING WITH THE CONDITION) 3 Highest prevalence occurs among white people of Nordic origin, in areas with moderate climates, and among higher income people. Approximately 400,000 adults have MS in the United States, while there are 2.5 million adults with this condition worldwide, with varying prevalence by country. 3 Prevalence peaks at about 50 years of age. 4 Women are affected by MS twice as often as men. Prevalence of MS is increasing as incidence increases (along with more effective treatments extending survival of patients with MS). 2

3 Effects on patients quality of life, productivity, functional capacity, mortality, use of health care services How strongly does this overall societal burden suggest that CER on alternative approaches to this problem should be given high priority? Options for Addressing the Issue Based on recent systematic reviews, what is known about the relative benefits and harms of the available management options? QUALITY OF LIFE (QOL) Patients QOL is affected by disability (such as impaired mobility, chronic pain, cognitive impairment, depression, and spasticity as well as bowel and bladder dysfunction and other neurologic impairments). 5 Based on a 2006 cost assessment and a quality-adjusted life-years valued at $60,000, the reduction in QOL due to MS was estimated to add $15,315 to annual costs per patient. 6 PRODUCTIVITY Based on a 2009 insurance claims database study, employees with MS had 29.8 disability days per year compared to 4.5 days for employees without MS. Employees with MS compared with employees without MS also had significantly higher annual disability costs ($3868 vs. $414). Absenteeism costs ($1901 vs. $1003), and total indirect costs ($5769 vs. $1417) are also increased. 7 FUNCTIONAL CAPACITY The extent of disability varies depending on the type of MS and risk factors. Natural history studies have also found varying degrees of progressive disability. Using the Expanded Disability Status Scale as the reference, one study reported that median time to development of significant disability (needing a cane to walk) was 28 years from disease onset. 3 MORTALITY MS is associated with higher mortality with a mean age of death of 58 years. 1 One study from Wales found that patients with MS are almost three times more likely to die prematurely than the general population. 9 COSTS Total direct medical cost for all patients with MS in the United States is estimated to be more than $10 billion per year. 10 MS has a significant impact on the functional status of young adults. Given the burden that this condition places on the QOL of patients, as well as the economic burden (both direct and indirect costs) of this condition, it is important to determine the most effective treatments for this condition. SCREENING/EARLY DIAGNOSIS There are currently no screening or early diagnostic tests in widespread use. Disease monitoring typically consists of tracking patient symptoms, recurrent physical examinations, MRI, spinal fluid analysis, and laboratory tests. TREATMENT FOR RELAPSING-REMITTING MS Drug treatment: o Acute attacks (or relapses) are often treated with oral or intravenous glucocorticoids (type of steroid hormone medication). 11 o Disease-modifying therapy with a medication that regulates your immunity (since MS is an autoimmune disorder) typically administered soon after diagnosis, with the goal of 3

4 What could new research contribute to achieving better patient-centered outcomes? Have recent innovations made research on this topic especially compelling? decreasing the rate of relapse and slowing the accumulation of brain lesions that are seen on MRI. Six disease- modifying drugs have been approved: interferon-beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, and, recently, dimethyl fumarate. 12 These agents have been shown to affect the rate of developing new brain lesions, but there is insufficient evidence to support their effect on functional outcomes. Physical therapy and rehabilitation: o Physical therapy, exercise, and behavioral interventions have been shown to improve: balance in patients with mild to moderate levels of disability, 13 symptoms of fatigue and depression, 14 and muscle strength. 15 o Exercise therapy compared with no exercise therapy showed improved muscle power, exercise tolerance, and mobility-related activities. There was also moderate evidence found for improving mood. 16 o In a meta-analysis of 22 uncontrolled trials of exercise, more benefits were associated with supervised exercise training and with exercise programs that were less than three months long. 17 Exercise training was also shown to be associated with a small improvement in walking mobility. 17 o No best dose of therapy or superiority of one therapy over another could be identified. 18 Inpatient rehabilitation showed short-term gains in disability despite no change in the level of impairment. Outpatient -and home-based rehabilitation showed limited short-term improvements in symptoms, disability, and QOL with high-intensity programs. Low-intensity programs over a longer period showed longer-term gains in QOL. 18 New research could contribute to achieving better patient-centered outcomes by identifying, developing, improving, and supporting outcome measures that reliably assess clinically meaningful disease progression, mobility, functional capacity, and QOL. New comparative-effectiveness research (CER)could provide data to help MS patients with decision making regarding their care (data regarding physical therapy and potential impact on disease clinical course, management of symptoms, and resulting disability, as well as QOL). New CER of treatment options could identify new and more effective treatments. Patient-centered outcomes might be improved if new research that compares comprehensive care with usual care demonstrates superiority of one of the approaches. There have been recent technical innovations that facilitate diagnosis and disease monitoring (eg, improved imaging techniques and laboratory tests to identify antibodies in the blood and spinal fluid), but there does not appear to be clearly improved methods for examining treatment options and how they impact patient-centered outcomes. The recent increase in medication treatments for MS has increased the need for CER to help guide patient decision making regarding risks and benefits to the variety of medication and nonmedication treatments for managing MS. 4

5 How widely does care now vary? What is the pace of other research on this topic (as indicated by recent publications and ongoing trials)? How likely is it that new CER on this topic would provide better information to guide clinical decision making? There is significant variability in the content of the number of MS clinical guidelines sponsored by organizations in both the United States and Europe. 19 Also, recommendations for the treatment of MS has been known to change relatively rapidly. RECENT PUBLICATIONS In the past two years, many systematic reviews have been published that evaluated the comparative effectiveness and safety of disease-modifying agents and behavioral interventions, including exercise and physical therapy. Another oral drug treatment, dimethyl fumarate, received FDA approval for relapsing MS in March Research at various stages is currently underway for many other new drug treatments and use of existing drugs in combination. ONGOING TRIALS ClinTrials.gov lists search for multiple sclerosis showed: o Total ongoing trials: 411 o Completed trials: 451 KEY UNCERTAINTIES IN CLINICAL DECISION MAKING What are the best outcome measures for monitoring disease progression and treatment efficacy, using outcomes that are meaningful to patients? What are the comparative efficacy, safety, and cost of the FDA-approved disease-modifying agents and other agents undergoing clinical development, by disease characteristics (eg, relapsing-remitting MS) and by patient subgroups? How do these treatments impact patient-centered outcomes? Do health care delivery innovations (such as comprehensive, coordinated care) improve processes and outcomes? LIKELIHOOD THAT CER WOULD BE ABLE TO REDUCE THESE UNCERTAINTIES There is high likelihood that CER would be able to reduce these uncertainties. These are answerable research questions that would guide clinical decision making. Potential for New Information to Improve Care and Patient-Centered Outcomes What are the facilitators and barriers that would affect the implementation of new findings in practice? How likely is it that the results of new research on this topic would be implemented in practice right away? FACILITATORS Most stakeholders (eg, patients, providers, payers) are likely to be interested in new information about MS and in implementing new findings that might lead to improvement in disease monitoring or treatment efficacy and safety. A neurologist is likely to participate in the care of most patients under treatment for MS in the United States. Disseminating new findings to this relatively small group of specialists should not be difficult. BARRIERS Rapid changes in published clinical guidelines are a potential barrier. The expected availability of still more drug treatment options could be a barrier. EVIDENCE OF BENEFIT Improved patient-centered outcome measures are likely to be used in practice right away if the evidence supporting them is compelling and if the outcomes are considered by both patients and providers to be meaningful and useful. EVIDENCE OF NO BENEFIT OR HARM New evidence that does not demonstrate benefits or demonstrates harm would likely be incorporated into clinical decision making. Would new A systematic review titled Comparative clinical and cost effectiveness of drug therapies for 5

6 information from CER on this topic remain current for several years, or would it be rendered obsolete quickly by subsequent studies? relapsing-remitting multiple sclerosis is listed in the Prospero registry as being underway, with an anticipated completion date of August The four review questions to be addressed in that review focus on comparative efficacy, safety, and cost-effectiveness for both individual disease-modifying agents and combination therapy for relapsing-remitting MS. However, as new drug treatments continue to be approved, any CER that compares current drug treatments may quickly become outdated. Information from CER on the topics of patient-centered outcome measures or coordinated vs. usual care for MS, however, is likely to remain current for several years because neither topic appears to be an area of currently active research. REFERENCES 1. UpToDate Giesser BS. Diagnosis of multiple sclerosis. Neurol Clin May;29(2): Tullman MJ. Overview of the epidemiology, diagnosis, and disease progression associated with multiple sclerosis. Am J Manag Care Feb;19(2 Suppl):s Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol May;9(5): doi: /S (10) Zwibel HL, Smrtka J. Improving quality of life in multiple sclerosis: an unmet need. Am J Manag Care May;17 Suppl 5:S Kobelt G, Berg J, Atherly D, Hadjimichael O. Costs and quality of life in multiple sclerosis: a cross-sectional study in the United States. Neurology. 2006;66(11): Ivanova JI, Birnbaum HG, Samuels S, Davis M, Phillips AL, Meletiche D. The cost of disability and medically related absenteeism among employees with multiple sclerosis in the US. Pharmacoeconomics. 2009;27(8): Tremlett H, Paty D, Devonshire V. Disability progression in multiple sclerosis is slower than previously reported. Neurology Jan 24;66(2): Hirst C, Swingler R, Compston DA, Ben-Shlomo Y, Robertson NP. Survival and cause of death in multiple sclerosis: a prospective population-based study. J Neurol Neurosurg Psychiatry Sep;79(9): doi: /jnnp Epub 2008 Feb Mathis SA. Managed Care Aspects of Managing Multiple Sclerosis. Am J Manag Care. 2013;19:S28-S Burton JM, O Connor PW, Hohol M, et al. Oral versus intravenous steroids for treatment of relapses in multiple sclerosis. Cochrane Database Syst Rev. 2012(12):CD Luessi F, Siffrin V, Zipp F. Neurodegeneration in multiple sclerosis: novel treatment strategies. Expert Rev Neurother. 2012;12(9): Paltamaa J, Sjögren T, Peurala SH, et al. Effects of physiotherapy interventions on balance in multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials. J Rehabil Med. 2012;44(10): Heesen C, Köpke S, Kasper J, et al. Behavioral interventions in multiple sclerosis: a biopsychosocial perspective. Expert Rev Neurother. 2012;12(9): Kjølhede T, Vissing K, Dalgas U. Multiple sclerosis and progressive resistance training: a systematic review. Mult Scler. 2012;18(9): Rietberg MB, Brooks D, Uitdehaag Bernard MJ, et al. Exercise therapy for multiple sclerosis. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; Snook EM, Motl RW. Effect of exercise training on walking mobility in multiple sclerosis: a meta-analysis. Neurorehabil Neural Repair Feb;23(2):

7 18. Khan F, Turner-Stokes L, Ng L, et al. Multidisciplinary rehabilitation for adults with multiple sclerosis. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; Trisolini MG. Comparison of Multiple Sclerosis Guidelines Underscores Need for Collaboration APPENDIX: Topic Questions Nominated by Institute of Medicine (IOM) 1) Compare the effectiveness of comprehensive, coordinated care and usual care on objective measures of clinical status, patient-reported outcomes, and costs of care for people with multiple sclerosis. Nominated by Web 1) The measurement of new lesions and relapses for determining the efficacy of a drug is flawed. The real measurement should include disease progression and mobility Population: All MS patients Importance: Because the treatments available for MS are crazy expensive. A patient can have lesions without progression. The real goal should be preventing or limiting progression. 2) My health insurance company has a $3000 annual cap for physical therapy. I reached that cap in April I requested additional PT along with copies of my PT progress note and a letter from my neurologist stating that continued therapy is medically necessary. I also included a statement explaining that in 2005 I was denied additional therapy therefore sought out other avenues to improve flexibility and strength. Unfortunately, I sustained a complete spiral fracture of my right femur while my personal yoga instructor assisted me with stretching my left hip. Well, the insurance company denied my 2012 appeal stating the notes do not reflect significant improvement. My question is (the insurance company will not provide detail) how can an insurance reviewer define what is significant improvement for an individual whom they have never met? Also, some conditions benefit from therapy even without improvement because without therapy the condition will deteriorate Population: Persons with chronic progressive disease of all backgrounds. Progressive diseases of the central nervous system will benefit, Importance: This is important because people are denied physical therapy because of arbitrary caps and restorative discrimination and therefore deteriorating not because the disease is progressing but because of disuse. This causes unnecessary pain, surgery and loss of participation in family and community life. 3) Which is (are) the best treatment(s) for recurring/remitting MS? Could MS be effectively treated less expensively? Population: All individuals diagnosed with recurring/remitting MS. Significantly more women than men. Most patients are diagnosed while still relatively young, so effective treatment could improve their quality of life over a long period of time. Importance: The treatments, none of which cure the disease or stop the progression, are all very expensive. With so much money being spent per patient to achieve such modest results, choosing the right treatment is critical. 7