Am J Manag Care. 2018;24:-S0
Economic Implications: Direct and Indirect Costs of ALS Therapy
As a chronic neurological disorder characterized by the progressive deterioration of neuromuscular function, amyotrophic lateral sclerosis (ALS) renders significant physical, psychological, and emotional tolls on patients, their families, and caregivers. Coupled with and contributing to the severe impact on quality of life are the substantial economic costs, which can be direct and indirect, and personal as well as societal. Understanding the magnitude and specifics of the costs accompanying ALS will provide useful perspectives to pharmacists who treat patients with ALS.
Available estimates on costs associated with amyotrophic lateral sclerosis (ALS) may differ substantially for a number of reasons, including the variations in ALS factors (eg, age of onset, severity, duration) and the variations in countries studied.1,2 Besides differences in cost of goods and national economic factors, the lack of universal healthcare in the United States also contributes to differences in ALS costs, particularly with respect to those borne by the patient.3 By keeping these factors in context, the cost estimates from other countries can help frame the scope of the costs linked to ALS. In a systematic review of pharmacoeconomic studies of ALS, Gladman and Zinman compared the estimates (normalized to 2015 US$) of total, direct, and indirect costs across several countries using studies published between January 2001 and January 2015.2 Total annual costs per patient varied from $11,251 for Greece to $69,475 for the United States while annual direct costs per patient ranged from $6501 for Greece to $53,459 for the United States (Figure 1).2 Similar total annual direct costs per patient ($63,693 for Greece and $63,848 for the United States) were reported in a study of claims data4 and an executive report prepared by the Lewin Group and commissioned by the Muscular Dystrophy Association to study the economic impact of ALS and other neuromuscular diseases.5
However, the actual total costs associated with ALS in the United States for an individual patient may be substantially higher. In a case study that followed a single patient’s direct costs over the 10-year disease duration period, total accumulated costs were $1,821,245 (adjusted for medical consumer price index [MCPI] and consumer price index [CPI] to 2013 US$), which averages to $182,125 annual total costs.6 The total direct costs were paid through a combination of insurance, out-of-pocket by patient/family, and charity. The out-of-pocket expenses (adjusted for MCPI and CPI to 2013 US$) totaled $157,673, which averages to $15,767 annually over the duration of the disease.6 The costs varied over the 10-year period,6 and other reports also suggest that costs associated with ALS will increase as patient disability declines.3 The total annual direct costs from this single case study are in line with another report that estimated the annual cost of care to be between $150,000 and $200,000 per patient, but substantially higher than those reported by Gladman and Zinman, Larkindale et al, and the Lewin Group.2,4,5,7 The differences in actual costs and estimated costs may be attributed to differences in methods as well as the single patient perspective of the case study. The implication from the case study is that average total costs paint a broad picture while the costs experienced by an individual may be markedly greater.
Costs associated with ALS can also be evaluated on the societal level. Estimated national economic burden (including medical, nonmedical, and indirect costs) of ALS ranges from $256M to $1.023B (2010 US$) depending on which prevalence numbers are used.4 With predictions that the number of ALS cases will increase in the United States by 34% by the year 2040 (Figure 2), the national economic burden will likely increase proportionally.8
Current Drugs and Their Costs
The 2 currently available drugs approved by the FDA for ALS are riluzole and edaravone. For both drugs, the mechanism of action in relation to ALS remains unknown, which is due in part to the unknown etiology of ALS. A common pharmacologic mechanism, however, appears to be a neuroprotective effect via inhibition of glutamatergic neurotransmission for riluzole9 and via scavenging of free radicals for edaravone.10 Riluzole, approved by the FDA in 1995 via the orphan drug program, is an orally administered tablet with a typical dose of 50 mg twice daily; it is used to slow the progression of ALS and may delay the need for a tracheostomy.11 The monthly wholesale acquisition cost (WAC) of generic riluzole ranges from $150 to approximately $700.12 Thus, yearly costs can range from $1800 to $8400 for the drug.
Edaravone, which gained FDA approval in May 2017, is administered via intravenous infusion and is used to slow the nerve damage associated with the worsening of ALS symptoms.13,14 The initial treatment cycle involves administration of edaravone 60 mg over 60 minutes daily for 14 days, followed by a 14-day drug-free period.14 Subsequent treatment cycles involve administration of edaravone 60 mg daily over 60 minutes on 10 of 14 days, followed by a 14-day drug-free period.14 With a WAC of nearly $1100 for a single infusion (2 x 30 mg/100 mL),12 the cost of edaravone is approximately $146,000 per patient per year, which excludes additional costs of administration (eg, costs of nursing services, supplies). Although approval of edaravone was based on a clinical trial with 6 cycles (6 months) of treatment, data from an open-label extension study (6 additional cycles) suggest that the drug may provide benefits beyond the 6-month time frame.15-17 In the open-label study, patients who also received edaravone in the initial double-blind study exhibited less decline in function as measured by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) compared with patients who originally received placebo in the initial double-blind study.15 Declines in ALSFRS-R over the entire 48-week period covering the double-blind and open-label studies were −8.0 (± 5.6) in the edaravone-edaravone group compared with −10.9 (± 6.9) in the placebo-edaravone group.15 Post hoc analysis of the data suggests that the differences in ALSFRS-R declines between the 2 treatment groups were significant.16 These results appear to support early initiation of edaravone therapy. This is important for managed care pharmacists to consider when developing prior authorization criteria as such policies must balance the benefits of access to care in an appropriate time frame with the costs of early initiation of therapy.
The differences in drug costs are worth considering when devising treatment plans for patients with ALS. Neither drug cures ALS, but the medications may prolong survival and/or time to tracheostomy, which can affect overall medical costs. Although ALS has a high mortality rate with a median survival time of 20 to 48 months from onset to death,18 medical costs for treatment, palliative care, and related expenses are substantial.
Benefit of Early Diagnosis
With respiratory failure being the most common cause of death in patients with ALS, the lethal disease has a mortality rate of 50% within 3 years and a median survival time that ranges from
20 months to 5 years.18-22 Although the mortality rate is high, a percentage of patients with ALS (10%-20%) may survive 10 years or longer.18 A prominent example of a long-lived patient with ALS is Stephen W. Hawking, PhD, the Cambridge University physicist and well-known public science educator, who recently died at the age of 76.23 Dr Hawking lived for 55 years after his diagnosis of ALS, and he famously attributed his longevity to the care provided by the United Kingdom’s National Health Service.24 Unfortunately, such lengths of survival are uncommon. The analyses of over
1000 patients from an ALS clinic provide additional insight with respect to patient survival time.25 In 1 study where the patient population demonstrated an overall median survival time from initial clinic visit of 14.3 months (95% CI, 13.1-15.3 months) and median survival time from diagnosis of 15.8 months, the 3 major factors that appeared to predict disease duration were age (increasing age correlating with shorter survival time), body mass index (<18.5 correlating with shorter survival time), and initial respiratory function measured by forced vital capacity (FVC) (<25% correlating with shorter survival time).25
Diagnosis of ALS from the onset of symptoms can range from 10 months to 18 months, with a median of approximately 11 months.26-29 Multiple factors contribute to the extended time to diagnosis. These factors include the slow onset of subtle symptoms, referrals to multiple physicians, and misdiagnoses.27,30 Early diagnosis, however, can benefit patients in critical ways, including extended survival time, improved quality of life (QOL), reduced healthcare costs, increased efficacy of prescription drugs, and added and maintained eligibility for insurance coverage of prescription drugs.19,27,31,32
Focusing on the drug-related aspects, the efficacy of riluzole appears to be greater when therapy is initiated in the earlier stages of ALS, which has prompted some clinicians to consider prescribing the drug before a definitive diagnosis.19,33,34 Similarly, edaravone may be less effective in later stages of ALS.35,36 With this information on efficacy, payers may restrict access to the 2 currently approved ALS drugs, riluzole and edaravone, to patients who have early/earlier stage disease (based on the inclusion and exclusion criteria used in the phase 3 trials that supported the FDA approval of these drugs). Therefore, if patients are diagnosed earlier, they can begin treatment sooner and benefit from the survival extension/delay of disease progression benefits offered by these therapies. Increasing use of big data analytics may come into play in the future for identifying patients before they present with full-fledged symptoms of ALS; this could assist in identifying patients earlier than current capabilities of diagnosis.37,38
Navigating Prior Authorizations and Cost Management
Prior Authorization for ALS Therapies
As with many high-cost medications, obtaining patient access to the drugs may require navigating the pharmacy and therapeutics (P&T) committee formulary process (for inpatient facilities and managed care payers) or the prior authorization pathways (for outpatient or retail pharmacy sites). When making formulary decisions, P&T committees have evolved to consider a broader scope of pharmacoeconomic and related data from typical drug acquisition and reimbursement costs to regulatory factors, increasingly costly specialty drugs, and pharmacoeconomic models that include QOL calculations.39-43 P&T decisions for riluzole and edaravone may also include consideration of the dearth of drugs available for ALS.44 Pharmacists should also keep in mind that a new formulation of riluzole may enter the market in 2019. On January 31, 2018, the FDA granted orphan drug designation to an oral soluble film formulation of riluzole and the manufacturer projects availability for mid-2019.45 Specifications on the prior authorization criteria for using riluzole or edaravone may require that patients match the inclusion criteria of the phase 3 trials that supported the FDA approval of each agent. As generic riluzole has been on the market for at least 5 years and is available through various manufacturers, the prior authorization criteria for riluzole may be less restrictive with just the requirements of a diagnosis of confirmed or probable ALS and that the prescription is being prescribed by or in consultation with a neurologist.46-48 For edaravone, prior authorization criteria mimics the criteria for the phase 3 trials, which include a diagnosis of confirmed or probable ALS; less than or equal to 2 years out from diagnosis/symptom onset; ALSFRS-R criteria with scores greater than or equal to 2 on all items at baseline, independent living status, FVC greater than or equal to 80% at start of treatment, prescribed by or in consultation with a neurologist, and some may require treatment failure or concomitant treatment with riluzole.49-51 The prior authorization requirements that restrict treatment to early stage ALS emphasize the importance of early diagnosis.
One of the primary benefits of riluzole and edaravone is that their use appears to extend the time to some medical services, particularly tracheostomy. The resulting delay in time to tracheostomy may help reduce overall healthcare costs, potentially balancing the cost of these prescription drugs over the duration of the disease.
Compassionate Use and “Right to Try” Legislation
With some activists and patients with ALS supporting “right to try” legislation (eg, the recently enacted Right to Try Act of 2017) for access to experimental drugs, pharmacists should be aware of similar laws, which are included in the legislation in at least 32 states.52-54 Pharmacists may want to counsel patients about attempting to obtain drugs via “right to try” pathways as those may not be the most efficient mechanisms to access medications54,55 and the FDA’s Expanded Access program (also known as compassionate use56) may be a more effective approach.54 When counseling patients, pharmacists should also be aware that the “right to try” laws generally focus on drug candidates that are in the later stages of clinical development but have not yet been approved by the FDA.
Best Practices to Prolong Life
Multidisciplinary Care Team Approach
The initiatives for collaborative, multidisciplinary approaches for healthcare in general are particularly important for a debilitating disease such as ALS.26,57,58 During the course of their illness, patients with ALS will require extensive healthcare resources, including medications, mechanical ventilation, supportive care, palliative care, and end-of-life planning.26,59 While ensuring the efficient coordination of the multitude of resources may be sufficient reason for multidisciplinary approaches in ALS, there is also evidence that such care can improve quality of care, extend patient survival, and improve QOL for patients.4,7,19,26,31,32,60-63 The American Academy of Neurology also emphasizes the need for a multidisciplinary care plan in their recommended quality measures.58
Patients with ALS present with a variety of medical needs reflective of the disease symptoms and manifestations. Those needs require professional care from a variety of healthcare specialists, and approaches to care that are centered on the patient and family are ideal (Figure 3).19,26,31,57 Pharmacists are integral partners in the multidisciplinary team and can manage drug therapy throughout the course of the disease process.19,64 When treating patients with ALS, multidisciplinary healthcare teams can encounter ethical dilemmas regarding the use of prescription drugs for treating ALS, the provision of palliative and supportive care, and end-of-life planning.19,35,65
ALS is a debilitating disease that leads to substantial physical disability and has a high mortality rate. Estimates on annual healthcare costs range from approximately $16,000 up to $200,000 and can vary depending on the stage of the illness. Indirect costs also add to the economic impact of the disease. Early diagnosis of ALS and access to care, including prescription therapy and care delivered by multidisciplinary teams, can extend survival time and improve QOL with the potential for reductions in healthcare costs. Current pharmacotherapy options for treating ALS, riluzole and edaravone, may slow disease progression and extend the time to tracheostomy. Data suggest that, when treatment is initiated at early stages of the disease, these therapies may be more effective and offer extended survival benefits. Riluzole, an orally administered drug, has been on the US market for 23 years and generic versions are available. Additionally, an oral soluble film formulation of riluzole is in development, and the manufacturer projects availability for mid-2019. Edaravone, approved by the FDA in May 2017, is the first treatment to be approved for ALS in more than 20 years. Due to its high cost, payers’ policies generally restrict the use of edaravone to patients who have early-stage disease and who are able to remain independent and retain functionality for most activities of daily living as well as normal respiratory function, as these factors were characteristic of the patients included in the clinical trials that supported the FDA approval of the drug. Managed care pharmacists should not just understand the particular drug costs, but also recognize the clinical benefits of the available treatments, including the potential for extended survival, improved clinical outcomes, and delay in time to tracheostomy, all of which may offer cost savings, and ensure that medical policies support appropriate access to care to eligible patients within a reasonable time frame.
Author affiliation: Senior Clinical Project Manager, Magellan Method (a division of Magellan Rx Management), Middletown, RI.
Funding source: This activity is supported by an educational grant from Mitsubishi Tanabe Pharma America, Inc.
Author disclosure: Dr Santaniello has the following relevant financial relationships with commerical interests to disclose:
EMPLOYMENT — Magellan Method/Magellan Health
MEETINGS/CONFERENCES — AMCP Annual, AMCP Nexus
STOCK OWNERSHIP — Magellan Health
Authorship information: Concept and design, acquisition of data, analysis and interpretation of data, and critical revision of the manuscript for intellectual content.
Address correspondence to: firstname.lastname@example.org.
Dr Santaniello gratefully acknowledges Thomas J. Cook, PhD, for his contributions to the development of this article.
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